Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([O:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: CS(=O)(=O)OCCCOCc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCCCOCc2ccccc2)c1

Procedure:
Alkylation reaction of phenol 58 with methane sulfonic acid 3-benzyloxy-propyl ester gave 2-(3-(3-(3-(benzyloxy)propoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.643 g, 44%): 1H NMR (400 MHz, DMSO-d6) δ 7.80-7.83 (m, 2H), 7.68-7.72 (m, 2H), 7.27-7.35 (m, 5H), 7.12-7.16 (m, 1H), 6.77 (d, J=7.6, 1H), 6.73 (s, 1H), 6.66 (d, J=8.0, 1H), 4.53 (s, 2H), 4.06 (t, J=6.0 Hz, 2H), 3.77 (t, J=6.2 Hz, 2H), 3.68 (t, J=5.0 Hz, 2H), 2.65 (t, J=7.8 Hz, 2H), 2.0-2.10 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[S:47](Cl)([CH3:50])(=[O:49])=[O:48]>C(Cl)Cl>[O:27]=[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25](=[O:26])[N:17]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:3][CH:4]=1)[CH2:28][CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([NH:37][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:35][CH:36]=1
Reactant: Nc1ccc(CCN(CCCCCCN2C(=O)c3ccccc3C2=O)CCOc2ccc(N)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(CCN(CCCCCCN2C(=O)c3ccccc3C2=O)CCOc2ccc(NS(C)(=O)=O)cc2)cc1
Temperature: 2 °C

Procedure:
2-[6-([2-(4-aminophenyl)ethyl]{2-[(4-aminophenyl)oxy]ethyl}amino)hexyl]-1H-isoindole-1,3(2H)-dione (108.3 mg) was dissolved in DCM (5 ml) and cooled to 0-4° C. in an ice-bath. Hunig's Base (0.227 ml) was added followed by the dropwise addition of mesylchloride (0.051 ml). The reaction was maintained at 0-4° C. for 0.5 h and then allowed to warm slowly to room temperature. After 3 h the reaction mixture was evaporated to dryness and used crude in next step.
Reaction SMILES: C(O[C@@:5]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])([C@H:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13])[CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)(=O)C.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>ClCCl>[CH2:26]([NH:30][S:14]([C:12](=[C:5]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])[CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)[CH3:13])(=[O:15])=[O:16])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN
Reactant: CC(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S(=O)(=O)Cl
Solvent: ClCCl
Product: CCCCNS(=O)(=O)C(C)=C(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.33 h
Yield: 8.6 %

Procedure:
In dichloromethane (4 ml) was dissolved (2R,3R)-3-chlorosulfonyl-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butyl acetate (125 mg). To the solution was added, under ice-cooling, n-butylamine (23 mg). The reaction mixture was stirred for 20 minutes under ice-cooling, which was concentrated. The concentrate was subjected to a silica gel chromatography (eluent: hexane/ethyl acetate=1/2→ethyl acetate) for purification to give, as the first eluate, N-butyl-3- (2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl) -2-butene-2-sulfonamide (isomer B, Compound 33, 10 mg) as a colorless oily substance, and, as the second eluate, N-butyl-3-(2,4-difluorophenyl)-4-(1H-1, 2,4-triazol-1-yl) -2-butene-2-sulfonamide (isomer A, Compound 32, 45 mg) as a colorless solid substance.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:5]=[CH:6][C:7]=1Br.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][C:20]1=[O:25].C(N(C(C)C)CC)(C)C>C(O)C>[Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:5]=[CH:6][C:7]=1[N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[C:20](=[O:25])[CH2:21]1
Reactant: O=c1c(Br)c(Br)cnn1Cc1ccc(F)cc1
Reactant: CN1CCNCC1=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cnn(Cc3ccc(F)cc3)c(=O)c2Br)CC1=O
Temperature: 100 °C

Procedure:
A mixture of 4,5-dibromo-2-(4-fluorobenzyl)pyridazin-3(2H)-one (0.8 g, 2.21 mmol), 1-methylpiperazin-2-one (0.33, 2.87 mmol; see Example 7, Step 3), and diisopropylethyl-amine (0.34 g, 3.32 mmol) in absolute ethanol (3 mL) was heated in a sealed tube in an oil bath at 100° C. overnight. The mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate and brine. The organic extract was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with hexanes and ethyl acetate gradient to give titled material.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=[C:7](Cl)[C:3]=1[C:4](O)=O.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18].C(N(CC)CC)C.C(O)(C)(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[C:3]([O:18][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][CH:22]=[C:14]([Br:13])[CH:15]=1)([CH3:7])([CH3:4])[CH3:2]
Reactant: O=C(O)c1c(Cl)cc(Cl)cc1Cl
Reactant: O=C(O)c1cccc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cccc(Br)c1
Reaction time: 0.25 h

Procedure:
2,4,6-Trichlorobenzoic acid (11.7 ml, 75 mmol) was added dropwise to a solution of 3-bromobenzoic acid (15 g, 75 mmol), triethyl amine (10.5 ml, 75 mmol) in THF (25 ml) at RT. The reaction was stirred 15 min. Then, t-butanol (7.1 ml, 150 mmol) and DMAP (18.3 g, 150 mmol) were added and the reaction was stirred overnight. The crude reaction was filtered through a pad of silica gel, concentrated, and was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]12[CH2:8][C:6]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=3)([CH2:7]1)[C:5](=[O:18])[NH:4][C:3]2=[O:19].C(O)C>COCCO.[Pd]>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]23[CH2:8][C:2]([CH3:1])([CH2:7]2)[C:3](=[O:19])[NH:4][C:5]3=[O:18])=[CH:14][CH:13]=1
Reactant: CC12CC(c3ccc([N+](=O)[O-])cc3)(C1)C(=O)NC2=O
Agent: [Pd]
Solvent: COCCO
Solvent: CCO
Product: CC12CC(c3ccc(N)cc3)(C1)C(=O)NC2=O

Procedure:
In a manner analogous to that described in Example 12a, 3.7 g of 5-methyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 80 ml of 2-methoxyethanol are hydrogenated in the presence of 0.4 g of 5% palladium-on-carbon and worked up. Melting point 216° (from ethanol).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][CH:20]=[N:21]4)[N:13]=[CH:12][C:11]=2[NH2:26])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:28](N)=[O:29].O>CN1CCCC1=O>[C:1]1([C@H:7]([N:9]2[C:10]3[CH:15]=[C:14]([C:16]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:17]=4[CH:18]=[CH:19][CH:20]=[N:21]5)[N:13]=[CH:12][C:11]=3[NH:26][C:28]2=[O:29])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(N)=O
Reactant: C[C@@H](Nc1cc(-c2cccc3ncccc23)ncc1N)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@H](c1ccccc1)n1c(=O)[nH]c2cnc(-c3cccc4ncccc34)cc21
Temperature: 185 °C
Yield: 32.4 %

Procedure:
1-((1R)-1-phenylethyl)-6-(5-quinolyl)-4-imidazolino[4,5-c]pyridine-2-one. ((1R)-1-Phenylethyl)(3-amino-6-(5-quinolyl)(4-pyridyl))amine (150 mg, 0.44 mmol) and urea (52.8 mg, 0.88 mmol) were combined in 1-methylpyrrolidin-2-one (4 mL) and heated at 185° C. for 2 h. Water (10 mL) was added and the crude product was collected by filtration. The product was purified by reverse-phase preparative HPLC (20-95% acetonitrile in water, over 30 min) to give the title compound (52.3 mg, 32.4%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H) 8.91 (dd, J=4.10, 1.56, 1H) 8.39 (d, J=0.78, 1H) 8.33 (ddd, J=8.74, 1.71, 0.88, 1H) 8.05 (d, J=8.49, 1H) 7.80 (dd, J=8.49, 7.13, 1H) 7.59 (dd, J=7.22, 1.37, 1H) 7.41-7.46 (m, 3H) 7.30-7.40 (m, 3H), 5.75 (d, J=7.22, 1H), 4.16 (d, J=0.98, 1H), 1.87 (d, J=7.22, 3H); MS (ESI) m/z 367.0 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.C([Li])(C)(C)C.[F:26]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>C1COCC1>[F:26][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Br)ccnc21
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)ccnc21
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
4-Bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (50 g, 141.5 mmol) in THF (2 L) at −78° C. was treated dropwise with tert-butyllithium (166.5 mL, 283.0 mmol, 1.7M in pentane). The reaction was then stirred for 15 minutes. N-Fluoro-N-(phenylsulfonyl)benzenesulfonamide (49.08 g, 155.6 mmol) in THF (200 mL) was then added dropwise, and the mixture was stirred at −78° C. After 2 hours, the reaction was quenched at −78° C. with saturated aqueous NH4Cl (200 mL). The aqueous phase was extracted with hexanes. The combined hexane phases were dried (MgSO4) and passed through a plug of silica gel eluting with hexanes. The combined hexanes fractions were concentrated in vacuo to provide 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (36.1 g, 87% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ □8.18 (dd, 1H), 7.25 (d, 1H), 6.76 (dd, 1H), 1.86-1.81 (m, 3H), 1.13 (d, 18H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([O:26][CH3:27])=[O:25])=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[C:3]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([O:26][CH3:27])=[O:25])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: C=C(c1cc2c(cc1C)C(C)(C)CCC2(C)C)c1ccccc1C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1C(C)c1cc2c(cc1C)C(C)(C)CCC2(C)C

Procedure:
A solution of methyl 2-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)vinyl]phenylcarboxylate (3.5 g, 9.7 mmol) in ethyl acetate, in the presence of palladium-on-charcoal (900 mg) at a pressure of 6 bar of hydrogen, is stirred at room temperature for 4 h. The mixture is filtered through Celite and then concentrated on a rotary evaporator under vacuum at 40° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH:9]=1)=[O:4].O.[OH-].[Li+]>CO.O>[C:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]([CH2:10][N:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=[N:7]2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cn(Cc2ccc(-c3ccccc3)cc2)nn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 1-Biphenyl-4-ylmethyl-1H-[1,2,3]triazole-4-carboxylic acid methyl ester (60 mg, 0.2 mmol) and lithiumhydroxide-hydrate (35 mg, 0.8 mmol) in 4 mL MeOH and 2 mL water was stirred at 80° C. for 2 h. The mixture was evaporated in vacuo, extracted with hexane and the aq. layer was acidified with 1 N aq. HCl. After extraction with ethyl acetate, the organic layer was dried over MgSO4, and evaporated to yield the crude product which was used in the next step without further purification. 1H-NMR (DMSO-d6, 400 MHz) 8.83 (s, 1H), 7.65-7.70 (m, 4H), 7.38-7.49 (m, 5H), 5.70 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][S:4](=[O:13])(=[O:12])[N:5]=[C:6]([CH2:8][CH2:9][S:10][CH3:11])[N:7]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[NH:3][S:4](=[O:13])(=[O:12])[N:5]=[C:6]([CH2:8][CH2:9][S:10]([CH3:11])=[O:22])[N:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCC1=NS(=O)(=O)NC(N)=N1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CS(=O)CCC1=NS(=O)(=O)NC(N)=N1
Yield: 96.9 %

Procedure:
To a solution of 3-amino-5-[2-(methylthio)ethyl]-1,2,4,6-thiatriazine-1,1-dioxide (1.22 gm, 5.5 mmol) in warm methanol (20 ml) there was added dropwise a solution of 80% pure m-chloroperbenzoic acid (1.2 gm, 5.6 mmol) in chloroform (20 ml). The product crystallized from solution during the addition and was collected by filtration and washed with diethyl ether to give 1.27 gm of pure product, m.p. 180°-182° C.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([NH:8][C:9](=[O:12])[O:10][CH3:11])[CH:4]=1.ClCC1N(C)N=C(C)N=1.[CH:22]1([C:27]2([CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([CH:43]([F:45])[F:44])=[C:39]([F:46])[CH:38]=3)[O:32][C:31](=[O:33])[CH2:30][C:29](=[O:34])[CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([C:27]2([CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([CH:43]([F:45])[F:44])=[C:39]([F:46])[CH:38]=3)[O:32][C:31](=[O:33])[C:30]([CH2:2][C:3]3[O:7][N:6]=[C:5]([NH:8][C:9](=[O:12])[O:10][CH3:11])[CH:4]=3)=[C:29]([OH:34])[CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)Nc1cc(CBr)on1
Reactant: O=C1CC(=O)OC(CCc2ccc(C(F)F)c(F)c2)(C2CCCC2)C1
Agent: Cc1nc(CCl)n(C)n1
Product: COC(=O)Nc1cc(CC2=C(O)CC(CCc3ccc(C(F)F)c(F)c3)(C3CCCC3)OC2=O)on1
Yield: 6 %

Procedure:
The title compound was prepared as described in Example B(53), using methyl 5-(bromomethyl)isoxazol-3-ylcarbamate (prepared as described: Sircar, J. C.; Capiris, T. U.S. Pat. No. 4,489,077, Dec. 18, 1984) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-cyclopentyl-6-{2-[4-(difluoromethyl)-3-fluorophenyl]ethyl}-dihydro-2H-pyran-2,4(3H)-dione (Example B(69), Step 3) in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 6%. 1H NMR (300 MHz, DMSO-d6) δ 1.18-1.75 (m, 8H), 1.94 (m, 2H), 2.35 (m, 1H), 2.40-2.70 (m, 3H, overlap with DMSO-d5), 2.76 (d, J=18.3 Hz, 1H), 3.59 (m, 2H, overlap with H2O), 3.63 (s, 3H), 6.31 (s, 1H), 7.08 (t, J=55 Hz, overlap with m, combined: 3H), 7.50 (t, J=7.5 Hz, 1H), 10.55 (s, 1H), 11.26 (s, 1H). LC-MS (APCI) calcd for C25H27F3N2O6: 508.18; found (M+H+): 509.1 m/z.
Reaction SMILES: O=[CH:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH:12]1([C:18]2[C:19]3[CH:20]=[CH:21][C:22]([C:39]([O:41][CH3:42])=[O:40])=[CH:23][C:24]=3[N:25]3[C:32]=2[C:31]2[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=2[O:29][CH2:28][C@H:27]([NH:37][CH3:38])[CH2:26]3)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(O)(=O)C.C([O-])(=O)C.[Na+]>CO.[Pd]>[C:7]([O:6][C:5]([NH:4][CH2:3][CH2:2][N:37]([CH3:38])[C@@H:27]1[CH2:26][N:25]2[C:24]3[CH:23]=[C:22]([C:39]([O:41][CH3:42])=[O:40])[CH:21]=[CH:20][C:19]=3[C:18]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[C:32]2[C:31]2[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=2[O:29][CH2:28]1)=[O:11])([CH3:10])([CH3:9])[CH3:8]
Reactant: CN[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCNC(=O)OC(C)(C)C)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of tert-butyl (2-oxoethyl)carbamate (1 eq; 0.38 M) in dry MeOH was added a mixture of methyl (7R)-14-cyclohexyl-7-(methylamino)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate(0.14 M), acetic acid (2 eq) and sodium acetate (1 eq) in dry MeOH, and the mixture stirred at RT for 15 min. Then Pd/C (0.3 weight eq) was added as a slurry in MeOH under N2. The atmosphere in the reaction vessel was charged with H2, and the reaction stirred vigorously under a H2 atmosphere (balloon) at 60° C. overnight. The reaction was allowed to cool to RT, flushed with N2 and filtered through a plug of CELITE. The filtrate was concentrated in vacuo and the residue purified by FC (PE/EtOAc 2.5:1 to 1.5:1 gradient) to afford the title compound (82%). (ES+) m/z 562 (M+H)+; [α]D +67.1, c=0.67, CHC13
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH3:22][C:23]#[N:24]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:22][C:23]#[N:24])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Product: N#CCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Yield: 999.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (6.0 g, 2.7 mmol), NaHCO3 (2.5 g, 3.0 mmol) chloroacetonitrile (2.5 g, 3.3 mmol) and CH3CN (150 mol) was stirred at reflux under N2 for 18 hours. The cooled reaction was poured into H2 and the aqueous solution was extracted with EtOAc. The EtOAc extract was washed with H2O, washed with brine, dried with MgSO4 and concentrated to yield 7.0 g of a tan solid. A 1.3 g sample was recrystallized from EtOAc to yield 0.65 g of a beige solid, m.p. 154-156° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:12])[CH3:11])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C)cc(C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A mixture of the 3,5-dimethylaniline (12.1 g, 100.0 mmol) and acetic anhydride (12.1 g, 118.6 mmol) was stirred at 100° C. for 1 h. The crude product was then recrystallized from methanol to provide N-(3,5-dimethylphenyl)acetamide (15.3 g, 93.9%) as a white flake; m.p. 140-142° C. (Lit. 139.6-140.2° C.5.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[CH3:16])=[CH:10][CH:9]=1)=[O:6].[OH-].[NH4+:26]>>[F:23][C:19]1[CH:18]=[C:17]([CH:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:26])=[O:2])=[CH:9][CH:10]=2)[CH3:16])[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)CC(=O)Nc1ccc(OC(C)c2cccc(F)c2)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(Oc1ccc(NC(=O)CC(N)=O)cc1)c1cccc(F)c1
Yield: 55 %

Procedure:
Prepared in analogy to example 3 from N-{4-[1-(3-fluoro-phenyl)-ethoxy]-phenyl}-malonamic acid methyl ester and ammonium hydroxide. Yield=55%. Colorless solid. MS: m/e=317.3 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.[CH:12]1([C:15]2[C:16]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:17][CH:18]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[CH:20]=2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:27]2[CH2:28][CH2:29][N:24]([C:16]3[C:15]([CH:12]4[CH2:13][CH2:14]4)=[CH:20][C:19]([CH:21]4[CH2:23][CH2:22]4)=[CH:18][N:17]=3)[CH2:25][CH2:26]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Agent: Cl
Product: O=C(c1ccc(Br)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 96.9 %

Procedure:
Using 6-bromonicotinic acid (2 g) and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine hydrochloride (3.2 g) described in Preparation Example 87 and by the reaction and treatment in the same manner as in Preparation Example 119, the title compound (4.1 g) was obtained.
Reaction SMILES: C(Cl)(Cl)Cl.Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31](=[O:32])[C:30]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]3[C:28]2=[O:37])=[CH:22][CH:21]=1)[C:11](=[NH:14])OC.[NH3:38]>CO>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:28](=[O:37])[C:29]3=[CH:36][CH:35]=[CH:34][CH:33]=[C:30]3[C:31]2=[O:32])=[CH:22][CH:21]=1)[C:11]([NH2:14])=[NH:38]
Reactant: COC(=N)c1ccc(OCc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c(OC)c1
Reactant: N
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=N)N)ccc1OCc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reaction time: 24 h

Procedure:
To a mixture of 100 ml of chloroform and 100 ml of anhydrous methanol, was added 3.0 g of methyl 3-methoxy-4-(4-phthalimidomethylbenzyloxy)benzimidate hydrochloride followed by 16 ml of a methanol solution of anhydrous ammonia (22 mg/ml). The mixture was stirred for 24 hours and then evaporated to dryness. The residue was dissolved in methanol, then poured into a large volume of chloroform, and filtered from precipitated colorless solids. The filtrate was evaporated to dryness and the residue was recrystallized from methanol to yield 1.4 g of 3-methoxy-4-(4-phthalimidomethylbenzyloxy)benzamidine; m.p. 228°-230° C. To obtain a methanesulfonate, the above benzamidine compound was suspended in methanol and admixed with an excess of methanesulfonic acid. Upon addition of ether to the resulting solution, there was obtained a colorless solid which was recrystallized from methanol to yield colorless needle crystals of 3-methoxy-4-(4-phthalimidomethylbenzyloxy)benzamidine methanesulfonate; m.p. 174°-176° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:15]([O:14][C:10](=[O:13])[CH:11]=[CH:12][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([F:1])[CH:7]=1)[CH3:16]
Reactant: Oc1ccc(Br)cc1F
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(O)c(F)c1
Temperature: 25 °C

Procedure:
A solution of 2-fluoro-4-bromophenol 14-1 (50 g, 261.8 mmol), ethyl acrylate (34 mL), Pd(OAc)2 (2.5 g), tri-o-tolylphosphine (5 g) and triethylamine (83 mL) was heated to 100° C. in a sealed tube for 12 h. The reaction was cooled to room temperature and diluted with dichloromethane (100 mL). The organic solution was washed with 10% aq. citric acid (40 mL), satd aq NaHCO3, and brine (40 mL). The organic solution was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (50:50 hexanes/EtOAc to 100% EtOAc) to give acrylic acid 14-2 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:11][O:12][C:13](=[O:33])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22](Cl)[C:23]3[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1>>[CH3:11][O:12][C:13](=[O:33])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:23]3[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc([N+](=O)[O-])sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(Cl)c(Cl)c3)c3cc([N+](=O)[O-])sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dichlorobenzylamine is reacted with 4-(4-chloro-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dichlorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[CH2:14][C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:12][C@H:11]1[C:22]([OH:24])=[O:23])=[O:9])(=O)C.N>>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH2:14][N:10]([C:8](=[O:9])[CH2:7][CH2:6][CH2:5][SH:4])[C@H:11]([C:22]([OH:24])=[O:23])[CH:12]=2)=[CH:16][CH:17]=1
Reactant: CC(=O)SCCCC(=O)N1CC(c2ccc(C)cc2)=C[C@H]1C(=O)O
Agent: N
Product: Cc1ccc(C2=C[C@@H](C(=O)O)N(C(=O)CCCS)C2)cc1

Procedure:
The product from part (b) is treated with concentrated ammonia according to the procedure of Example 4 to yield (2S)-2,5-dihydro-4-[(4-methyl)phenyl]-1-(4-mercapto-1-oxobutyl)-1H-pyrrole-2-carboxylic acid.