Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([NH:17][NH2:18])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([CH:24]=[C:25]2[CH2:34][CH2:33][C:32]3[CH:31]=[C:30]([C:35]([O:37][CH3:38])=[O:36])[CH:29]=[CH:28][C:27]=3[C:26]2=O)[CH2:23][CH2:22][CH2:21][CH2:20]1>Cl.C(O)C>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([N:17]2[CH:24]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:25]3[C:26]([C:27]4[CH:28]=[CH:29][C:30]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][C:32]=4[CH2:33][CH2:34]3)=[N:18]2)[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)CCC(=CC1CCCC1)C2=O
Reactant: N#Cc1ccc(NN)cc1OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(OCc3ccccc3)c2)C1C1CCCC1
Temperature: 80 °C
Reaction time: 64 h
Yield: 96 %

Procedure:
A mixture of 2-(benzyloxy)-4-hydrazinylbenzonitrile; Preparation 13 (358 mg, 1.5 mmol), Methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate; Preparation 18 (284 mg, 1.0 mmol), ethanol (7 mL), and 1 drop of concentrated hydrogen chloride was stirred under argon at 80° C. for 64 hours. The mixture was cooled to room temperature, concentrated and purified by normal phase flash column chromatography on a 40 g silica gel column (20-80% ethyl acetate/hexanes gradient). Pure fractions were pooled and concentrated in vacuo to yield methyl 2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate (yellow foam, 485 mg, 0.96 mmol, 96% yield). The title compound was largely present as (±)-(3RS,3aSR)-methyl 2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.51 (m, 7H), 1.56-1.68 (m, 1H), 1.82 (ddd, J=25.85, 12.96, 3.89 Hz, 1H), 1.95-2.08 (m, 1H), 2.15-2.31 (m, 1H), 2.82-2.95 (m, 1H), 3.11 (d, J=16.38 Hz, 1H), 3.53-3.63 (m, 1H), 3.87 (s, 3H), 4.91 (dd, J=9.53, 5.50 Hz, 1H), 5.31 (q, J=12.35 Hz, 2H), 6.85 (d, J=8.32 Hz, 1H), 6.96 (s, 1H), 7.35 (t, J=7.25 Hz, 1H), 7.39-7.57 (m, 5H), 7.80-7.92 (m, 2H), 8.10 (d, J=8.32 Hz, 1H). ES-MS m/z 506 (M+H).
Reaction SMILES: [CH3:1][Sn:2](Cl)([CH3:4])[CH3:3].C1COCC1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1.CCOCC>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Sn:2]([CH3:4])([CH3:3])[CH3:1])=[CH:14][CH:13]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: C[Sn](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Sn](C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a 1M solution of trimethyltin chloride in THF (92 ml, 92 mmol) was slowly added a 1M solution of 4-chlorophenylmagnesium bromide in Et2O (92 ml, 92 mmol) over a 40 min period at −10° C. so that the temperature never exceed 0° C. After the addition, the cooling bath was removed and the resulting suspension was stirred at RT for 1 h. A saturated aqueous solution of NH4Cl (14 ml) was added followed by water until complete dissolution of the precipitate. The mixture was transferred into a separating funnel and extracted with Et2O (3×). The combined organic fractions were dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; isocratic elution with cyclohexane) to yield the title compound (24.47 g, 89 mmol, 97%) as a colorless oil. TLC: RF=0.76 (cyclohexane/AcOEt 95:5); HPLC: AtRet=3.25 min; 1H NMR (400 MHz, CDCl3): 0.31 (s, 9H) 7.32-7.36 (m, 2H) 7.41-7.45 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])=[C:11]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:10]3=[N:9]2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:44])[C:32]([O:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([F:43])[CH:37]=1)([CH3:34])[CH3:33])[CH3:29]>S(Cl)(Cl)=O.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:28]([O:30][C:31](=[O:44])[C:32]([O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:14](=[O:15])[CH:13]([C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:11]=23)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:38]([F:43])[CH:37]=1)([CH3:34])[CH3:33])[CH3:29]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(N)c(F)c1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCCC3)C2CCCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 24.3 %

Procedure:
A solution of [2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-cyclohexyl-acetic acid (40 mg, 103 umol) in thionyl chloride (2 ml) was heated under reflux conditions for 45 min. The solvent was removed under reduced pressure and the resulting crude [2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-cyclohexyl-acetyl chloride was dissolved in CH2Cl2 (1 ml) and added to a solution of 2-(4-amino-3-fluoro-phenoxy)-2-methyl-propionic acid ethyl ester (37 mg, 155 umol) and DMAP (38 mg, 310 umol) in CH2Cl2 (1 ml). The reaction mixture was stirred at ambient temperature for 14 h. Ice water/brine 1/1 was added and the mixture was extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a brown oil which was purified by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water to obtain the title compound (15 mg, 25 umol; 24%) as brown solid. MS: m/e=610.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:24]([O-])([O-])OCC.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[N:9]([CH2:10][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)[CH:24]=[N:5][C:4]=2[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC([O-])[O-]
Reactant: Nc1cccc(Cl)c1NCc1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Clc1cccc2ncn(Cc3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Yield: 77.3 %

Procedure:
A mixture of 3-chloro-2-(4-phenoxybenzylamino)aniline (0.300 g) and ethyl ortho-formate (0.178 g) was heated at 120° to 130° C. for 5 hours while stirring and then cooled to room temperature. Toluene (100 ml) and a 5% sodium hydroxide solution (50 ml) were added thereto, followed by stirring for 10 minutes. The toluene layer was separated and washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove toluene. The residue was purified by silica gel column chromatography to give 7-chloro-1-(4-phenoxybenzyl)benzimidazole (0.239 g) as a colorless liquid. nD28.5 1.6362.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:11])[C:3]=1[NH2:12].C(=O)(O)[O-].[Na+].[C:18](Cl)(Cl)=[S:19]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10]2)[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]=[C:18]=[S:19]
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(C2CC2)cc(Cl)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C2CC2)cc(Cl)c1N=C=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
Compound 2 (775 mg, 4.3 mmol) was dissolved in 9 mL of dichloromethane. Sodium bicarbonate (4.5 mL, sat. solution) and thiophosgene (0.33 mL, 4.3 mmol) were added and the mixture stirred at room temperature for 1 h. Then, the organic layer was separated, dried over sodium sulfate and concentrated to afford 935 mg of 1-chloro-5-cyclopropyl-2-isothiocyanato-3-methylbenzene (3) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23]1(/[CH:29]=[CH:30]/B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](/[CH:30]=[CH:29]/[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: OB(O)/C=C/c1ccccc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(/C=C/c4ccccc4)c3O2)cc1
Yield: 77.6 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (8.0 g, 20.9 mmol) with trans-2-phenylvinylboronic acid (4.63 g, 31.3 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.82 g, 1.04 mmol), and potassium carbonate (7.21 g, 52.2 mmol) generally according to the procedure described for Intermediate 37 provided 6.59 g (78%) of (±)-{7-[(E)-2-phenylvinyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a light yellow solid. mp 120-122° C.; Anal. calcd. for C24H22O4S: C, 70.91; H, 5.45. Found: C, 70.78; H, 5.56.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([OH:7])[CH:4]=[C:3]([CH2:8][C@H:9]([NH2:13])[C:10]([OH:12])=[O:11])[CH:2]=1.[CH2:14]=O>S(=O)(=O)(O)O>[OH:7][C:5]1[CH:4]=[C:3]2[C:2](=[CH:1][CH:6]=1)[CH2:14][NH:13][CH:9]([C:10]([OH:12])=[O:11])[CH2:8]2
Reactant: C=O
Reactant: N[C@@H](Cc1cccc(O)c1)C(=O)O
Agent: O=S(=O)(O)O
Product: O=C(O)C1Cc2cc(O)ccc2CN1
Temperature: 70 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To 61.5 g of D, L-m-tyrosine suspended in 250 ml of 0.05N sulfuric acid aqueous solution, 48 ml of 37% formalin aqueous solution was added dropwise. The reaction mixture was stirred at 70° C. for 12 hours, and subjected to crystallization under ice cooling for 2 hours. The obtained crystal were filtered off, and dried at 60° C. under reduced pressure to obtain 65.6 g of Compound 1 (yield 100%). Compound 1 thus obtained was dissolved in an aqueous solution of 2N sodium hydroxide, and was then adjusted to pH 5 with concentrated hydrochloric acid. The precipitate was filtered off, washed with water and dried at 60° C. under reduced pressure to obtain 52.5 g of purified product of Compound 1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]#[N:12])([O-:3])=[O:2].[H-].[Na+].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19](S(C)(=O)=O)[N:18]=1.Cl>CN(C)C=O.O>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([CH:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[C:11]#[N:12])[N:18]=1
Reactant: N#CCc1ccccc1[N+](=O)[O-]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)nc(C(C#N)c2ccccc2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
50 g (0.31 M) of 2-(2-nitrophenyl)acetonitrile was dissolved in 500 ml of dimethylformamide. Thereto was added 24.7 g (0.62 M) of 60% sodium hydride. The mixture was stirred at room temperature for 2 hours. Then, 68 g (0.31 M) of 4,6-dimethoxy-2-methanesulfonylpyrimidine was added. The mixture was stirred at 80° C. for 1 hour to give rise to a reaction. The reaction mixture was poured into water, followed by neutralization with dilute hydrochloric acid. The mixture was subjected to extraction with ethyl acetate. The extract was washed with water, dried and subjected to vacuum distillation to remove the solvent. The residue was recrystallized from ethanol to obtain 73.3 g (yield: 79%) of 2-(4,6-dimethoxypyrimidine-2-yl)-2-(2-nitrophenyl)acetonitrile as a white powder (melting point: 88 to 89° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Yield: 94.8 %

Procedure:
A solution of piperazine-1-carboxylic acid tert-butyl ester (1.90 g, 10.2 mmol) and triethylamine (1.55 mL, 11.1 mmol) in CH3CN (9 mL) was treated with 1-bromomethyl-4-nitro-benzene (2.00 g, 9.26 mmol) as a solution in CH3CN (15 mL) at RT for 20 min. The mixture was concentrated in vacuo. The residue was taken up in CH2Cl2 (20 mL) and washed with water (1×20 mL). The aqueous layer was extracted with CH2Cl2 (2×20 mL), and the combined organic layers were washed with water (1×40 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue on a 50-g Isolute SPE column on a FlashMaster system with 10-25% EtOAc-hexane afforded the title compound (2.82 g, 95%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C16H23N3O4, 322.2 (M+H). found 321.9.
Reaction SMILES: ClCCl.[CH3:4][C@@:5]1([OH:32])[C@H:10]([O:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[O:13])[C@@H:9]([CH2:21][O:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[O:24])[O:8][CH:6]1O.CS(Cl)(=O)=O>C(N(CC)CC)C>[C:28]1([CH3:31])[CH:29]=[CH:30][C:25]([C:23]([O:22][C@@H:21]2[C@@H:9]([CH2:10][O:11][C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:13])[O:8][C@@H:6]3[O:32][C@:5]23[CH3:4])=[O:24])=[CH:26][CH:27]=1
Reactant: Cc1ccc(C(=O)OC[C@H]2OC(O)[C@](C)(O)[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)OC[C@H]2O[C@@H]3O[C@]3(C)[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a 72 L vessel was charged dry dichloromethane (32 L), triethylamine (3.0 L), and diol 2-2 (3.44 kg, 90 wt % pure). The mixture was warmed to 30° C., then methanesulfonyl chloride (0.79 L) was added over 40 min. After 1 h, the batch was partitioned between pH 7 buffer (20 L) and methyl tert-butyl ether (44 L). The organic phase was washed with 1M aqueous NaCl (38 L) then switched to toluene by vacuum distillation followed by concentration to about 9 L. The resulting solution of epoxide was used directly in Step B.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([BH3-])#[N:16].[Na+]>CO.Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:8][CH2:1][CH2:2][NH:16][C:15]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1ccc(CN2CCC(NCCNc3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
To the solution of 12.6 g of N-phenylethyleneidamine in 200 ml of methanol, 50 ml of 4.1 N ethanolic hydrogen chloride are added dropwise followed by 18.9 g of 1-benzyl-4-piperidone in 100 ml of methanol. Then, 9.45 g sodium cyanoborohydride are added in portions while stirring at room temperature. After 72 hours the mixture is filtered, the residue dissolved in water and the solution made basic with 12.5% aqueous sodium hydroxide. It is extracted with methylene chloride, dried and evaporated to yield the 1-benzyl-4-(2-phenylaminoethylamino)-piperidine.
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.Br[CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (2.0 g, 5.4 mmol, intermediate 8) in DMF (10 mL) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (1.35 g, 6.5 mmol, intermediate 2), potassium carbonate (1.49 g, 10.8 mmol). The mixture was stirred at 50° C. overnight. It was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product which was washed with ethanol and dried under vacuum to give 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-purine-2,6(3H,7H)-dione (2.10 g, 74.4%) as a white solid. LCMS retention time 1.669 min LCMS MH+-THP 415.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([NH2:22])=[O:21])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCC[C@H]1C(N[CH2:31][C:32]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:33])=O.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([NH:22][CH2:31][C:32]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:33])=[O:21])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)N1CCC[C@H]1C(N)=O
Reactant: CCCCCCCCCCCCCCOC(=O)CNC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine (1, 480 mg, 1.76 mmol) which was synthesized in accordance with the method described in the literature (Synthtic Commun., 20, 3507, (1990)), the compound (10) (650 mg, 1.76 mmol), and N-hydroxybenzotriazole (70 mg, 0.528 mmol) in N,N-dimethylformamide (20 ml) was added DCC (380 mg, 1.848 mmol) and the resulting mixture was stirred overnight at room temperature. After the precipitation which appeared was filtered off, the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and the precipitation which appeared was filtered off again. The filtrate was concentrated in vacuo. The residue was subjected to silica gel column chromatography (ethyl acetate:toluene=9:1) to give 1.02 g of the compound (13).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[N:17]([CH3:21])[C:18]([CH3:20])=[CH:19][C:6]1=2)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH3:21][N:17]1[C:7]2[C:8](=[O:16])[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]([C:3](=[O:4])[CH2:2][N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[C:6]=2[CH:19]=[C:18]1[CH3:20]
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(n1C)C(=O)Nc1ccccc1N2C(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc2c(n1C)C(=O)Nc1ccccc1N2C(=O)CN1CCN(C)CC1

Procedure:
A solution of 303 mg (0.001 mole) of 4-chloroacetyl-1,2-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one and 200 mg (0.002 mole) of N-methylpiperazine in 10 ml of dry dioxane is boiled under reflux for 2 hours. 20 ml of saturated aqueous sodium bicarbonate solution are added thereto, and then the mixture is extracted several times with ethyl acetate. The combined extracts are dried over sodium sulfate and concentrated in vacuo. The resulting oil is chromatographed on neutral silica gel (methylene chloride/methanol). Yield: 280 mg.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][Cl:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][CH2:13][CH2:14][Cl:15])=[O:24])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1ccc(SCCCCl)cc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(S(=O)CCCCl)cc1
Reaction time: 8 h

Procedure:
A solution of 1.22 g (0.005 mole) of 3-(p-acetamidophenylthio)propyl chloride in 25 ml of methylene chloride is cooled in an ice bath while 0.88 g (0.005 mole) of m-chloroperbenzoic acid is added in portions. After keeping at room temperature overnight the reaction mixture is washed with excess 0.5 N sodium hydroxide, dried, and concentrated to a light brown oil. By triturating with ether, 1.06 g of 3-(p-acetamidophenylsulfinyl)propyl chloride are obtained. Anal. Calcd for C11H14ClNO2S: C, 50.86; H, 5.45; N, 5.39; Cl, 13.65. Found: C, 50.53; H, 5.59; N, 5.23; Cl, 13.67.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1)(=[O:29])[CH3:28]
Reactant: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(NC(C)=O)cc1

Procedure:
1.0 g of cis-6-(4-aminophenyl)-1,2,3,4,4a,10b-hexahydro-8,9-dimethoxy-2-methyl-benzo[c][1,6]naphthyridine (produced as in Example 5) is heated to 60° in a mixture of 2 cc of pyridine and 2 cc of acetic anhydride for 2 hours. The reaction mixture is then evaporated to dryness in a vacuum and the residue is crystallized from acetone. M.P. 173°-175°.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:31])[C:7]1([CH2:30][CH2:29][CH2:28][CH2:27]1)[NH:8][S:9]([C:12]1[CH:21]=[C:20]2[C:15]([C:16]([Cl:26])=[CH:17][N:18]=[C:19]2[NH:22][C:23]([NH2:25])=[NH:24])=[CH:14][CH:13]=1)(=[O:11])=[O:10])C.Cl>CO>[Cl:26][C:16]1[C:15]2[C:20](=[CH:21][C:12]([S:9]([NH:8][C:7]3([C:6]([OH:31])=[O:5])[CH2:30][CH2:29][CH2:28][CH2:27]3)(=[O:10])=[O:11])=[CH:13][CH:14]=2)[C:19]([NH:22][C:23]([NH2:25])=[NH:24])=[N:18][CH:17]=1
Reactant: CCOC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NC3(C(=O)O)CCCC3)cc12
Temperature: 45 °C
Yield: 97.5 %

Procedure:
A solution of NaOH (75 mL, 2 M, 150 mmol) was added to a solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]cycloleucine ethyl ester (1.39 g, 3.16 mmol) in MeOH (75 mL) and the mixture heated at 40-50° C. for 24 h. The cooled mixture was neutrilised with dilute HCl (75 mL, 2 M) to give a precipitate and the MeOH was evaporated in vacuo. The solid was collected by filtration, with copious water washing, and dried under high vacuum to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]cycloleucine (1.27 g, 3.08 mmol) as a white powder.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[C:15]([O:22][CH3:23])[CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]2[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:7][CH:6]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[C:15]([O:22][CH3:23])[CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(C2Nc3c(OC)cccc3C(=O)N2c2ccc(OCCCl)cc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc3c(OC)cccc3c(=O)n2-c2ccc(OCCCl)cc2)cc1

Procedure:
To a solution of 17.28 g (0.0394 mol) of 3-[4-(2-chloro-ethoxy)-phenyl]-8-methoxy-2-(4-methoxy-phenyl)-2,3-dihydro-1H-quinazolin-4-one in 300 mL of toluene was added 8.94 g (0.0394 mol) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The reaction mixture was stirred and heated to reflux for 3 hours. The toluene then was removed in a rotary evaporator. Methanol (300 mL) was added to the reaction flask which was allowed to stir at room temperature overnight. The precipitate (mp 209-211° C.) was collected by vacuum filtration and amounted to 15.8 g.