Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=O.[I-].[Na+].[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH:29][C:30]([NH2:32])=[S:31])[CH2:22][CH2:21]1>CC(C)=O.C(=O)([O-])O.[Na+].O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:5]2([C:3]3[N:32]=[C:30]([NH:29][CH2:28][CH2:27][CH2:26][N:23]4[CH2:22][CH2:21][O:20][CH2:25][CH2:24]4)[S:31][CH:2]=3)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:12][CH:13]=1
Reactant: NC(=S)NCCCN1CCOCC1
Reactant: O=C(CCl)C1(c2ccc(Cl)cc2)CCCCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Clc1ccc(C2(c3csc(NCCCN4CCOCC4)n3)CCCCC2)cc1
Temperature: 50 °C

Procedure:
A solution of 2-chloro-1-[1-(4-chloro-phenyl)-cyclohexyl]-ethanone (191.5 mg, 0.71 mmol) and sodium iodide (105.8 mg, 0.71 mmol) in acetone (5 mL) was stirred at room temperature for 10 min. Next, 1-(3-morpholinopropyl)-2-thiourea (143.6 mg, 0.71 mmol) was added. The resulting mixture was heated at 50° C. overnight. After the mixture was allowed to cool to room temperature, it was diluted with 5% sodium hydrogen carbonate in water and then extracted with ethyl acetate (3×20 mL). The extracts were combined, and dried over anhydrous sodium sulfate, filtered and concentrated to give an oil. The crude was purified by column chromatography on silica gel using dichloromethane/2 N ammonia in ethanol (95:5) to give {4-[1-(4-chloro-phenyl)-cyclohexyl]-thiazol-2-yl}-(3-morpholin-4-yl-propyl)-amine, 94, as an oil (187.1 mg, 63%). 1H (CDCl3, 300 MHz) δ 7.31–7.21 (m, 4H), 6.01 (s, 1H), 5.93 (s, 1H), 3.70–1.52 (m, 24H) ppm; 13C(C6D6, 75 MHz) δ 23.5, 25.5, 26.9, 36.7, 45.7, 46.4, 54.2, 57.7, 67.4, 101.3, 128.8, 129.4, 132.0, 146.8, 160.1, 169.5 ppm.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=2)[C:18]([CH3:30])([CH3:29])[CH2:17]1)=O)(C)(C)C>C(Cl)Cl>[NH2:15][CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=2)[C:18]([CH3:30])([CH3:29])[CH2:17]1
Reactant: COC(=O)c1ccc2c(c1)C(NC(=O)OC(C)(C)C)CC2(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C(N)CC2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (0.7 ml, 9 mmol, 13 eq.) was added to a stirred solution of methyl 3-(tert-butoxycarbonylamino)-1,1-dimethyl-2,3-dihydro-1H-indene-5-carboxylate (220 mg, 0.69 mmol, 1 eq.) in methylene chloride (10 ml) at 0° C. and the mixture was stirred at RT for 2 h. After complete deprotection (checked by TLC) the solvent was removed under reduced pressure. The residue was diluted with methylene chloride (50 ml) and washed with water (10 ml) and brine (10 ml). The organic part was evaporated under reduced pressure to give the crude product which was directly used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:44]=[CH:43][C:39]3=NO[N:42]=[C:38]3[CH:37]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[NH2:8][C:6]1[N:7]=[CH:2][C:39]2[C:38](=[CH:37][CH:36]=[C:44]([C:2]3[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]4[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=4[CH3:25])=[O:16])[C:5]4[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=4[N:7]=3)[CH:43]=2)[N:42]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reactant: CC1(C)OB(c2ccc3nonc3c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4nc(N)ncc4c3)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reaction time: 8 h

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.180 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,1,3-benzoxadiazole (57.7 mg, 0.235 mmol), DMSO(2 mL), sodium carbonate (0.271 mL, 0.541 mmol), and bis(triphenylphosphine)palladium(II) chloride (12.67 mg, 0.018 mmol), wherein the reaction time was 8 h. The final product was collected as 28 mg (31%). LCMS E-S (M+H)=497.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (d, J=6.8 Hz, 6 H), 2.12 (s, 3 H), 2.26 (s, 3 H), 4.41 (d, J=5.0 Hz, 2 H) 5.30 (quin, J=6.6 Hz, 1 H), 5.89 (s, 1 H), 7.16 (br. s., 2 H), 7.56 (d, J=9.1 Hz, 1 H), 7.78 (s, 1 H) 8.60 (dd, J=8.8, 2.0 Hz, 1 H), 8.69 (d, J=1.8 Hz, 1 H), 8.76 (t, J=4.9 Hz, 1 H), 9.28 (s, 1 H), 11.53 (s, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=2[N+:22]([O-:24])=[O:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][C:15]=2[N+:22]([O-:24])=[O:23])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(CO)ccc1Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a solution of 4-[4-(benzyloxy)-phenoxy]-3-nitrobenzaldehyde (2.48 g, 7.1 mmol) in ethanol (100 ml) was added sodium borohydride (0.27 g, 7.3 mmol), followed by stirring at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The solvent was dried and evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform - ethyl acetate (4:1)] to give 4-[4-(benzyloxy)phenoxy]-3-nitrobenzyl alcohol (2.48 g).
Reaction SMILES: C(N(CC)CC)C.Br[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10]1>C1COCC1>[C:11]1(=[O:18])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: O=C1CC(Br)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (4.5 mL; 32 mmol; 1.2 equiv.) was added to 3-bromo-indan-1-one (5.6 g; 27 mmol) in 100 mL THF at 0° C. and stirred 1 h at r.t. The reaction mixture was filtered to remove triethylammonium bromide and concentrated in vacuo to give inden-1-one. 7-Fluoroindole (3.3 g, 22 mmol ) and Sc(OTf)3 (550mg, 5 mol %) were added to inden-1-one in 100 mL CH2Cl2 at 0° C. The reaction mixture was allowed to warm to room temperature over night. 100 mL ethyl acetate was added and the mixture was filtered through a silica gel plug and concentrated in vacuo. After flash chromatography (heptane/ethyl acetate, silica gel) 5.9 g 3-(7-fluoro-1H-indol-3-yl)-indan-1-one (82%) was isolated.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=4)[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][N:8]=3)[N:3]=2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CN(C)Cc1ccc(Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc(-c2ccc3ncc(S(C)(=O)=O)c(Nc4ccc(CN(C)C)cc4)c3n2)cc(Cl)c1O
Yield: 71.5 %

Procedure:
Following general procedure II, 6-chloro-N-{4-[(dimethylamino)methyl]phenyl}-3-(methylsulfonyl)-1,5-naphthyridin-4-amine (50 mg, 0.14 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (60 mg, 0.21 mmol) followed by formation of the dihydrochloride salt to afford the desired product (44 mg, 54%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.11 (s, 1H), 8.50 (d, J=9.0 Hz, 1H), 8.36 (d, J=9.0 Hz, 1H), 7.62-7.50 (m, 4H), 7.34 (d, J=2.1 Hz, 1H), 6.68 (d, J=2.0 Hz, 1H), 4.40 (s, 2H), 3.92 (s, 3H), 3.47 (s, 3H), 2.83 (s, 6H); ESI MS m/z 513 [M+H]+; HPLC>99% (AUC), tR=10.56 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]([NH:12][C:13](=[O:16])[CH2:14]Cl)([CH3:11])[CH2:9][OH:10])[CH:7]=1.CC([O-])(C)C.[K+]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2([CH3:11])[NH:12][C:13](=[O:16])[CH2:14][O:10][CH2:9]2)[CH:7]=1
Reactant: CC(CO)(NC(=O)CCl)c1cc(Br)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CC1(c2cc(Br)ccc2F)COCC(=O)N1

Procedure:
The cyclization of the (RS)-N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide [preparation of building block B e)] with potassium tert-butylate yielded, after chromatography on silica gel using a gradient of dichloromethane/methanol=100/0 to 75/25 as the eluent, the title compound as a white solid. Mass (calculated) C1H11BrFNO2 [288.118]; (found) [M+H]+=288 and [M+2+H]+=290.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.[C:11](Cl)(Cl)=[S:12]>CC(C)=O.C(Cl)(Cl)Cl>[N:1]([C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1)=[C:11]=[S:12]
Reactant: Nc1cccc(B(O)O)c1
Reactant: S=C(Cl)Cl
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: OB(O)c1cccc(N=C=S)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a cooled (0° C.) solution of 3-aminophenylboronic acid (2.24 g, 0.013 mol) in acetone (5 ml) was added dropwise a solution of thiophosgene (1 ml, 0.013 mol) in chloroform (5 ml) over a period of 0.5 hour. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 12 hours. The solvent was evaporated on a rotary evaporator and the residue was triturated with ether and filtered to remove the triethylamine hydrochloride. The ether solution was evaporated to a brown oil. This was chromatographed on silica gel (30 g) using acetone-chloroform (7:3) as eluent. Fractions containing the product were collected and evaporated to give a light brown solid. This solid was crystallized from ethyl acetate/hexane. M.P. 166°-67° C. Anal. Calcd. for C7H6NSBO2O: C, 46,00; H,3.59; N, 7.67; S, 17.54. Found: C, 46.17; H, 3.48; N, 7.59; S, 17.71.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:35])[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:20]=[C:21]([C:23]([O:25]C)=[O:24])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:35])[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])[CH:20]=[C:21]([C:23]([OH:25])=[O:24])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(-c2cc3ccccc3n2C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(-c2cc(C(=O)O)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Yield: 85 %

Procedure:
Intermediate (1b), 2-[5-methoxycarbonyl-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester (2.88 g, 5.78 mmol) was stirred in a mixture of tetrahydrofuran (40 mL) and water (20 mL). Lithium hydroxide (0.469 g, 11.2 mmol) was added and the reaction stirred at reflux for 2 hours. After cooling the reaction mixture was concentrated in vacuo, and the residue was taken up in water and the pH adjusted to 5 with the careful addition of an aqueous 2M hydrochloric acid solution. This aqueous solution was extracted with dichloromethane (×3), and the combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to afford the desired title compound as a yellow solid 2.30 g, 85%.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[C:24]([CH3:26])([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:27]([O:29]C)=[O:28])[CH:21]=4)[NH:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH:15]3[C:24]([CH3:26])([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:27]([OH:29])=[O:28])[CH:21]=4)[NH:16]3)=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)c3ccc(F)cc3)cc1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(NC(=O)c2ccc(F)cc2)cc1
Yield: 95 %

Procedure:
To a mixture of methyl 2-(4-(4-fluorobenzamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (43 mg, 0.01 mmol) in methanol (3 mL) and water (1.5 mL) was add a solution of sodium hydroxide (68 mg, 0.17 mmol.) in water (1.5 mL). The resultant mixture was heated to reflux until the completion of the reaction (monitored by thin layer chromatography). The methanol was removed under vacuum. The residue was acidified with 2 M hydrochloric acid to pH=1. The precipitates were collected by filtration to afford 2-(4-(4-fluorobenzamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow solid, 40 mg, Yield 95% MS (ESI+APCI) M+1=419.6.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[OH:28][C@@H:29]([CH2:35][CH3:36])[CH2:30][C:31](OC)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C@@H:29]([OH:28])[CH2:35][CH3:36])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CC[C@H](O)CC(=O)OC
Agent: Cl
Product: CC[C@H](O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (66 mg, 77%), MS (ISP) m/z=431.4 [(M+H)+], mp 158° C., was prepared in accordance with the general method of example 2 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and (S)-methyl 3-hydroxy-pentanoate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18]O)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O.O.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18][Cl:22])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: OCc1cccc2c(-c3ccc(Br)cc3)nccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: ClCc1cccc2c(-c3ccc(Br)cc3)nccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Bromophenyl)-5-hydroxymethylisoquinoline (17 g) was dissolved in 300 ml of tetrahydrofuran, and 15 ml of phosphorus oxychloride was added. The mixture was stirred at room temperature for 1 hour. After the reaction, water was added, and the reaction mixture was neutralized with an aqueous solution of sodium hydroxide. The mixture was extracted with benzene, and dried. The solvent was distilled off. The residue was recrystallized from ether-hexane to afford 13.2 g of 1-(4-bromophenyl)-5-chloromethylisoquinoline as colorless prisms having a melting point of 115.5° to 118.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[C:24]([O:32][C:33]([F:36])([F:35])[F:34])[CH:23]=1>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:20][C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([O:8][C:9]3[S:10][C:11]4[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=4[N:13]=3)=[C:6]([Cl:19])[CH:5]=2)(=[O:30])=[O:29])=[C:24]([O:32][C:33]([F:35])([F:34])[F:36])[CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1
Product: O=S(=O)(Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1)c1ccc(Br)cc1OC(F)(F)F

Procedure:
4-Bromo-N-[3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]-2-trifluoromethoxy-benzenesulfonamide was synthesized (83%) from 3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (420) and 4-bromo-2-trifluoromethoxybenzenesulfonyl chloride (Maybridge) in a similar manner as described in Examples 70-91.
Reaction SMILES: [OH:1][CH:2]([CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2.[CH3:29][C:30](C)=[O:31].C(Cl)(=O)C.N.O>O>[C:30]([O:1][CH:2]([CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:22]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2)(=[O:31])[CH3:29]
Reactant: CC(C)=O
Reactant: O=C1CCc2c(cccc2OCC(O)CN2CCN(c3ccccc3)CC2)N1
Agent: N
Solvent: CC(=O)Cl
Solvent: O
Product: CC(=O)OC(COc1cccc2c1CCC(=O)N2)CN1CCN(c2ccccc2)CC1

Procedure:
2 Grams of 5-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril are mixed with 30 ml of acetone and further 12 ml of acetyl chloride are added followed by heating for 10 hours under refluxing conditions. After cooling the reaction mixture, the product precipitated is collectd by filtration and washed with acetone. The crude crystals thus obtained are dissolved in 80 ml of water and made basic with ammonia-water, then extracted with chloroform, dried and chloroform is removed by distillation. The residue is purified by silica gel chromatography to obtain 0.5 g of 5-[2-acetyloxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless crystals with a melting point of 159°-161° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([C:9]([O:11]C)=O)=[N:7][N:6]2[C:13]([NH:16][CH3:17])=[N:14][N:15]=[C:5]2[C:4]=1[CH3:18].[CH2:19]([NH2:21])[CH3:20]>CO>[CH2:19]([NH:21][C:9]([C:8]1[C:3]([CH3:2])=[C:4]([CH3:18])[C:5]2[N:6]([C:13]([NH:16][CH3:17])=[N:14][N:15]=2)[N:7]=1)=[O:11])[CH3:20]
Reactant: CCN
Reactant: CNc1nnc2c(C)c(C)c(C(=O)OC)nn12
Agent: Cl
Solvent: CO
Product: CCNC(=O)c1nn2c(NC)nnc2c(C)c1C
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Methyl 7,8-dimethyl-3-methylamino-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylate hydrochloride (W1.220; 1.3 g) was dissolved in methanol (30 ml), cooled to 0° C., slowly admixed dropwise with ethylamine (11.44 ml; 2 M in THF) and stirred at 0° C. for 6 h. Then four further equivalents ethylamine were added and the mixture was left to stand at RT over the weekend. Subsequently, the mixture was concentrated and purified using silica gel (40 g cartridge, dichloromethane/methanol gradient of 0-20% in 60 min). 1.12 g of the title compound were obtained. LC-MS rt: 0.81 min [M+H]+: 249.1 (met. b)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[CH2:3][CH2:2]1.O=[CH:16][CH2:17][C:18]1([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][CH:4]2[CH2:5][CH2:6][N:1]([CH2:16][CH2:17][C:18]3([C:24]([O:26][CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:2][CH2:3]2)=[N:9][CH:10]=1
Reactant: Cc1ccc(NC2CCNCC2)nc1
Reactant: O=CCC1(C(=O)OCc2ccccc2)CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc(NC2CCN(CCC3(C(=O)OCc4ccccc4)CCCCC3)CC2)nc1
Yield: 86.3 %

Procedure:
To a solution of 2-(piperidin-4-ylamino)-5-methylpyridine (277 mg) and benzyl 1-(2-oxoethyl)cyclohexanecarboxylate (360 mg) in tetrahydrofuran (15 mL) was added acetic acid (207 mg) and triacetoxyborohydride (731 mg) at room temperature. After stiring the solution for 18 hours, saturated aqueous sodium bicarbonate solution was added thereto and it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by chromatography (NH silica gel, hexane:ethyl acetate=2:1) to give the title compound (520 mg).
Reaction SMILES: CO[C:3](=[O:20])[CH2:4][NH:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:16]([NH2:17])=[N:15][C:14]([NH2:18])=[C:13]([Cl:19])[N:12]=1)=[O:10].[CH2:21]([NH2:24])[CH2:22][NH2:23]>>[NH2:17][C:16]1[C:11]([C:9]([NH:8][CH2:7][CH2:6][NH:5][CH2:4][C:3]([NH:23][CH2:22][CH2:21][NH2:24])=[O:20])=[O:10])=[N:12][C:13]([Cl:19])=[C:14]([NH2:18])[N:15]=1
Reactant: COC(=O)CNCCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCN
Product: NCCNC(=O)CNCCNC(=O)c1nc(Cl)c(N)nc1N
Yield: 100 %

Procedure:
A solution of 7.45 g (24.6 mmol) of N-[2-[[(3,5-diamino-6-chloropyrazinyl)carbonyl]amino]ethyl]glycine methyl ester and 22.48 ml (373.9 mmol) of ethylenediamine was stirred at ambient temperature for two days. The excess diamine was evaporated. There was obtained 8.14 g (24.6 mmol, 100%) of 3,5-diamino-N-[2-[[2-[(2-aminoethyl)amino]2-oxoethyl]amino]ethyl]-6-chloropyrazinecarboxamide as a yellow solid: Rf=0.28, Solvent System A.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][CH2:13][CH2:14]Br)[CH3:11].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:10]([O:12][CH2:13][CH2:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[CH3:11]
Reactant: CCOCCBr
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOc1ccc(CO)cc1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture of 4-hydroxybenzyl alcohol (3.00 g), 2-bromoethyl ethyl ether (4.1 ml), potassium carbonate (6.68 g) and DMF (30 ml) was stirred at 90° C. for 3 days. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with a 1 N aqueous solution of sodium hydroxide and 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→1:1) to obtain 4-(2-ethoxyethoxy)benzyl alcohol (2.45 g) as a light yellow, oily substance.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:7][CH2:6]1)=[O:4].[CH3:35][C:36]([CH3:38])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH2:24]([O:23][C:20]1[CH:19]=[CH:18][C:17]([N:11]([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@@H:2]([NH:1][CH:36]([CH3:38])[CH3:35])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:6][CH2:7]2)=[CH:22][CH:21]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)=O
Reactant: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)[C@@H](N)CC(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)[C@H](CC(C)C)NC(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A solution of (S)-2-Amino-1-{4-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one (Example 20) (0.20 g, 0.43 mmol) and acetone (25 mg, 0.43 mmol) in CH2Cl2 (4 mL) was cooled to 0° C., treated with NaBH(OAc)3, allowed to warm to room temperature as ice melted and stir overnight. The reaction was diluted with EtOAc (100 mL), washed with saturated sodium bicarbonate solution and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 5% MeOH/CH2Cl2 to give 176 mg (81%) of the desired product.