Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1.C(=O)([O-])[O-:28].[K+].[K+].NC1C2C(=CC(Cl)=CC=2)NC=1C(=O)C1C=CC=C(C#N)C=1>C(O)C.O>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH2:25])=[O:28])[CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)n1c(C(=O)c2cccc(C#N)c2)c(N)c2ccc(Cl)cc21
Agent: N#Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1

Procedure:
A mixture of 3-amino-6-chloro-2-(3-cyanobenzoyl)-1-(ethoxycarbonyl)indole (step 1, 10.4 g, 28 mmol) and potassium carbonate (20 g, 140 mmol) in ethanol (100 ml) and water (100 ml) was heated at reflux for 4 h. The mixture was cooled and concentrated, and the residue partitioned between water (100 ml) and ethyl acetate (250). The organic layer was dried (MgSO4) and concentrated. The residual oil was purified by flash column chromatography eluting with hexane/ethyl acetate (2/1) to give; 3-Amino-6-chloro-2-(3-cyanobenzoyl)indole (Example 127):
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8](=O)[N:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]=2[C:5]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:8]1[N:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]2[C:5]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[N:9]=1
Reactant: CCOC(=O)Cn1c(=O)[nH]c2c(Cl)ccc(C(CC)CC)c21
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 90 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
A mixture of ethyl [4-chloro-7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate (2.57 g, 7.91 mmol) and phosphorus oxychloride (15 mL) was stirred at 90° C. for 3 days. After cooling, phosphorus oxychloride was evaporated in vacuo. The residue was poured into ice-cold 2N aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-20% ethyl acetate/n-hexane gradient mixture to give the title compound (2.49 g, 7.25 mmol, 92%) as an oil.
Reaction SMILES: C([NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:36][CH3:37])=[C:11]([NH:13][C:14](=[O:35])[C:15](=[N:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([N+]([O-])=O)[C:22]=2[O:33][CH3:34])[C:16](=[O:18])[CH3:17])[CH:12]=1)(=O)C.CN1C(=O)CCC1.Cl>O>[NH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:36][CH3:37])=[C:11]([NH:13][C:14](=[O:35])[C:15](=[N:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=2[O:33][CH3:34])[C:16](=[O:18])[CH3:17])[CH:12]=1
Reactant: COc1ccc(CCNC(C)=O)cc1NC(=O)C(=NNc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1OC)C(C)=O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1NN=C(C(C)=O)C(=O)Nc1cc(CCN)ccc1OC
Temperature: 112 °C
Reaction time: 8 h
Yield: 104.6 %

Procedure:
The product described in the previous step, N-[5-(2-acetamidoethyl)-2-methoxyphenyl]-2-[(2-methoxy-4-nitronitrophenyl)-hydrazono]-3-oxobutyramide (4.6 g) was mixed with 150 mL of NMP and 20 mL of concentrated HCl and heated at 112° C. for 6 hours. The reaction mixture was poured into 1000 mL of water and left overnight. The resulting precipitate was filtered off, washed with water and then with a dilute aqueous NaHCO3 solution to a neutral pH, and finally dried in a vacuum to give 4.0 g (95.2%) of N-[5-(2-aminoethyl)-2-methoxyphenyl]-2-[(2-methoxy-4-nitro-phenyl)-hydrazono]-3-oxo-butyramide (AePY74) as a yellow powder. 1HNMR (DMSO-d6) spectrum was consistent with the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C(Cl)Cl.C(OCC)(=O)C>[C:31]([NH:1][CH2:2][CH:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC(CN)CNC(=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NCC(CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of benzyl tert-butyl (3-aminopropane-1,2-diyl)biscarbamate (8.0 g, 25 mmol) and triethylamine (7.9 g, 78 mmol) in DCM (100 mL) was added acetic anhydride (2.8 g, 27 mmol) at 0° C. After 1 hour, the reaction mixture was diluted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was purified by chromatography on silica gel to give benzyl tert-butyl [3-(acetylamino)propane-1,2-diyl]biscarbamate. MS ESI calc'd. for C18H28N3O5 [M+H]+ 366. found 366. 1H NMR (400 MHz, CD3OD) δ 7.34-7.30 (m, 5H), 5.01 (s, 2H), 3.59-3.51 (m, 3H), 2.87-2.77 (m, 2H), 2.0 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: ClCc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2cc(OCc3ccccc3Cl)ccc2S(=O)(=O)CC1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 2-chlorobenzyl chloride (0.25 ml), potassium carbonate (309 mg) and DMF (10 ml) was stirred at 60° C. for 5 hours. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:2) to obtain methyl 7-[(2-chlorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (413 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([C@H:4]1[O:6][C@@H:5]1[C:7]([O:9]C)=O)[CH2:2][CH3:3].C(O)C.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>C(OCC)(=O)C>[CH:14]1([NH:17][C:7]([C@@H:5]2[C@@H:4]([CH2:1][CH2:2][CH3:3])[O:6]2)=[O:9])[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: CCC[C@H]1O[C@@H]1C(=O)OC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC[C@H]1O[C@@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 55.8 %

Procedure:
Methyl (2S,3R)-3-propyl-2-oxiranecarboxylate (0.26 g, 1.8 mmol), ethanol (1 ml) and cyclopropylamine (1.03 g, 18 mmol) were mixed, and the mixture was stirred at room temperature for 14 hours. Ethyl acetate (20 ml) was added, and the mixture was washed with 1 N HCl (5 ml) and water (5 ml). The solvent was evaporated away under reduced pressure to obtain the title compound as a pale yellow solid (0.17 g, yield: 55%).
Reaction SMILES: C(N(C(C)C)[CH:4]([CH3:6])[CH3:5])C.[CH2:10](Br)[CH:11]=[CH2:12].[NH2:14][CH2:15][C:16]1[O:20][C:19]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]4[CH2:35][CH2:36][C@H:26]4[C:25]=23)=[N:18][N:17]=1>C(Cl)Cl>[CH2:10]([N:14]([CH2:15][C:16]1[O:20][C:19]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]4[CH2:35][CH2:36][C@H:26]4[C:25]=23)=[N:18][N:17]=1)[CH2:6][CH:4]=[CH2:5])[CH:11]=[CH2:12]
Reactant: NCc1nnc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)o1
Reactant: C=CCBr
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCN(CC=C)Cc1nnc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)o1
Reaction time: 12 h
Yield: 76.7 %

Procedure:
2 ml (11.5 mmol) of N-ethyldiisopropylamine and 0.97 ml (8 mmol) of allyl bromide were added to a solution of 0.500 g (1.52 mmol) of (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one in 30 ml of methylene chloride, whereupon the mixture was stirred at 70° for 12 hours. The reaction solution was diluted with methylene chloride and washed with 2N sodium carbonate solution. The aqueous phase was washed twice with methylene chloride and the organic phases were dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl acetate/methanol 10:1) yielded 0.476 g (77%) of (S)-1-[5-diallylaminomethyl-1,3,4-oxadiazol-2-yl]-11,11a-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colourless foam, Rf=0.36 (silica gel, ethyl acetate/methanol 20:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[N:13]=[C:12]([C:28]3[CH:33]=[CH:32][C:31](Cl)=[CH:30][CH:29]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[N:13]=[C:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccc(Cl)cc3)nn(Cc3ccc([N+](=O)[O-])cc3)c2CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)nn(Cc3ccc(N)cc3)c2CC1
Yield: 90.7 %

Procedure:
3-(4-Chloro-phenyl)-1-(4-nitro-benzyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 98, 70 mg) was dissolved in 25 mL of anhydrous EtOH and treated with 10% palladium on carbon (20 mg). The mixture was subjected to hydrogen for 4 h at 30 psi. The mixture was filtered through diatomaceous earth. The filtrate was concentrated and dried via vacuum line to afford 55 mg of 1-(4-amino-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. The intermediate aniline was then dissolved in 1 mL of MeOH and treated with 5 mL of 1 N HCl in Et2O. After 6 h, the volatiles were removed in vacuo. The resulting yellow semi-solid was purified by preparative TLC (9:1 CH2Cl2/2 M NH3 in MeOH) to afford 0.007 g of the title compound as a light yellow solid. MS (ESI): exact mass calculated for C20H22N4, 318.18; found, m/z 319.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-7.47 (m, 2H), 7.44-7.41 (m, 2H), 7.37-7.34 (m, 1H), 6.94-6.90 (m, 2H), 6.68-6.65 (m, 2H), 5.23 (s, 2H), 3.11-3.06 (m, 4H), 2.99-2.96 (m, 2H), 2.91-2.88 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[O:23][C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[N:21][N:20]=5)[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)[N:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>O1CCOCC1.O>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[O:23][C:22]([NH:24][CH2:25][C:26]([F:28])([F:29])[F:27])=[N:21][N:20]=5)[CH:17]=4)[NH:12][CH:11]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(C4CC4)n3)c3cc(-c4nnc(NCC(F)(F)F)o4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)CNc1nnc(-c2ccc3[nH]cc(-c4nccc(C5CC5)n4)c3c2)o1
Temperature: 100 °C
Yield: 22.7 %

Procedure:
5-(3-(4-Cyclopropylpyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-amine (117 mg, 0.211 mmol) in a 5 mL glass microwave tube, was suspended in dioxane (1.5 mL). The suspension was treated with NaOH 1.000 n (2 mL, 2.000 mmol) (Fluka Analytical). The tube was sealed and the contents were stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 10 min. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (eluting with 0-8% MeOH in DCM) to give 5-(3-(4-cyclopropylpyrimidin-2-yl)-1H-indol-5-yl)-N-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-amine (19.1 mg, 0.048 mmol, 22.61%) as a pale yellow amorphous solid. MS (ESI, pos. ion) m/z: 401.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.95 (br. s., 1H), 9.01 (s, 1H), 8.50-8.59 (m, 2H), 8.27 (d, J=2.3 Hz, 1H), 7.70 (dd, J=8.5, 1.5 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.16 (d, J=5.3 Hz, 1H), 4.05-4.21 (m, 2H), 2.08-2.20 (m, 1H), 1.20-1.29 (m, 2H), 1.07-1.16 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:19]([F:20])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[O:7])=[C:4]([OH:21])[CH:3]=1.[C:22]1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:20][C:19]1[C:2]([F:1])=[CH:3][C:4]2[O:21][CH2:22][N:8]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=3)[C:6](=[O:7])[C:5]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1cc(F)c(F)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2cc(F)c(F)cc2OCN1c1ccc([N+](=O)[O-])cc1
Yield: 0.7 %

Procedure:
To 4,5-difluoro-2-hydroxy-N-(4-nitrophenyl)benzamide (0.13 g, 0.44 mmol) in toluene (5 ml) was added paraformadehyde (0.3 g, 10 mmol) and p-toluenesulfonic acid (0.01 g, 0.05 mmol) and the reaction heated to 120° C. for 3 hr with azeotropic removal of water. Saturated sodium bicarbonate (10 ml) was added and product extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give 0.11 mg (81%) of 6,7-difluoro-3-(4-nitrophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-one. RP-HPLC: 2.54 min; ES-MS (M+H)+=307.0; 1H-NMR (MeOH-d4) δ (ppm): 5.78 (s, 2 H), 7.04 (dd, 1 H), 7.64 (d, 2 H), 7.82 (dd, 1 H), 8.3 (d, 2 H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([OH:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[N:5]1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=1>CN(C)C(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:9][C:8]2[N:4]([CH3:3])[N:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=2)[N:16]=1
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: Clc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1nc(C(F)(F)F)cc1Oc1cccc(Cl)n1
Temperature: 135 °C

Procedure:
1.8 g (71 mmol) of sodium hydride (95 percent) was suspended in 25 ml of N,N-dimethylacetamide. A solution of 12.46 g (67 mmol) of 1-methyl-5-hydroxy-3-(trifluoromethyl)pyrazole (J. Heterocycl. Chem. 1990, 27, 243) in 40 ml of N,N-dimethylacetamide was added dropwise over 1 hour at 22° C. The resulting solution was added dropwise over 3 hours, under nitrogen, to a solution of 18.5 g (125 mmol) of 2,6-dichloropyridine in 37.5 ml of N,N-dimethylacetamide, heated to 135° C. After a further 5 hours of reaction time, the mixture was cooled to room temperature, the sodium chloride which had precipitated out was filtered off and the filtrate was concentrated. The residue was taken up with toluene and water and the organic phase was washed with saturated sodium chloride solution and concentrated. The solid residue was distilled under vacuum. The title compound distills at 175° C. under 25 mbar. This gave 12.5 g of crude product in the form of a yellow solid (96 percent pure, GC). This was purified by recrystallization from diisopropyl ether. The yield was 11:55 g (62 percent) of colorless crystals, content (GC): 99.9 percent. Other data concerning the product was:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:13][C:14]1[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[CH2:20]([N:23]([CH2:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22].C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH2:20]([N:23]([CH2:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:12][CH2:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:6][C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH2:13][C:14]2[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=2)=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]
Reactant: Cn1ccnc1CN(CCCCN)Cc1ncc[nH]1
Reactant: CCCN(CCC)Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)Cc1ccc(CNCCCCN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (349 mg) obtained in Example 117-4 was dissolved in methanol (7.0 ml). Then, the solution was added with the compound (323 mg) obtained in Example 117-1 and trimethyl orthoformate (0.340 ml) and stirred at room temperature for 2 hours, followed by cooling to 0° C. The solution was added with sodium borohydride (75.5 mg) and stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and washed with an aqueous sodium bicarbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform) and treated with hydrochloric acid, thereby obtaining hydrochloride (89.8 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:16]1([CH3:28])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25].O>CN(C)C=O>[C:16]1([CH3:28])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([N:8]1[CH:9]=[C:10]([CH:12]=[O:13])[N:11]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:25])=[O:26]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)n2cc(C=O)nc2-c2ccccc2)c(C)c1
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.73 g) in N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 523 mg) at room temperature, and the mixture was stirred for 1 hr. Mesitylsulfonyl chloride (2.42 g) was added, and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, 3% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:3→3:2) to give the title compound as a pale-yellow oil (yield 1.76 g, 49%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:39])([F:38])[C:8]1[CH:9]=[C:10]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:11][N:12]([CH3:30])[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH:16]1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[CH3:29])=[O:14]>C1COCC1>[CH3:1][S:2]([O:21][CH:18]1[CH2:19][CH2:20][N:15]([C:13](=[O:14])[N:12]([CH2:11][C:10]2[CH:9]=[C:8]([C:7]([F:6])([F:38])[F:39])[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=2)[CH3:30])[CH:16]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[CH3:29])[CH2:17]1)(=[O:4])=[O:3]
Reactant: Cc1cc(F)ccc1C1CC(O)CCN1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C1CC(OS(C)(=O)=O)CCN1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Methanesulphonyl chloride (20 μL) was added to a solution of 2-(4-fluoro-2-methyl-phenyl)-4-hydroxy-piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methylamide (intermediate 11a and 11b—mixture of syn and anti diastereoisomers—85 mg) and TEA (50 μL) in dry THF (5 mL) previously cooled to 0° C. under a nitrogen atmosphere. After 1.5 hours, the solution was quenched with brine (4 mL) and extracted with AcOEt (3×5 mL). The organic layer was dried and concentrated in vacuo to a residue which was purified by flash chromatography (CH/AcOEt 7:3) to give methanesulfonic acid, 1-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-2-methyl-phenyl)-piperidin-4-yl ester in two fractions:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:34](F)=[CH:33][C:18]([C:19]([C:21](=[CH:27][NH:28][CH:29]([CH3:32])[CH2:30][OH:31])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])=[C:17](F)[C:16]=2[F:37])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(OCC)(=O)C.Cl>CN(C)C=O.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:16]([F:37])=[CH:17][C:18]3[C:19](=[O:20])[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][N:28]4[CH:29]([CH3:32])[CH2:30][O:31][C:34]=2[C:33]=34)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=CNC(C)CO)C(=O)c1cc(F)c(C2(NC(=O)OCc3ccccc3)CC2)c(F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cn2c3c(c(C4(NC(=O)OCc5ccccc5)CC4)c(F)cc3c1=O)OCC2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.8 %

Procedure:
In 25 ml of N,N-dimethylformamide was dissolved 3.07 g of ethyl 2-[4-(1-benzyloxycarbonylaminocyclopropyl)-2,3,5-trifluorobenzoyl]-3-(2-hydroxy-1-methylethylamino)acrylate. To the resulting solution was added 519 mg of 60% sodium hydride with ice-cooling. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was added to a mixture of 50 ml of ethyl acetate and 50 ml of water. The resulting mixture was adjusted to pH 1 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: toluene/ethyl acetate=1/1) to obtain 760 mg (yield: 26.9%) of ethyl 10-(1-benzyloxycarbonylaminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate.
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[N:12]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=3)[C:11]2=[S:30])=[CH:6][CH:5]=1.[CH3:32][NH2:33]>>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([N:12]2[C:13](=[O:17])[C:14]([CH3:15])([CH3:16])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:33][CH3:32])=[O:31])=[CH:5][CH:6]=3)[C:11]2=[S:30])=[CH:19][C:20]=1[C:26]([F:29])([F:28])[F:27])#[N:25]
Reactant: CN
Reactant: COC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1
Product: CNC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1
Reaction time: 15 h
Yield: 51 %

Procedure:
A mixture of 4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]benzoic acid methyl ester (49c) (0.02 g, 0.0435 mmol) and methylamine (2 ml distilled from its 40% aqueous solution) was kept at −20° C. for 15 hours. After evaporation of the methylamine, the mixture was chromatographed (dichloromethane:acetone, 80:20) to yield 4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]-N-methylbenzamide (49d) [RD153] (0.01 g, 0.0224, 51%), the structure of which is illustrated in Formula 20. The ester 4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]benzoic acid methyl ester (49c) (0.08 g, 0.0179 mmol, 41%) was also recovered.