Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=N[OH:9])C1C=CC=CC=1.[H-].[Na+].C(O[C:15](=[O:36])[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:20]=1[C:29]#[C:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])([CH3:18])[CH3:17])C>CN(C=O)C.O1CCOCC1>[OH:9][C:29]1[C:20]2[C:19](=[CH:24][CH:23]=[CH:22][C:21]=2[C:25]([F:27])([F:28])[F:26])[C:16]([CH3:17])([CH3:18])[C:15](=[O:36])[C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: ON=Cc1ccccc1
Reactant: CCOC(=O)C#Cc1c(C(F)(F)F)cccc1C(C)(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(O)c2c(C(F)(F)F)cccc2C(C)(C)C1=O
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
Benzaldehyde oxime (112 mg, 0.92 mmol) in 6 mL dry DMF under argon, was added via syringe to a suspension of NaH (22 mg, 0.92 mmol) in dry dioxane (6 mL) under argon at room temperature. The mixture was stirred for 30 minutes, and ethyl 3-(2-(1-ethoxy-2-methyl-1-oxopropan-2-yl)-6-(trifluoromethyl)phenyl)propiolate (275 mg, 0.77 mmol) was added as a solution in dry DMF (6 mL) via syringe. The reaction was stirred at room temperature for 11 hours. The dioxane was removed under vacuum, and the remaining DMF was partitioned between EtOAc and water. The layers were separated, and the organic layer was washed with twice with water and once with brine. The combined aqueous extracts were back extracted twice with EtOAc, and these organic layers were added to the organic layer already obtained. The combined extracts were dried over MgSO4, concentrated under vacuum, and the resulting residue was purified by column chromatography to give the product as a light yellow oil (50 mg). MS (m/z)=329 (M+H)+
Reaction SMILES: [CH:1]([C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:29][C:30]([CH3:35])([CH3:34])[C:31]([OH:33])=[O:32])=[CH:5][CH:4]=1)=[O:2].F[C:39]1(F)CCCN[CH2:40]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl>C(Cl)Cl.O>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:29][C:30]([CH3:35])([CH3:34])[C:31]([O:33][CH2:39][CH3:40])=[O:32])=[CH:36][CH:37]=1)=[O:2]
Reactant: FC1(F)CCCNC1
Reactant: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(C=O)cc1)C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 10 mL flask were added 3-(1-(4-formylbenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoic acid (160 mg, 0.31 mmol), 3,3-difluoropiperidine (58 mg, 0.37 mmol), sodium triacetoxyborohydride (130 mg, 0.61 mmol) and DCE (3.0 mL) and was stirred at RT overnight. The mixture was diluted with DCM (5 mL) and poured into water (10 mL) then extracted with DCM (3×10 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified using FCC to provide the title compound. MS (ESI): mass calcd. for C37H40F2N4O3, 626.75; m/z found, 627.2 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.17 (d, J=8.5, 1H), 8.09 (d, J=8.5, 1H), 7.80 (t, J=11.1, 1H), 7.72 (ddd, J=13.3, 7.6, 3.9, 2H), 7.55-7.50 (m, 1H), 7.35 (d, J=2.3, 1H), 7.22 (t, J=10.3, 2H), 7.07 (t, J=10.5, 1H), 6.99-6.93 (m, 3H), 5.42 (s, 2H), 5.34 (s, 2H), 4.09 (q, J=7.1, 2H), 3.53 (s, 2H), 3.05 (s, 2H), 2.61-2.53 (m, 2H), 2.40 (dd, J=16.1, 11.1, 2H), 1.90-1.80 (m, 2H), 1.78-1.70 (m, 2H), 1.36 (s, 6H), 1.16 (t, J=7.1, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[NH:6][C:7](=[O:10])[CH2:8][Cl:9])(=[O:3])[NH2:2].[CH2:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.C(#N)C>C(O)C>[ClH:9].[ClH:9].[C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[NH:6][C:7](=[O:10])[CH2:8][N:25]1[CH2:26][CH2:27][N:22]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:23][CH2:24]1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1ccccc1NC(=O)CCl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cl
Product: NC(=O)c1ccccc1NC(=O)CN1CCN(Cc2ccccc2)CC1

Procedure:
40 Grams of o-carbamoyl-α-chloroacetanilide, 40 g of benzylpiperazine, 52.4 ml of triethylamine and 250 ml of acetonitrile were heated at 50° C. for 5 hours with stirring, and crystals formed were collected by filtration. The crystals collected were extracted with chloroform and 1 N-sodium hydroxide aqueous solution, the chloroform layer was washed with water, dried then chloroform was removed by distillation. To the residue obtained was added ethanol and insoluble material formed was collected by filtration. Then the insoluble material was suspended in ethanol and was added hydrochloric acid/ethanol to make the pH of the mixture to about 1, then the solvent was removed by distillation. The residue obtained was crystallized by adding acetone, and recrystallized from methanol to obtain 54 g of o-carbamoyl-α-(4-benzyl-1-piperazinyl)acetanilide dihydrochloride. Colorless powdery crystals. Melting point: 218.5°-219.5° C. (decomposed).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=O.CN(C)C=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>O>[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:14]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=3[O:12][CH3:13])=[O:16])=[CH:37][CH:36]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COc1cccc2c(O)c(C(=O)O)cnc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Temperature: 37 °C
Reaction time: 20 h

Procedure:
To a mixture of 0.50 g of 4-hydroxy-8-methoxy-3-quinolinecarboxylic acid (J. Amer. Chem. Soc., 68, 1268 (1946)) and 10 mL of dimethylformamide is added 0.41 g of carbonyldiimidazole. The mixture is stirred 20 h at 37° C. and then it is cooled to ° C. The mixture is treated with 0.25 mL of distilled water and stirred for 5 min. To the resulting solution is added 0.31 mL of 4-chlorobenzylamine. After stirring for 18 hours the mixture is warmed to 40° C. and stirred an additional 24 h. The solution is then cooled to 25° C. and it is diluted with 10 mL of distilled water. After minutes the precipitate is collected by filtration and it is washed with two successive 5 mL portions of 10% aqueous acetic acid. It is dried for 18 h in a stream of air at 25° C. This procedure yields the title compound as 485 mg of a tan solid.
Reaction SMILES: [OH-:1].[Na+].Br.[C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:7]=1)#[N:5]>CO.O1CCCC1>[C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:7]=1)(=[O:1])[NH2:5]
Reactant: [OH-]
Reactant: N#Cc1ccnc(-c2csc(N=C(N)N)n2)c1
Agent: Br
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1ccnc(-c2csc(N=C(N)N)n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1N-Aqueous sodium hydroxide (10 ml) was added to a suspension of 4-(4-cyanopyridin-2-yl)-2-(diaminomethyleneamino)thiazole hydrobromide (1.00 g) in a mixture of methanol (10 ml) and tetrahydrofuran (10 ml). After the mixture was stirred for one day at ambient temperature, the solvent was evaporated in vacuo and the residue was mixed with water (10 ml). The resulting precipitate was collected by filtration, washed with water and recrystallized from a mixture of N,N-dimethylformamide and water to give 4-(4-carbamoylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.45 g).
Reaction SMILES: C([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2C(C(O)=O)=[C:17]2[CH2:28][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:30](=[O:31])[C:16]=12)(C1C=CC=CC=1)C1C=CC=CC=1.C(NCC)C.[CH:45]([N:48]([CH:51]([CH3:53])C)[CH2:49][CH3:50])([CH3:47])C.F[P-](F)(F)(F)(F)F.N1([O:70]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH2:51]([N:48]([CH2:49][CH3:50])[C:45]([C:47]1[C:19]2[CH:20]=[CH:21][CH:22]=[N:23][C:24]=2[C:15]([OH:14])=[C:16]2[C:30](=[O:31])[N:29]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[CH2:28][C:17]=12)=[O:70])[CH3:53]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.5 %

Procedure:
9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid 213 (0.02 g, 0.0386 mmol) was dissolved in 0.3 mL of dimethylformamide. To this was added diethylamine (0.0056 mL, 0.0772 mmol), diisopropylethylamine (0.027 mL, 0.1544 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at room temperature. After 15 hours, starting material was consumed. Purified by reverse phase HPLC (0.1% TFA, H2O/ACN) to give 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid diethylamide 322 (0.0134 g, 0.033 mmol, 86%.) 1H NMR (CDCl3) δ 9.07 (dd, 1H), 8.18 (d, 1H), 7.65 (m, 3H), 7.07(dd, 2H), 4.72 (dd, 2H), 4.56 (d, J=17 Hz, 1H), 4.23 (d, J=17 Hz, 1H), 3.66 (q, 2H), 3.11 (q, 2H), 1.35 (t, 3H), 0.965 (t, 3H.) MS: 408 (M+1).
Reaction SMILES: C=O.[BH3-][C:4]#N.[Na+].[C:7]1([CH:13]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:14][NH:15][CH:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][N:27]=4)=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CC(O)=O.CO>[C:35]1([CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14][N:15]([CH3:4])[CH:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][N:27]=4)=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCC(c2ccccc2)c2ccccc2)nc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CC(c1ccccc1)c1ccccc1)C1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.2 %

Procedure:
Add paraformaldehyde (57 mg) and NaBH3CN (46 mg, 0.734 mmol) to a solution of 6-[1-(2,2-Diphenyl-ethylamino)-indan-5-yloxy)-nicotinamide (example 9, 110 mg, 0.245 mmol) in 5% AcOH/MeOH (3 ml) and stir at ambient temperature for two days. Concentrate the reaction mixture and partition remaining residue between EtOAc and 1M aq. K2CO3. Separate layers and wash organic with 1M aq. K2CO3 and brine before drying (MgSO4) and concentrating. Purify on silica gel (5% (1N NH3/MeOH)/45% EtOAc/DCM) to obtain 74 mg of the title compound as a white solid. Mass spectrum (ion spray): m/z=464 (M+1); 1HNMR (CDCl3): 8.54 (s, 1H), 8.15 (d, 1H), 7.30-7.15 (m, 10H), 6.95-6.81 (m, 4H), 5.81 (br. s, 2H), 4.39 (t, 1H), 4.20 (t, 1H), 3.02 (d, 2H), 2.94-2.75 (m, 2H), 2.27 (s, 3H), 2.06 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]2[C:14]3[C:23]([OH:24])=[CH:22][C:21]([CH:25]([CH:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:26])=[CH:20][C:15]=3[O:16][C:17]([CH3:19])([CH3:18])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34].[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])[CH2:37][CH2:36]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:34].[CH2:1]([N:8]1[CH2:13][C:12]2[C:14]3[C:23]([O:24][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][N:38]4[CH2:37][CH2:36][O:35][CH2:40][CH2:39]4)=[CH:22][C:21]([CH:25]([CH:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:26])=[CH:20][C:15]=3[O:16][C:17]([CH3:19])([CH3:18])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(Cc2ccccc2)CC1
Reactant: O=C(O)CCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CN(Cc2ccccc2)CC1

Procedure:
2-Benzyl-5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, γ-morpholinobutyric acid hydrochloride and dicyclohexyl-carbodiimide are combined in equimolar amounts in methylene chloride and reacted as in Example 1 to give the desired product.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[CH3:23][CH:24]([CH3:27])[CH2:25][NH3+:26]>>[CH3:23][CH:24]([CH3:27])[CH2:25][NH:26]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Reactant: CC(C)C[NH3+]
Agent: CC(=O)[O-]
Product: CC(C)CN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 69 %

Procedure:
Prepared as in Example 35 from 2-benzoyl-benzo[b]thiophen-3-ol and (2-methylpropyl)ammonium acetate with a yield of 69% of theory; m.p. 125°-126° C. (ethyl acetate/petroleum ether 1:2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][C@@H:19]4[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]4)=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.[CH:26]([C:28]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1)=O.C(C1(C(OC)=O)CCC1)=O>>[OH:25][C@@H:22]1[CH2:23][CH2:24][C@H:19]([O:18][C:14]2[C:13]3[C:9]([O:8][CH2:7][CH:4]4[CH2:5][CH2:6][N:1]([CH2:26][C:28]5([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]5)[CH2:2][CH2:3]4)=[N:10][O:11][C:12]=3[CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21]1
Reactant: COC(=O)C1(C=O)CCCC1
Reactant: O[C@H]1CC[C@@H](Oc2cccc3onc(OCC4CCNCC4)c23)CC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(O[C@H]5CC[C@@H](O)CC5)c34)CC2)CCCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using cis-4-{[3-(piperidin-4-ylmethoxy)-1,2-benzisoxazol-4-yl]oxy}cyclohexanol (EXAMPLE 43, Step 2) and methyl 1-formylcyclopentanecarboxylate (Synthesis 1997, 32-34) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH2:13])[CH2:8][CH2:7]1.[C:18]([N:25]1[CH:29]=[CH:28][N:27]=C1)(N1C=CN=C1)=[S:19].N1C=CN=C1.[N+]([C:38]1[C:39](N)=C(N)C=[CH:42][CH:43]=1)([O-])=O>C(#N)C>[NH2:27][C:28]1[CH:42]=[CH:43][CH:38]=[CH:39][C:29]=1[NH:25][C:18]([NH:13][CH2:12][CH:9]1[CH2:10][CH2:11][N:6]([CH2:5][C:4]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=2)[CH2:7][CH2:8]1)=[S:19]
Reactant: NCC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Agent: c1c[nH]cn1
Solvent: CC#N
Product: Nc1ccccc1NC(=S)NCC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After dissolving C-[1-(3,4-dichloro-benzyl)-piperidin-4-yl]-methylamine (80 mg) in acetonitrile (2 ml), thiocarbonyldiimidazole (80 mg) and imidazole (6 mg) were added at 0° C. The mixture was stirred at room temperature for 2 hours and 30 minutes, and then 3-nitro-1,2-phenylenediamine (66 mg) was added and the temperature was raised to 50° C. prior to stirring for 12 hours. The reaction mixture was filtered, the solvent was removed under reduced pressure, and the obtained residue was purified by thin-layer silica gel chromatography (hexane/ethyl acetate/dichloromethane/methanol=60/25/10/5) to obtain 1-(2-amino-phenyl-3-[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-thiourea. The compound was identified by LC-MS.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:18](=O)[CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+].O>C(Cl)Cl.CO>[NH2:26][CH:18]1[C:13]2[C:14]3[C:15](=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[NH:8][C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:16][CH2:17]1
Reactant: [BH3-]C#N
Reactant: O=C1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Temperature: 25 °C
Reaction time: 72 h
Yield: 52 %

Procedure:
A portion (2.3 g) of the compound obtained in Example 41 was dissolved in a mixed solvent of methylene chloride (450 ml) and methanol (450 ml) and to the solution were added ammonium acetate (7.12 g) and sodium cyanoborohydride (0.76 g). The mixture was stirred for 3 days at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate/methanol=9:1) to yield 1.2 g (52%) of the titled compound as pale brown crystals.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])(=O)=O.[CH3:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[C:27](O)=[N:28][C:29](/[CH:32]=[CH:33]/[C:34]3[N:52]=[C:37]4[C@H:38]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=5[C:48]([F:51])([F:50])[F:49])[CH2:39][CH2:40][CH2:41][N:36]4[N:35]=3)=[CH:30][CH:31]=2)[CH:25]=1.CN(C=O)C>C(OCC)(=O)C.O>[CH3:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]3[N:52]=[C:37]4[CH:38]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=5[C:48]([F:50])([F:51])[F:49])[CH2:39][CH2:40][CH2:41][N:36]4[N:35]=3)=[N:28][C:27]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH:25]=1
Reactant: Cc1cn(-c2ccc(/C=C/c3nc4n(n3)CCC[C@H]4c3ccccc3C(F)(F)F)nc2O)cn1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cn(-c2ccc(/C=C/c3nc4n(n3)CCCC4c3ccccc3C(F)(F)F)nc2OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Cesium carbonate (83.7 mg) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (35.7 μL) were added to a mixture of 3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}pyridin-2-ol synthesized in Example 344 (100 mg) and DMF (1.2 mL), and the reaction solution was stirred at room temperature for four hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=4:1→ethyl acetate) to obtain a racemate of the title compound (110 mg). The resulting racemate (110 mg) was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase: hexane:ethanol=5:5, flow rate: 11 mL/min) to obtain the title optically active compound with a retention time of 13 minutes and positive optical rotation (51 mg) and the title optically active compound with a retention time of 18 minutes and negative optical rotation (53 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]([CH3:19])=[C:6]([S:8]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)(=[O:10])=[O:9])[CH:7]=1.[Cl:21][C:22]1[N:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[C:24]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:25]=1N=[C:27]2Cl.[CH3:38][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:21][C:22]1[C:23]2[C:28](=[C:27]([NH:1][C:2]3[C:3]([CH3:20])=[CH:4][C:5]([CH3:19])=[C:6]([S:8]([NH:11][CH2:12][C:13]4[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=4)(=[O:10])=[O:9])[CH:7]=3)[CH:38]=[C:25]3[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:24]3=2)[CH:29]=[CH:30][N:31]=1
Reactant: Fc1ccc2nc(Cl)c3ccnc(Cl)c3c2c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1cc(C)c(S(=O)(=O)NCc2cccnc2)cc1N
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)NCc2cccnc2)cc1Nc1cc2ccc(F)cc2c2c(Cl)nccc12
Temperature: 0 °C

Procedure:
To a solution of 5-amino-2,4-dimethyl-N-(pyridin-3-ylmethyl)benzenesulfonamide (300 mg, 1.0 mmol) and 1,5-dichloro-9-fluorobenzo[c]-2,6-naphthyridine (Example 1, Step 5) (250 mg, 0.94 mmol) in THF (4.7 mL) at 0° C. was added NaHMDS (2.8 mL, 1 M in THF, 2.8 mmol). The deep red solution was stirred at 0° C. for ten minutes and then quenched by the addition of sat. aq. NaHCO3 solution. The reaction was extracted with EtOAc and the organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification by silica gel column chromatography (0-5% MeOH/DCM) afforded the title compound.
Reaction SMILES: [F:1][C:2]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7]/[C:6]/1=[N:10]\[C:11](=[C:13]([C:19](OCC)=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:12].[O-]CC.[Na+].CCO.Cl.O>CN(C)C=O>[F:1][C:2]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:6]2=[N:10][C:11]([CH3:12])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([OH:20])=[C:7]2[CH2:8][CH2:9]1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)/N=C1\CCCN1Cc1cccc(F)c1F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(C)nc2c(c1O)CCN2Cc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a solution of (E)-diethyl 2-(1-((1-(2,3-difluorobenzyl)pyrrolidin-2-ylidene)amino)ethylidene)malonate (36.3 g, 69.9 mmol) in N,N-dimethylformamide (DMF) (140 mL) was added sodium ethoxide (78 mL, 210 mmol) (21% wt./EtOH) and the mixture was placed in a pre-heated oil bath at 100° C. and stirred for 1 h. The mixture was cooled to ambient temperature and then poured slowly into cold 1 N HCl/water (−150 mL) and then more 1N HCl/water was added to pH 8-9. After stirring at 0° C. for 30 min The solid was filtered, washed with water and dried in vacuo for 18 h to provide ethyl 1-(2,3-difluorobenzyl)-4-hydroxy-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (10 g, 27.3 mmol, 39.0% yield) as a light tan solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (t, J=7.12 Hz, 3 H), 2.66 (s, 3 H), 2.95 (t, J=8.68 Hz, 2 H), 3.53 (t, J=8.78 Hz, 2 H), 4.39 (q, J=7.02 Hz, 2 H), 4.72 (s, 2 H), 6.90-7.20 (m, 3 H), 11.94 (s, 1 H); LCMS (m/z) ES+=349 (M+1).
Reaction SMILES: [C:1](Cl)([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.OC[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([Br:29])[CH:24]=1.CN([CH:33]=[O:34])C>CN(C1C=CN=CC=1)C.C([O-])(O)=O.[Na+]>[Br:29][C:25]1[CH:24]=[CH:23][C:28]([CH2:33][O:34][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:27][N:26]=1
Reactant: CN(C)C=O
Reactant: OCc1ccnc(Br)c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Product: Brc1ccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 80 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
Trityl chloride (3.90 g, 14 mmol), 4-DMAP (2.08 g, 17 mmol) and 2-bromo-5-hydroxymethylpyridine 33 (1.88 g, 10 mmol) (Ellingboe, J. W., et al., J. Med. Chem. 1994, 37, 542–550) were dissolved in DMF (15 mL) and the solution was stirred at 80° C. for 48 hours. A white precipitate formed during this time. After cooling, the mixture was diluted with NaHCO3 (sat., 25 mL) and extracted with EtOAc (3(50 mL). The combined extract was washed with brine, with a few drops of NaOH (1 M) added (2(100 mL). After drying and evaporation, the solid residue was purified by flash chromatography (silica, hexanes:EtOAc 15:1) to yield 34 as a white solid (4.46 g, 100%). TLC Rf=0.30 (silica, hexanes:EtOAc 15:1); IR (film) vmax 3057, 1448, 1086, 764, 700, 632 cm−1; MALDI-FTMS m/z 430.0792 (MH+), calcd for C25H21BrNO 430.0801.