Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6]1)=[O:4].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCC(O)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-oxo-cyclopentanecarboxylic acid methyl ester (2.0 g, 1.0 eq) was dissolved in methanol (15 mL) and cooled to 0° C. NaBH4 (0.53 g) was added and the mixture was stirred at 0° C. for 30 min. The mixture was quenched with acetic acid (0.5 mL) and the methanol was evaporated. The residue was taken up in ethyl acetate, washed with water, dried and evaporated. Purification by flash chromatography on silica gel with a dichloromethane/ethyl acetate gradient yielded the title compound as mixture of the cis and trans isomers. Colorless liquid, 1.6 g, 78%.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]([CH2:19][OH:20])=[C:9]1[Cl:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][C:10]([CH:19]=[O:20])=[C:9]1[Cl:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc(-c2ccccc2)n(Cc2ccccc2)c1Cl
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1cc(-c2ccccc2)n(Cc2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A solution (0.1 M) of (1-benzyl-2-chloro-5-phenyl-1H-pyrrol-3-yl)methanol in DCM at 0° C. was treated with N-methylmorpholine oxide (1.5 eq.) and TPAP (0.05 eq.). The mixture was stirred at RT for 1 h then it was filtered through a pad of silica gel and washed with DCM. The combined organic phase was concentrated affording the title compound (77%) as an oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:50]=[CH:49][C:13]([CH2:14][C@@:15]2([CH3:48])[N:19]3[C:20]([S:23]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[C:31]([NH:33][C@H:34](C)[C:35](O)=[O:36])=[O:32])(=[O:25])=[O:24])=[CH:21][N:22]=[C:18]3[N:17]([C:39]3[CH:44]=[C:43]([Cl:45])[CH:42]=[C:41]([Cl:46])[CH:40]=3)[C:16]2=[O:47])=[CH:12][CH:11]=1)#[N:9]>CN(C=O)C.CCOC(C)=O>[OH:36][CH2:35][CH2:34][NH:33][C:31]([C@@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[S:23]([C:20]1[N:19]2[C@@:15]([CH2:14][C:13]3[CH:12]=[CH:11][C:10]([C:8]#[N:9])=[CH:50][CH:49]=3)([CH3:48])[C:16](=[O:47])[N:17]([C:39]3[CH:40]=[C:41]([Cl:46])[CH:42]=[C:43]([Cl:45])[CH:44]=3)[C:18]2=[N:22][CH:21]=1)(=[O:24])=[O:25])=[O:32]
Reactant: C[C@@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(S(=O)(=O)N3CCC[C@H]3C(=O)NCCO)n21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.5 %

Procedure:
The above amine HCl salt (0.93 g) was dissolved in anhydrous DMF (9 mL) by vigorously stirring at room temperature for 30 min. When all the amine salt was dissolved, triethylamine (1 mL) was added to the solution. (R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl chloride (see Example 5) (1.18 g) in anhydrous DMF (1 mL) was then added to the reaction mixture and stirred at room temperature for 30 min. The reaction mixture was then diluted with EtOAc and washed with water (×2), 1N HCl, saturated NaHCO3 and brine. The organic phase was then dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography using CH2Cl2 and MeOH (gradient 0-5% MeOH) as an eluent to afford 1.18 g of the title compound as a white foam (M+1, 617.2)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[O:16][C:11]1([CH2:15][CH2:14][NH:13][CH2:12]1)[CH2:10][C:9]2=[O:20].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[O:16][C:11]1([CH2:15][CH2:14][N:13]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12]1)[CH2:10][C:9]2=[O:20]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNC1)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)C1)O2

Procedure:
(−)-(E)-3-[4-Oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (110 mg, 0.38 mmol) was treated with benzaldehyde and NaBH(OAc)3 according to the procedure used for Example 2, Step A to give (+)-(E)-3-[1′benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (45 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[C:13]3([CH2:14][OH:15])[C:10]([CH3:16])([CH2:11][O:12]3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CN1C=CN=C1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:13]3([CH2:14][O:15][S:38]([C:35]4[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=4)(=[O:40])=[O:39])[C:10]([CH3:16])([CH2:11][O:12]3)[CH2:9][CH2:8]2)=[CH:17][CH:18]=1
Reactant: CC12CCC(Cc3ccc(Cl)cc3)C1(CO)OC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cn1ccnc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC23OCC2(C)CCC3Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.6 %

Procedure:
In 1 ml of toluene, 50 mg of Compound 8a-1 synthesized in Production Example 19 was dissolved. To the solution thus obtained, 39.5 μl of triethylamine, 22.2 μl of N-methylimidazole, and 53.6 mg of p-toluenesulfonyl chloride were added, and the resulting mixture was stirred at room temperature for 1.5 hours. After the reaction, water was added to the reaction solution thus obtained, and extraction with ethyl acetate was then carried out. The organic layer thus extracted was washed with an aqueous solution of hydrochloric acid, an aqueous solution of sodium hydrogen carbonate, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was then purified by silica gel column chromatography to obtain 77.0 mg of Compound 9a-1-2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=2[CH2:11]1.ClC([O:24][CH2:25][CH2:26]Cl)=O>N1C=CC=CC=1>[OH:24][CH2:25][CH2:26][NH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=2[CH2:11]1
Reactant: COc1ccc(C2CCc3cc(O)ccc3C2)c(N)c1
Reactant: O=C(Cl)OCCCl
Solvent: c1ccncc1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCO)c1
Temperature: 180 °C
Reaction time: 6.5 h

Procedure:
To a solution of 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (1.6 g) in pyridine (6 ml) was added dropwise 2-chloroethyl chloroformate (1.4 ml) on an ice bath, and the solution was stirred for 6.5 hours. The solution was diluted with ice water, and then extracted with ethyl acetate. The solution was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. To the residue were added potassium hydroxide (3.0 g) and ethylene glycol (15 ml), and the solution was heated for 3 hours at 180° C. The solution was diluted with ice water, and then extracted with ethyl acetate. The solution was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (800 mg).
Reaction SMILES: N[C:2]1([NH2:16])[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]1=[N:4][CH:5]=[N:6]2.C([O-])([O-])=O.[K+].[K+].[O:23]1[CH:25]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24]1>CN(C=O)C>[NH2:16][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:24][CH:25]([OH:23])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COCCOC1=NC(N)(N)C2=NC=NC2=N1
Reactant: c1ccc(OCC2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1nc(N)c2ncn(CC(O)COc3ccccc3)c2n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a suspension of 6-amino-2-(2-methoxyethoxy)adenine (300 mg, 1.43 mmol) in DMF (3 ml) was added K2CO3 (200 mg, 1.43 mmol). Then 1,2-epoxy-3-phenoxy-propane (321 mg, 2.14 mmol) was added. The reaction mixture was stirred at 70° C. overnight. The solvent was removed and the residue was taken up in CH2Cl2 and washed with water. The aqueous phase was extracted with DCM. The organic layer was dried over NaSO4, filtered, concentrated, and purified by silica gel chromatography, using linear gradient of MeOH in DCM as eluent to give 350 mg product. 1H NMR (CDCl3): δ 3.43 (s, 3H), δ 3.74 (t, 2H), δ 3.90-4.06 (m, 2H), δ 4.30-4.35 (m, 1H), δ 4.30-4.50 (m, 4H), δ 6.00 (bs, 2H), δ 6.88-7.01 (m, 3H), δ 7.27-7.32 (m, 2H), δ 7.70-7.73 (m, 1H); MS: 360.2 (M+1).
Reaction SMILES: C(NC(C1SC(N2C=C(C(OCC)=O)N=N2)=NC=1C)=O)C1C=CC=CC=1.[CH2:27]([NH:34][C:35]([C:37]1[S:41][C:40]([N:42]2[C:46]([CH3:47])=[C:45]([C:48]([O:50]CC)=[O:49])[N:44]=[N:43]2)=[N:39][C:38]=1[CH3:53])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][C:35]([C:37]1[S:41][C:40]([N:42]2[C:46]([CH3:47])=[C:45]([C:48]([OH:50])=[O:49])[N:44]=[N:43]2)=[N:39][C:38]=1[CH3:53])=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1nnn(-c2nc(C)c(C(=O)NCc3ccccc3)s2)c1C
Agent: CCOC(=O)c1cn(-c2nc(C)c(C(=O)NCc3ccccc3)s2)nn1
Product: Cc1nc(-n2nnc(C(=O)O)c2C)sc1C(=O)NCc1ccccc1
Yield: 73 %

Procedure:
Following the procedure as described in Example 17, making variations as necessary to replace ethyl 1-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-1H-1,2,3-triazole-4-carboxylate with ethyl 1-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxylate, the title compound was obtained as a white solid in 73% yield (0.24 g): MS (ES+) m/z 358.3 (M+1).
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].Cl.[NH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[NH:22][C:21]3[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:20]2=3)=[O:18])=[CH:13][C:12]=1[F:35].C(N(CC)CC)C>ClCCl>[CH3:29][N:24]1[C:23]2[NH:22][C:21]3[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:20]=3[N:19]([C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH2:10][NH:9][S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[C:12]([F:35])[CH:13]=3)=[O:18])[CH2:28][C:27]=2[CH:26]=[N:25]1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CN)c(F)c1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)NCc1ccc(C(=O)N2Cc3cnn(C)c3Nc3cc(C)ccc32)cc1F
Reaction time: 1 h
Yield: 51 %

Procedure:
1-Propanesulfonyl chloride (0.016 ml, 0.14 mmol) was added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E98.2 (50 mg, 0.12 mmol) in dichloromethane (2 ml) and triethylamine (0.038 ml, 0.27 mmol) at room temperature. The mixture was stirred for 1 h then concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to give a white solid identified as the title compound (30 mg, 51%).
Reaction SMILES: [OH-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16]>O1CCCC1.O>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]1[O:16][CH2:8]1
Reactant: C[S+](C)C
Reactant: O=Cc1ccccc1Cl
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Clc1ccccc1C1CO1

Procedure:
A mixture of 42.0 g of 57% sodium hydroxide dispersed in oil and 700 ml of dimethyl sulfoxide is stirred at 70°-75° for one to one and one-half hours. The solution is diluted with 700 ml of dry tetrahydrofuran and cooled to 0°, under nitrogen. A 200 g of (1.0 mol) sample of trimethylsulfonium iodide is added in portions, maintaining the temperature between 0°-5°. The mixture is stirred for 15 minutes and then a solution of 70.4 g (0.50 mol) of o-chlorobenzaldehyde in 300 ml of dry tetrahydrofuran is added dropwise. The resulting mixture is stirred at room temperature for four hours, poured into water and extracted with ether. The extract is washed with brine, dried and evaporated in vacuo to leave o-chlorostyrene oxide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([NH2:14])[CH3:13]>C(O)C>[CH2:12]([NH:14][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH3:13]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: CCN
Solvent: CCO
Product: CCNc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 89 %

Procedure:
A mixture of 26 g of 2,5-dichloro-nitrobenzene, 400 ml of ethanol and 25 ml of ethylamine was refluxed for 24 hours while adding 5 ml of ethylamine at 6 hour intervals and the mixture was cooled and filtered. The orange needles were washed with a small amount of an ethanol-ether mixture and dried over P2O5 under vacuum to obtain 24.4 g (89% yield) of N-ethyl-4-chloro-2-nitro-aniline melting at 90°-91° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:15]Br.O>C(O)(=O)C>[Br:15][C:6]1[N:7]=[C:2]([Cl:1])[C:3]([NH2:8])=[N:4][CH:5]=1
Reactant: BrBr
Reactant: Nc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncc(Br)nc1Cl
Temperature: 25 °C

Procedure:
3-Chloro-pyrazin-2-ylamine (0.750 g, 5.79 mmol) is suspended in acetic acid (7 ml) with stirring at room temperature and sodium carbonate (0.675 g, 6.37 mmol) is added. When all the gas has evolved bromine (0.171 ml, 3.34 mmol) in acetic acid (4 ml) is added dropwise. Sodium carbonate (0.675 g, 6.37 mmol) is added and a gas evolves. Once all gas has evolved bromine (0.171 ml, 3.34 mmol) in acetic acid (4 ml) is added. The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is poured onto iced water and left to stir for 30 minutes. A pale yellow suspension has formed. This solid is filtered off and rinsed with cold water to give 5-Bromo-3-chloro-pyrazin-2-ylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[C:45]1([N:51]=[C:52]=[O:53])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1(C)C=CC=CC=1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:52]([NH:51][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:53]
Reactant: Nc1ccccn1
Reactant: O=C=Nc1ccccc1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccccn1

Procedure:
29.04 g of a catalyst mixture of 2-aminopyridine/dibutyl tin dilaurate (molar ratio 1:1) in 37 ml of toluene are reacted with 4.76 g of phenyl isocyanate at room temperature. Petroleum ether is added to the resulting suspension after 11/2 hours and the colorless precipitate is suction filtered. 7 g of N-(2-pyridyl)-N'-phenyl urea, m.p. 186°-188° C. are isolated.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[C:12]([CH3:23])=[N:11][C:10]=2[OH:24])[CH:5]=[N:6][CH:7]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>CCO.CCOC(C)=O.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.C(COC)OC>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[C:12]([CH3:23])=[N:11][C:10]([OH:24])=[C:9]2[CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:3]=1
Reactant: COc1cc2c(C)nc(O)c(Cc3cncc(Br)c3)c2cc1OC
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: COc1cc2c(C)nc(O)c(Cc3cncc(-c4ccccc4)c3)c2cc1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 4-((5-bromopyridin-3-yl)methyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 34166 (66 mg, 170 μmol) in absolute EtOH (0.9 mL) in a 20 mL microwave vial equipped with a magnetic stirrer were added phenylboronic acid (20 mg, 164 μmol), Pd(PPh3)2Cl2 (10 mg, 14 μmol), a 2 N aq. Na2CO3 solution (0.30 mL, 0.60 mmol), H2O (2.7 mL) and dimethoxyethane (3.5 mL) and the resulting mixture was stirred at 140° C. for 25 min. After cooling to RT, the mixture was diluted with EtOAc (30 mL) and the solution was filtered through a celite plug, then washed with brine (10 mL). The organic layer was isolated and the celite plug was then further washed with CH2Cl2 (50 mL) and the organic layer was washed with brine (20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 92:8) provided 60 mg of 6,7-dimethoxy-1-methyl-4-((5-phenylpyridin-3-yl)methyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to give 6,7-dimethoxy-1-methyl-4-((5-phenylpyridin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 15 as a pale brown solid (71 mg, 91% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:23]([CH2:27][C:28](Cl)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[C:4]([NH:13][C:28](=[O:29])[CH2:27][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:3]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1cc(Br)ccc1NCC1CC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC(=O)Nc1cc(Br)ccc1NCC1CC1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
To a solution of 4-bromo-N1-(cyclopropylmethyl)benzene-1,2-diamine (Step B, 11.3 g, 46.9 mmol) and N,N′-diisopropylethylamine (6.06 g, 46.9 mmol) in ethyl acetate (88 mL) was added tert-butylacetyl chloride (6.31 g, 46.9 mmol) at 0° C. and the mixture was allowed to warm to room temperature for 15 h. The mixture was washed with saturated sodium hydrogencarbonate aqueous solution-(100 mL×2), brine (50 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethyl acetate to afford the title compound (11.2 g, 70%) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7](C(C)=C)[C:6]1=[O:17].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CC(C)CC(=O)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[NH:7][C:6]3=[O:17])[CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:24]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: C=C(C)n1c(=O)n(CCCCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: O=C(c1ccc(F)cc1)C1CCN(CCCn2c(=O)[nH]c3ccccc32)CC1
Reaction time: 0.5 h
Yield: 20 %

Procedure:
A mixture of 5 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 4.5 parts of (4-fluorophenyl) (4-piperidinyl) methanone, 10 parts of sodium carbonate, 0.2 parts of potassium iodide and 80 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. After cooling, the reaction mixture is poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is taken up in 2-propanone and 2-propanol, previously saturated with gaseous hydrogen chloride, is added. After boiling for 30 minutes, the mixture is evaporated. A diluted hydrochloric acid solution is added to the residue and the whole is stirred and warmed at 40°-45° C for 1 hour. After the addition of 4-methyl-2-pentanone, the mixture is alkalized with ammonium hydroxide and the layers are separated. The organic phase is dried, filtered and and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 1.5 parts (20%) of 1-{3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 163.9° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH:8]=2)[N:3]=1.[CH3:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>N1C=CC=CC=1>[CH3:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([N:1]([C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)[C:2]2[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N:22]4[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]4)[CH:8]=3)[N:3]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: CN1CCN(c2ccc3nc(N)c(C#N)c(NCc4ccccc4)c3c2)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N(C(=O)c2ccc(OC)cc2)c2nc3ccc(N4CCN(C)CC4)cc3c(NCc3ccccc3)c2C#N)cc1
Temperature: 0 °C

Procedure:
To the solution of 0.6 g of 2-amino-3-cyano-4-benzylamino-6-(4-methylpiperazino)quinoline in 2 mL of pyridine, 0.6 mL of 4-methoxybenzoyl chloride is added under stirring and cooling. The reaction mixture is stirred at 80° C. for 8 hours, and then poured onto 5 mL of ice-water. The precipitated material is filtered off, washed twice with 3 mL of water. After drying 0.63 g of the title compound is obtained, m.p.: 176° C.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][S:15][C:16]([S:18][C@H:19]2[NH:22][C:21](=[O:23])[C@@H:20]2[O:24][CH3:25])=[S:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:28]([C:31]1[CH:45]=[CH:44][C:34]([CH2:35][O:36][C:37](=[O:43])[CH:38](OCC)[OH:39])=[CH:33][CH:32]=1)([O-:30])=[O:29]>C1(C)C=CC=CC=1.CN(C)C=O>[N+:28]([C:31]1[CH:32]=[CH:33][C:34]([CH2:35][O:36][C:37](=[O:43])[CH:38]([N:22]2[C@H:19]([S:18][C:16]([S:15][CH2:14][CH2:13][NH:12][C:10]([O:9][CH2:8][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:27][CH:26]=3)=[O:11])=[S:17])[C@@H:20]([O:24][CH3:25])[C:21]2=[O:23])[OH:39])=[CH:44][CH:45]=1)([O-:30])=[O:29]
Reactant: CO[C@H]1C(=O)N[C@@H]1SC(=S)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CO[C@H]1C(=O)N(C(O)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(=S)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
Analogously to Example 23, 646 mg (1.5 mmole) of (3S,4R)-4-(2-p-nitrobenzyloxycarbonylaminoethylthiothiocarbonylthio)-3-methoxy-2-oxoazetidine in 22 ml of absolute toluene and 5.5 ml of absolute dimethylformamide are reacted with 848 mg of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester in the presence of freshly dried molecular sieves. After working up and chromatography over silica gel the title compound is obtained.