Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[O:19]1[C:23]2([CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)[C:22](=[O:29])[NH:21][C:20]1=[O:30].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:16][C:15]([CH3:18])([CH3:17])[CH2:14][N:13]1[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH2:2][N:21]1[C:22](=[O:29])[C:23]2([CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)[O:19][C:20]1=[O:30]
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Reactant: O=C1NC(=O)C2(CCSCC2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(CN2C(=O)OC3(CCSCC3)C2=O)cc2cnc(C#N)nc21
Reaction time: 18 h
Yield: 39.5 %

Procedure:
To a solution of 200 mg (0.52 mmoles) of 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile and 146 mg (0.78 mmoles) of 1-oxa-8-thia-3-aza-spiro[4.5]decane-2,4-dione in 5 ml of DMF, 117 mg (0.846 mmoles) of K2CO3 is added at ambient temperature. After being stirred for 18 hours, the reaction mixture is quenched with H2O and extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by reverse-phase HPLC to give 85 mg of disired 7-(2,2-dimethyl-propyl)-6-(2,4-dioxo-1-oxa-8-thia-3-aza-spiro[4.5]dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (NVP-TAB516-NX) in 32% yield.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccc2ccccc2c1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1c(OCc2ccccc2)ccc2ccccc12
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a suspension of 1-bromo-2-naphthol (15.0 g, 67.3 mmol) and K2CO3 (18.6 g, 135 mmol) in DMF (100 mL) was added benzyl bromide (9.6 mL, 81 mmol) and the mixture was stirred at 60° C. for 5 h. After cooling to room temperature, the solvent was evaporated in vacuo and the residue, dissolved in a small amount of CH2Cl2, passed through a thin pad of flash silica. Fractions containing the product were evaporated in vacuo to give an off-white solid. Crystallisation from CH2Cl2/petrol gave the title compound, 1-bromo-2-(phenylmethoxy)naphthalene, as a white crystalline solid (16.0 g, 76%). The mother liquor was concentrated and purified by flash chromatography (petrol/CH2Cl2, 2/1) to give an additional amount of the product (3.7 g, 17%; total yield: 93%). Rf=0.50 (petrol/CH2Cl2, 2/1); mp 104-106° C. (CH2Cl2/petrol); 1H NMR (250 MHz, CDCl3) δ5.35 (s, 2H), 7.32 (d, J=9.0 Hz, 1H), 7.38-7.50 (m, 4H), 7.57-7.66 (m, 2H), 7.79-7.86 (m, 3H), and 8.31 (d, J=8.5 Hz, 1H); 13C NMR (63 MHz, CDCl3) δ71.81, 110.0, 115.6, 124.6, 126.3, 127.2, 127.8, 128.1 (2C), 128.7, 128.9, 130.1, 133.2, 136.7 and 153.0; IR (CHCl3) νmax 1626, 1596, 1502, 1350, and 1268 cm−1; MS (EI+) m/z (rel intensity) 314/312 (25%, M+) and 91 (100); HRMS calcd for C17H13BrO (M+) 312.0150. found 312.0150. Anal. Calcd for C17H13BrO: C, 65.19; H, 4.18; Br, 25.51. Found: C, 64.94; H, 4.12; Br, 25.71.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.CC(C)([O-])C.[K+].Cl.Cl[C:21]1[CH:26]=[CH:25][NH+:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:5]=1
Reactant: COC(OC)c1cccc(O)c1
Reactant: Clc1cc[nH+]cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)c1cccc(Oc2ccncc2)c1
Temperature: 25 °C

Procedure:
A solution of 1 g of 3-hydroxybenzaldehyde dimethyl acetal and 2 g of potassium tert.butoxide in 10 ml of anhydrous dimethylformamide was heated at 60° C. under an atmosphere of dry nitrogen for 1 hour. The mixture was then cooled to room temperature and 900 mg of 4-chloropyridinium hydrochloride were added portionwise over a period of 20 minutes. The mixture was then heated at 160° C. for 18 hours, cooled, 100 ml of water were added and the product was extracted with ethyl acetate. The combined extracts were washed with 1M aqueous sodium hydroxide solution and with brine, and then dried over anhydrous magnesium sulphate. Evaporation to dryness left a brown oil which was purified by column chromatography on silica gel using hexane/ethyl acetate (gradient: 90:10 to 20:80) for the elution to give 3-(4-pyridyloxy)-benzaldehyde dimethyl acetal as a light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:32]([CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(O)(=O)C.ClCCl>[C:35]([O:34][C:33]([N:32]([CH2:31][C:29]1[CH:28]=[CH:27][C:26]2[O:21][CH2:22][CH2:23][O:24][C:25]=2[CH:30]=1)[CH:40]1[CH2:45][CH2:44][N:43]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]2=[O:16])[CH2:42][CH2:41]1)=[O:39])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)c1cc(=O)n(CC=O)c2cc(OC)ccc12
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(OC)ccc12
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To 0.19 g of methyl 1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylate, 2 mL of 90% aqueous trifluoroacetic acid solution was added and stirred for 14 hours. The solvent was removed under reduced pressure, and aqueous saturated sodium hydrogen carbonate solution and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.19 g of methyl 7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxylate. (2) To 3 mL of a dichloromethane solution containing 0.17 g of methyl 7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxylate, 0.24 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 34 μL of acetic acid were added and stirred for 1 hour. To the reaction mixture, 0.19 g of sodium triacetoxyborohydride was added and stirred for 1 hour. Ethyl acetate and aqueous sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=100:1] to give 0.25 g of methyl 1-(2-(4-((tert-butoxycarbonyl) (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylate as a brown oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1.[NH2:18][CH:19]([CH3:22])[CH2:20][OH:21]>O>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:18][CH:19]([CH3:22])[CH2:20][OH:21])=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Reactant: CC(N)CO
Solvent: O
Product: CC(CO)Nc1ccc(-c2cccc(C(F)(F)F)c2)nn1
Temperature: 130 °C

Procedure:
A mixture of 0.5 g of 3-chloro-6-[3-(trifluoromethyl)phenyl]pyridazine and 3 ml of 2-amino-1-propanol was heated at 130° C. for 24 hours, cooled and poured into water. The mixture was extracted with three 20 ml portions of dichloromethane. The combined extracts were washed with water, dried over magnesium sulfate and concentrated. The residual oil was dissolved in ethyl acetate and the solution passed through a short pad of silica gel. The filtrate was concentrated in vacuo and the residue was crystallized from dichloromethane-hexane to give 0.3 g of 2-[[6-[3-(trifluoromethyl)phenyl]-3-pyridazinyl]amino]-1-propanol as white crystals, mp 143°-144° C.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:5]1=[O:17])=[N+:2]=[N-:3].C1COCC1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[NH4+].[Cl-]>O>[N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:6][CH:5]1[OH:17])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])C(=O)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])C(O)C1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of Compound 201A prepared above in dry THF (2 mL) cooled at −78° C. was added L-Selectride (1.0 M in THF, 0.98 mL, 0.98 mmol). The mixture was stirred at −78° C. for 2.0 hrs. Saturated NH4Cl (2 mL) was added and the reaction mixture was allowed to warm to room temperature. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed once with brine and dried over anhydrous Na2SO4. Concentration in vacuo followed by flash chromatography (hexane-EtOAc 4:1) on silica gel gave 44 mg of Compound 201B as an oil. 1H-NMR (400 mHz, CDCl3): 3.84 (m, 1H), 3.69 (m, 1H), 3.58 (m, 2H), 3.40 (m, 1H), 3.30 (m, 1H), 1.96 (m, 1H), 1.73 (m, 1H), 1.46 (s, 9H).
Reaction SMILES: [N+](C1C=C[C:7]([O:10][P:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])[O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18](C(=O)C)[N:17]=[CH:16]3)=CC=1)([O-])=O.ClCCl.N12CCCN=C1CCCCC2>CO>[CH3:7][O:10][P:11]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2
Reactant: CC(=O)n1ncc2cc(OP(=O)(Oc3ccc([N+](=O)[O-])cc3)c3ccccc3)ccc21
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: COP(=O)(Oc1ccc2[nH]ncc2c1)c1ccccc1
Yield: 10.4 %

Procedure:
Phenylphosphonic acid 1H-indazol-5-yl ester methyl ester is prepared according to procedure F using 219 mg of phenyl-phosphonic acid 1-acetyl-1H-indazol-5-yl ester 4-nitrophenyl ester, 5 ml of dichloromethane, 74.8 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene and 202 μl of methanol. The crude is purified by flash chromatography on silica with a particle size of 35-70 μm. Eluent: cyclohexane then 80:20 cyclohexane/ethyl acetate to obtain 15 mg of phenylphosphonic acid 1H-indazol-5-yl ester methyl ester in the form of a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C@@H:6]([C:24]1[CH:32]=[CH:31][C:27]2[CH2:28][CH2:29][O:30][C:26]=2[CH:25]=1)[NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][NH:17][C:16]=2[N:15]=1)[CH3:2].[C:34]([O-])([O-])=[O:35].[K+].[K+].C(Cl)(Cl)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][C@@H:6]([C:24]1[CH:32]=[CH:31][C:27]2[CH2:28][CH2:29][O:30][C:26]=2[CH:25]=1)[N:7]1[CH2:8][CH2:9][N:10]([CH2:11][CH2:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[CH2:20][CH2:19][CH2:18][NH:17][C:16]=3[N:15]=2)[C:34]1=[O:35])[CH3:2]
Reactant: CCOC(=O)C[C@H](NCCNCCCc1ccc2c(n1)NCCC2)c1ccc2c(c1)OCC2
Reactant: O=C([O-])[O-]
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](c1ccc2c(c1)OCC2)N1CCN(CCCc2ccc3c(n2)NCCC3)C1=O
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 2-11 (11.8 mmol), CH2Cl2 (3 mL) and 20% K2CO3 was added phosgene (1.93 M toluene, 6.7 ml, 13.0 mmol) dropwise over 20 minutes. After stirring for 30 minutes, the organic layer was separated and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 5-10% methanol/ethyl acetate) to give 2-12 as a yellow oil. TLC Rf =0.25 (silica, 70:20:10 chloroform/ethyl acetate/methanol) 1H NMR (300 MHz, CDCl3) δ 7.12 (d, J=7.6 Hz, 1H), 7.02 (d, J=7.3 Hz, 1H), 6.80 (d, J=7.6 Hz, 1H), 6.70 (s, 1H), 6.34 (d, J=7.3 Hz, 1H), 5.46 (t, J=7.9 Hz, 1H), 4.74 (s, 1H), 4.55 (t, J=8.9 Hz,2H), 4.10 (q, J=7.3 Hz, 2H), 3.41 (m, 2H), 3.21 (m, 6H), 2.95 (m,3H), 2.67(t, J=6.1 Hz, 2H), 2.52 (t, J=7.6 Hz, 2H), 1.88 (m, 5H), 1.20 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C1C(=O)N([Br:19])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>FC(F)(F)C1C=CC=CC=1>[Br:19][CH2:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: O=[N+]([O-])c1ccc(CBr)cc1Cl

Procedure:
A solution of 3-chloro-4-nitrotoluene (2.0 g, 12 mmol), NBS (2.62 g, 14.6 mmol) and 2,2′-azo-bis-isobutyronitrile (0.195 g, 1.16 mmol) in α,α,α-trifluorotoluene (200 mL) was heated at 80° C. under an atmosphere of nitrogen for 3 h. Solvent was removed in vacuo and the residue was partitioned between EtOAc and water and separated. The aqueous layer was extracted with EtOAc (3×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was taken to the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:24])[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]4[CH2:23][O:22]4)=[CH:15][CH:14]=3)=[CH:9][O:10]2)=[CH:5][CH:4]=1.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(O)C>[CH:25]1([NH:31][CH2:23][CH:21]([OH:22])[CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([C:8]3[C:7](=[O:24])[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[O:10][CH:9]=3)=[CH:14][CH:15]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1ccc2c(=O)c(-c3ccc(OCC4CO4)cc3)coc2c1
Reactant: NC1CCCCC1
Solvent: CCO
Product: COc1ccc2c(=O)c(-c3ccc(OCC(O)CNC4CCCCC4)cc3)coc2c1
Yield: 66.1 %

Procedure:
A mixture of compound 3 (obtained from example 1) (0.32 g, 1 mmol), cyclohexylamine (0.50 g, 5 mmol), and ethanol (30 mL) was refluxed for 4 hrs (TLC monitoring). After removal of solvent in vacuo, the residue was treated with H2O (50 mL). The resulting precipitate was collected and purified by column chromatography (MeOH/CH2Cl2=1:20) to give the title compound 5c (0.28 g, 67% yield). M.p.: 125-126° C.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH2:11][N:12]([CH3:40])[C:13]1[C:18]([C:19]2[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]3[C:31]4[N:32]=[C:33]([NH2:35])[S:34][C:30]=4[CH:29]=[CH:28][CH:27]=3)[CH:20]=2)=[CH:17][CH:16]=[C:15]([C:36]([F:39])([F:38])[F:37])[N:14]=1)[CH:2]([CH3:4])[CH3:3].[C:41](OC(=O)C)(=[O:43])[CH3:42]>N1C=CC=CC=1>[CH2:1]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH2:11][N:12]([CH3:40])[C:13]1[C:18]([C:19]2[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]3[C:31]4[N:32]=[C:33]([NH:35][C:41](=[O:43])[CH3:42])[S:34][C:30]=4[CH:29]=[CH:28][CH:27]=3)[CH:20]=2)=[CH:17][CH:16]=[C:15]([C:36]([F:38])([F:37])[F:39])[N:14]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)CN1CCCCC1CN(C)c1nc(C(F)(F)F)ccc1-c1cc(Oc2cccc3sc(N)nc23)ncn1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4N(C)CC4CCCCN4CC(C)C)ncn3)cccc2s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-(6-(2-(((1-isobutylpiperidin-2-yl)methyl)(methyl)amino)-6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yloxy)benzo[d]thiazol-2-amine, Example 24(d), (0.14 g, 0.24 mmol) and acetic anhydride (5 mL, Aldrich) in pyridine (20 mL) was stirred at 25° C. for 24 h. The reaction mixture was partitioned between aqueous solution of NaHCO3 and EtOAc. The organic phase was separated, washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. Purification of the residue by silica gel column chromotography (gradient: 50-100% EtOAc/hexane) afforded the title compound as a yellow solid. MS (ESI, pos. ion.) m/z: 614 (M+1). Mp: 123.2-125.4° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12][C:13]([OH:15])=[O:14])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:21][O:14][C:13](=[O:15])[CH2:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: COc1ccc(C(C)=O)c(CC(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(OC)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of (2-acetyl-5-methoxy-phenyl)-acetic acid (5.00 g, 24.0 mmol) in methanol (50 mL) was added concentrated sulfuric acid (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours after which it was concentrated to a low volume. Dichloromethane (50 mL) was added and the solution was washed with 1N sodium hydroxide (50 mL). The layers were separated and the organic layer was dried over magnesium sulfate, filtered, and concentrated to an oil which solidified on standing to afford (2-acetyl-5-methoxy-phenyl)-acetic acid methyl ester (4.70 g, 88%). M.p. 74-76° C. 1H NMR (300 MHz, CDCl3) δ2.58 (s, 3), 3.74 (s, 3), 3.89 (s, 3), 3.95 (s, 2), 6.78 (d, 1, J=2.6), 6.89 (dd, 1, J=8.7, 2.6), 7.89 (d, 1, J=8.6). 13C NMR (75 MHz, CDCl3) δ29.65, 42.35, 53.11, 56.69, 113.17, 120.00, 130.52, 134.39, 138.90, 163.54, 173.23, 200.35. IR 1739, 1665, 1605, 1568, 1321, 1247, 1165 cm−1. Analysis calculated for C12H14O4: C, 65.85; H, 6.35. Found: C, 64.87; H, 6.44.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][CH2:13][OH:14])[C:5]#[N:6].C1(C)C=CC=CC=1.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.C(OCC)(=O)C>Cl.[Cl-].[Na+].O>[OH:14][CH2:13][CH2:12][CH2:11][N:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[NH:1][C:23]1=[O:25]
Reactant: N#Cc1ccc(NCCCO)c(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
100 mg (0.52 mmol) of 3-amino-4-[(3-hydroxypropyl)amino]benzonitrile (Intermediate 12) are dissolved in 2.5 ml of 2N aqueous HCl and 1.5 ml of toluene are added. 150 mg (0.51 mmol) of triphosgene are added and the system is stirred at rt for 18 hr. After adding 75 additional mg of triphosgene and prosecuting the stirring for 1 hour 5 ml of brine and 25 ml of ethyl acetate are added and the system is stirred for 10 minutes. The organic layer is isolated and the aqueous one is extracted with 4×10 ml of ethyl acetate. The combined organic phases are washed with brine, dried and concentrated to give 106 mg (93% yield) of 100 pure (UPLC) title compound.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[C:13]([C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:42]2[NH:47][C:46](=[O:48])[C:45]([CH2:49][CH2:50][C:51]([OH:53])=O)=[CH:44][CH:43]=2)=[CH:24]\[C@H:25]2[CH2:29][CH2:28][C:27](=[O:30])[N:26]2[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=2[O:40][CH3:41])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].N>O1CCCC1>[C:13]([C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:42]2[NH:47][C:46](=[O:48])[C:45]([CH2:49][CH2:50][C:51]([NH2:3])=[O:53])=[CH:44][CH:43]=2)=[CH:24]\[C@H:25]2[CH2:29][CH2:28][C:27](=[O:30])[N:26]2[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=2[O:40][CH3:41])=[CH:19][CH:18]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCC(=O)O)c(=O)[nH]2)c(OC)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCC(N)=O)c(=O)[nH]2)c(OC)c1
Reaction time: 15 h

Procedure:
1,1′-Carbonyldiimidazole (24.8 mg) was added to a solution of 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-oxo-1,2-dihydropyridin-3-yl)propanoic acid (77.8 mg) in tetrahydrofuran (1.6 mL). 28% aqueous ammonia (0.2 mL) was further added, followed by stirring for 15 hours. The reaction system was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) to give 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-oxo-1,2-dihydropyridin-3-yl)propanamide as a colorless amorphous (82.6 mg).
Reaction SMILES: C([N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[N:6]1)(C)(C)C>C(O)=O.Cl>[C:18]1([CH3:21])[CH:17]=[CH:16][C:15]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[N:12][C:13]=3[NH2:14])[NH:5][N:6]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(-c2nn(C(C)(C)C)c3ncnc(N)c23)cc1
Agent: Cl
Solvent: O=CO
Product: Cc1ccc(-c2n[nH]c3ncnc(N)c23)cc1
Reaction time: 0.5 h

Procedure:
1-tert-butyl-3-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine was dissolved in a solution of formic acid (1 mL) and conc. HCl (0.1 mL) and heated to reflux. The reaction was allowed to proceed 30 min., then concentrated in vacuo and the products purified by RP-HPLC (MeCN:H2O:0.1% TFA). ESI-MS (M+H)+ m/z calcd 226.1, found 226.3.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH:3]=[O:4].S([O-])([O-])=[O:12].[Na+].[Na+].B(O)(O)O.Cl.S(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)=O>C([O-])(=O)CCCCCCC/C=C\CCCCCCCC.[Na+].O>[CH3:1][CH:2]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH:3]=[O:4].[CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][C:8]([CH3:10])([OH:12])[CH3:9])[CH:3]=[O:4]
Reactant: O=S([O-])[O-]
Agent: CC(C)=CCCC(C)C=O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Agent: Cl
Solvent: O
Product: CC(C=O)CCCC(C)(C)O
Reaction time: 2 h
Yield: 90.1 %

Procedure:
An aqueous emulsion of 2,6-dimethyl-5-heptenal is prepared by stirring a solution of 3 grams of sodium oleate, and 400 mls of water, with 490 grams 2,6-dimethyl-5-heptenal. The emulsion is added at 250° C. to a solution comprising 1072 grams of sodium sulfite, 326 grams of boric acid and 5 liters of water. The resulting mixture is stirred for two hours resulting in the formation of a white flocculant solid. To this reaction mass is added 3000 mls of 30% hydrochloric acid. The addition is accompanied by release of sulfur dioxide fumes and a temperature rise to 30° C. Stirring is continued for 30 minutes whereupon a clear liquid is formed. Over a 30 minute period, 1783 grams of sodium carbonate is added accompanied by release of carbon dioxide. The reaction mixture is extracted twice with 500 ml portions of toluene. The toluene extracts are washed with water and distilled to afford 2,6-dimethyl-6-hydroxy heptanal (249 grams). The GC profile for this material is set forth in FIG. 3. Fractional distlllation through a 1.5"×12" Goodloe column affords the pure product (b.p. 112° C., 4 mm).
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[C:28]([Cl:29])=[CH:27][C:26]([C:30](=[O:32])[CH3:31])=[C:25]([OH:33])[C:24]=2[CH2:34][CH2:35][CH3:36])[C:8]=1[CH2:37][CH2:38][CH3:39])C.[OH-].[Na+]>CO>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:40])=[O:3])=[C:8]([CH2:37][CH2:38][CH3:39])[C:9]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:28]([Cl:29])=[CH:27][C:26]([C:30](=[O:32])[CH3:31])=[C:25]([OH:33])[C:24]=1[CH2:34][CH2:35][CH3:36])(=[O:15])[CH3:14]
Reactant: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCCCOc1c(C(C)=O)ccc(OCC(=O)OCC)c1CCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCCCOc1c(C(C)=O)ccc(OCC(=O)O)c1CCC
Yield: 80.8 %

Procedure:
A solution of 0.94 g (0.0016 mole) of [4-acetyl-3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]acetic acid ethyl ester in 50 ml of methanol and 8.2 ml (0.0082 mole) of 1.0N sodium hydroxide was stirred at reflux for 2 hours. Most of the solvent was removed in vacuo and the pH of the residue was adjusted to 2.0. The product was extracted with methylene chloride and the dried (magnesium sulfate) extract was concentrated in vacuo. The residue was crystallized from etherhexane to give 0.710 g (79% yield) of [4-acetyl-3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]acetic acid, melting point 77°-80°.