Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1.CC(C)=O>[N:13]1([C:2]2[C:3]3[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: Cc1[nH]c2ncnc(Cl)c2c1C
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: Cc1[nH]c2ncnc(N3CCCc4ccccc43)c2c1C

Procedure:
This product is prepared in a manner analogous to that described in Example 1 from 4-chloro-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine and 1,2,3,4-tetrahydroquinoline (4 equivalents, Fluka, Buchs, Switzerland). M.p: 263-264° C.; FAB-MS: (M+H)+ =279 (corresponds to C17H18N4); Rf value (toluene-acetone--(4:6))=0.29.
Reaction SMILES: [CH:1]1([S:7]([CH2:10][CH2:11][CH2:12][OH:13])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:13][CH2:12][CH2:11][CH2:10][S:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)(=[O:8])=[O:9])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(CCCO)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCS(=O)(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-cyclohexylsulfonyl-1-propanol (37 g) and triethylamine (30 ml) in methylene chloride (400 ml) was treated dropwise at -5° C. with methanesulfonyl chloride (15 ml). After stirring for 2 h at room temperature the mixture was washed with water and dried over magnesium sulfate. Removal of solvent in vacuo gave a viscous oil (49 g) of 3-cyclohexylsulfonyl-1-propyl methanesulfonate.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH2:11])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CN1C(=O)CCC1>O1CCOCC1>[O:15]1[CH2:16][CH2:17][N:12]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH2:11])[CH:3]=2)[CH2:13][CH2:14]1
Reactant: C1COCCN1
Reactant: Nc1cc(Cl)n2nccc2n1
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Nc1cc(N2CCOCC2)n2nccc2n1
Temperature: 100 °C
Yield: 38 %

Procedure:
7-Chloropyrazolo[1,5-a]pyrimidin-5-amine (1E, 10 g, 30 mmol) and morpholine were added to NMP (20 ml) and dioxane (80 ml). The mixture was heated to 100° C. and the resulting suspension was concentrated in vacuo to remove most of the dioxane. Brine was added and the mixture was extracted with EtOAc five times. Combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Trituration of the residue with Et2O gave the desired product 7-morpholinopyrazolo[1,5-a]pyrimidin-5-amine (9A, 5.0 g, 38%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:12][C:8]=1[C:9]([OH:11])=O)[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH3:30]>>[CH2:29]([N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[CH2:23][NH:22][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][C:7]=1[O:6][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])[CH3:30]
Reactant: CC(C)=CCOc1ccc(OCC=C(C)C)c(C(=O)O)c1
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cc(OCC=C(C)C)ccc1OCC=C(C)C
Yield: 70 %

Procedure:
In a manner identical to Example 15, 2,5-diprenyloxybenzoic acid (1.45 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.40 g (70%) of the aimed compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9](F)[CH:10]=2)[N:5]=[C:4]([CH3:16])[CH:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:16][C:4]1[CH:3]=[C:2]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:10]=2)[N:5]=1
Reactant: C1CCNC1
Reactant: Cc1cc(Cl)c2cc(F)c([N+](=O)[O-])cc2n1
Product: Cc1cc(N2CCCC2)c2cc(N3CCCC3)c([N+](=O)[O-])cc2n1
Yield: 86.1 %

Procedure:
A solution of 0.29 g (1.21 mmol) of 4-chloro-6-fluoro-2-methyl-7-nitro-quinoline in pyrrolidine (2 ml, 24 mmol) was heated at 80° C. (bath temperature) for 18 h. The excess pyrrolidine was removed in vacuo, the residue taken up in methylene chloride, which was washed with water, brine and then dried over magnesium sulfate. The solvent was removed in vacuo to give 0.34 g (79%) of the desired 2-methyl-7-nitro-4,6-di-pyrrolidin-1-yl-quinoline as dark red solid. ISP mass spectrum, m/e: 327.3 (M+1 calculated for C18H22N4O2: 327).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.[CH3:17][NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1)(=[O:21])=[O:20].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH3:17][NH:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:30][CH2:29]2)=[CH:26][CH:27]=1)(=[O:20])=[O:21]
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: CNS(=O)(=O)c1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNS(=O)(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 105 °C
Yield: 52.9 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), N-methyl-4-(piperazin-1-yl)benzenesulfonamide (116 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 10-95% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-methanol (2:1, 6 mL) and dried in vacuum to afford (S)—N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzenesulfonamide (110 mg, 0.241 mmol, 52.8% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.88-2.04 (m, 3 H) 2.15-2.27 (m, 1 H) 2.38 (d, J=4.80 Hz, 3 H) 2.51 (d, J=4.29 Hz, 4 H) 3.32 (br. s., 4 H) 3.38-3.49 (m, 3 H) 3.57-3.69 (m, 1 H) 3.97-4.07 (m, 1 H) 7.02 (d, J=1.52 Hz, 1 H) 7.07 (d, J=9.09 Hz, 2 H) 7.15 (q, J=4.72 Hz, 1 H) 7.59 (d, J=8.84 Hz, 2 H) 7.66 (d, J=1.77 Hz, 1 H) 10.48 (s, 1 H). [M+H] calc'd for C24H29ClN6O2, 457; found, 457.
Reaction SMILES: C(O)(CC)C.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]=[N:16][C:17]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:18]=1[OH:27])([O-:8])=O.[N+](C1C=CC=CC=1N=NC1C=C(C(C)(C)C)[CH:42]=[C:41]([C:49](C)(C)C)[C:40]=1O)([O-])=O>C(O)CCCCCCC>[OH:27][C:18]1[C:19]([C:41]([CH3:49])([CH3:42])[CH3:40])=[CH:20][C:21]([C:23]([CH3:26])([CH3:24])[CH3:25])=[CH:22][C:17]=1[N:16]1[N+:6]([O-:8])=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[N:15]1
Reactant: CC(C)(C)c1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Reactant: CC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Solvent: CCCCCCCCO
Solvent: CCC(C)O
Product: CC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(C)C)c1
Yield: 82.9 %

Procedure:
The same procedure as in Example 7 was repeated, except that secondary butanol 80 g was replaced by n-octanol 50 g, and that 2-nitro-2'-hydroxy-5'-t-butylazobenzene 19.9 g was replaced by 2-nitro-2'-hydroxy-3',5'-di-t-butylazobenzene 23.7 g, thus producing 18.7 g of 2-(2-hydroxy-3,5-di-t-butylphenyl)benzotriazole-N-oxide having a melting point of 168° to 171° C. at the yield of 83.0%.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[CH:27]=[C:26](/[CH:28]=[CH:29]/[CH:30]([C:35]2[CH:40]=[C:39]([Cl:41])[C:38]([Cl:42])=[C:37]([Cl:43])[CH:36]=2)[C:31]([F:34])([F:33])[F:32])[CH:25]=[CH:24][C:10]=1[C:11]([NH:13][CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)=[O:12]>C(Cl)Cl>[NH2:16][CH2:15][CH2:14][NH:13][C:11](=[O:12])[C:10]1[CH:24]=[CH:25][C:26](/[CH:28]=[CH:29]/[CH:30]([C:35]2[CH:40]=[C:39]([Cl:41])[C:38]([Cl:42])=[C:37]([Cl:43])[CH:36]=2)[C:31]([F:34])([F:32])[F:33])=[CH:27][C:9]=1[Br:8]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.4 %

Procedure:
TFA (0.5 mL) was added to a stirred solution of (E)-tert-butyl 2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)ethylcarbamate (200 mg, 0.31 mmol) in CH2Cl2 (10 mL) at 0° C. and the reaction mixture was then stirred at ambient temperature for 18 h. The volatiles were evaporated under reduced pressure; water was added to the residue and the mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 1-5% MeOH in CH2Cl2 to afford the title compound as a brown solid (50 mg, 31%): 1H NMR (400 MHz, DMSO-d6) δ 8.56 (bs, 1H), 7.70 (bs, 2H), 7.94-7.91 (m, 3H), 7.62-7.59 (m, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.00 (dd, J=15.6, 9.2 Hz, 1H), 6.77 (d, J=15.6 Hz, 1H), 4.84-4.81 (m, 1H), 3.46-3.41 (m, 2H), 2.95-2.92 (m, 2H); ESIMS m/z 528.72 ([M+H]+); IR (thin film) 3435, 1671, 1113, 722, 555 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:12][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1F
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccc1F
Temperature: 100 °C
Yield: 65.9 %

Procedure:
(S)-1-[6-Fluoro-1-(2-fluorophenyl)-1H-benzoimidazol-2-yl]ethylamine (0.22 g, 0.81 mmol) was dissolved in n-butanol (5 mL) and 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.193 g, 0.81 mmol) and DIPEA (0.70 mL, 4.03 mmol) added. The reaction mixture was heated at 100° C. overnight. The resultant mixture was allowed to cool to RT and then concentrated in vacuo. The residue was passed down an Isolute® SCX-2 cartridge, eluting with DCM, MeOH and 2M NH3 in MeOH to afford a light yellow gum. This was purified by column chromatography (silica gel, gradient 0-5% MeOH in DCM) to afford 195 as an off-white solid (209 mg, 67%). LCMS (Method K): RT 3.34/3.52 min [M+H]+ 392.0 1H NMR (DMSO-d6, 400 MHz): δ 8.16-7.79 (3H, m), 7.77-7.64 (2H, m), 7.58-7.21 (3H, m), 7.16-7.09 (1H, m), 6.92-6.83 (1H, m), 5.63-5.38 (1H, m), 1.69 (1.5H, d, J=6.85 Hz), 1.58 (1.5H, d, J=6.86 Hz). NMR signals represent a mixture of rotamers
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16](/[N:18]=[CH:19]/[N:20](C)C)=O)=[CH:10]3)=[CH:4][CH:3]=1.Cl.[CH:24]([NH:27]N)([CH3:26])[CH3:25]>CC(O)=O>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]2[N:27]([CH:24]([CH3:26])[CH3:25])[N:20]=[CH:19][N:18]=2)=[CH:10]3)=[CH:4][CH:3]=1
Reactant: CN(C)/C=N/C(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: CC(C)NN
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 100 °C

Procedure:
To a solution of 13-bromo-N-[(1E)-(dimethylamino)methylidene]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-4-carboxamide (2.2 g, 6.1 mmol) in AcOH (20 mL) was added isopropylhydrazine hydrochloride (0.73 g, 6.6 mmol). The mixture was heated at 100° C. for 1 h. Most of the solvent was removed and water (50 mL) was added. The solid was collected by filtration, washed with water and dried in vacuo to afford 13-Bromo-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene, also named as 10-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1.8 g, 74% yield) as a yellow solid. LCMS (ESI) m/z: 376.1 [M+H+].
Reaction SMILES: [NH:1]([C:5]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:27])[NH:10]2)[C:2]([CH3:4])=[O:3].[OH:28]O>>[NH:1]([C:5]1[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:28])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:27])[NH:10]2)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1c(OCCCCSc2ccccc2)ccc2[nH]c(=O)ccc12
Reactant: OO
Product: CC(=O)Nc1c(OCCCCS(=O)c2ccccc2)ccc2[nH]c(=O)ccc12

Procedure:
Prepared analogous to Example 123 from 5-acetamino-6-(4-phenylmercapto-butoxy)-carbostyril and hydrogen peroxide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15]([O:17][CH3:18])=[O:16])=[S:13].Cl.[CH3:20][N:21]([CH3:26])[CH2:22][C:23](Cl)=[O:24]>CN(C)C=O.C(OCC)C>[CH2:9]([S:8][C:6]1[CH:5]=[CH:4][C:3]([NH:11][C:12]([NH:14][C:15]([O:17][CH3:18])=[O:16])=[S:13])=[C:2]([NH:1][C:23](=[O:24])[CH2:22][N:21]([CH3:26])[CH3:20])[CH:7]=1)[CH3:10]
Reactant: CN(C)CC(=O)Cl
Reactant: CCSc1ccc(NC(=S)NC(=O)OC)c(N)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCSc1ccc(NC(=S)NC(=O)OC)c(NC(=O)CN(C)C)c1
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
A stirred solution of 2-amino-4-ethylthio-1-(3-methoxycarbonyl-2-thioureido)benzene (8.35 g.) in dry dimethylformamide (60 ml.) was treated at room temperature with N,N-dimethylglycyl chloride hydrochloride (5.53 g.). The mixture was heated to 40°-50° C. for 45 minutes, then cooled, and diluted with diethyl ether (900 ml.). An oil precipitated which crystallised on standing. This solid was filtered off, washed with diethyl ether (100 ml.), and suspended in a mixture of chloroform (100 ml.) and water (100 ml.). Sodium carbonate (3.5 g.) was added and the mixture was stirred for 20 minutes. The chloroform layer was separated and the aqueous layer was extracted twice with chloroform (2× 50 ml.). The organic layers were combined, dried over magnesium sulphate and evaporated to dryness. The residual solid was recrystallised from isopropanol to give 4-ethylthio-1-(3-methoxycarbonyl-2-thioureido)-2-(2-dimethylaminoacetamido)benzene (8.5 g.), m.p. 142° C. (with decomposition).
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH3:14])[N:8]=[CH:9]2)=[C:2]=[S:3].[OH:15][CH2:16][CH2:17][CH:18]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][NH:19]1>C(O)C>[OH:15][CH2:16][CH2:17][CH:18]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][N:19]1[C:2](=[S:3])[NH:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH3:14])[N:8]=[CH:9]2
Reactant: Cc1cc2c(N=C=S)cccc2cn1
Reactant: OCCC1Cc2ccccc2CN1
Solvent: CCO
Product: Cc1cc2c(NC(=S)N3Cc4ccccc4CC3CCO)cccc2cn1
Temperature: 20 °C
Reaction time: 17 h
Yield: 99.5 %

Procedure:
5-Isothiocyanato-3-methylisoquinoline (8.8 g) is added to a solution of (RS)-3-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline (7.8 g) in ethanol (150 cc). A white precipitate rapidly forms. After stirring for 17 hours at a temperature of about 20° C., the mixture is evaporated to dryness at 40° C. under reduced pressure (30 mm Hg). (RS)-3-(2-Hydroxyethyl)-N-(3-methylisoquinol-5-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (16.5 g) is thus obtained in the form of pale yellow crystals.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[Cl:41][C:42]([Cl:47])([Cl:46])[C:43](Cl)=[O:44]>ClCCl>[Cl:41][C:42]([Cl:47])([Cl:46])[C:43]([C:3]1[N:4]2[C:5]([CH2:6][N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10]2)=[CH:1][CH:2]=1)=[O:44]
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1C
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
To a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)-methanone of Step C (1.5 g, 3.67 mmol) in dichloromethane (20 mL) was added N,N-diisopropylethyl amine (1.28 mL, 7.35 mmol) followed by slow addition of trichloroacetyl chloride (1.23 mL, 11.0 mmol). The reaction mixture was stirred overnight at room temperature then quenched with water. The organic phase was washed with 0.1 N hydrochloric acid followed by water, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a green oil. Purification by flash chromatography on silica gel using a solvent system of 20% ethyl acetate in hexane provided 2.1 g of title compound. The material was redissolved in dichloromethane and evaporated to dryness to provide a yellow foam, which was used in the next step.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH3:12])=[O:4].[CH2:13](O)[CH2:14][OH:15].[Na+].[Cl-]>C1(C)C(C)=CC=CC=1.O>[Cl:1][CH2:2][C:3]1([C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=2[CH3:12])[O:15][CH2:14][CH2:13][O:4]1
Reactant: Cc1ccc(C)c(C(=O)CCl)c1
Reactant: OCCO
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1ccc(C)c(C2(CCl)OCCO2)c1
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A mixture of 18.3 g [0.1 mol] of 2-chloro-1-(2,5-dimethylphenyl)ethanone, 12.6 g [0.2 mol] of ethylene glycol, 1.9 g [0.01 mol] of p-TsOH hydrate and 100 ml of xylene is heated to boiling with a water trap for about 3 hours. 40 ml of water and 20 ml of saturated aqueous NaCl solution are then added to the reaction mixture at room temperature. After addition of 20 ml of xylene, the organic phase is separated off and extracted with 20 ml each of water and saturated aqueous NaCl solution. The organic phase is dried over sodium sulfate and concentrated in vacuo. 18.35 g of oil result with, according to GC, 95.3% product (77.2% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]([OH:27])=O)[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH2:10][CH2:9]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:41][C@@H:42]([C:46]([NH2:48])=[O:47])[CH:43]([CH3:45])[CH3:44].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[NH2:48][C:46]([C@H:42]([NH:41][C:25]([C:4]1[CH:5]=[N:6][C:7]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][O:16][C:15]3=[O:24])[CH2:12][CH2:13]2)=[C:2]([Cl:1])[CH:3]=1)=[O:27])[CH:43]([CH3:45])[CH3:44])=[O:47]
Reactant: O=C(O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Reactant: CC(C)[C@@H](N)C(N)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](NC(=O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
The product of step (i) (0.14 g) was dissolved in 1-methyl-2-pyrrolidinone (4 ml) and to this solution was added carbonyldiimidazole (0.064 g) the mixture was stirred at room temperature for 1 h and then treated with D-valinamide hydrochloride (0.11 g) and N,N-diisopropylethylamine (0.10 g). After stirring for 18 h at room temperature the mixture was partitioned between aqueous sodium bicarbonate and ethyl acetate, the organic layer was washed with water, dried and evaporated under reduced pressure. The resultant solid was washed with ethyl acetate to yield 0.06 g of product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CC(C)([O-])C.[Na+].O1CCCC1>C1(C)C=CC=C(C)C=1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[NH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:7]=1
Reactant: Nc1cccc(Cl)n1
Reactant: C1CNCCN1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1cccc(C)c1
Product: Nc1cccc(N2CCNCC2)n1
Yield: 5.3 %

Procedure:
To a solution of 6-chloro-2-pyridinylamine (406 mg, 3.16 mmol) and piperazine (381 mg, 4.42 mmol) in m-xylene (10 ml), were added sodium tert-butoxide (425 mg, 4.42 mmol) and bis-(tri-o-tolylphosphine)palladium(II) dichloride (124 mg, 0.158 mmol). The mixture was heated at reflux under N2 for 24 h. The reaction was cooled down and tetrahydrofuran (THF, 10 ml) added, and the mixture was filtered on a celite pad. The filtrate was evaporated and purified via flash chromatography (CH2Cl2/MeOH/NH4OH) affording 30 mg of 2-amino-6-(piperazin-1-yl)pyridine (intermediate “Ia”) as a tan solid (5% yield). H-NMR (CD3OD): 2.95 (m, 4H), 3.47 (m, 4H), 5.93 (m, 1H), 6.01 (m, 1H), 7.24 (m, 1H). M+=179.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[C:14]([N:21]([CH3:34])[CH2:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:15]2[O:19][CH:18]=[CH:17][C:16]=2[CH:20]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:33][N:25]([CH2:24][CH2:23][CH2:22][N:21]([CH3:34])[C:14]1[C:15]2[O:19][CH:18]=[CH:17][C:16]=2[CH:20]=[C:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:13]=1)[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:31])[CH3:29]
Reactant: CN(CCCN(C)c1cc(N)cc2ccoc12)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(CCCN(C)c1cc(NS(=O)(=O)c2ccccc2)cc2ccoc12)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
Benzenesulfonyl chloride (115 μL, 0.9 mmol) was added to a mixture of tert-butyl 3-[(5-amino-1-benzofuran-7-yl)(methyl)amino]propyl(methyl)carbamate (Intermediate 2; 250 mg, 0.75 mmol) in DCM (2 mL) followed by addition of pyridine (1 mL). The reaction mixture was stirred at room temperature for 4 h. The volatiles were evaporated in vacuo and the residue obtained was purified using RP-HPLC (Gilson/YMC AQ C18; 150×30 mm) to give the title compound as a beige oil (202 mg, 43% over 4 steps); HPLC 93%, RT: 2.49 min (System A); 95%, RT: 2.27 min (System B); 1H NMR (CDCl3) δ ppm 1.41 (s, 9H), 1.60-1.75 (m, 2H), 2.74 (s, 3H), 2.93 (s, 3H), 3.13-3.25 (m, 2H), 3.42-3.53 (m, 2H), 6.19-6.69 (m, 2H), 6.87-7.06 (m, 1H), 7.33-7.58 (m, 4H), 7.71-7.79 (m, 2H); MS m/z 474 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]=O)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][N:35]([CH2:19][C:12]3[C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=3)[CH2:34][CH2:33]2)[CH:27]=1)=[O:24]
Reactant: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cn(S(=O)(=O)c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 1-(phenylsulfonyl)-1H-indole-3-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 516.1 (M+H)+.