Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(O[C:11]([CH:13]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[C:20](=[O:30])[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][N:25]=4)[N:23]=[C:14]23)=[O:12])=CC=1)([O-])=O.[CH3:31][O:32][C:33]1[C:38]([NH2:39])=[CH:37][CH:36]=[C:35]([O:40][CH3:41])[N:34]=1>C(#N)C.CN(C)C1C=CN=CC=1.O.ClCCl>[CH3:31][O:32][C:33]1[C:38]([NH:39][C:11]([CH:13]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[C:20](=[O:30])[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][N:25]=4)[N:23]=[C:14]23)=[O:12])=[CH:37][CH:36]=[C:35]([O:40][CH3:41])[N:34]=1
Reactant: COc1ccc(N)c(OC)n1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C1CCCCn2c1nc(-c1ccncn1)cc2=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: COc1ccc(NC(=O)C2CCCCn3c2nc(-c2ccncn2)cc3=O)c(OC)n1
Yield: 26 %

Procedure:
To a solution of 0.450 g (1.10 mmol) of (+/−)-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-10-carboxylic acid 4-nitro-phenyl ester in 10 mL of dry acetonitrile in a sealed tube, were added 0.341 g (2.21 mmol) of 2,6-dimethoxy-pyridin-3-ylamine and 0.270 g (2.21 mmol) of dimethyl-pyridin-4-yl-amine. The resulting mixture was stirred under reflux for 16 hours. The mixture was dissolved in water and dichloromethane. The organic phases were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography (dichloromethane/methanol/ammoniac in proportions of 100/0/0 to 98/2/02) to afford 0.121 g (26%) of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:25]=3[O:32][CH2:33][CH3:34])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:43][S:44]([CH2:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)(=[O:46])=[O:45]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:35])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:53]3[CH2:54][CH2:55][N:50]([CH2:49][CH2:48][CH2:47][S:44]([CH3:43])(=[O:45])=[O:46])[CH2:51][CH2:52]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:25]=3[O:32][CH2:33][CH3:34])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Reaction time: 0.5 h

Procedure:
A solution of rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (˜175 mg, 0.26 mmol) in dichloromethane (10 mL) and triethylamine (0.35 g, 3.34 mmol) at 0° C. was treated with 1-(3-methanesulfonylpropyl)piperazine (0.11 g, 0.39 mmol, prepared as described in Fotouhi, N. et a. WO 2005110996) for 0.5 h. The reaction was washed with cold water, dried over anhydrous magnesium sulfate, filtered and evaporated to give a solid. Trituration with ether and filtration gave the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C35H40N5O4SCl2 [(M+H)+] 696.2173, observed 696.2167.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[C:12]#[C:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1>C(O)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[NH:3][N:2]=2)=[CH:7][CH:6]=1
Reactant: O=C(C#Cc1cccs1)c1ccc(Cl)cc1
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: O
Product: Clc1ccc(-c2cc(-c3cccs3)[nH]n2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
Hydrazine hydrate (228 mg, 4.6 mM) and pyridinium p-toluenesulfonate (50 mg) were added to a solution of 1-(4-chlorophenyl)-3-(2-thienyl)-2-propyn-1-one (750 mg, 3.0 mM) in ethanol (30 ml), and this mixture was heated under reflux for 2 hours. After the mixture was allowed to cool to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate (50 ml). This solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain 634 mg of 3-(4-chlorophenyl)-5-(2-thienyl)-1H-pyrazole, m.p. 217° C., in an 80% yield.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH2:7]([S:9][C:10]1[C:11]2[N:12]([CH:19]=[C:20]([C:22]3[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[CH:21]=2)[N:13]=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])[CH3:8]>O.CC(C)=O>[CH2:7]([S:9]([C:10]1[C:11]2[N:12]([CH:19]=[C:20]([C:22]3[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[CH:21]=2)[N:13]=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])=[O:1])[CH3:8]
Reactant: CCSc1c(C(N)=O)cnn2cc(-c3ccc(OC)nc3)cc12
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCS(=O)c1c(C(N)=O)cnn2cc(-c3ccc(OC)nc3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of oxone (3.30 g, 5.37 mmol) in water (Volume: 40 mL) was added dropwise to a yellow suspension of impure 4-(ethylthio)-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (0.787 g, 2.441 mmol) in acetone (Ratio: 1.000, Volume: 40 mL) at rt. The resulting suspension was stirred at rt for 3 h. LCMS and HPLC showed that the starting material was consumed and the desired product was formed. The suspension was filtered, washed with water (2×10 mL), and dried under high vacuum to give a green-yellow solid. 1H NMR and HPLC indicated that the desired product was the major component, but the material was impure. The amount of the material is more than theoretical weight and the material is not totally soluble when making NMR solution, indicating the possible presence of inorganic salt. The material was treated with water (10 mL), stirred for 15 min, filtered, washed with H2O (2×5 mL), and dried under high vacuum to give a green-yellow solid (591.3 mg; 44% yield over 2 steps). 1H NMR, LCMS and HPLC indicated that the material was not pure, but the major component is consistent with the desired product. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.83 (1 H, d, J=1.54 Hz), 8.54 (1H, s), 8.28 (1 H, br. s.), 8.07 (1 H, d, J=1.54 Hz), 8.03 (2H, d, J=8.36 Hz), 7.89 (2 H, d, J=8.36 Hz), 7.80 (1 H, br. s.), 3.31-3.46 (2 7H, m), 1.35 (3 H, t, J=7.48 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([OH:23])=[C:18]([Cl:24])[CH:17]=1)(=[O:14])=[O:13].[H-].[Na+].Cl[C:28]1[S:29][C:30]2[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:31]=2[N:32]=1>CN(C=O)C.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C:28]2[S:29][C:30]3[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:31]=3[N:32]=2)=[C:18]([Cl:24])[CH:17]=1)(=[O:13])=[O:14]
Reactant: O=S(=O)(Nc1cc(Cl)c(O)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2nc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)cc3Cl)sc2c1
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
To a solution of 2-chloro-N-(3,5-dichloro-4-hydroxy-phenyl)-4-trifluoromethyl-benzenesulfonamide (421, 1.52 g, 3.41 mmol) in 10 mL of DMF, was added NaH (Aldrich, 288 mg, 60%, 7.2 mmol). The mixture was stirred for 10 min, then 2-chloro-6-nitrobenzothiazole (411, 765 mg, 3.56 mmol) was added. The reaction mixture was stirred until no 421 remained by TLC. The mixture was diluted with EtOAc and 2N HCl, extracted 3× with EtOAc (100 mL). The organic layers were washed twice with a brine solution (100 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography (15%-20% EtOAc/hexanes) to give 1.5 g (74%) of product. 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 9.08 (d, J=2.4 Hz, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.26 (dd, J=9.0, 2.4 Hz, 1H), 8.22 (s, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.33 (s, 2H). MS (EI): m/z 596 (M−H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:14][C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[C:18]([CH3:29])[CH:17]=1)[C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:6]=2[N:5]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[Cl:13][C:11]1[CH:10]=[CH:9][C:7]2[NH:8][C:4]([C@@H:3]([NH:14][C:15](=[O:30])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[C:18]([CH3:29])[CH:17]=3)[CH2:2][NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[N:5][C:6]=2[CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C(=O)N[C@@H](CN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N[C@@H](CNS(C)(=O)=O)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
90 mg (0.2 mmol) of N-[(1S)-2-amino-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide is placed in 2 mL of dichloromethane, combined with 0.03 g (0.25 mmol) of triethylamine and while being cooled in the ice bath combined with 0.03 g (0.23 mmol) of methanesulfonic acid chloride. Then the mixture is heated to ambient temperature and stirred for 24 hours. Then the solvent is eliminated in vacuo and the residue purified by chromatography on silica gel (gradient: dichloromethane/methanol=100:5). Yield: 27 mg (25%); Rf value: 0.20 (silica gel; dichloromethane/methanol=95:5); C23H26ClN5O4S (504.01); mass spectrum: (M+H)+=504/506 (chlorine isotope).
Reaction SMILES: [CH3:1][C:2]([C:5]([CH3:13])([CH2:10][CH:11]=[O:12])[C:6]([O:8][CH3:9])=O)([CH3:4])[CH3:3].[NH2:14][OH:15].Cl>N1C=CC=CC=1>[CH3:1][C:2]([C:5]([CH3:13])([CH2:10][CH:11]=[O:12])[C:6](=[N:14][OH:15])[O:8][CH3:9])([CH3:4])[CH3:3]
Reactant: NO
Reactant: COC(=O)C(C)(CC=O)C(C)(C)C
Agent: Cl
Solvent: c1ccncc1
Product: COC(=NO)C(C)(CC=O)C(C)(C)C
Temperature: 0 °C
Yield: 103.9 %

Procedure:
A solution of the aldehyde, methyl 2-(I,1-dimethylethyl)-2-methyl-4-oxobutanoate (2.05 g, 11 mmol) and H2NOH·HCl (1.15 g, 16.5 mmol) in dry pyridine (10 mL) was stirred at 60° C. for 4 h in a nitrogen atmosphere. After cooling the reaction mixture was poured into ice cold HCl (3 N, 50 mL), and extracted with ether (3×40 mL). The combined ether extract was washed sequentially with 40 mL portions of saturated NaHCO3, water, and brine, and dried over MgSO4. The solvent was removed in vacuo to give 2.30 g of pale brown colored viscous liquid. Flash chromatography over silica gel (hexanes-EtOAc, 4:1) followed by bulb-to-bulb distillation (pot temp. 100-105° C. (0.4 mmHg)) afforded the anti- and syn- oxime mixture (2.03 g, 92%) in the ratio of 58/42 as a colorless viscous liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]([CH3:16])[CH3:15].[NH2:17][CH2:18][C:19]1[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=1[CH3:25].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH:17][CH2:18][C:19]3[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[O:13])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)c1c[nH]c2c(C(=O)O)cc(Br)cc12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c(C(C)C)c[nH]c23)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
To a stirred suspension of 5-bromo-3-(1-methylethyl)-1H-indole-7-carboxylic acid (400 mg, 1.418 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (300 mg, 1.590 mmol) and HOAt (220 mg, 1.616 mmol) in DMF (15 mL) was added N-methylmorpholine (180 μL, 1.637 mmol) and EDC free base (330 mg, 2.127 mmol). The reaction was stirred for 18 h at RT. LCMS showed that the reaction was complete. The reaction was evaporated to near dryness under vacuum. Water (˜15 mL) was added and the solids which precipitated out were triturated, filtered and dried under vacuum to give 5-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-(1-methylethyl)-1H-indole-7-carboxamide (571 mg, 1.372 mmol, 97% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (br. s., 1H), 11.03 (br. s., 1H), 8.58 (t, J=4.55 Hz, 1H), 7.85 (d, J=1.26 Hz, 1H), 7.82 (s, 1H), 7.12 (d, J=2.02 Hz, 1H), 5.89 (s, 1H), 4.35 (d, J=4.55 Hz, 2H), 3.13 (ddd, J=6.57, 6.69, 13.52 Hz, 1H), 2.20 (s, 3H), 2.13 (s, 3H), 1.27 (d, J=6.82 Hz, 6H). MS (ES) [M+H]+ 415.9, 418.0.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=O.[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.C(O)(=O)C.O>CCO>[N:29]1[CH:30]=[CH:31][C:26]([CH2:25][NH:24][C:3]([C:5]2[N:6]=[CH:7][C:8]3[C:9](=[O:23])[N:10]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:11]=[CH:12][C:13]=3[C:14]=2[OH:15])=[O:2])=[CH:27][CH:28]=1
Reactant: NCc1ccncc1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: O=C(NCc1ccncc1)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 79 °C
Yield: 65.7 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (40 mg, 0.13 mmol) and 4-(aminomethyl)-pyridine (0.050 mL, 0.45 mmol) in 2 mL of EtOH was heated at 79° C. for 4 h. Acetic acid (0.1 mL) and water (3 mL) were added, and the resulting suspension was allowed to come to r.t. The solid was isolated by filtration and dried under high vacuum to afford 33 mg of the title compound as a light yellow solid. MS: (+) m/z 386.40 (M+1).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:5]=[C:4]([CH3:15])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:22][C:23]([CH2:25]Cl)=[CH2:24].CN(C)C=O>O>[Cl:22][C:23](=[CH2:24])[CH2:25][O:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: CCCCCCNc1nc(C)cc(O)n1
Reactant: C=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(Cl)COc1cc(C)nc(NCCCCCC)n1
Temperature: 25 °C

Procedure:
42.0 g 6-Hydroxy-4-methyl-2-n-hexylamino-pyrimidin (0.2 Mol), 27.6 g K2CO3 (0.2 Mol), 24.4 g 2,3-dichloro-1-propene (0.22 Mol) and 150 ml dimethylformamide are charged in a sulphonation flask. The mixture is heated for about 3 hours at a bath temperature of 110°, then cooled to room temperature and thereafter poured in 500 ml water. This mixture is extracted with ether, the ether extract dried with Na2SO4 and concentrated with the aid of a flask rotary vacuum evaporator at a temperature of up to 60°. The impure title compound is obtained as a brown oil, which is purified chromatographically with ether/hexane 1:3 on silicagel to give a yellow oil that slowly crystallises. m.p. 36°-37°.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:18]([CH2:19][O:20][CH3:21])[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[NH:10][C:9]=2[CH2:8][NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.C(OCl)(C)(C)C>C1(C)C=CC=CC=1.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1NCc2[nH]c3cccc(Cc4ccccc4Cl)c3c2C1COC
Agent: CC(C)(C)OCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc2[nH]c3cccc(Cc4ccccc4Cl)c3c2c1COC
Temperature: 25 °C
Yield: 33.6 %

Procedure:
1 g (0.0024 mol) of 1,2,3,4-tetrahydro-5-(2-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester is mixed in a mixture of 20 ml of toluene and 7 ml of dichloromethane at -15° C. with 1.2 ml of triethylamine. Then 0.9 ml (0.0074 mol) of tert.butylhypochlorite, dissolved in 12 ml of dichloromethane, is instilled. The reaction mixture is stirred at room temperature for two more hours. The evaporation residue is chromatographed on silica gel with equal parts of acetone and dichloromethane and yields 0.33 g (33% of theory) of 5-(2-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester, melting point 182°-184° C. (from ethanol).
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12]N1C(=O)CCC1=O.[OH-].[Na+]>O1CCCC1>[Br:12][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:2][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(N2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Brc1ccc(N2CCCC2)cc1
Reaction time: 4 h
Yield: 85.9 %

Procedure:
To a solution of N-phenylpyrrolidine (73.8 g, 0.501 moL) in tetrahydrofuran (500 mL) was added N-bromosuccinimide (124.8 g, 1.4 equivalents) at 20° C. to 30° C., and the mixture was stirred at the same temperature for 4 hr. 1 mol/L Aqueous sodium hydroxide solution (300 mL) was added to the mixture at 27° C., and the mixture was partitioned. The organic layer was dried over anhydrous magnesium sulfate and filtered naturally, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from methanol to give the title compound (97.4 g, brown crystals). yield 86%. melting point 88.1° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[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]2[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:13][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][N:26]4[CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[CH2:11][CH3:12])[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:20]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Yield: 89.1 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propylamine (55 mg, 0.20 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (49 mg, 0.20 mmol) and DIPEA (105 μL, 0.60 mmol) in IPA (0.5 mL) was heated for 24 h at 90° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PPC, gradient 0-5% MeOH in DCM) to afford the title compound as a pale brown oil (84 mg, 89%). LCMS (Method J): RT=3.30 min, [M+H]+=471.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:14][CH:13]2[NH:15][CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH:32]=O)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([CH:8]1[CH2:14][CH:13]2[N:15]([CH2:32][CH2:31][CH2:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:25][CH:26]=3)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CC3CCC(C2)N3)cc1
Reactant: O=CCCc1ccc(OCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: c1ccc(COc2ccc(CCCN3C4CCC3CC(Cc3ccccc3)C4)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.6 %

Procedure:
A mixture of 0.18 g of 3-benzyl-8-aza-bicyclo[3.2.1]octane, 0.30 g of 3-(4-benzyloxy-phenyl)-propionaldehyde, 5 mL of 1,2-dichloroethane and 0.3 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was diluted with 50 mL chloroform and 10 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×25 mL of chloroform and the combined organic layers dried over magnesium sulfate and concentrated under reduced pressure. Purification by chromatography eluting with 80:20 EtOAc:MeOH gave 0.28 g of 3-benzyl-8-[3-(4-benzyloxy-phenyl)-propyl]-8-aza-bicyclo[3.2.1]octane as a 2:1 mixture of exo:endo isomers. Hydrogenation at 1 atm over 0.2 g of 10% Pd/C in 50 mL of ethanol gave 0.17 g of 4-[3-(3-benzyl-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-phenol as a 2:1 mixture of exo:endo isomers: MS (m+1)=336.4; 1H NMR (400 MHz, CDCl3) 7.25-7.1 (complex, 5H), 6.8 (d, 2H), 6.5 (d, 2H), 3.35 (br s, 2H), 2.75 (d, 0.6 H), 2.5-2.3 (complex, 5.4 H), 2.1 (m, 2H), 1.95 (m, 1H), 1.85 (m, 3H), 1.5 (m, 3H), 1.4 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:29][S:30]([CH2:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)(=[O:32])=[O:31]>>[ClH:1].[CH3:29][S:30]([CH2:33][C:34]1[CH:40]=[CH:39][C:37]([NH:38][C:2]2[N:7]=[C:6]([N:8]([CH3:28])[C:9]3[CH:27]=[CH:26][C:12]4[N:13]([CH3:25])[C:14]([NH:16][CH:17]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH3:18])=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:36][CH:35]=1)(=[O:31])=[O:32]
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Reactant: CC(Nc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C)c1ccccc1
Product: CC(Nc1nc2cc(N(C)c3ccnc(Nc4ccc(CS(C)(=O)=O)cc4)n3)ccc2n1C)c1ccccc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example two with N5-(2-Chloro-pyrimidin-4-yl)-1,N5-dimethyl-N2-(1-phenyl-ethyl)-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and 4-[(methylsulfonyl)methyl]aniline (46 mg, 0.25 mmol) as a white solid (66 mg, 46%). 1H NMR (400 MHz, d6-DMSO) δ 9.18 (s, 1H), 7.72-7.77 (M, 3H), 7.42 (d, J=7.6 Hz, 2H), 7.16-7.21 (m, 4H), 7.10 (d, J=8.0 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.79 (dd, J=8.4 and 2.0 Hz, 1H), 5.58 (d, J=5.6 Hz, 1H), 5.12 (m, 1H), 4.31 (s, 2H), 3.58 (s, 3H), 3.38 (s, 3H), 2.82 (s, 3H), 1.50 (d, J=6.8 Hz, 3H). MS (ESI) m/z=542 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][N:7](N)[C:6]=2[CH:15]=1.[C:16]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][N:7]3[C:6]=2[C:15]=1[C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=13
Reactant: O=C1CCCCC1
Reactant: CN1CCc2ccc(Cl)cc2N(N)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCCO
Product: CN1CCc2ccc(Cl)c3c4c(n(c23)CC1)CCCC4
Temperature: 25 °C
Yield: 48 %

Procedure:
To a solution of 9-chloro-4-methyl-3,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-1-ylamine (4.9 g, 22.0 mmole) in 1-propanol (300 mL) was added cyclohexanone (25.0 ml, 240.0 mmole), followed by p-toluenesulfonic acid monohydrate (10.0 g, 50.0 mmole), and the resulting reaction mixture was refluxed for 30 hours. The reaction mixture was cooled to room temperature and solvent removed in vacuo to produce a brown residue. The residue was diluted with methylene chloride (300 mL) and washed with saturated aqueous sodium bicarbonate (200 mL), saturated aqueous sodium chloride (200 mL), dried (sodium sulfate) and concentrated in vacuo. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 1:1) provided 3.05 g of the title compound. 0.335 g of the free amine was treated with one equivalent of fumaric acid in ethanol to form a fumarate salt (0.544 g, mp 212-214° C.). MS (ES) m/z 289 ([M+H]+).