Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:13][C:14]([C:16]1[C:24]2[C:19](=[N:20][CH:21]=[C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[NH:27][N:26]=3)[N:23]=2)[NH:18][CH:17]=1)=[O:15])([CH3:12])[CH2:3][NH:4]C(=O)OC(C)(C)C.[ClH:35]>C(OCC)(=O)C>[ClH:35].[NH2:4][CH2:3][C:2]([NH:13][C:14]([C:16]1[C:24]2[C:19](=[N:20][CH:21]=[C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[NH:27][N:26]=3)[N:23]=2)[NH:18][CH:17]=1)=[O:15])([CH3:1])[CH3:12]
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CNC(=O)OC(C)(C)C)c4n3)n[nH]c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CN)c4n3)n[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
tert-Butyl 2-methyl-2-(2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)propylcarbamate (100 mg, 0.22 mmol) was added to a saturated solution of HCl gas in ethyl acetate (20 mL) and the mixture was stirred at room temperature for 3 hours. The solid obtained was filtered and washed with 5 mL of ethyl acetate to give N-(1-amino-2-methylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide hydrochloride (25 mg, 32%) as a yellow solid. MS: (M+H)+=364; 1H NMR (300 MHz, DMSO): δ 13.45 (s, 1H), 12.96 (s, 1H), 9.19 (s, 1H), 8.47-8.40 (m, 2H), 8.12-8.10 (m, 3H), 7.46 (s, 1H), 7.12 (d, 1H, J=8.4 Hz), 3.84 (brs, 5H), 3.42 (d, 2H, J=4.8 Hz), 2.52 (s, 3H), 1.58 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:26])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH3:24])[CH2:12][O:11][C@@H:10]([O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C@@H:9]1[CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34](OC(=O)C)(=[O:36])[CH3:35].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:26])[C@@H:15]([NH:25][C:34](=[O:36])[CH3:35])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH3:24])[CH2:12][O:11][C@@H:10]([O:27][CH2:28][C:29]([CH3:31])([CH3:30])[CH3:32])[C@@H:9]1[CH3:33])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCc1ccccc1C[C@H](N)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccccc1C[C@H](NC(C)=O)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Yield: 53.3 %

Procedure:
Dissolve the diastereomeric mixture of amines from the previous reaction which contains (2R,3S,5R)-5-[(1S,2S)-2-amino-3-(2-ethylphenyl)-1-hydroxypropyl]-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (418 mg, 0.9 mmol) in dry dichloromethane (7 mL) under a nitrogen atmosphere and add acetic anhydride (90 μL, 0.95 mmol) and triethylamine (150 μL, 1.1 mmol). After 4 hours quench with methanol, concentrate and purify (silica gel chromatography) to give a mixture of amide diastereomers containing the title compound (243 mg). Purify the resulting mixture by HPLC, eluting with 65:35 acetonitrile:water with 8 μM hydrochloric acid, to give the title compound as a single diastereomer (47 mg, 10% overall).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[I:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>>[I:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: BrCc1cccc(I)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc(I)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-iodobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:16]3=[O:32])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[H-].[Na+].I[CH3:36]>CN(C=O)C>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([N:21]([CH3:36])[C:22](=[O:31])[O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:16]3=[O:32])[CH2:13][CH2:14]2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cnc(N2CCC(N3CCC[C@H](NC(=O)OCc4ccccc4)C3=O)CC2)nc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(N3CCC[C@H](N(C)C(=O)OCc4ccccc4)C3=O)CC2)nc1
Reaction time: 0.08 h
Yield: 38.5 %

Procedure:
(S)-benzyl 1′-(5-ethylpyrimidin-2-yl)-2-oxo-1,4′-bipiperidin-3-ylcarbamate (Example 58, Steps A-B; 0.250 g, 0.571 mmol) was dissolved in DMF (5 mL). 60% NaH (0.0274 g, 0.686 mmol) was added and stirred for 5 minutes. Iodomethane (0.071 mL, 1.1 mmol) was added and stirred at ambient temperature overnight. The reaction was concentrated and purified over silica gel (25-100% EtOAc in hexanes) to afford (S)-benzyl 1′-(5-ethylpyrimidin-2-yl)-2-oxo-1,4′-bipiperidin-3-yl(methyl)carbamate (100 mg, 0.22 mmol, 39% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:12])[C:2]=12.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([O:12][S:21]([CH3:20])(=[O:23])=[O:22])[C:2]=12
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCCCc2cccnc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCCCc2cccnc21
Yield: 82.7 %

Procedure:
To a stirred solution of 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (41.70 g, 0.255 mol) in CH2Cl2 (300 mL) at 0° C. was added triethylamine (72 mL, 0.517 mol) followed by methanesulfonyl chloride (30 mL, 0.388 mol). The resultant mixture was stirred at room temperature over night. The mixture was poured into water (200 mL) and the phases were separated. The organic phase was washed with brine (2×150 mL), dried (Na2SO4), and concentrated to give 50.87 g of crude methanesulfonic acid 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl ester.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Br[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.Cl>O1CCOCC1.O>[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: Brc1ncccn1
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C(C(=O)OC)c1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
To dimethyl malonate (41.6 g) in 1,4-dioxane (900 ml) was added sodium hydride (60% dispersion in mineral oil; 18.9 g) portionwise. To the resultant gel was added 2-bromopyrimidine (50.0 g) in 1,4-dioxane (200 ml) dropwise. The mixture was stirred at room temperature for 1 h, then at reflux overnight. To the cooled solution was added water (400 ml), and 5 N hydrochloric acid until the pH was ˜1. The solution was washed with ethyl acetate (2×400 ml), the organic layers combined, washed with saturated sodium hydrogen carbonate solution (1×400 ml) and saturated sodium chloride solution (1×400 ml), dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, eluent =0 to 20% ethyl acetate in dichloromethane) to yield dimethyl 2-(pyrimidin-2-yl)malonate as a yellow/orange oil (24.1 g). 1H NMR (250 MHz, CDCl3) δ3.83 (6 H, s), 5.16 (1 H, s)7.28 (1 H, t, J=5.0 Hz), 8.87 (2 H, d, J=5.0 Hz); MS (ES+) m/e 211 [MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:7][C:6]=2[CH:14]=1.[C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)#[N:16]>>[OH:13][CH2:12][CH2:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:21]3[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=3)[C:15]#[N:16])=[CH:14][C:6]=2[CH:7]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: OCCCc1cc2cc(Br)ccc2o1
Product: N#Cc1cccc(-c2ccc3oc(CCCO)cc3c2)c1

Procedure:
The product from Example 170A(193 mg, 0.80 mmol) and 3-cyanophenylboronic acid is processed as described in Example 112C to provide the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[C:20]([CH:22]=[O:23])[CH:19]=[CH:18][C:17]=2[O:24][C:25]([F:28])([F:27])[F:26])[C:8]2[O:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]=2[CH:15]=1)=[O:4].[OH-].[K+]>CO>[CH:22]([C:20]1[CH:19]=[CH:18][C:17]([O:24][C:25]([F:26])([F:27])[F:28])=[C:16]([C:7]2[C:8]3[O:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]=3[CH:15]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[CH:21]=1)=[O:23]
Reactant: COC(=O)c1cc(-c2cc(C=O)ccc2OC(F)(F)F)c2c(c1)C(C)(C)CO2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)COc2c(-c3cc(C=O)ccc3OC(F)(F)F)cc(C(=O)O)cc21
Yield: 6.1 %

Procedure:
A mixture of 7-(5-Formyl-2-trifluoromethoxy-phenyl)-3,3-dimethyl-2,3-dihydro-benzofuran-5-carboxylic acid methyl ester (1.76 g, 4.82 mmol) (example 8) and 5N potassium hydroxide (2 mL) in methanol (20 mL) was heated at reflux for 1 hour. The solvent was then evaporated. The mixture was diluted with water and washed twice with diethyl ether. The aqueous layers were acidified with 1N HCl and extracted twice with ethyl acetate. The organic combined extract was further washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica gel (30% ethyl acetate in hexane) to afford 112 mg of 7-(5-formyl-2-trifluoromethoxy-phenyl)-3,3-dimethyl-2,3-dihydro-benzofuran-5-carboxylic acid. 10% yield. 1H-NMR (300 MHz, CDCl3): 1.43 (s, 6H), 4.36 (s, 2H), 7.51 (d, J=8.2 Hz, 1H), 7.92–8.04 (m, 4H), 10.05 (s, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[CH:14]1[CH2:19][CH:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:16][NH:15]1.CCN(C(C)C)C(C)C.[C:33](Cl)(=[O:36])[O:34][CH3:35].Cl>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[CH:14]1[CH2:19][CH:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:16][N:15]1[C:33]([O:34][CH3:35])=[O:36]
Reactant: COC(=O)C1CCNC(c2ccc(OC(F)(F)F)cc2F)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(OC(F)(F)F)cc2F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.3 %

Procedure:
Methyl 2-(2-fluoro-4-(trifluoromethoxy)phenyl)piperidine-4-carboxylate hydrochloride (4.97 g, 13.89 mmol) was dissolved in dichloromethane (50 mL) and DIPEA (6.05 mL, 34.73 mmol). Methyl carbonochloridate (1.313 mL, 16.67 mmol) was added and the reaction mixture was stirred at room temperature for 4 h. 0.1 M HCl was added and the aqueous layer extracted with DCM. The combined organic layers were filtered through a phase separator and evaporated. Crude dimethyl 2-(2-fluoro-4-(trifluoromethoxy)phenyl)piperidine-1,4-dicarboxylate (5.39 g, 102%) was obtained as a yellow oil. MS m/z 380 (M+H)+
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]([CH3:34])[CH3:33])/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:60][C@@H:61]1[C:79](=[O:80])[N:63]2[C:64]([C:76]([OH:78])=[O:77])=[C:65]([CH2:68][S:69][C:70]3[N:74]([NH2:75])[N:73]=[N:72][N:71]=3)[CH2:66][S:67][C@H:62]12.C(N(CC)CC)C.NC1C(CSC2N(NC(C)C)N=NN=2)=C(C(O)=O)N2C(=O)C[C@H]2S1>CC(N(C)C)=O.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]([CH3:34])[CH3:33])/[C:27]([NH:60][C@@H:61]2[C:79](=[O:80])[N:63]3[C:64]([C:76]([OH:78])=[O:77])=[C:65]([CH2:68][S:69][C:70]4[N:74]([NH2:75])[N:73]=[N:72][N:71]=4)[CH2:66][S:67][C@H:62]23)=[O:28])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1N
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 60.9 %

Procedure:
A solution of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-isopropoxyiminoacetic acid (3.06 g, 6.5 mmol), 1-hydroxybenzotriazole (1.01 g, 7.47 mmol) and N,N'-dicyclohexylcarbodiimide (1.47 g, 7.15 mmol) in dimethylacetamide (36 ml) was stirred at room temperature for 3 hours. To the solution was added a solution of 7β-amino-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.35 g, 7.15 mmol) and triethylamine (1.44 g, 14.2 mmol) in dimethylacetamide (18 ml) and water (2.4 ml) and the mixture was stirred at room temperature for 17 hours. Then the mixture was treated in a manner similar to that described in Example 6, (c) to give pale brown powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-isopropoxyiminoacetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (3.10 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[F:11].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([N:10]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)[CH:7]=[CH:6][C:5]=1[F:11]
Reactant: COC(=O)c1cc(N)ccc1F
Reactant: O=Cc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N=Cc2cccc(Br)c2)ccc1F
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture solution of 5-amino-2-fluoro-benzoic acid methyl ester (26 g, 153.8 mmol), 3-bromo-benzaldehyde (28.5 g, 153.8 mmol) and p-toluenesulfonic acid (590 mg, 3.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 5-[(3-bromo-benzylidene)-amino]-2-fluoro-benzoic acid methyl ester (51.7 g, quant.) as a pale-white solid: MS calcd. for C15H11BrFlNO2 337.16, obsd. (ESI+) [(M+H)+]336.0 & 338.0.
Reaction SMILES: CC(C)C(BC(C(C)C)C)C.[BH4-].[Na+].CC(=CC)C.[CH3:19][C:20]([O:28][Si](C)(C)C)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:21][C:22]#[CH:23].C[N+]([O-])(C)C.[OH-].[Na+].[I:40]I>C(COC)OC.O1CCCC1>[I:40]/[CH:23]=[CH:22]/[CH2:21][C:20]([OH:28])([CH3:19])[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: II
Reactant: C#CCC(C)(CCCC)O[Si](C)(C)C
Agent: CC(C)C(C)BC(C)C(C)C
Agent: CC=C(C)C
Agent: C[N+](C)(C)[O-]
Solvent: COCCOC
Solvent: C1CCOC1
Product: CCCCC(C)(O)C/C=C/I
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 400 ml of 0.5 M bis-(3-methyl-2-butyl)borane in glyme, prepared from sodium borohydride, 2-methyl2-butene, and boronitrifluoride etherate as in Example 107, is added 63.7 g (0.30 moles) of 4-methyl-4-trimethylsilyloxy-1-octyne (Example 125) at -10° C. The solution is stirred at ambient temperature for 2.5 hours, cooled to -10° C., and treated during 30 minutes with 158 g (2.1 moles) of solid trimethylamine oxide with cooling. The mixture is stirred at ambient temperature for 2 hours and then poured into a stirred, ice-cold solution of 15% aqueous sodium hydroxide; the stirred mixture is treated immediately with a solution of 426 g (1.68 moles) of iodine in 1100 ml of tetrahydrofuran, After 4 hours the mixture is extracted with ether. The extract is washed successively with water, aqueous sodium thiosulfate, and brine and dried over magnesium sulfate. The extract is concentrated, and the residue is subjected to chromatography on silica gel with hexane to provide an oil, p.m.r. (CDCl3): δ 1.18 (singlet, 4-CH3 group).
Reaction SMILES: [Br:1][C:2]1[N:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(CC)CC)C.ClC(OCC)=O>O1CCCC1>[Br:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[C:9]([Br:11])[N:10]=1
Reactant: O=C(O)c1ccc(Br)nc1Br
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCc1ccc(Br)nc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1.51 g of 2,6-dibromonicotinic acid (Helvetica Chimica Acta, 1976, 59, 229), 0.72 ml of triethylamine and 30 ml of tetrahydrofuran was added 0.57 ml of ethyl chloroformate at 0° C. After stirring at room temperature for 30 minutes, an insoluble matter was filtered. To the filtrate was added 30 ml of tetrahydrofuran, and then 717 mg of sodium borohydride was added thereto. To this mixture was added 13 ml of methanol at 5° C. followed by stirring for 15 minutes. The reaction mixture was diluted with ethyl acetate and then washed with an aqueous solution of saturated ammonium chloride and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated to give the title compound.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[C:37]1([NH:36][S:33]([C:29]2[CH:28]=[C:27]([NH:26][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:13])[CH:32]=[CH:31][CH:30]=2)(=[O:34])=[O:35])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Nc1cccc(S(=O)(=O)Nc2ccccc2)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)Nc2ccccc2)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-phenyl-benzenesulfonamide [commercially available] according to general procedure II. Yellow solid. MS (ISP) 586.2 [(M−H)−]; mp 228° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:11]([C:18](OCC)=[O:19])=[C:12]([CH3:17])[NH:13][C:14](=[O:16])[CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].OS(O)(=O)=O>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:11]([CH2:18][OH:19])=[C:12]([CH3:17])[NH:13][C:14](=[O:16])[CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCOC(=O)c1c(Sc2cc(C)cc(C)c2)cc(=O)[nH]c1C
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(Sc2cc(=O)[nH]c(C)c2CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.4 %

Procedure:
Under nitrogen atmosphere, the intermediate 14 (500 mg; 1.6 mmol) was suspended in dry tetrahydrofurane (20 ml) and LiAlH4 (120 mg; 3.2 mmol) was added at 0° C. The mixture was stirred at room temperature for 18 hours and poured in ethyl acetate (50 ml) at 0° C. and a solution 10% H2SO4 (100 ml) was added dropwise. The mixture was extracted with ethyl acetate (2×100 ml) and the organic layer was removed under reduced pressure giving the intermediate 15 (310 mg; 71%) m.p.=268–270° C.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][N:4]=1.[NH2:17][CH2:18][CH2:19][S:20][CH2:21][C:22]1[O:26][C:25]([CH2:27][N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=1>>[CH3:30][N:28]([CH2:27][C:25]1[O:26][C:22]([CH2:21][S:20][CH2:19][CH2:18][NH:17][C:3]2[NH:8][C:7](=[O:9])[C:6]([O:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:5][N:4]=2)=[CH:23][CH:24]=1)[CH3:29]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSc1ncc(Oc2cccnc2)c(=O)[nH]1
Product: CN(C)Cc1ccc(CSCCNc2ncc(Oc3cccnc3)c(=O)[nH]2)o1
Yield: 49.7 %

Procedure:
A mixture of 2-(methylthio)-5-(3-pyridinyloxy)-4(3H)-pyrimidinone (1.18 g) and 5-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-furanmethanamine (2.14 g) was heated at 140° for 6 h. the residue was chromatographed (silica/ethyl acetate-methanol, 1:1) to give the title compound (1.0 g) as a yellow gum.
Reaction SMILES: [CH2:1]([O:8]CC1C=CC=CC=1)[C:2]1C=CC=C[CH:3]=1.[O:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>[Pd]>[O:16]1[CH2:21][CH2:20][O:19][CH:18]1[CH2:17][CH2:3][CH2:2][CH2:1][OH:8]
Reactant: c1ccc(COCc2ccccc2)cc1
Reactant: C1COCCO1
Agent: [Pd]
Product: OCCCCC1OCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
Benzyl ether of step 3 (2.00 g, 8.46 mmol, 1.0 equiv) was dissolved under argon in 1,4-dioxane (20 mL). Pd/C (10% Pd, 50 mg, 2.5 weight-%) was added. The mixture was purged with argon, and subsequently with hydrogen. The mixture was stirred at room temperature for 16 h. The solution was filtered (GF/A glass microfiber) and concentrated under reduced pressure to give the resulting alcohol (1.24 g, 8.46 mmol, 100%) as clear, colourless oil which was used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ=4.86 (t, J=4.7 Hz, 1H), 4.00-3.91 (m, 2H), 3.90-3.80 (m, 2H), 3.65 (t, J=6.5 Hz, 2H), 1.74-1.66 (m, 2H), 1.66-1.58 (m, 2H), 1.56-1.46 (m, 2H), 1.40 (br s, 1H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([CH:15]1[CH:19]=[CH:18][C:17](=[O:20])[O:16]1)[CH2:9][CH:10]([CH3:14])[CH2:11][CH:12]=[CH2:13])([CH3:4])([CH3:3])[CH3:2].[C:22]1(C)C=CC=CC=1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu].[Cu].[Cu].[Cu].[Cu].[Cu]>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([CH:15]1[CH2:19][CH:18]([CH3:22])[C:17](=[O:20])[O:16]1)[CH2:9][CH:10]([CH3:14])[CH2:11][CH:12]=[CH2:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCC(C)C[C@@H](NC(=O)OC(C)(C)C)C1C=CC(=O)O1
Reactant: Cc1ccccc1
Agent: [Cu]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: C=CCC(C)C[C@@H](NC(=O)OC(C)(C)C)C1CC(C)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere to 20 ml thoroughly degassed toluene are subsequently added 0.63 g (0.31 mmol) hydrido(triphenylphosphine)copper(I) hexamer, 2.9 ml polymethylhydrosiloxane and a (degassed) solution of 5.7 g (19.3 mmol) [(R)-3-methyl-1-(5-oxo-2,5-dihydro-furan-2-yl)hex-5-enyl]-carbamic acid tert-butyl ester in toluene. After stirring for 2 h at 25° C. 6 mg (0.01 mmol) of R(+)-2,2′-bis-(diphenylphosphino)-6,6′-dimethoxy-1,1-biphenyl are added as an accelerating ligand for the copper complex. After 12 h the mixture is diluted with ethyl acetate and washed with water, 5% aqueous citric acid and 5% aqueous NaHCO3. Chromatography on silica gel (EtOAc/hexane 1:9, then 1:3) provides the title compound as a diastereomeric mixture.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27]Br)[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].[CH2:30]([O:32][P:33]([O:37]CC)[O:34][CH2:35][CH3:36])[CH3:31]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27][P:33]([O:34][CH2:35][CH3:36])([O:32][CH2:30][CH3:31])=[O:37])[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21]
Reactant: COC(=O)C(CC=CCBr)CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(CC=CCC(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)C(=O)OC)OCC
Yield: 44.5 %

Procedure:
A solution of 2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester 4B (140 mg, 0.30 mmol) and triethylphosphite (600 mg, 3.6 mmol) in toluene (30 mL) was stirred at reflux for 20 hours. The mixture was concentrated and chromatographed on silica gel eluting with ethyl acetate (60% to 100%)/hexanes, affording 2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester 4C as an oil (70 mg, 43%); 1H NMR (300 MHz, CDCl3) δ 1.27 (m, 6H), 1.79 (s, 3H), 2.0-2.7 (m, 8H), 3.37 (d, J=6.6 Hz), 3.52 (s, 3H), 3.75 (s, 3H), 4.08 (m, 4H), 5.20 m, 3H), 5.45 (m, 2H) ppm.