Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=1)[CH:3](OCC)OCC.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]([NH2:27])=[S:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO.O>[CH3:17][S:16][C:12]1[N:11]=[C:10]([C:2]2[S:26][C:25]([NH:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)=[N:27][CH:3]=2)[CH:15]=[CH:14][N:13]=1
Reactant: CCOC(OCC)C(Br)c1ccnc(SC)n1
Reactant: NC(=S)Nc1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CSc1nccc(-c2cnc(Nc3ccccn3)s2)n1

Procedure:
4-(1-Bromo-2,2-diethoxy-ethyl)-2-methylsulfanyl-pyrimidine (18-3, 0.050 g, 0.156 mmol) and 2-pyridylthiourea (0.024 g, 0.16 mmol) were stirred in 1 mL EtOH and 0.10 mL water. p-Toluenesulfonic acid monohydrate (5 mg, 0.03 mmol) was added and the reaction was heated to reflux. After 8 h an addional 30 mg (0.156 mmol) p-toluenesulfonic acid monohydrate and the reaction was refluxed an additional 16 h. The reaction was concentrated and purified by flash column chromatography (elute with a gradient: 3-6% MeOH in DCM). 1H NMR (DMSO-d6) δ 11.75 (s, 1H), 8.50 (d, 1H, J=5.4 Hz), 8.49 (m, 2H), 7.77 (t, 1H, J=6.7 Hz), 7.60 d, 1H, J=5.5 Hz), 7.13 (d, 1H, 8.2 Hz), 7.02 (t, 1H, J=6.6 Hz), 2.55 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.I[C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]2[CH:39]=[C:38]([CH3:40])[C:32]3[N:33]([CH3:37])[C:34]([CH3:36])=[N:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([NH:28][C:29]5[CH:39]=[C:38]([CH3:40])[C:32]6[N:33]([CH3:37])[C:34]([CH3:36])=[N:35][C:31]=6[CH:30]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Nc2cc(I)ncn2)cc2nc(C)n(C)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Nc4cc(C)c5c(c4)nc(C)n5C)ncn3)CC1)C(=O)N2
Temperature: 150 °C

Procedure:
80 mg (0.29 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.10 g (0.26 mmol) (6-iodo-pyrimidin-4-yl)-(1,2,7-trimethyl-1H-benzimidazol-5-yl)-amine and 0.15 mL (0.87 mmol) DIPEA were combined in 1.5 mL DMF and stirred at 150° C. The reaction mixture was then purified by preparative HPLC. The product-containing fractions were combined, evaporated down and the residue was dried. This was taken up in DMF and purified again by preparative HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([NH:12][C:13]([O:15]C)=O)[CH2:7]1)=[O:5])[CH3:2].I[Si](C)(C)C.[F:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[C:29]1[C:33](C(O)=O)=[C:32]([CH3:37])[O:31][N:30]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([NH:12][C:13]([C:33]2[C:29]([C:28]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[F:22])=[N:30][O:31][C:32]=2[CH3:37])=[O:15])[CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1onc(-c2ccncc2F)c1C(=O)O
Reactant: CCOC(=O)C1CCCC(NC(=O)OC)C1
Agent: CCN=C=NCCCN(C)C
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCCC(NC(=O)c2c(-c3ccncc3F)noc2C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
Dissolve 3-methoxycarbonylamino-cyclohexanecarboxylic acid ethyl ester (513 mg, 2.24 mmol) in dry dichloromethane (10 mL). Add iodotrimethylsilane (0.48 mL, 3.4 mmol) and stir the resulting mixture for 2.5 h at ambient temperature. Quench with methanol (5 mL) and concentrate in vacuo. Concentrate the resulting residue twice from diethyl ether and use the crude amine salt directly without purification. Combine this amine salt with 3-(3-fluoro-pyridin-4-yl)-5-methyl-isoxazole-4-carboxylic acid (500 mg, 2.24 mmol),1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (430 mg, 2.24 mmol), 1-hydroxy-7-azabenzo-triazole (305 mg, 2.24 mmol), and N,N-diisopropylethyl amine (2.0 mL, 11.5 mmol) in N,N-dimethylformamide (15 mL) and stir overnight at ambient temperature. Concentrate the mixture in vacuo and take up in water and extract with dichloromethane. Dry the combined extracts over sodium sulfate and concentrate in vacuo. Elute the resulting residue over silica gel using methanol/dichloromethane which to give 720 mg (86%) of the desired amide as a white solid. MS(ES): (M+1)+ 376.2, 377.3 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([F:24])[C:5]([O:6][C:7]([C:10]2O[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=3)=[N:12][N:11]=2)([CH3:9])[CH3:8])=[C:4]([F:25])[CH:3]=1.Cl.[CH2:27]([NH2:29])[CH3:28]>CO>[Cl:1][C:2]1[CH:23]=[C:22]([F:24])[C:5]([O:6][C:7]([C:10]2[N:29]([CH2:27][CH3:28])[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=3)=[N:12][N:11]=2)([CH3:9])[CH3:8])=[C:4]([F:25])[CH:3]=1
Reactant: CCN
Reactant: CC(C)(Oc1c(F)cc(Cl)cc1F)c1nnc(-c2ccnc(N)c2)o1
Agent: Cl
Solvent: CO
Product: CCn1c(-c2ccnc(N)c2)nnc1C(C)(C)Oc1c(F)cc(Cl)cc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 2.9 %

Procedure:
Methanol was added to a mixture of 4-{5-[1-(4-chloro-2,6-difluorophenoxy)-1-methylethyl]-1,3,4-oxadiazol-2-yl}pyridin-2-amine (258 mg) and ethylamine hydrochloride (1.0 g), followed by homogenizing. The solvent was evaporated under reduced pressure, followed by melting at 150° C. for 7 hours. The reaction solution was cooled to room temperature, equivalent amounts of water and saturated brine were added thereto, followed by extraction with ethyl acetate, the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol), and the resulting solid was washed with diisopropylether, to obtain, as an ocher solid, 4-{5-[1-(4-chloro-2,6-difluorophenoxy)-1-methylethyl]-4-ethyl-4H-1,2,4-triazol-3-yl}pyridin-2-amine (8.0 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:20])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1([C:25]([OH:27])=[O:26])[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[Cl:20][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:4]1[CH:3]=[C:2]([NH:21][C:22]3([C:25]([OH:27])=[O:26])[CH2:24][CH2:23]3)[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18]
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(Cl)cc21
Reactant: NC1(C(=O)O)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(NC3(C(=O)O)CC3)c2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Yield: 39.9 %

Procedure:
A solution of 2-(3-bromo-phenyl)-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (200 mg, 0.57 mmol), copper(I) iodide (33 mg, 0.17 mmol), 1-amino-cyclopropanecarboxylic acid (235 mg, 2.29 mmol) and potassium carbonate (240 mg, 1.7 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 1-[3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-cyclopropanecarboxylic acid (84.3 mg, 40.0%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 371.1.
Reaction SMILES: [OH-].[Li+].[N:3]1[C:8]2[NH:9][CH:10]=[CH:11][C:7]=2[C:6]([N:12]2[C@H:20]3[C@H:15]([N:16]([CH2:21][CH2:22][CH2:23][C:24]4[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=4)[CH2:17][CH2:18][CH2:19]3)[CH2:14][CH2:13]2)=[N:5][CH:4]=1>CO>[N:3]1[C:8]2[NH:9][CH:10]=[CH:11][C:7]=2[C:6]([N:12]2[C@H:20]3[C@H:15]([N:16]([CH2:21][CH2:22][CH2:23][C:24]4[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=4)[CH2:17][CH2:18][CH2:19]3)[CH2:14][CH2:13]2)=[N:5][CH:4]=1
Reactant: COC(=O)c1ccc(CCCN2CCC[C@@H]3[C@H]2CCN3c2ncnc3[nH]ccc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CCCN2CCC[C@@H]3[C@H]2CCN3c2ncnc3[nH]ccc23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An aqueous 0.5 M solution of lithium hydroxide (625 μL, 0.081 mmol) was added to a stirred room temperature solution of the product of Example 13 (11 mg, 0.026 mmol) in methanol (100 μL). The mixture was stirred for 16 hours at room temperature and was then concentrated in vacuo to a crude solid/liquid mixture. The residue was purified by mass triggered reverse phase HPLC. The product containing fractions were lyophilized to give the title compound (TFA salt) as a white solid. LRMS calc'd for C23H28N5O2 [M+H]+, 407; found 406. Jak1 activity: +.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[CH:24]=[N:23][NH:22][C:21]=1[C:25](O)=[O:26]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:21]3[NH:22][N:23]=[CH:24][C:20]=3[Cl:19])=[O:26])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1[nH]ncc1Cl
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3[nH]ncc3Cl)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 4-chloro-2H-pyrazole-3-carboxylic acid following procedure I yielded the title compound. MS (ISP): m/z=388.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=2[N:6]=1.[CH3:13][NH:14][CH3:15]>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([N:14]([CH3:15])[CH3:13])=[N:6][C:5]=2[CH:7]=1
Reactant: COc1ccc2oc(Cl)nc2c1
Reactant: CNC
Solvent: O
Product: COc1ccc2oc(N(C)C)nc2c1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-5-methoxy-benzooxazole (1.52 g, 8.31 mmol) and a 40% solution of dimethylamine in water (15 mL) was refluxed for two hours before it was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a black oil (1.14 g): MS: (+) m/z 397.19 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[C:14]([CH:18]([N:25]([CH3:39])[C:26](=[O:38])[CH2:27][N:28]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[CH3:29])[CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:15]=[CH:16][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([N:25]([CH3:39])[C:26](=[O:38])[CH2:27][N:28]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH3:29])[CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CN(CC(=O)N(C)C(CN1CCCC1)c1cccc(Br)c1)c1ccc(Cl)c(Cl)c1
Product: CN(CC(=O)N(C)C(CN1CCCC1)c1cccc(-c2ccc(Cl)cc2)c1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared according to the procedure described for example 33, using 4-chlorophenylboronic acid and the intermediate from step c) above. MS (ES) m/e 532 [M+H]+.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:20]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[O:37][CH:38]=[CH:39][N:40]=3)=[CH:32][C:31]=2[F:41])[C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:27]O)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([N:20]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[O:37][CH:38]=[CH:39][N:40]=3)=[CH:32][C:31]=2[F:41])[C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:27][F:7])(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)cc1F)[C@@H]1CCCC[C@H]1CO
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)cc1F)[C@@H]1CCCC[C@H]1CF
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
DAST (4-dimethylamino-N-methyl-4-stilbazolium tosylate, 9 μL, 0.06 mmol) was added to a solution of 4-chloro-N-(2-fluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (25 mg, 0.05 mmol) in 2 mL anhydrous methylene chloride at −20° C. The reaction was stirred at room temperature for 1 h, then purified by flash chromatography on silica gel with 0 to 50% ethyl acetate in hexane to yield 4-chloro-N-(2-fluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(fluoromethyl)cyclohexyl)benzenesulfonamide (8 mg, 33%). 1H NMR (400 MHz, CDCl3) δ ppm 7.82 (1H, dd, J=8.06, 1.51 Hz), 7.69-7.78 (4H, m), 7.67 (1H, dd, J=10.83, 1.51 Hz), 7.40-7.49 (2H, m), 7.23-7.26 (1H, m), 4.46 (2H, dd, J=34.50, 15.61 Hz), 3.97-4.22 (2H, m), 3.58 (1H, br. s.), 1.75-1.76 (1H, m), 1.59-1.74 (3H, m), 1.46 (2H, br. s.), 0.94-1.30 (3H, m). 19F NMR (376 MHz, CDCl3) δ ppm −111.85 (s), −118.19 (s). Analytical HPLC R.T.=25.91 min. MS [M+H]30 =481, [M+Na+]=503. HRMS [M+H]+ calc'd 481.1164, found 481.1176. Chiral LC: R.T.=6.08 min., >96% ee.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([NH:33]C(=O)C)([CH2:28][O:29]C(=O)C)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][CH:12]=1)(=O)C.O.[OH-].[Li+]>CO.O>[NH2:33][C:7]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][CH:12]=1)([CH2:6][CH2:5][OH:4])[CH2:28][OH:29]
Reactant: CCCCCCCCCCCc1ccc(CCCC(CCOC(C)=O)(COC(C)=O)NC(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCc1ccc(CCCC(N)(CO)CCO)cc1
Yield: 25.9 %

Procedure:
3-Acetamido-3-acetoxymethyl-6-(4-undecylphenyl)hexyl acetate (1.70 g) and lithium hydroxide monohydrate (1.42 g) were dissolved in methanol (17 ml) and water (17 ml), and the mixture was refluxed under heating for 3 hours while stirring. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was distilled away. The crude crystals obtained were recrystallized from ether-hexane-ethyl acetate (2:2:1) to give the subject compound (330 mg) as white crystals, melting at 73-76° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21]/[CH:22]=[CH:23]/[CH2:24][CH3:25].CC([O-])(C)C.[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21]/[CH:22]=[CH:23]/[CH2:24][CH3:25])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: CC/C=C/CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CC/C=C/CN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 37.1 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.47 g) is alkylated using (E)-1-bromo-2-pentene (1 g; 6.71 mmol) and KOtBu (0.75 g; 6.71 mmol) at RT for 20 h. After aqueous work-up and flash chromatography on silica gel eluting with light petroleum/EtOAc (2.5:1) the pure alkylated acetamide (0.85 g; 2.58 mmol) is de-acetylated under reflux conditions using DBU (0.6 ml) in MeOH (60 ml). (E)-5-amino-3,3-dimethyl-6-nitro-1-(pent-2-enyl)-1,3-dihydro-indol-2-one (0.6 g) is obtained after an aqueous work-up.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[C:4]([C:10](N)=[O:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.[OH-:14].[K+].Cl>CCO>[CH3:1][N:2]([CH3:13])[C:3]1[C:4]([C:10]([OH:14])=[O:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1
Reactant: Cc1ccc(N(C)C)c(C(N)=O)n1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(N(C)C)c(C(=O)O)n1
Temperature: 90 °C

Procedure:
To the title compound of Step A (91 mg, 0.5 mmol) in EtOH (1 mL) was added 4M KOH (0.5 μL). The reaction was then heated at 90° C. for 18 h. The reaction was then cooled to rt, acidified with 1N HCl (aq) to pH=3, concentrated and used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH:9](=[O:12])[CH2:10][CH3:11]>CC(C)=O.CCCCCC>[CH3:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:4][N:3]=1
Reactant: CCC=O
Reactant: Cc1nccnc1C
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCC(=O)c1cnc(C)c(C)n1
Yield: 25 %

Procedure:
The reaction of 2,3-dimethylpyrazine and freshly distilled propionaldehyde is carried out as described in Example I on the same molar scale. Preparative thick layer chromatography (2000μ silica gel GF, developed in 5% acetone/hexane) of the crude reaction product gives a 25% yield of 1-(2,3-dimethyl-5-pyrazinyl)-1-propanone.
Reaction SMILES: I[CH2:2][C:3]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[N:7]1)([CH3:5])[CH3:4].[N-:14]=[N+:15]=[N-:16].[Na+].O>CN(C)C=O>[N:14]([CH2:2][C:3]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[N:7]1)([CH3:5])[CH3:4])=[N+:15]=[N-:16]
Reactant: CC(C)(CI)n1cc([N+](=O)[O-])cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CN=[N+]=[N-])n1cc([N+](=O)[O-])cn1
Temperature: 140 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a solution of 1-(1-iodo-2-methylpropan-2-yl)-4-nitro-1H-pyrazole (14 g) obtained in Step B of Example 115 in N,N-dimethylformamide (100 mL) was added sodium azide (4.8 g), and the mixture was stirred overnight at 140° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (10 g).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Li+].[OH-].Cl>CO.O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:16][O:15][C:13]([NH:12][CH:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:3]([OH:32])=[O:2])=[O:14])=[CH:22][CH:21]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)OCc1ccc(COc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(NC(Cc1ccccc1)C(=O)O)OCc1ccc(COc2ccc(F)cc2)cc1
Reaction time: 2 h
Yield: 66.5 %

Procedure:
2-[4-(4-Fluoro-phenoxymethyl)benzyloxycarbonyl]amino-3-phenyl-propionic acid methyl ester 38 (115 mg) was dissolved in 10 ml methanol, then treated with 1.1 equiv LiOH in water. After 2 hrs at 60° C., the mixture was poured into water, acidified with HCl, and extracted The organic phase was dried, evaporated and recrystallized to yield about 74 mg of 2-[4-(4-fluorophenoxymethyl) benzyloxycarbonyl]amino-3-phenyl-propionic acid 40, mp. 111.8–113.4° C.
Reaction SMILES: C[O:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[CH3:16])=[CH:5][CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:3]([OH:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)=[C:10]([CH3:16])[CH:11]=1
Reactant: COc1ccccc1-c1ccc(Cl)cc1C
Agent: BrB(Br)Br
Product: Cc1cc(Cl)ccc1-c1ccccc1O
Yield: 97.5 %

Procedure:
Treatment of 2-bromo-5-chlorotoluene (5.0 g, 24.33 mmol) with 2-methoxybenzeneboronic acid (4.8 g, 31.63 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.478 g, 0.608 mmol), and potassium carbonate (8.41 g, 60.83 mmol) generally according to the procedure described for Intermediate 37 provided 5.05 g (89%) of 4′-chloro-2′-methyl-1,1′-biphenyl-2-yl methyl ether. Treatment of 4′-chloro-2′-methyl-1,1′-biphenyl-2-yl methyl ether (5.05 g, 21.48 mmol) with boron tribromide (5.37 g, 1.0 M in dichloromethane) generally according to the procedure described for Intermediate 163 provided 4.58 g (97%) of 4′-chloro-2′-methyl-1,1′-biphenyl-2-ol as a yellow oil. Anal. calcd. for C13H11ClO: C, 71.4; H, 5.07. Found: C, 71.03; H, 4.84.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]1[CH2:14][C@H:13]([OH:15])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>N1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:23])[C@@H:10]1[CH2:14][C@H:13]([O:15][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)OCc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
To a solution of Boc-Pro(4-cis-OH)-OBn (8.45 g, 26.3 mmol) in pyridine (65 mL) at 0° C., was added methanesulfonyl chloride (3.4 mL, 44 mmol) dropwise over 7 min. The reaction mixture was allowed to warm to room temperature over 2 h, then stirred overnight. A solution of 10% water in pyridine (20 mL) was added over 15 min and the reaction mixture was concentrated. The residue was dissolved in water and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water (2×50 mL) saturated aqueous sodium bicarbonate (50 mL) and saturated aqueous sodium chloride (50 mL), dried (sodium sulfate), filtered and concentrated. The resulting residue was dissolved in toluene (100 mL) and concentrated to remove traces of pyridine. The residue was dried in vacuo for 30 min to afford the title compound (10.7 g, 102%), then used in the next step without purification.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[CH3:10].[CH3:11][Si:12](Cl)([CH3:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Cl-].[NH4+]>O1CCCC1>[CH3:11][Si:12]([CH3:21])([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[CH3:10]
Reactant: CCCCCCCC[Si](C)(C)Cl
Reactant: Cc1ccc(C)c(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCCCC[Si](C)(C)c1cc(C)ccc1C
Temperature: 70 °C
Yield: 42.7 %

Procedure:
1.95 g (80.2 mmol) of finely cut magnesium metal was placed in a 200 ml four-necked flask, and 50 ml of anhydrous tetrahydrofuran was further charged. The mixture was heated up to 70° C. while stirring, and 50 ml of a solution of 5 g (27.0 mmol) of 2-bromo p-xylene in anhydrous tetrahydrofuran was added dropwise while caring for steep reaction (reflux). After completion of the addition, it was refluxed for 30 minutes, then, cooled to 40° C., and to this was added 6.7 g (32.4 mmol) of dimethyloctylsilyl chloride while stirring. The solution was again heated and refluxed for 3 hours. The reaction mixture was charged in an aqueous saturated ammonium chloride solution, and extracted (toluene/water) and the organic phase was dried over sodium sulfate. After concentration, the product was purified and isolated by silica gel column chromatography (n-hexane) to obtain 3.19 g of 2-(dimethyloctylsilyl)-p-xylene.