Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8]Cl)[CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][N:17]([CH3:16])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=1
Reactant: ClCCn1cc(Br)cn1
Reactant: CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(CCn1cc(Br)cn1)Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-bromo-1-(2-chloroethyl)-1H-pyrazole (317 mg, 1.513 mmol, for a preparation see Intermediate 54) was dissolved in N,N-dimethylformamide (DMF) (5 mL) and cesium carbonate (740 mg, 2.270 mmol) added with N-methyl-1-phenylmethanamine (0.973 mL, 7.57 mmol, available from Aldrich). The mixture was heated to 80° C. for 3 hours then allowed to stir at 80° C. overnight. The mixture was cooled to room temperature and loaded on to a 20 g SCX cartridge. The SCX was eluted with MeOH (100 ml) and 2M methanolic ammonia (100 ml). The basic fraction was evaporated to a colourless oil, loaded on to a 25+M Biotage silica column and eluted with a gradient of 0 to 2.5% 2M methanolic ammonia in DCM. The product containing fractions were evaporated to a pale yellow oil (155 mg). LCMS (Method C): Rt=0.67, MH+=294
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[CH2:28]([NH2:33])[CH2:29][CH:30]([CH3:32])[CH3:31]>>[CH3:31][CH:30]([CH3:32])[CH2:29][CH2:28][NH:33][C:9]([C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)=[O:27]
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Reactant: CC(C)CCN
Product: CC(C)CCNC(=O)c1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and iso-amylamine. The crude product was used without further purification (95%, oil). HPLC-MS: m/z=341.2 (M+1); Rt: 3.99 min.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[I-].[K+].Cl[CH:11]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>CN(C=O)C>[F:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[CH:11]([N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH2:12][CH2:13][CH2:14]2
Reactant: C1CNCCNC1
Reactant: Fc1ccc2c(c1)CCCC2Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)CCCC2N1CCCNCC1
Reaction time: 2 h
Yield: 17403.6 %

Procedure:
Under nitrogen atmosphere, a 3-necked 500 ml round-bottomed flask was charged with homopiperazine (20 mg), DMF (130 ml) and potassium iodide (0.35 g). A solution of 7.70 g (41.7 mmol) of 1-chloro-6-fluoro-1,2,3,4-tetrahydronaphthalene in 39 ml of DMF was added over a five minute period. The mixture was stirred at 55°-60° C. for two hours and then at ambient temperature overnight. Tlc analysis on silica gel (diethyl ether:hexane 5:95) showed the absence of the starting halide, Rf 0.77. Most of the DMF was then removed in vacuo (35° C., 0.6 torr) using a rotary evaporator. The residue was treated with 300 ml of water and extracted with ethyl acetate which was then dried (MgSO4). Filtration and removal of solvent in vacuo gave a yellow oil which was kugelrohr distilled to give the title compound, (8.63 g), bp (air bath temperature) 155°-166° C. at 0.26 torr, as a viscous yellow oil. 1H NMR (300 MHz, CDCl3) δ 3.86 (t, 1H, ArCHN), 6.78 (dd, 1H), 6.85 (m, 1H), 7.75 (m, 1H). Anal: Calcd. for C15H21FN2: C, 72.55; H, 8.52; N, 11.28. Found: C, 72.05; H, 8.53; N. 10.95. 1-Chloro-6-fluoro-1,2,3,4-tetrahydronaphthalene was prepared as follows:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9]2)[CH:3]=1.[C:23]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)(=O)C>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:9]2)[C:3]=1[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: Cn1nc(C2CCN(C(=O)OCc3ccccc3)C2)cc1N
Reactant: O=C1CCCCC1
Solvent: CC(=O)O
Product: Cn1nc(C2CCN(C(=O)OCc3ccccc3)C2)c(C2=CCCCC2)c1N
Yield: 52.8 %

Procedure:
A solution of EXAMPLE 24C (1.78 g, 5.92 mmol) and cyclohexanone (1.23 mL, 11.85 mmol) in acetic acid (10 mL) was stirred at ambient temperature overnight and at 55° C. for 1 day. The acetic acid was removed and the residue partitioned between sodium bicarbonate solution and ethyl acetate. The organic phase was washed with water, concentrated and the residue purified by flash chromatography on silica gel using 70-90% ethyl acetate in hexane to provide the title compound as a light yellow solid (1.19 g, 53%). MS (DCI): m/z 381 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>N1C=CC=CC=1>[O:10]1[CH2:11][CH2:12][CH2:13][CH:14]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[N:4]([CH:11]2[CH2:12][CH2:13][CH2:14][O:10]2)[C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C1=COCC1
Solvent: c1ccncc1
Product: O=c1c(F)cn(C2CCCO2)c(=O)n1C1CCCO1
Temperature: 150 °C

Procedure:
In 20.8 ml of pyridine were dissolved 5.2 g (40 m mol) of 5-fluorouracil and 14 g (200 m mol) of 2,3-dihydrofuran. The solution were heated at about 150° C. in a closed tubular reactor under agitation for 6 hours. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in chloroform and the solution was passed through a column of silica gel. The column was eluated with chloroform and the effluent was concentrated to dryness under reduced pressure. The residue was washed with a small amount of petroleum ether to give the above-mentioned compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.C([Li])CCC.CN([CH:18]=[O:19])C.Cl>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:18]=[O:19])=[C:4]([F:9])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(F)cc(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1c(F)cc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 41.6 %

Procedure:
To a −78° C. solution of 1-chloro-3,5-difluoro-benzene (5.0 g, 34 mmol) in THF (70 mL) at was added n-butyl lithium (1.6 M in hexane, 19 mL). After 50 min, DMF (5.2 mL, 67 mmol) was added and the reaction was allowed to warm to rt over 18 h. After the addition of 0.5 M HCl (150 mL) and ether (150 mL), the aqueous layer was extracted with Et2O (3×). The combined organic extracts were dried and concentrated to provide a yellow solid. The crude material was dissolved in warm hexanes and a small amount of white solid formed upon cooling. This white solid was filtered off and discarded. The filtrate was concentrated to provide the title compound as a light yellow solid (2.5 g, 41%). 1H NMR (CDCl3): 10.3 (s, 1H), 7.06 (d, J=8.1 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][S:14][C:12]=2[N:13]=1.S(Cl)([Cl:20])=O.CN(C)C=O>C(Cl)(Cl)Cl>[Cl:20][C:10]1[C:11]2[CH:16]=[CH:15][S:14][C:12]=2[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c(-c2ccccc2F)nc2sccc12
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1ccccc1-c1nc(Cl)c2ccsc2n1
Yield: 45.3 %

Procedure:
2-(2-Fluoro-phenyl)-3H-thieno[2,3-d]pyrimidin-4-one (900 mg, 3.65 mmole) was dissolved in chloroform and thionyl chloride (0.532 ml, 7.30 mmole) was added to the mixture followed by 1 ml dimethylformamide. Heated the reaction mixture to reflux for 2.5 hours, the cooled mixture was washed with 10% sodium carbonate, dried the chloroform solution over sodium sulfate (anh) and removed solvent. The crude product was chromatographed on silica gel, eluting with chloroform. Upon removal of solvent obtained 438 mg product (yield: 45%).
Reaction SMILES: O[C:2]1([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21]>C(OCC)(=O)C.CCCCCC>[CH3:21][C:3]1([CH3:22])[CH:2]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4]1
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)CCc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2CCc1ccccc1
Yield: 92 %

Procedure:
Using N-(3-hydroxy-2,2,6,7-tetramethyl-3-(2-phenylethyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 240, the title compound was synthesized in the same manner as in Example 271. Yield: 92%. Melting point: 158-159° C. (ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].Cl[C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.CN(C=O)C>O>[CH2:1]([S:3][C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:18]=[CH:17][N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Nc1cc(C(F)(F)F)ccn1)c1ncccc1Cl
Reactant: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cccnc1C(=O)Nc1cc(C(F)(F)F)ccn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
0.86 g of sodium ethanethiolate was added to a mixture of 1.23 g of 3-chloro-N-(4-trifluoromethylpyridin-2-yl)picolinamide and 3 mL of DMF, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture cooled to room temperature was poured to water, and the precipitated solid was taken by filtration. The resulting solid was dissolved in ethyl acetate, and the mixture was extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 1.23 g of 3-ethylsulfanyl-N-(4-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 8).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Reactant: Clc1ccccc1N1CCNCC1
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ccccc2Cl)CC1
Yield: 87 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 87%). 1H NMR (200 MHz, CDCl3): δ 3.14 (s, 4H), 3.79 (s, 3H), 4.13 (s, 4H), 6.97-7.05 (m, 2H), 7.22-7.28 (m, 2H), 7.33-7.40 (m, 2H), 7.46-7.51 (d, J=10.2 Hz, 1H), 7.66-7.73 (m, 1H).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccc(C#N)cc2)CC1
Yield: 11 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 4-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown solid (11%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3C(OC(C)(C)C)=O)[CH:22]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:37].CCOCC>CO>[ClH:37].[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)[CH:22]=2)[CH2:15][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CCC(CCOCc3ccccc3)CC2)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: c1ccc(COCCC2CCN(c3cncc(OC[C@@H]4CCCN4)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[4-[2-(benzyloxy)ethyl]-1-piperidinyl]-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (120 mg, 0.24 mmol) in MeOH (0.5 mL) was added 2N anhydrous HCl/ether (2 mL) under Ar at room temperature. The mixture was stirred at room temperature overnight. After the solvent was evaporated, the residue was dissolved in deionized water. The aqueous solution was washed three times with EtOAc, then filtered over a cotton plug. The water was removed under reduced pressure at 35° C., and the residue was purified by preparative HPLC (ACE AQ 150×21.2 mm; UV detection at 254 and 280 nm; flow 10.0 mL/min; gradient of 0 to 50% CH3CN in water [both containing 0.05 vol % CF3COOH] in 25 min, to 100% in another 5 min; tR 12.8-19.4 min) to obtain, after evaporation, the trifluoroacetate (131 mg). This salt was treated with PL-HCO3 MP anion exchange resin (Polymer Laboratories) in MeOH to afford the free amine, which was dissolved in MeOH (0.5 mL) and treated again with 2N anhydrous HCl/ether (2 mL) under Ar protection at room temperature. The mixture was stirred at room temperature overnight. After the solvent was evaporated, the residue was dissolved in deionized water (approx. 25 mL). The solution was filtered over a cotton plug, and the water was removed under reduced pressure at 35° C. After lyophilization from water, the hydrochloride (103 mg) was obtained as a yellow glass. [α]20D+1.8 (c 0.555 g/L, MeOH). 1H NMR (D2O, 400 MHz) δ 7.89 (s, 1H), 6.67 (s, 1H), 7.32 (s, 1H), 7.26-7.18 (m, 5H), 4.49 (m, 3H), 4.37 (m, 1H), 4.17 (m, 1H), 3.63 (m, 2H), 3.44 (t, 2H, J=6.8 Hz), 3.27 (t, 2H, J=6.8 Hz), 2.82 (m, 2H), 2.16-2.13 (m, 1H), 2.02-1.93 (m, 2H), 1.90-1.79 (m, 1H), 1.60 (m, 2H), 1.42 (m, 1H), 1.38 (m, 2H), 1.11 (m, 2H). 13C NMR (D2O, 100 MHz) δ 156.4, 148.8, 137.0, 128.2, 128.0, 127.7, 121.8, 117.3, 114.3, 72.0, 67.2, 58.1, 47.5, 45.6, 34.5, 31.2, 30.0, 25.4, 23.0. HRMS (ESI) calcd for C24H34N3O2 (M+H+) m/z 396.2651, found 396.2637. Anal. Calcd. for C24H33N3O2.3.0HCl.0.85H2O: C, 55.41; H, 7.30; N, 8.08; Cl, 20.44. Found: C, 55.64; H, 7.57; N, 8.21; Cl, 20.43.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[CH:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3cccc(C=O)c3)ccc2-n2c(C)nnc21
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3cccc(CN4CCCC4)c3)ccc2-n2c(C)nnc21
Reaction time: 0.08 h

Procedure:
(S)-2-(6-(4-Chlorophenyl)-8-(3-formylphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (for a preparation see Intermediate 5) (95 mg) was dissolved in DCM (5 ml). Pyrrolidine (24 μl) and acetic acid (8.62 μl) were added and the reaction mixture was stirred for 5 min. Sodium triacetoxyborohydride (202 mg) was added and the reaction mixture was stirred at room temperature, under nitrogen, overnight. Saturated sodium hydrogen carbonate solution (5 ml) was added and the reaction mixture was stirred for 10 min. The organic phase was separated and the saturated sodium hydrogen carbonate solution was extracted with DCM (10 ml). The DCM extracts were combined, dried and the solvent was evaporated. The residue was chromatographed (0-15% methanol:DCM), triturated with diethyl ether and dried in a vacuum dessicator at 40° C. over the weekend to give (S)-2-(6-(4-chlorophenyl)-1-methyl-8-(3-(pyrrolidin-1-ylmethyl)phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (71.7 mg) as a white solid. LCMS (formate): MH+ 553/555, RT 0.76 min
Reaction SMILES: [C:1]1([CH:7]([NH:12][C:13]([NH2:15])=[S:14])[C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16]I>CC(C)=O>[C:1]1([CH:7]([NH:12][C:13](=[NH:15])[S:14][CH3:16])[C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=S)NC(c1ccccc1)C(F)(F)F
Reactant: CI
Solvent: CC(C)=O
Product: CSC(=N)NC(c1ccccc1)C(F)(F)F

Procedure:
14.5 g N-(α-phenyltrifluoroethyl) thio Urea are dissolved in 270 ml acetone and this solution is heated to reflux. A solution of 17.6 g methyl iodide in 7.75 ml acetone is added thereto while keeping the heating at reflux during the addition and for a further period of three hours. The solvent is thereafter evaporated off and 25 of an oily product is obtained. The crystallisation thereof is initiated by scraping in the presence of benzene. The crystals melt at 138°-144°. A further crystallisation supplies 18.5 g of pure N-(α-phenyl trifluoroethyl) S-methylisothiourea in the form of its hydriodide melting at 142°-144°.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:12]3[S:13][C:14]4[CH2:19][NH:18][CH2:17][CH2:16][C:15]=4[C:11]=3[C:10]3=[N:20][CH:21]=[N:22][N:9]3[C:8]2=[O:23])=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:40](=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12]3[S:13][C:14]4[CH2:19][N:18]([CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH2:17][CH2:16][C:15]=4[C:11]=3[C:10]3=[N:20][CH:21]=[N:22][N:9]3[C:8]2=[O:23])=[CH:24][CH:25]=1
Reactant: O=c1n(Cc2ccc(Cl)cc2)c2sc3c(c2c2ncnn12)CCNC3
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1n(Cc2ccc(Cl)cc2)c2sc3c(c2c2ncnn12)CCN(Cc1ccccc1)C3
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.2 %

Procedure:
6-(4-Chlorobenzyl)-8,9,10,11-tetrahydropyrido[4′,3′:4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (80 mg, 0.22 mmol), sodium tri(acetoxy)borohydride (68 mg, 0.32 mmol), benzaldehyde (27 mg, 0.25 mmol) and THF (2 ml) were combined and stirred at room temperature for 18 hours. The mixture was concentrated, diluted with methanol, filtered and purified via reverse phase HPLC to yield 102 (50 mg, 40%) as the trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Na+:21]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([C:13]([O-:15])=[O:14])=[N:11][N:10]=[N:9]2)=[CH:18][CH:19]=1.[Na+:21]
Reactant: CCOC(=O)c1nnnn1Cc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2nnnc2C(=O)[O-])cc1

Procedure:
Following the procedure of Example 2, 1-(p-methoxybenzyl)-5-carboethoxy tetrazole is dissolved in warm absolute ethanol. A slight stoichiometric excess of NaOH in water is added to precipitate the sodium salt.
Reaction SMILES: F[B-](F)(F)F.C([O+]([CH2:11][CH3:12])CC)C.[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[C:21]([Cl:23])[CH:22]=1)[NH:19][N:18]=[CH:17]2>C(OCC)(=O)C>[Br:13][C:14]1[CH:22]=[C:21]([Cl:23])[C:20]2[C:16](=[CH:17][N:18]([CH2:11][CH3:12])[N:19]=2)[CH:15]=1
Reactant: Clc1cc(Br)cc2cn[nH]c12
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: CCn1cc2cc(Br)cc(Cl)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethyl oxonium tetrafluoroborate (2.5 g) was added to a solution of 5-bromo-7-chloro-1H-indazole (1.38 g) in ethyl acetate (15 mL), and the reaction solution was stirred at room temperature overnight. After dilution with ethyl acetate, the reaction solution was washed successively with water and a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 5-bromo-7-chloro-2-ethyl-2H-indazole.
Reaction SMILES: [OH:1][C:2]1[C:3](C)=[C:4]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:8]([C:24]#[N:25])[CH:7]=[N:6][N:5]2[CH:26]=1.[C:28](O)(C(F)(F)F)=[O:29].O.C(O)(C(F)(F)F)=O.CC#N>>[OH:1][C:2]1[C:3]([O:29][CH3:28])=[C:4]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=3)=[C:8]([C:24]#[N:25])[CH:7]=[N:6][N:5]2[CH:26]=1
Reactant: Cc1c(O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: COc1c(O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 0.13 h
Yield: 76 %

Procedure:
The title compound (26 mg, 76%) was prepared from Example 398 (38 mg, 0.092 mmol) by a route analogous to that used for the preparation of compound 397A. It has a retention time of 6.08 min. (Column: HTS, 5 u, 4.6×50 mm; Gradient: 5-100% B in 8.0 min; A=0.1% TFA/H2O; B=0.1% TFA/CH3CN; Run time 10 min; Det: 215 nM; FR: 1.2 ml/min); MS Found: (M+H)+=373.2
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[NH2:18][S:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20]>>[OH:13][S:12]([NH:11][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:26]3[CH:27]=[C:22]([S:19]([NH2:18])(=[O:21])=[O:20])[CH:23]=[CH:24][CH:25]=3)[CH:3]=2)[CH2:7]1)([OH:14])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(I)cc2C1
Reactant: NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)S(O)(O)NC1Cc2ccc(-c3cccc(S(N)(=O)=O)c3)cc2C1

Procedure:
The title compound was prepared from N-(5-iodo-2,3-dihydro-1H-inden-2-yl)-2-propanesulfonamide and [3-(aminosulfonyl)phenyl]boronic acid (WO2003004472) in a similar manner to Example 1.
Reaction SMILES: [I-].[NH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N+:9]([CH3:14])=[C:10]2[CH3:13])=[CH:5][CH:4]=1.[CH3:15][Mg]Cl.O>C1COCC1>[NH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH3:14])[C:10]2([CH3:15])[CH3:13])=[CH:5][CH:4]=1
Reactant: C[Mg]Cl
Reactant: CC1=[N+](C)CCc2ccc(N)cc21
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCc2ccc(N)cc2C1(C)C
Temperature: -78 °C
Reaction time: 18 h
Yield: 8 %

Procedure:
7-Amino-1,2-dimethyl-3,4-dihydroisoquinolinium iodide (1.44 g, 4.8 mmol) was suspended in THF (200 ml), cooled to −78° C. and treated with methyl magnesium chloride (10 ml of a 3M solution in THF) added as a single portion. The reaction was allowed to reach room temperature over 18 h and poured into water (200 ml). The organic solvent was removed in vacuo and the resultant oily residue extracted into dichloromethane (3×50 ml). Evaporation in vacuo and chromatography through silica gel eluting with (0.5% 0.88 NH3: 4.5% CH3OH: 95% CH2Cl2) yielded the title compound as a yellow oil (0.07 g, 8%). For ease of handling the product was converted into a monohydrochloride.