Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]2[C:9]3[CH:16]=[CH:15][S:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:6]([CH3:17])[CH2:5][N:4]([CH2:18][C:19]([NH:21][C:22]2[CH:27]=[C:26]([CH2:28][N:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)[CH:25]=[CH:24][C:23]=2[CH3:42])=[O:20])[CH2:3]1.[ClH:43]>O1CCOCC1>[ClH:43].[CH3:1][C@H:2]1[N:7]([C:8]2[C:9]3[CH:16]=[CH:15][S:14][C:10]=3[N:11]=[CH:12][N:13]=2)[C@@H:6]([CH3:17])[CH2:5][N:4]([CH2:18][C:19]([NH:21][C:22]2[CH:27]=[C:26]([CH2:28][N:29]3[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]3)[CH:25]=[CH:24][C:23]=2[CH3:42])=[O:20])[CH2:3]1
Reactant: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=O)CN1CC(C)N(c2ncnc3sccc23)C(C)C1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(CN2CCNCC2)cc1NC(=O)CN1C[C@@H](C)N(c2ncnc3sccc23)[C@@H](C)C1

Procedure:
The product from step (iii) (0.17 mg) was dissolved in 4M hydrogen chloride in 1,4-dioxane (2 ml). After 48 h the solvents were evaporated under reduced pressure to leave the title compound as a white solid. Yield: 0.16 g
Reaction SMILES: O(CC)[C:2]([S-])=[S:3].[K+].[NH2:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[OH:16]>CCO>[Br:15][C:13]1[CH:12]=[CH:11][C:10]2[O:16][C:2](=[S:3])[NH:8][C:9]=2[CH:14]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1cc(Br)ccc1O
Agent: [K+]
Solvent: CCO
Product: S=c1[nH]c2cc(Br)ccc2o1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
Potassium ethyl xanthate (416 mg, 2.60 mmol) was added to a solution of 2-amino-4-bromophenol (244 mg, 1.30 mmol) in EtOH (3.24 mL). The reaction mixture was heated at reflux for 4 h. Upon cooling to RT the mixture was concentrated and the resulting residue was dissolved in water. Acetic acid was added until pH=5 and a white solid precipitated from the solution. The solid was filtered, washed with water and dried to afford 270 mg (90%) of a tan powder which was used without further purification: 1H NMR (d6-DMSO, 400 MHz) δ 14.02 (s, 1H), 7.47-7.38 (m, 3H); 13C (d6-DMSO, 400 MHz) δ 181.4, 148.1, 133.7, 127.1, 117.8, 118.8, 112.2; MS (Cl) m/z 229.8 (M−1); HPLC retention time=4.34 min.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([O:21]CC)=[O:20])[CH:13]=[N:14][CH:15]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>CO.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([OH:21])=[O:20])[CH:13]=[N:14][CH:15]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cccc(-c2cncc(-c3ccc(C(C)C)cc3)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1ccc(-c2cncc(-c3cccc(C(=O)O)c3)c2)cc1
Temperature: 45 °C
Yield: 87.1 %

Procedure:
Part C. A solution of ethyl 3-[5-(4-isopropyl-phenyl)-pyridin-3-yl]-benzoate (100 mg) in methanol-water (3 mL/1 mL) is treated with lithium hydroxide hydrate (50 mg), and the solution is heated to 40-50° C. for 12 h. After cooling, the solution is neutralized to pH 7 with 3 N HCl and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, filtered and evaporated to afford the title compound as a powder (80 mg, 87%), m.p. 155-156° C. 1H NMR (300 MHz, CDCl3): δ 8.93-8.90 (2H, m), 8.44 (1H, s), 8.21-8.19 (2H, m), 7.89 (1H, d, J=7 Hz), 7.64 (1H, t, J=8 Hz), 7.61 (2H, d, J=9 Hz), 7.39 (2H, d, J=9 Hz), 3.00 (1H, heptet, J=7 Hz), 1.30 (6H, d, J=7 Hz). MS (ES+): m/e 319 (22), 318 (100).
Reaction SMILES: C[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([N:11]2[CH2:16][C@H:15]([CH3:17])[O:14][C@H:13]([CH3:18])[CH2:12]2)[C:5]([CH3:19])=[C:4](F)[C:3]=1[C:21](=[N:27][OH:28])[C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C([O-])([O-])=O.[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:18][C@H:13]1[O:14][C@@H:15]([CH3:17])[CH2:16][N:11]([C:6]2[C:7]([C:8]([OH:10])=[O:9])=[CH:2][C:3]3[C:21]([C:22]4[S:23][CH:24]=[CH:25][N:26]=4)=[N:27][O:28][C:4]=3[C:5]=2[CH3:19])[CH2:12]1
Reactant: Cc1c(C(=NO)c2nccs2)c(F)c(C)c(N2C[C@@H](C)O[C@@H](C)C2)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(N2C[C@@H](C)O[C@@H](C)C2)c(C(=O)O)cc2c(-c3nccs3)noc12

Procedure:
A solution of methyl 2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-4-fluoro-5-[(hydroxyimino)(1,3-thiazol-2-yl)methyl]-3-methylbenzoic acid (Intermediate 195, 0.31 g, 0.8 mmol), K2CO3 (0.4 g, 2.3 mmol) and potassium iodide (0.03 g, 0.2 mmol) in DMF (10 mL) was heated at 130° C. for 12 hours. Solvents were removed under vacuum and the residue was treated with 1.5N hydrochloric acid and extracted with ethyl acetate, which was dried over sodium sulfate. Removal of solvent by vacuum afforded product. Yield: 0.18 g (62%).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[NH:18][C:6]2[N:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]=[C:10](O)[C:5]=2[CH:4]=1.P(Cl)(Cl)([Cl:21])=O>O>[ClH:21].[Cl:1][C:10]1[C:5]2[CH:4]=[C:3]([CH3:2])[NH:18][C:6]=2[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=1
Reactant: Cc1cc2c(O)nc(-c3ccccc3)nc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: O
Product: Cc1cc2c(Cl)nc(-c3ccccc3)nc2[nH]1
Temperature: 25 °C
Yield: 97 %

Procedure:
A heterogeneous mixture of 4 (4.0 g, 17.76 mmol) and phosphorus oxychloride (125 mL) was heated to reflux. After 14 h the homogeneous solution was cooled to room temperature and concentrated in vacuo yielding a black oil. Water was added to the oil and the mixture was warmed. The resulting solid was filtered, washed with water and dried at room temperature to yield 4.22 g of a brown solid (97%). 1H NMR (200 MHz, DMSO-d6): δ 2.43 (s, 3H), 6.31 (s, 1H), 7.49 (m, 3H), 8.34 (m, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:14]([CH2:22][C:23](=[O:27])[C:24](C)=[CH2:25])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11](C)=[CH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H]1C=C(C)C(=O)CN1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][C@@H:10]1[C:11]([CH3:12])=[C:24]([CH3:25])[C:23](=[O:27])[CH2:22][N:14]1[C:15]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:21])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C=C(C)C(=O)CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C(=C)C
Agent: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1=O
Product: CC1=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1=O
Temperature: 115 °C
Yield: 69.1 %

Procedure:
The title compound was prepared from (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-methylbut-3-en-2-yl(3-methyl-2-oxobut-3-enyl)carbamate (Intermediate 189, 3.72 g, 9.36 mmol) following the procedure described for Intermediate 7 except the reaction mixture was heated at 110-120° C. for 48 hours and doubling the catalyst loading (0.6 equivalents). Silica gel chromatography (0%-15% ethyl acetate/hexanes) afforded the desired product as a light tan oily solid (2.39 g, 69%).
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:31]=[C:30]5[C:25]([CH2:26][CH2:27][NH:28][CH2:29]5)=[CH:24][CH:23]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:31]=[C:30]5[C:25]([CH2:26][CH2:27][N:28]([CH3:34])[CH2:29]5)=[CH:24][CH:23]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: N#CCC(C1CC1)n1cc(-c2nc(-c3ccc4c(c3)CNCC4)cc3nccn23)cn1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCc2ccc(-c3cc4nccn4c(-c4cnn(C(CC#N)C5CC5)c4)n3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
To 3-cyclopropyl-3-(4-(7-(1,2,3,4-tetrahydroisoquinolin-7-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 54; 10 mg, 0.024 mmol) in DCM/MeOH (1 mL/1 mL) was added formaldehyde (49 mg, 0.49 mmol) and sodium triacetoxyborohydride (16 mg, 0.073 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to give the final product (5.0 mg, 48% yield). MS (apci) m/z=424.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.[CH:11]([N-]C(C)C)(C)C.[Li+].C1CCCCC1.CI.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH3:11]
Reactant: CC(C)[N-]C(C)C
Reactant: Brc1csc2cnccc12
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1sc2cnccc2c1Br
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a cooled (−78° C.) solution of 3-bromothieno[2,3-c]pyridine (250 mg, 1.17 mmol) in THF (10 mL) was added 1.5 M lithium diisopropylamide in cyclohexane (0.86 mL, 1.28 mmol) and the mixture stirred at −78° C. for 15 min. Methyl iodide (80 μL, 1.28 mmol) was added at −78° C. The mixture was stirred from −78° C. to room temperature and stayed at room temperature for 30 min. Saturated aqueous NH4Cl solution was added and the mixture extracted with DCM. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The crude product was purified by ISCO chromatography (0 to 25% EtOAc:heptane) to afford 178 mg (67%) of the title compound as a white solid. 1H NMR (400 MHz, CD3Cl): δ 8.81 (s, 1 H), 8.39 (d, J=5.6 Hz, 1 H), 7.36 (dd, J=5.3, 0.8 Hz, 1 H), 2.41 (s, 3 H); MS (ESI): 228.30, 230.30 [M+H]+; HPLC tR=0.68 min (HPLC: Analytical—2 min).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:15][C:14]1[CH:16]=[CH:17][CH:18]=[C:12]([Cl:11])[CH:13]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1cccc(Cl)c1
Product: Clc1cccc(Nc2nc3ccccc3[nH]2)c1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3-chloroaniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 252-257° C.). MS(ES+) m/z 244 ([M+1]+, 100).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]1([S:19]([CH3:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[CH:24]([C:30](N(C)OC)=[O:31])[CH2:23]2.P(=O)(O)(O)O>O1CCCC1>[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[CH:24]([C:30](=[O:31])[CH2:21][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:20])[CH2:23]2
Reactant: CON(C)C(=O)C1CN2CCC1CC2
Reactant: CS(=O)c1ccccc1
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(CS(=O)c1ccccc1)C1CN2CCC1CC2
Temperature: -20 °C
Yield: 109.2 %

Procedure:
To a stirred solution of n-butyllithium (2.7 ml of a 1.6M solution in hexanes, 4.3 mmol) in dry tetrahydrofuran (5 ml) cooled to -78° C. under nitrogen was added dropwise a solution of diisopropylamine (0.44 g, 4.3 mmol) in dry tetrahydrofuran (5 ml). The mixture was allowed to warm to -20° C., and was maintained at this temperature for 15 min. After cooling to -78° C. a solution of methyl phenyl sulphoxide (0.55 g, 3.9 mmol) in dry tetrahydrofuran (2 ml) was added dropwise while maintaining the temperature below -65° C. The reaction was stirred for a further 5 rain and then a solution of (±) 1-azabicyclo[2.2.2] oct-3-yl-N-methyl-N-methoxycarboxamide (EP 322182, Description 22) (0.65 g, 3.3 mmol) in dry tetrahydrofuran (5 ml) was added rapidly while ensuring that the temperature did not rise above -60° C. After stirring at -78° C. for 1 h, the reaction was allowed to warm to -30° C., and maintained at this temperature for 30 min. The reaction was then poured into vigorously stirred orthophosphoric acid (20ml of a 5% H3PO4 solution) cooled below 0° C. The aqueous layer was separated, washed with ether (3×20 ml) and then saturated with potassium carbonate. After extraction with chloroform (3×25 ml) the combined organic extracts were dried over sodium sulphate and concentrated in vacuo to give the title compound (D1) as an oil (1.0 g) consisting of a 1:1 mixture of diastereomeric keto sulphoxides. 1H NMR (CDCl3) δ:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.N1C=CC=CC=1.O.[NH2:21][NH2:22]>O>[NH:21]([C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1)[NH2:22]
Reactant: Clc1cnc(-c2ccccc2)cn1
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: NNc1cnc(-c2ccccc2)cn1

Procedure:
A mixture of 1.0 g. of 2-chloro-5-phenylpyrazine, m.p. 98°-99° C., 5.0 ml. of pyridine and 5.0 ml. of hydrazine hydrate is heated at reflux for 1.5 hours. The solution is cooled, and 20 ml. of water is added. The colorless crystalline product is collected and air dried. The crude product is recrystallized from aqueous ethanol to yield 0.35 g. of the product of the example as colorless needles, m.p. 128°-130° C.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:11]1[N:15]2[N:16]=[C:17]([CH3:25])[CH:18]=[C:19]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[C:14]2=[N:13][C:12]=1[CH3:26].[Cu][C:28]#[N:29].CN(C=O)C.N>CO.CCOC(C)=O.CCCCCC>[CH2:21]([CH:20]([C:19]1[C:14]2[N:15]([C:11]([C:3]3[S:4][C:5]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[C:2]=3[C:28]#[N:29])=[C:12]([CH3:26])[N:13]=2)[N:16]=[C:17]([CH3:25])[CH:18]=1)[CH2:23][CH3:24])[CH3:22]
Reactant: N#C[Cu]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc4cccnc4c3Br)c(C)nc12
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCC(CC)c1cc(C)nn2c(-c3sc4cccnc4c3C#N)c(C)nc12
Temperature: 120 °C
Yield: 16 %

Procedure:
50 mg of 3-(3-Bromo-thieno[3,2-b]pyridin-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.12 mmol) and 32 mg of copper (I) cyanide (0.36 mmol) are placed into a reaction vial with 2.0 ml of dry DMF. The vial is capped with a Teflon cap and heated at 120° C. overnight. The reaction mixture is applied onto a silica-gel chromatography column (1st column; Hexane:AcOEt=5:1, 2nd column; Hexane:AcOEt:2M NH3 in MeOH=20:4:1) to give 7.2 mg of the title compound (16%). mass spectrum (m/e): 376; 1H-NMR (CDCl3): 8.86 (m, 1H), 8.22 (m, 1H), 7.40 (dd, 1H, J=8.2 Hz, 4.6 Hz), 6.83 (s, 1H), 3.32 (m, 1H), 2.73 (s, 3H), 2.60 (s, 3H), 1.85 (m, 4H), 0.88 (t, 6H, J=7.5 Hz) ppm.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)([O-])C.[K+].Cl>O1CCCC1>[C:23]1([S:29]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:15]2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2c[nH]c3ccccc23)C1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(C2CCCNC2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-(1H-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (75 mg, 0.25 mmol) and phenylsulfonyl chloride (50 mg, 0.27 mmol) in tetrahydrofuran (THF) at room temperature is treated with potassium tert-butoxide (0.275 mL, 1 M solution in THF, 0.275 mmol), shaken at room temperature for 16 hours, treated with HCl (4 N in dioxane, 0.5 mL), shaken for 2 hours and concentrated in vacuo to give a residue. Purification of the residue by HPLC1 affords the title product, characterized by HPLC and mass spectral analyses [M+H] 341.45, LCMS2 retention time 1.67 min.
Reaction SMILES: [CH:1]1([CH:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][S:22][CH2:21][CH2:20]4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:20][CH2:21][S:22][CH2:23][CH2:24]4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OC4CCSCC4)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(OC3CCSCC3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Ethyl 3-[{[4-({cyclohexyl[3-methyl-5-(tetrahydro-2H-thiopyran-4-yloxy)-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (0.14 g) synthesized in the above-mentioned (1) was dissolved in ethanol (3 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (1.0 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:1, volume ratio) to give the title object compound (0.06 g, 46%) as a colorless solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([C:24]2[N:28]=[CH:27][NH:26][N:25]=2)=[C:6]([NH:9][C:10](=[O:23])[CH2:11][N:12]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][C:13]2=[O:22])[S:7][CH:8]=1.I[CH3:30]>CN(C=O)C.O>[Br:3][C:4]1[C:5]([C:24]2[N:28]=[CH:27][N:26]([CH3:30])[N:25]=2)=[C:6]([NH:9][C:10](=[O:23])[CH2:11][N:12]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][C:13]2=[O:22])[S:7][CH:8]=1
Reactant: CI
Reactant: O=C(CN1C(=O)CCc2ncccc21)Nc1scc(Br)c1-c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cnc(-c2c(Br)csc2NC(=O)CN2C(=O)CCc3ncccc32)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (4.2 mg of a 60% dispersion in mineral oil, 0.107 mmol) was added to a solution of N-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide (31 mg, 0.0715 mmol) in DMF (0.1 mL) at 0° C. The suspension was stirred for 5 minutes after which iodomethane (12 mg, 0.058 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes then diluted with water, extracted with ethyl acetate, dried (Na2SO4), filtered, concentrated under vacuum and purified by preparative HPLC to give N-(4-bromo-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide. Retention time (min)=1.740, method [7], MS (ESI) 447.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.47 (s, 1H), 8.33 (d, J=5.2 Hz, 1H), 7.85 (bs, 1H), 7.61 (bs, 1H), 7.11 (s, 1H), 4.94 (s, 2H), 4.02 (s, 3H), 3.41-3.36 (m, 2H), 3.01-2.97 (m, 2H).
Reaction SMILES: C(OC(C1N(CC2C3C(=CC=C(F)C=3)C=CC=2)C2C(C=1CN)=CC=CC=2)=O)C.Cl.C([O:32][C:33]([C:35]1[N:36]([CH2:50][C:51]2[C:60]3[C:55](=[CH:56][CH:57]=[C:58]([F:61])[CH:59]=3)[CH:54]=[CH:53][CH:52]=2)[C:37]2[C:42]([C:43]=1[CH2:44][NH:45][C:46]([O:48][CH3:49])=[O:47])=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])C>>[F:61][C:58]1[CH:59]=[C:60]2[C:55]([CH:54]=[CH:53][CH:52]=[C:51]2[CH2:50][N:36]2[C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:43]([CH2:44][NH:45][C:46]([O:48][CH3:49])=[O:47])=[C:35]2[C:33]([OH:34])=[O:32])=[CH:56][CH:57]=1
Reactant: CCOC(=O)c1c(CNC(=O)OC)c2ccccc2n1Cc1cccc2ccc(F)cc12
Agent: CCOC(=O)c1c(CN)c2ccccc2n1Cc1cccc2ccc(F)cc12
Agent: Cl
Product: COC(=O)NCc1c(C(=O)O)n(Cc2cccc3ccc(F)cc23)c2ccccc12

Procedure:
3-Aminomethyl-1-(7-fluoro-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester; salt with HCl was converted to 1-(7-fluoro-naphthalen-1-ylmethyl)-3-(methoxycarbonylamino-methyl)-1H-indole-2-carboxylic acid ethyl ester as described in Example 77.1. which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give 1-(7-fluoro-naphthalen-1-ylmethyl)-3-(methoxycarbonylamino-methyl)-1H-indole-2-carboxylic acid as a white solid. MS: 405.5 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:23])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:11]([CH3:14])[C:12]=1O.[OH:24][CH2:25][CH2:26][NH:27][NH2:28]>C(O)C>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:10]2[C:9](=[O:23])[N:27]([CH2:26][CH2:25][OH:24])[N:28]=[C:12]([CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:11]=2[CH3:14])[CH:20]=[CH:19][CH:18]=1
Reactant: NNCCO
Reactant: COc1cccc(C2=C(C)C(O)=C(c3ccccc3F)C2=O)c1
Solvent: CCO
Product: COc1cccc(-c2c(C)c(Cc3ccccc3F)nn(CCO)c2=O)c1

Procedure:
A solution of 2-(2-fluorophenyl)-3-hydroxy-4-methyl-5-(3-methoxyphenyl)-2,4-cyclopentadienone (620 mg, 2 mmol) and hydroxylethylhydrazine (360 mg, 45 mmol)) in ethanol (5 mL) was heated at reflux for 6 hours. The resulting solution was concentrated in vacuo and the residue was dissolved in ethyl acetate (80 mL), washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired compound as colorless oil. MS: 369 (MH+).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:27][CH2:26][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23]O)[C:12]2=[O:25])[CH2:10][CH2:9]1)=[O:7].[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1>>[F:33][C:31]([F:32])([F:34])[C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([C:2]([F:36])([F:1])[F:35])[CH:30]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23][N:37]3[CH:41]=[CH:40][N:39]=[CH:38]3)[C:12]2=[O:25])[CH2:26][CH2:27]1)=[O:7]
Reactant: c1c[nH]cn1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCO)CN2c1ccccc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCn1ccnc1)CN2c1ccccc1

Procedure:
The title compound, MS: m/e=566.2 (M+H+), was prepared in accordance with the general method of example 49 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy-ethyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and imidazole.
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:19]1([CH2:25][CH2:26][C:27](Cl)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:27](=[O:28])[CH2:26][CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.6 M of n-Butyllithium in hexanes (35 mL) was added to a solution of (S)-4-benzyloxazolidin-2-one (10 g, 56.4 mmol) in THF (150 mL) at −78° C. After 15 minutes, intermediate (7a) (9.5 g, 56.4 mmol) in THF (20 mL) was added dropwise at −78° C. After 30 minutes, the mixture was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated in vacuo and the crude material was extracted with EtOAc (3×200 mL) and water (100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to yield intermediate (7b), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>O>[CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: CNC(=O)c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNC(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
Methyl 4-(methylaminocarbonyl)benzoate (1.9 g, 0.0098 mol) was added to 10 mL 1.5M NaOH (1.5 eq) and 30 mL water in a 125-mL Erlenmeyer flask. The suspension was stirred for 1 h at room temperature. The solid gradually dissolved during this time. The solution was filtered and acidified to produce a white solid. The solid was removed by filtration, washed twice with water, and dried in vacuo to give 1.60 g (90%) of the title compound, mp 270° C.