Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[N:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[N:32]#CBr.O>CS(C)=O>[C:20]1([S:17]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([N:5]3[CH2:4][CH2:3][N:2]([C:1]#[N:32])[CH2:7][CH2:6]3)=[N:9]2)(=[O:18])=[O:19])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#CBr
Reactant: CN1CCN(c2nn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CN1CCN(c2nn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a stirred mixture of 3-(4-methyl-1-piperazinyl)-1-phenylsulfonyl-1H-indazole (237 g, 0.67 mole), K2CO3 (102 g, 0.74 mole) and dimethylsulfoxide (DMSO, 2000 ml), under nitrogen, was added cyanogen bromide (72 g, 0.68 mmol) dissolved in DMSO (525 ml). The reaction was stirred at ambient temperature for 5.5 hours and was then poured into H2O (7 1). The solid, which precipitated from solution, was collected by filtration and was washed well with H2O affording 168 g (68%) of product. A 5.2 g sample was recrystallized twice from ethanol-H2O yielding 4.0 g of 4-[1-(phenylsulfonyl)-1H-indazol-3-yl]-1-piperazinecarbonitrile, m.p.=178°-180° C.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[CH:20]=[C:19]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[CH2:24][C@@H:23]3[O:32][CH3:33])[N:18]=[CH:17][N:16]=2)[CH2:11][C@H:10]1[CH2:34][OH:35])(C(C)(C)C)(C)C.CN(C)C(=O)C.Cl[S:43]([NH2:46])(=[O:45])=[O:44].Cl.C(=O)([O-])[O-].[Na+].[Na+].O>>[S:43](=[O:45])(=[O:44])([O:35][CH2:34][C@@H:10]1[CH2:11][C@@H:12]([O:14][C:15]2[CH:20]=[C:19]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[CH2:24][C@@H:23]3[O:32][CH3:33])[N:18]=[CH:17][N:16]=2)[CH2:13][C@@H:9]1[OH:8])[NH2:46]
Reactant: NS(=O)(=O)Cl
Reactant: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](COS(N)(=O)=O)[C@@H](O)C2)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methanol (16) (11.5 g, 0.0221 mol) in N,N-dimethylacetamide (160 mL, 1.7 mol) was added chlorosulfonamide (6.64 g, 0.0575 mol), and the reaction stirred at room temperature for 1 hour. The reaction mixture was then cooled to 0° C., at which point 12 M hydrochloric acid (90 mL, 1.1 mol) was added dropwise via an addition funnel over 25 min, keeping the internal reaction temp below 50° C. Once the addition was complete, the cooling bath was removed and the reaction was allowed to warm to room temperature with stirring for 2 hours. The reaction was next quenched carefully via slow addition of a suspension of sodium carbonate (70.30 g, 0.6633 mol) in water (200.0 mL, 11.10 mol). The resulting suspension was filtered and the solids were rinsed with EtOAc (3 rinses, total—800 mL). The solids were set aside, and the filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted 3×EtOAc (total EtOAc—2000 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified via column chromatography (applied with CH2Cl2, 400 g column, eluent 0-10% MeOH:CH2Cl2 over 80 min then 10% MeOH: CH2Cl2 for 20 min) to afford {(1S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl sulfamate (10.3 g, 96%). LCMS: (FA) ES+ 485; 1H NMR (400 MHz, MeOD) δ 8.16 (s, 1H), 7.25 (s, 1H), 7.22-7.13 (m, 2H), 5.98 (s, 1H), 5.52 (d, J=32.8, 1H), 5.34 (s, 1H), 4.43-4.35 (m, 1H), 4.32 (dd, J=7.5, 9.8, 1H), 4.22 (td, J=2.5, 5.0, 1H), 4.16 (dd, J=7.3, 9.8, 1H), 3.34 (s, 4H), 3.10 (dd, J=2.1, 16.6, 1H), 3.02 (dd, J=4.8, 16.6, 1H), 2.58-2.46 (m, 1H), 2.28 (ddd, J=2.2, 6.9, 14.8, 1H), 2.12-1.90 (m, 4H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:8]2=[O:24].[NH2:26][NH2:27]>CO>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:9]2[C:8](=[O:24])[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([CH2:4][C:3]([NH:26][NH2:27])=[O:2])[CH:6]=3)[N:11]=[CH:10]2)=[CH:21][CH:20]=1
Reactant: NN
Reactant: COC(=O)Cc1ccc2ncn(Cc3ccc(OC)cc3)c(=O)c2c1
Solvent: CO
Product: COc1ccc(Cn2cnc3ccc(CC(=O)NN)cc3c2=O)cc1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
[3-(4-Methoxy-benzyl)-4-oxo-3,4-dihydro-quinazolin-6-yl]-acetic acid methyl ester (0.050 g, 0.148 mmol) and hydrazine (0.047 g, 0.148 mmol) were stirred at 50° C. in methanol (5 mL) for several hours. The reaction was then cooled to room temperature and filtered to give 0.030 g (60%) of [3-(4-methoxy-benzyl)-4-oxo-3,4-dihydro-quinazolin-6-yl]-acetic acid hydrazide. 1H NMR (400 MHz, CD3OD) δ 10.09 (s, 1H), 9.33 (s, 1H), 8.85 (m, 1H), 8.53 (d, 1H, J=2.0, 8.4 Hz), 8.42 (d, 1H, J=8.4 Hz), 8.14 (d, 2H, J=8.4 Hz), 7.70 (d, 2H, J=8.4 Hz), 5.93 (s, 2H), 5.04 (bs, 2H), 4.52 (s, 3H), 4.31 (s, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2OC)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrCC1C=CC=CC=1[S:39][C:40]([F:43])([F:42])[F:41]>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:39][C:40]([F:43])([F:42])[F:41])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: FC(F)(F)Sc1ccccc1CBr
Product: OC(Cc1ccccc1SC(F)(F)F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 1a, 1-(4-benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using 1-bromomethyl-2-trifluoromethylsulfanyl-benzene (available from Fluorochem Ltd.) as starting material and making non-critical variations, to yield the title compound. 1H NMR (300 MHz, CDCl3) δ: 2.05-2.33 (m, 3H), 2.49-2.65 (m, 1H), 3.10-3.35 (m, 2H), 3.43-3.55 (m, 1H), 3.67-3.89 (m, 2H), 3.91-4.08 (m, 2H), 4.09-4.22 (m, 1H), 6.91-7.05 (m, 1H), 7.10-7.42 (m, 12H), 7.50-7.63 (m, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[CH:27](=O)[CH3:28].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([N:8]([CH2:27][CH3:28])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1
Reactant: COC(=O)c1cc(Br)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
To a stirred solution of tert-butyl 4-((5-bromo-3-(methoxycarbonyl)-2-methylphenyl)amino)piperidine-1-carboxylate (5 g, 11.70 mmol) and acetaldehyde (1.58 g, 35.12 mmol) in dichloroethane (60 mL), acetic acid (4.24 g, 70.66 mmol) was added and reaction stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (7.44 g, 35.09 mmol) was added at 0° C. and reaction stirred at room temperature for 2 h. On completion, the reaction was quenched with aqueous sodium bicarbonate, organic phase was separated and aqueous phase was extracted with dichloromethane. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to give crude material was purified by column chromatography to afford the desired product (5 g, 93.45%).
Reaction SMILES: [ClH:1].Cl.[C@H]1(CN2CCC([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([CH3:44])[C:41]([CH3:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])CC2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.N[CH:49]1[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][N:57]2[CH2:62][CH2:61][C@H:60]([OH:63])[C@@H:59]([CH3:64])[CH2:58]2)[CH2:51][CH2:50]1>>[ClH:1].[ClH:1].[OH:63][C@H:60]1[CH2:61][CH2:62][N:57]([CH2:56][CH2:55][N:52]2[CH2:53][CH2:54][CH:49]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([CH3:44])[C:41]([CH3:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:50][CH2:51]2)[CH2:58][C@@H:59]1[CH3:64]
Reactant: Cc1cc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)c2cc1C
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: Cc1cc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)c2cc1C

Procedure:
This compound is synthesized from 4-(5,6-dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (127, see example 104) and amine 14 analogously to the method described in example 1.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:5]1[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH:18]=[O:19])[N:4]=1
Reactant: COc1ccc(C=O)cc1O
Reactant: Cc1oc(-c2ccco2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)cc1OCc1nc(-c2ccco2)oc1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (20.0 g), 3-hydroxy-4-methoxybenzaldehyde (13.97 g), potassium carbonate (13.96 g) and N,N-dimethylformamide (200 mL) was stirred at 90° C. for 3 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-4-methoxybenzaldehyde as colorless crystals (19.4 g, yield 67%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 125-126° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10][S:11][CH:12]([C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)[CH2:13][N+:14]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[NH2:14][CH2:13][CH:12]([S:11][CH2:10][C@@H:9]([C:22]([OH:24])=[O:23])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:17]1[CH:21]=[CH:20][S:19][CH:18]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSC(C[N+](=O)[O-])c1ccsc1)C(=O)O
Agent: [Pd]
Product: CC(C)(C)OC(=O)N[C@@H](CSC(CN)c1ccsc1)C(=O)O
Yield: 73.2 %

Procedure:
74.8 g of N-t-butoxycarbonyl-S-[2-nitro-1-(3-thienyl)ethyl]-L-cysteine were reduced with hydrogen in the presence of 10% w/w palladium-on-carbon, as described in Example 63(b), to give 50.4 g of the title compound as a powder.
Reaction SMILES: Cl.NC[CH:4]1[CH2:33][CH2:32][N:7]2[C:8]3[C:13]([C:14]([C:15]4[C:16](=[O:31])[NH:17][C:18](=[O:30])[C:19]=4[C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH3:29])[CH:21]=4)=[C:6]2[CH2:5]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C1N=C[N:36]([C:39](N2C=NC=C2)=[S:40])C=1>CN(C)C=O.O1CCCC1>[N:36]([CH:4]1[CH2:33][CH2:32][N:7]2[C:8]3[C:13]([C:14]([C:15]4[C:16](=[O:31])[NH:17][C:18](=[O:30])[C:19]=4[C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH3:29])[CH:21]=4)=[C:6]2[CH2:5]1)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:39]=[S:40]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CN)C4)C(=O)NC2=O)c2ccccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(N=C=S)C4)C(=O)NC2=O)c2ccccc21
Yield: 59.9 %

Procedure:
A solution of 505 mg of the pyrroledione product of Example 2 in 20 ml of dimethylformamide was treated with a solution of 222 mg of 1,1-thiocarbonyldiimidazole in 5 ml of tetrahydrofuran. After 17 hours the solvent was evaporated and the residue was purified by chromatography on silica gel with methanol/dichloromethane (1:99). Trituration with n-hexane gave 297 mg of 3-[6,7,8,9-tetrahydro-8-isothiocyanato-pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione in the form of a red solid of melting point 285°-287° C.
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:33])(=[O:32])[N:17]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]([CH3:27])[CH3:26])=[CH:20][N:19]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.ClCCl>FC(F)(F)C(O)=O>[F:1][C@H:2]1[C@@H:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([S:16]([N:17]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]([CH3:26])[CH3:27])=[CH:20][N:19]=3)(=[O:32])=[O:33])=[CH:14][CH:15]=2)[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: Cc1cc(C(C)C)cnc1N(CC(C)C)S(=O)(=O)c1ccc(OC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(C)C)cnc1N(CC(C)C)S(=O)(=O)c1ccc(OC[C@H]2CCNC[C@H]2F)cc1
Yield: 51.2 %

Procedure:
tert-Butyl cis-3-fluoro-4-((4-(N-isobutyl-N-(5-isopropyl-3-methylpyridin-2-yl)sulfamoyl)phenoxy)methyl)piperidine-1-carboxylate (53 mg, 0.09 mmol) was dissolved in trifluoroacetic acid (TFA) (1 mL) and dichloromethane (DCM) (1 mL) and stirred under nitrogen, at room temperature for 30 minutes. The reaction was concentrated under a stream of nitrogen, then purified by mass directed autoprep (ammonium carbonate modifier) to give the title compound (22 mg). LCMS (2 min, formic) Rt 1.06 min, m/z (ES+) 478 (M+H).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH2:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])([O-:14])=[O:13].CCN(CC)CC.N#N>C1COCC1>[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:11][CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)(=[O:23])=[O:22])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NC1CCCc2cccnc21
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCCc2cccnc21
Yield: 93 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-quinolin-8-ylamine (1.73 g, 12.0 mmol) dissolved in THF (80 mL) was added 2-nitrobenzenesulfonyl chloride (2.92 g, 13.0 mmol) and Et3N (2.4 mL, 18.0 mmol). The mixture was stirred for 16 hours at room temperature under a positive pressure of N2. The reaction mixture was quenched with saturated aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford 2-nitro-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-benzenesulfonamide as a dark brown solid (3.72 g, 94%). 1H NMR (CDCl3) δ 1.59 (m, 1H), 1.89 (m, 2H), 2.50 (m, 1H), 2.76 (m, 2H), 4.35 (m, 1H), 6.86 (m, 1H), 7.04 (m, 1H), 7.35 (m, 1H), 7.74 (m, 2H), 7.99 (m, 1H), 8.12 (m, 1H), 8.26 (m, 1H).
Reaction SMILES: [OH-].[K+].[OH:3][NH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:11][CH2:12][CH2:13]Br.BrC(Br)(C)C>C(O)C>[CH2:8]([O:7][C:5]([N:4]1[CH2:13][CH2:12][CH2:11][O:3]1)=[O:6])[CH3:9]
Reactant: BrCCCBr
Reactant: CCOC(=O)NO
Agent: CC(C)(Br)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N1CCCO1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
To a solution of KOH (6.4 g, 0.11 mol) and hydroxyurethane (12 g, 0.11 mol) in ethanol (50 mL) was added 1,3-dibromopropane (5.8 mL, 0.057 mol). The resulting suspension was heated at reflux for 1 hour. After the mixture was cooled to room temperature, an additional portion of KOH (3.2 g, 0.055 mol) and of dibromopropane (2.9 mL, 0.028 mol) was added. The mixture was then refluxed for 1 hour, cooled to room temperature, and solvent was evaporated. The residue was suspended in boiling ether three times and filtered. The combined filtrates were dried over sodium sulfate, filtered, and evaporated. A portion of 3 g of the crude product was purified by flush column chromatography (EtOAC/Hexane, gradient elution), yielding 1.18 g of N-(ethoxycarbonyl)isoxazolidine. 1 H NMR (CDCl3) δ 1.15(t, 3H), 2.15 (q, 2H), 3.55(t, 2H), 3.8 (t, 2H),4.1(q, 2H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[C:14]([Cu])#[N:15]>CN(C=O)C>[C:14]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1)#[N:15]
Reactant: Cc1ccc2nc(C)cc(Br)c2c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: Cc1ccc2nc(C)cc(C#N)c2c1
Yield: 55.5 %

Procedure:
First, 4-bromo-2,6-dimethylquinoline (5.0 g) and CuCN (4.82 g) were added to DMF (70 ml) and were allowed to react for 6 hours at a temperature of 140° C. Ice was poured to the reaction solution and the produced precipitate was removed through filtering. The filtrate was extracted using ethyl acetate, the solvent was removed under reduced pressure, and the residue was purified through column chromatography (silica gel, hexane/ethyl acetate=4/1) to obtain 4-cyano-2,6-dimethylquinoline (2.14 g) represented by the following chemical formula (47).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([F:15])[CH:5]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:31])=[CH:27][C:28](O)=[O:29])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].O1CCCC1>C(N(CC)CC)C>[F:15][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][NH:2][C:28](=[O:29])[CH:27]=[C:26]([C:23]1[CH:22]=[CH:21][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:25][CH:24]=1)[CH3:31]
Reactant: CC(=CC(=O)O)c1ccc(C(C)(C)C)cc1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=CC(=O)NCc1ccc(NS(C)(=O)=O)c(F)c1)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 18 %

Procedure:
To the 50 ml of round bottom flask were put N-(4-aminomethyl-2-fluoro-phenyl)-methanesulfonamide hydrochloride (0.14 g, 0.55 mmol), 3-(4-t-butylphenyl)-but-2-enoic acid (1.0 eq, 0.12 g) and DMTMM (1.2 eq, 0.183 g). To this mixture was poured 25 ml tetrahydrofuran, added triethylamine (excess, 0.5 ml) and stirred 12 hours at room temperature. After confirming the completion of the reaction with TLC, the reaction mixture was extracted with ethylacetate, washed 1N HCl solution. The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was purified with column chromatography (n-hexane/ethyl acetate=1/1) to yield the title compound (41.5 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:36][O:37][C:38](=[O:52])[CH2:39][NH:40][C:41](=[O:51])[CH:42]([NH2:50])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(#N)C>[CH3:36][O:37][C:38](=[O:52])[CH2:39][NH:40][C:41](=[O:51])[CH:42]([NH:50][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COC(=O)CNC(=O)C(N)Cc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: COC(=O)CNC(=O)C(Cc1ccccc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 5.0 mmol of 5-chloro-1H-indole-2-carboxylic acid (50 mL of a 0.1 M solution in acetonitrile) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 mL of a 0.10 M solution in acetonitrile, 5.0 mmol), 1-hydroxybenzotriazole (50 mL of a 0.10 M solution in acetonitrile, 5.0 mmol), followed by (2-amino-3-phenyl-propionylamino)-acetic acid methyl ester (50 mL of a 0.10 M solution in acetonitrile, 5.0 mmol). The reaction was agitated overnight at 80° C. and then concentrated to dryness to give the title compound.
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH:15]1[CH2:20][N:19](CC2C=CC=CC=2)[CH2:18][CH2:17][N:16]1CC1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)C.O.[Pd]>[CH2:1]([O:13][CH2:14][CH:15]1[CH2:20][NH:19][CH2:18][CH2:17][NH:16]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCOCC1CNCCN1

Procedure:
An 8 g portion of the above piperazine in 130 ml of ethanol and 10 ml of water was hydrogenated with 10% palladium on carbon for 4 hours then filtered and the filtrate evaporated, giving 4.5 g of 2-[(dodecyloxy)methyl]piperazine.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:29][C:30](=[O:36])[NH:31][CH:32]2[CH2:35][NH:34][CH2:33]2)=[N:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:37]([Si:41]([CH3:51])([CH3:50])[O:42][CH:43]1[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]1)([CH3:40])([CH3:39])[CH3:38]>>[C:8]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:26])([F:25])[F:27])=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:29][C:30](=[O:36])[NH:31][CH:32]2[CH2:33][N:34]([CH:46]3[CH2:47][CH2:48][CH:43]([O:42][Si:41]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:50])[CH3:51])[CH2:44][CH2:45]3)[CH2:35]2)=[N:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)NC(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)n1nc(NCC(=O)NC2CN(C3CCC(O[Si](C)(C)C(C)(C)C)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of 3-[(azetidin-3-ylcarbamoylmethyl)-amino]-5-trifluoromethyl-indazole-1-carboxylic acid tert-butyl amide TFA salt (as prepared in Example 81, Step D) and 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21]Cl)=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21][N:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:25][CH:26]([CH3:28])[CH3:27])=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(-c3nnc(CCl)o3)ncn2-c2cccc(Cl)c2C1=O
Reactant: CC(C)CNCC(C)C
Solvent: CN(C)C=O
Product: CC(C)CN(Cc1nnc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)o1)CC(C)C
Yield: 86.8 %

Procedure:
1.09 g (3 mmol) of 7-chloro-3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature overnight with 0.97 g (7.5 mmol) of diisobutylamine and 15 ml of N,N-dimethylformamide. After evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.19 g (86%) of 7-chloro-3-(5-diisobutylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 181°-182°, which was converted into the hydrochloride of m.p. 161°-163°.