Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([CH2:11][C:12]2[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=3)=[CH:9][CH:10]=1)=[O:5])C.[OH-].[Li+].Cl>O1CCOCC1>[C:4]([C:6]1[O:7][C:8]([CH2:11][C:12]2[N:13]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:16][CH:15]=3)=[CH:9][CH:10]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(Cc2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc2c(c1)cc(Cc1ccc(C(=O)O)o1)n2Cc1ccc(F)cc1
Reaction time: 2 h
Yield: 35.5 %

Procedure:
To a solution of the compound obtained in Example 30 (6) (0.003 g) in 1,4-dioxane (0.5 ml), a 10% aqueous lithium hydroxide solution (0.5 ml) was added at −5° C. under argon atmosphere and the mixture was stirred for 2 hours. To the reaction solution was then added a 10% aqueous hydrochloric acid solution and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (chloroform:methanol=9:1) to obtain 0.001 g of the desired product.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][CH2:14]1.O[C:24]1[CH:33]=[C:32]2[C:27]([C:28](=[O:42])[N:29]([CH2:34][O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[CH:30]=[N:31]2)=[CH:26][C:25]=1[O:43][CH3:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:44][O:43][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:24]=1[O:22][CH2:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1)[N:31]=[CH:30][N:29]([CH2:34][O:35][C:36](=[O:41])[C:37]([CH3:38])([CH3:39])[CH3:40])[C:28]2=[O:42]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Reactant: OCCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
Diethyl azodicarboxylate (2.67 ml, 17 mmol) was added dropwise to a solution of 3-morpholinopropan-1-ol (1.54 g, 10 mmol), 7-hydroxy-3,4-dihydro-6-methoxy-3-((pivaloyloxy)methyl)quinazolin-4-one (2.6 g, 8.5 mmol) and triphenylphosphine (4.45 g, 17 mmol) in methylene chloride (40 ml). After stirring for 2 hours at ambient temperature, the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (97/3 followed by 95/5) to give 3,4-dihydro-6-methoxy-3-((pivaloyloxy)metyl)-7-(3-morpholinopropoxy)quinazolin-4-one (3.6 g, 97%).
Reaction SMILES: [C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CCCCCC(O)CCCC(Cc1ccc(C=CC(=O)O)cc1)C(C)=O
Agent: [Pd]
Solvent: CCO
Product: CCCCCC(O)CCCC(Cc1ccc(CCC(=O)O)cc1)C(C)=O

Procedure:
p-(2-Acetyl-6-hydroxyundecyl)cinnamic acid (2.6 g., 0.0072 mole) in ethanol (30 ml.) is hydrogenated over 0.7 g. of a 5% Pd on charcoal catalyst at 1 atmosphere pressure and room temperature. The theoretical amount of hydrogen (0.0072 mole) is absorbed in 7 minutes. The catalyst is filtered off, solvent removed in vacuo, and the residue chromatographed on 45 g. of silica gel with 2% methanol in chloroform elution. The title compound is obtained as a colorless, viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:9]([NH2:15])([CH2:11][C:12]([CH3:14])=[CH2:13])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ClCCl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@:9]([NH:15][C:25]([NH:24][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[S:26])([CH2:11][C:12]([CH3:14])=[CH2:13])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C=C(C)C[C@](C)(N)c1ccc(F)c(Br)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C(C)C[C@](C)(NC(=S)NC(=O)c1ccccc1)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of (S)-2-(3-bromo-4-fluorophenyl)-4-methylpent-4-en-2-amine (1.3 g, 4.6 mmoles, 1.0 equiv) in THF (5 mL) is added benzoyl isothiocyanate (0.63 mL, 4.6 mmoles, 1 equiv). The reaction is stirred at room temperature for 3 h. The solvent is removed under reduced pressure and the residue is purified by silica gel chromatography eluting with a linear gradient of 20% dichloromethane: hexanes to 50% dichloromethane: hexanes to give the title compound (84% yield): MS (m/z): 457, 459 (M+23).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]1[C:22](=O)[C:21]2[C:20]([C:24]([O:26]C)=O)=[CH:19][CH:18]=[CH:17][C:16]=2[NH:15][CH:14]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:35][NH2:36]>CO>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]1[C:22]2=[N:35][NH:36][C:24](=[O:26])[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([C:21]=32)[NH:15][CH:14]1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1C(=O)C(c1nccn1Cc1ccccc1)C(c1ccccc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1nccn1Cc1ccccc1
Yield: 27 %

Procedure:
Methyl 3-(1-benzyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (3.7 g, 8.46 mmol) in hydrazine monohydrate (25 mL) and methanol (100 mL) was stirred at room temperature for 5 h. The resulting mixture was filtered to give 9-(1-benzyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as a white solid (950 mg, yield 27%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.61-4.64 (d, J=11.2 Hz, 1H), 4.99-5.12 (m, 1H), 6.83-6.89 (m, 4H), 7.14-7.28 (m, 1H), 7.36-7.38 (d, J=7.6 Hz, 1H), 7.54-7.58 (t, J=8.0 Hz, 7H), 12.20 (s, 1H). LC-MS (ESI) m/z: 420 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]([CH:22]2[CH2:26][CH2:25][N:24]([CH3:27])[C:23]2=[O:28])=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH3:29][NH:30][C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]([CH:22]2[CH2:26][CH2:25][N:24]([CH3:27])[C:23]2=[O:28])=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:36]3[CH:37]=[CH:38][C:33]([C:31](=[O:32])[NH:30][CH3:29])=[CH:34][CH:35]=3)[S:17][C:10]=12
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Reactant: CN1CCC(C(=O)Nc2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)C5CCN(C)C5=O)cc4F)c3s2)cc1
Temperature: 60 °C
Yield: 26.1 %

Procedure:
A round-bottomed flask was charged with N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-1-methyl-2-oxopyrrolidine-3-carboxamide (20.0 mg, 0.039 mmol), 4-(methylcarbamoyl)phenylboronic acid (21.0 mg, 0.117 mmol), tetrakis(triphenylphosphine)palladium (9.04 mg, 0.0078 mmol), Na2CO3 (0.098 ml, 0.20 mmol) and DME (10 mL). The reaction mixture was stirred at 60° C. until the starting material had been consumed (overnight). Then the reaction mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product (5.3 mg, the yield is 26.1%). LRMS (APCI neg): >99% purity, 254 nm, m/e 517 (M−1). 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.50 (m, 1H), 7.79-7.87 (m, 5H), 7.21-7.33 (m, 2H), 6.51 (d, 1H), 6.17 (d, 1H), 3.38-3.49 (m, 3H), 3.05 (d, 3H), 2.95 (s, 3H), 2.38-2.70 (m, 2H).
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[S:25]>C1C=CC=CC=1.CCCCCC>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:25]
Reactant: S=C=Nc1ccccc1Cl
Reactant: CCCCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CCCCCCC(=N)NC(=S)Nc1ccccc1Cl

Procedure:
Following a procedure similar to that described in Example 42 but using 3.4 g. sodium in 300 ml. acetone, 24.7 g. heptanamidine hydrochloride, and 25.9 g. 2-chlorophenyl isothiocyanate (b.p. 70°-74°C./0.5-1.0 mm.; prepared from 2-chloroaniline) in 125 ml. dry acetone there was obtained 1-(2-chlorophenyl)-3-(heptanimidoyl)-2-thiourea, m.p. 75°-77°C. (from benzene-n-hexane); hydrochloride (33.5 g.), m.p. 158°-160°C. (from acetonitrile).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([CH:10]=[CH2:11])[C:7]=1[CH2:8][OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH3:12][C:3]1[C:2]([O:1][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:7]([CH2:8][OH:9])[C:6]([CH:10]=[CH2:11])=[CH:5][N:4]=1
Reactant: ClCc1ccccc1
Reactant: C=Cc1cnc(C)c(O)c1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=Cc1cnc(C)c(OCc2ccccc2)c1CO
Reaction time: 8 h

Procedure:
To a mixture of 0.1 mole 3-hydroxy-4-hydroxymethyl-2-methyl-5-vinylpyridine in 500 ml. of acetone and 25 gm. potassium carbonate is added 0.11 mole of benzyl chloride. The reaction mixture is stirred overnight, filtered, and the acetone removed in vacuo to yield 2-methyl-3-benzyloxy-4-hydroxymethyl-5-vinylpyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(O)(C(F)(F)F)=O.[N+:30]([O-])([OH:32])=[O:31]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([N+:30]([O-:32])=[O:31])=[CH:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(OCC2CCN(C)CC2)c(OC)c1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(OC)c(OCC2CCN(C)CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A solution of ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (30.6 g, 89 mmol) in methylene chloride (75 ml) was cooled to 0–5° C. TFA (37.5 ml) was added followed by the dropwise addition over 15 minutes of a solution of fuming 24M nitric acid (7.42 ml, 178 mmol) in methylene chloride (15 ml). After completion of the addition, the solution was allowed to warm up and stirred at ambient temperature for 2 hours. The volatiles were removed under vacuum and the residue was dissolved in methylene chloride (50 ml). The solution was cooled to 0–5° C. and ether was added. The precipitate was collected by filtration, and dried under vacuum at 50° C. The solid was dissolved in methylene chloride (500 ml) and 3M hydrogen chloride in ether (30 ml) was added followed by ether (500 ml). The solid was collected by filtration and dried under vacuum at 50° C. to give ethyl 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)-6-nitrobenzoate (28.4 g, 82%).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([N:15]3[CH2:20][CH2:19][N:18](C(OCC4C=CC=CC=4)=O)[CH:17]([C:31]([NH:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:16]3)[CH:10]=2)=[N:5][CH:4]=1)#[N:2].C1(OC)C=CC=CC=1>F>[C:1]([C:3]1[S:7][C:6]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH:17]([C:31]([NH:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:16]3)[CH:10]=2)=[N:5][CH:4]=1)#[N:2]
Reactant: CC(C)NC(=O)C1CN(c2cc(Nc3ncc(C#N)s3)ncn2)CCN1C(=O)OCc1ccccc1
Agent: F
Solvent: COc1ccccc1
Product: CC(C)NC(=O)C1CN(c2cc(Nc3ncc(C#N)s3)ncn2)CCN1

Procedure:
47-3 (0.23 g, 0.46 mmol) was wetted with 1 mL of anisole before treatment with 10 mL of hydrofluoric acid for 1 hour at 0° C. The hydrofluoric acid was then evaporated off and the residue was suspended in ethyl ether, filtered and then purified on a silica column to give 48-1. Hi-Res MS: calc: 373.1554 found: 373.1550. 1H-NMR (CD3OD): 8.40(s, 1H); 7.99(s, 1H); 6.17(s, 1H); 4.30(d, 1H); 3.98(m, 2H); 3.37(m, 1H); 3.18(m, 2H); 3.06(m, 1H); 2.82(m, 1H); 1.16(m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH2:21][CH3:22]>C(#N)C>[F:11][C:5]1[CH:4]=[C:3]([O:12][CH2:20][CH2:21][CH3:22])[C:2]([F:1])=[CH:7][C:6]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(F)c(O)cc1F
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 60 °C
Reaction time: 15 h
Yield: 46.9 %

Procedure:
To a solution of 2,5-difluoro-4-nitro-phenol (1.71 g, 9.77 mmol) in acetonitrile (20 mL), potassium carbonate (2.7 g, 19.5 mmol) and 1-iodopropane (1.14 mL, 11.7 mmol) were added. After stirring at 60° C. for 15 hours, mixture was concentrated and extracted with methylene chloride and 2M NaOH solution. Organic phases were dried over magnesium sulfate, filtered, and concentrated to give 1,4-difluoro-2-nitro-5-propoxy-benzene as a yellow solid (0.995 g, 47%). 1HNMR (CDCl3, 400 MHz) δ 7.92-7.88 (m, 1H), 6.83-6.78 (m, 1H), 4.08-4.05 (t, J=6.5 Hz, 2H), 1.95-1.86 (m, 2H), 1.10-1.06 (t, J=7.4 Hz, 2H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[O:9][C:8]([C:10]2[CH:29]=[CH:28][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[O:26][N:25]=[C:24]([CH3:27])[CH:23]=3)=[CH:12][CH:11]=2)=[N:7][CH2:6]1.[CH3:30]I>O1CCCC1>[CH3:30][O:3][CH2:4][CH:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[O:26][N:25]=[C:24]([CH3:27])[CH:23]=3)=[CH:28][CH:29]=2)=[N:7][CH2:6]1
Reactant: CI
Reactant: Cc1cc(CCCCCCCOc2ccc(C3=NCC(CO)O3)cc2)on1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1CN=C(c2ccc(OCCCCCCCc3cc(C)no3)cc2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a stirred suspension of 1.08 g of sodium hydride (60% in mineral oil) in 50 ml of dry tetrahydrofuran was added over 33 minutes a solution of 6.6 g of 5-{7-[4-(4,5-dihydro-5-hydroxymethyl-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole (Example 23). The mixture was heated at gentle reflux for one hour, then cooled to room temperature, and 4.30 g of methyl iodide in 25 ml of dry tetrahydrofuran was added over a 15 minute period. The reaction mixture was stirred overnight at room temperature, then filtered and concentrated in vacuo. The residue was washed with n-pentane and dissolved in ethyl acetate and the soluble portion isolated (6.31 g, m.p. 53°-55° C.). The latter was recrystallized from hexane to give 5.1 g of 5-{7-[4-(4,5-dihydro-5-methoxymethyl-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole, m.p. 60°-61° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18](=[O:38])[C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:20]=3[O:29][CH2:30][C@H:31]([CH3:37])[CH:32]=[N:33]C(C)C)=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:6][CH:7]=1.Cl>>[ClH:1].[NH2:33][CH2:32][C@@H:31]([CH3:37])[CH2:30][O:29][C:20]1[CH:21]=[C:22]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C:16]1[C:11]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:38]
Reactant: CC(C)N=C[C@@H](C)COc1cc(S(C)(=O)=O)ccc1C(=O)Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Agent: Cl
Product: C[C@H](CN)COc1cc(S(C)(=O)=O)ccc1C(=O)Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Yield: 69 %

Procedure:
N-(5-Chloropyridin-2-yl)-3-[2-[(2R)-2-methyl-3-(2-propylimino)propoxy]-4-methylsulfonylbenzoylamino]-pyridine-2-carboxamide was treated with 1 N HCl and purified by HPLC (Vydac C18, 5-70% 0.1% TFA/CH3CN in 0.1% TFA/H2O; Rt: 27.6 m) to give the title compound as a solid (205 mg, 69%).
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C1(C#C)C=CC=CC=1.[C:20]([O:28][CH2:29][CH2:30][O:31]CCl)(=O)[C:21]1C=CC=C[CH:22]=1.[OH-].[Na+]>C1COCC1.C(O)C.O>[C:8]1([C:22]#[C:21][CH2:20][O:28][CH2:29][CH2:30][OH:31])[CH:7]=[CH:6][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCC
Reactant: O=C(OCCOCCl)c1ccccc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: OCCOCC#Cc1ccccc1
Temperature: 78 °C
Reaction time: 24 h
Yield: 94.6 %

Procedure:
Butyl lithium in hexane (30 mmol) was added to phenylacetylene (3.29 ml, 30 mmol) in dry THF (20 ml) at -78° C. The mixture was allowed to reach room temperature, cooled to 78° C. and 2-chloromethoxyethyl benzoate (6.4 g 30 mmol) added. The mixture was kept at 0° C. for 24 hours, quenched with water and extracted into ether. The crude product obtained from the organic phase was treated with 8% sodium hydroxide in ethanol (100 ml) and heated under reflux for 0.5 hours. The crude product was poured into water and extracted into ether. The ether extracts were washed with water, dried and the solvent removed to give 5 g of 2-(3-phenyl-2-propynoxy)ethanol.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[N:9]=[C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[N:5]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.O>CC(N(C)C)=O>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([C:6]2[N:5]=[C:4]([CH2:3][CH2:2][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:9]=[C:8]([NH:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:7]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc(-c2cc(Nc3cccnc3)nc(CCBr)n2)c1
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cccc(-c2cc(Nc3cccnc3)nc(CCN3CCOCC3)n2)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Compound 15 (1 eq) is dissolved in 3 ml of dimethyl acetamide and morpholine (5 eq) is added. The reaction mixture is stirred at 60° C. for 4 h, then cooled down to room temperature. Water is added to the mixture and the crash out is filtered off, washed with water and purified by reverse phase preparatory HPLC, obtaining [6-(3-methoxyphenyl)-2-(morpholin-4-ylethyl)pyrimidin-4-yl]-3-pyridylamine 16.
Reaction SMILES: [N+:1]([CH:4]([CH3:7])[CH2:5][OH:6])([O-:3])=[O:2].S(=O)(=O)(O)[O-].[Na+].[CH2:14]=[C:15]([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[C:15]([O:6][CH2:5][CH:4]([N+:1]([O-:3])=[O:2])[CH3:7])([CH3:17])([CH3:16])[CH3:14]
Reactant: C=C(C)C
Reactant: CC(CO)[N+](=O)[O-]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(COC(C)(C)C)[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a solution of 36.6 g (0.34 mol) of crude 2-nitro-propan-1-ol [prepared according to Example 1a]in 200 ml of toluene in a pressure vessel is added 2 g of sodium bisulfate [NaHSO4]. Through the closed autoclave is added at room temperature 48 g (0.85 mol) of isobutene. The reaction mixture is maintained at 60° C. for 8 hours. The reaction mixture is cooled to room temperature, diluted with toluene and filtered to give a crude solution of 1-tert-butoxy-2-nitro-propane in toluene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][C:15]([NH:19]CC4C=CC(OC)=CC=4)=[N:14][C:13]=3[N:12]([C:29]34[CH2:33][CH:31]([CH2:32]3)[CH2:30]4)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][C:42]([OH:44])=O)=[N:39][CH:40]=1.CCCP(O)(O)=O>C1COCC1>[NH2:19][C:15]1[N:16]=[CH:17][C:18]2[C:10]([C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:42](=[O:44])[CH2:41][C:38]4[CH:37]=[CH:36][C:35]([F:34])=[CH:40][N:39]=4)[CH:7]=[N:6][CH:5]=3)=[O:9])=[CH:11][N:12]([C:29]34[CH2:32][CH:31]([CH2:33]3)[CH2:30]4)[C:13]=2[N:14]=1
Reactant: O=C(O)Cc1ccc(F)cn1
Reactant: COc1ccc(CNc2ncc3c(C(=O)c4cncc(N)c4)cn(C45CC(C4)C5)c3n2)cc1
Agent: CCCP(=O)(O)O
Solvent: C1CCOC1
Product: Nc1ncc2c(C(=O)c3cncc(NC(=O)Cc4ccc(F)cn4)c3)cn(C34CC(C3)C4)c2n1
Reaction time: 18 h
Yield: 31 %

Procedure:
To a solution of (5-amino-pyridin-3-yl)-[7-bicyclo[1.1.1]pent-1-yl-2-(4-methoxy-benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-methanone (Preparation 287) (50 mg, 0.11 mmol) in THF (5 mL) at room temperature was added 5-fluoro pyridine-2-yl acetic acid (27 mg, 0.17 mmol), TEA (0.08 mL, 0.56 mmol) and 1-propylphosphonic acid cyclic anhydride (50% solution in EtOAc, 0.20 mL, 0.34 mmol). The resulting mixture was before stirred for 18 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between saturated sodium bicarbonate solution (10 mL) and ethyl acetate (25 mL). The organic phase was dried over sodium sulphate and concentrated under reduced pressure. TFA (1.5 mL) was added and the resulting mixture stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue partitioned between saturated sodium bicarbonate (10 mL) and ethyl acetate (30 mL). The organic phase was dried over sodium sulphate, concentrated under reduced pressure purified by Preparative TLC (MeOH:DCM 5:95) to afford the title compound as off white solid in 31% yield, 16 mg. 1H NMR (400 MHz, DMSO-d6) δ: 2.32 (s, 6H), 2.66 (s, 1H), 3.94 (s, 2H), 6.57 (s, 2H), 7.49 (m, 1H), 7.69-7.73 (m, 2H), 8.38 (s, 1H), 8.50 (d, 1H), 8.65 (d, 1H), 8.92 (s, 1H), 8.96 (d, 1H), 10.67 (s, 1H); LCMS (System 10): Rt=2.85 min; m/z 458 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][NH:27][CH3:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C(Cl)(Cl)Cl>[C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([N:27]([CH3:28])[CH3:26])=[O:16])=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(NC(=O)C(c2ccccc2)c2ccccc2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)c1ccc(NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 62 %

Procedure:
A solution of 4-diphenylacetylamino-benzoic acid (150 mg, 0.45 mmol), dimethylamine (2.0 M in THF, 203 mg, 0.24 mL, 4.5 mmol), EDC (86 mg, 0.45 mmol) and HOBT (61 mg, 0.45 mmol) in CH2Cl2 (15 mL) was stirred at room temperature for 17 h. The reaction mixture was diluted with CHCl3 and washed with 10 N HCl (4 mL), sat'd aq NaHCO3 (4 mL) and sat'd aq brine. The organic solution was dried and concentrated in vacuo to give the title compound as a white solid (100 mg).