Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([N:12]2[CH2:15][CH2:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.CN(C)C=O.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[N:12]1([C:10]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]3=[CH:8][N:9]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: O=C(NCc1nccnc1Cl)N1CCC1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Clc1nccn2c(N3CCC3)ncc12
Yield: 51.5 %

Procedure:
To a stirred solution of N-((3-chloropyrazin-2-yl)methyl)azetidine-1-carboxamide (41.9 mmol, 9.5 g) in acetonitrile (130 mL) were added N,N-dimethylformamide (7.12 mmol, 0.55 mL), pyridine (419 mmol, 33.8 mL) and finally phosphorous oxychloride (210 mmol, 19.5 mL). After 7 minutes the reaction mixture was quenched by adding it to a cooled (0° C.) mixture of anhydrous 7N ammonia in methanol (150 mL) and acetonitrile (200 mL) and subsequently concentrated in vacuo. The residue was dissolved in dichloromethane, water (150 mL) and saturated aqueous sodium hydrogencarbonate (150 mL) were added and this mixture extracted six times with dichloromethane (100 mL). The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo. Purification by column chromatography (silica gel; dichloromethane/methanol) gave 4.5 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4](=[O:16])[C:5]2[C:14]([CH:15]=1)=[N:13][CH:12]=[C:11]1[C:6]=2[CH:7]=[CH:8][CH:9]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([O:1][C:2]1[NH:3][C:4](=[O:16])[C:5]2[C:14]([CH:15]=1)=[N:13][CH:12]=[C:11]1[C:6]=2[CH:7]=[CH:8][CH:9]=[CH:10]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=c1[nH]c(O)cc2ncc3ccccc3c12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(OCc2ccccc2)cc2ncc3ccccc3c12
Temperature: 60 °C

Procedure:
The hydrobromide salt 4d (100 mg, 0.34 mmol) was dissolved in 3 mL DMF. Potassium carbonate (100 mg) and benzyl bromide (60 μL, 0.50 mmol) were added to the solution and the mixture was heated to 60° C. for 14 h. The solvent was removed in vacuo and the residue was washed with water (5 mL) and boiling MeOH (10 mL) and filtered. The solid 4e (47 mg, 46%) was pure while the filtrate contained a mixture of isomers. Mp=271–276° C. 1H NMR (d6-DMSO) δ 11.68 (bs, 1H), 8.71 (d, 1H), 8.30 (d, 1H), 7.93 (t, 1H), 7.74 (m, 2H), 7.55 (d, 2H), 7.40 (t, 2H), 7.32 (t, 1H), 7.09 (d, 1H), 5.54 (s, 2H). Anal Calcd. for C19H14N2O2 (H2O): C, 71.24; H, 5.03; N, 8.74. Found: C, 71.28; H, 4.83; N, 8.38.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[NH2:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:20][C:19]1[CH:21]=[C:22]([C:24]([F:26])([F:27])[F:25])[CH:23]=[C:17]([O:16][CH3:15])[CH:18]=1)=[O:11]
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1cc(NC(=O)c2cc(C(N)=O)ccc2OC)cc(C(F)(F)F)c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 3-methoxy-5-trifluoromethylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14]1(OB(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: OB(O)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Bromo-3-nitrobenzoic acid (1.0 g, 2.5 mmol) was dissolved in 1,4-dioxane (30 mL), and, thereto were added phenyl boric acid (610 mg, 5.0 mmol), cesium carbonate (6.5 g, 20.0 mmol), 1,1-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (204 mg, 0.10 mmol), and purified water (10 mL). The reaction mixture was stirred under a nitrogen flow at 80° C. overnight. The reaction solution was filtered through celite, alumina, and Florisil, and, thereafter, was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3-nitro-4-phenylbenzoic acid as a crude material.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](/[CH:24]=[CH:25]/[C:26]2[CH:39]=[CH:38][C:29]([C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:31])=[CH:28][CH:27]=2)=[N:16]1.C(OC([N:47]1[CH2:54][CH2:53][CH2:52][C@H:48]1[C:49](O)=[O:50])=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[NH:47]1[CH2:54][CH2:53][CH2:52][C@H:48]1[C:49]([N:35]1[CH2:36][CH2:37][N:32]([C:30](=[O:31])[C:29]2[CH:28]=[CH:27][C:26](/[CH:25]=[CH:24]/[C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:15][N:16]=3)=[CH:39][CH:38]=2)[CH2:33][CH2:34]1)=[O:50]
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CN1CCOCC1
Solvent: CO
Solvent: O
Product: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCN(C(=O)[C@@H]2CCCN2)CC1
Temperature: 60 °C
Yield: 19.6 %

Procedure:
The product obtained using dihydrochloride of Compound 18 (100 mg, 0.25 mmol), N-(tert-butoxycarbonyl)-L-proline (53 mg, 0.25 mmol), 1-hydroxybenzotriazole monohydrate (43 mg, 0.33 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (66 mg, 0.35 mmol) and N-methylmorpholine (0.06 mL, 0.50 mmol) in a similar manner to Example 5, was dissolved in methanol (2.00 mL), and the solution was added with 4 moL/L hydrogen chloride-methanol solution (1.50 mL) followed by heating under reflux at 60° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was added with saturated sodium hydrogencarbonate solution and ethyl acetate, followed by extraction. The crude product was crystallized from acetone to obtain Compound 140 (21 mg, 20%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH:17]2[CH2:20][CH2:19][N:18]2CC=C)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH:17]2[CH2:20][CH2:19][NH:18]2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCN1CCC1[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: CO
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC[C@@H](C2CCN2)C1
Temperature: 25 °C
Reaction time: 64 h
Yield: 89 %

Procedure:
To a solution of (R)-3-(1-allylazetidin-2-yl)piperidine-1-carboxylic acid benzyl ester (163 mg, 0.518 mmol) in DCM (10 mL) was added 1,3-dimethylbarbituric acid (243 mg, 1.56 mmol) and Pd(PPh3)4 (60 mg, 0.052 mmol). The mixture was stirred at RT for 64 h, then diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3/MeOH. Further purification by column chromatography (Si-PCC, gradient 3-15% 2M NH3/MeOH in DCM) afforded the title compound (126.5 mg, 89%) as a colourless oil. LCMS (Method B): RT1.99 & 2.07 min [M+H]+ 275.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.N.C(=O)=O.[Na]>C(O)C.C(O)(C)(C)C>[NH2:1][C:2]1[C:11]2[CH2:10][CH:9]=[CH:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2ccccc12
Agent: N
Agent: O=C=O
Agent: [Na]
Solvent: CCO
Solvent: CC(C)(C)O
Product: Nc1cccc2c1CC=CC2
Reaction time: 8 h
Yield: 97 %

Procedure:
1-Aminonaphthalene (79 g, 0.55 mol), ethanol (300 ml), t-butyl alcohol (50 ml), and NH3 (200-300 ml) were placed in a three-necked, round-bottomed flask equipped with a condenser cooled with dry ice. Sodium (30 g, 1.3 mol) was added in portions over a 4 hour period. Then another 50 ml t-butyl alcohol was added. After an hour, 100 ml absolute ethanol was added slowly. This mixture was stirred overnight and then quenched by careful addition of NH4Cl (50 g) and H2O (400 ml). The aqueous and organic layers were separated. The aqueous layer was extracted twice with ether. The ether extracts were combined with the organic layer, which was then extracted with H2O (2x) and sat. NaCl. The organic layer was dried over Na2SO4 and filtered through MgSO4. Following evaporation of ether and most of the t-butyl alcohol at 65° C., colorless 1-amino-5,8-dihydronaphthalene was obtained by vacuum distillation (mp 37°-39° C.; yield 97%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:13]3[C:14]([C:26]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[CH:32][CH:31]=4)=[C:27]([CH2:28][CH3:29])[C:12]3=[CH:11][CH:10]=1)=[C:15]([C:22]([O:24]C)=[O:23])[C:16]=2[C:18]([O:20]C)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O.Cl>CO>[CH2:1]([O:8][C:9]1[C:17]2[N:13]3[C:14]([C:26]([C:30]4[CH:31]=[CH:32][C:33]([O:36][CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[CH:34][CH:35]=4)=[C:27]([CH2:28][CH3:29])[C:12]3=[CH:11][CH:10]=1)=[C:15]([C:22]([OH:24])=[O:23])[C:16]=2[C:18]([OH:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(C(=O)OC)c(C(=O)OC)c3c(OCc4ccccc4)ccc1n32
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(C(=O)O)c(C(=O)O)c3c(OCc4ccccc4)ccc1n32
Temperature: 25 °C

Procedure:
Dimethyl 7-Benzyloxy-3-(4-benzyloxyphenyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate (1.0 g, 1.7 mmol) was dissolved in 100 ml of methanol. Potassium hydroxide (3.37 g, 60 mmol) and 2 ml of water was added and the mixture was heated to reflux for 4 days. The reaction mixture was allowed to cool to room temperature and acidified with concentrated hydrochloric acid until pH=1. The resulting precipitate was filtered off, and washed with water and ethanol. This gave 0.89 g (96%) of 7-benzyloxy-3-(4-benzyloxyphenyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid as yellow crystals. M.p. 151-161° C. MS(SP): m/z 545 (M+). 1H-NMR (DMSO-d6, 200 MHz) δ: 1.32 (t, 3H); 3.02 (q, 2H); 5.18 (s, 2H); 5.52 (s, 2H); 7.15 (d, 2H); 7.29-7.56 (m, 10H); 7.61-7.71 (m, 3H); 8.18 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[C:4]([CH3:11])[N:3]=1.FC(F)(F)S(O[CH2:18][C:19]([F:22])([F:21])[F:20])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:11][C:4]1[CH:5]=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([O:1][CH2:18][C:19]([F:22])([F:21])[F:20])[N:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(=O)c1cc(C)nc(O)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C)nc(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.8 %

Procedure:
A mixture of 1-(2-hydroxy-6-methylpyridin-4-yl)ethanone (82 mg, 0.542 mmol, Step-2), 2,2,2-trifluoroethyl trifluoromethanesulfonate (86 microL, 0.60 mmol) and cesium carbonate (350 mg, 1.09 mmol) in DMF (5 mL) is stirred at room temperature for 1.5 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (10 mL) and extracted with ethyl acetate (30 mL). The organic layer is washed with saturated aqueous sodium hydrogen carbonate (10 mL×2) and dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (1:1) to give 44 mg (35% yield) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][C:3](=[O:7])[CH2:4][CH2:5][CH3:6].Br[CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([CH:2]([C:3](=[O:7])[CH2:4][CH2:5][CH3:6])[CH2:1][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: BrC1CCCC1
Reactant: CCCC(=O)CCC(=O)OCC
Product: CCCC(=O)C(CC(=O)OCC)C1CCCC1

Procedure:
The preparation was carried out analogously to Example I from 4.04 g (25.0 mmol) of ethyl hexan-3-onecarboxylate and 2.95 ml (4.10 g, 27.3 mmol) of bromocyclopentane. Purification was carried out chromatographically (silica gel, petroleum ether: ethyl acetate 20:1). MS (EI): 226 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:19]1[CH:36]=[C:35]2[C:22]([CH2:23][CH2:24][C:25]3([C:28]42[N:32]=[C:31]([NH2:33])[C:30]([CH3:34])=[N:29]4)[CH2:27][CH2:26]3)=[CH:21][CH:20]=1>>[F:8][C:6]1[CH:5]=[C:4]([C:19]2[CH:36]=[C:35]3[C:22]([CH2:23][CH2:24][C:25]4([C:28]53[N:32]=[C:31]([NH2:33])[C:30]([CH3:34])=[N:29]5)[CH2:26][CH2:27]4)=[CH:21][CH:20]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC1(C)OB(c2cc(F)cc(F)c2)OC1(C)C
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CCC21CC1
Product: CC1=NC2(N=C1N)c1cc(-c3cc(F)cc(F)c3)ccc1CCC21CC1
Yield: 61.5 %

Procedure:
The title compound was prepared following the procedure described for Example 2, starting from (3,5-difluorophenyl)boronic acid pinacol ester (113 mg, 0.47 mmol) and 7′-bromo-5″-methyl-3′,4′-dihydrodispiro[cyclopropane-1,2′-naphthalene-1′,2″-imidazol]-4″-amine (Example 1, 100 mg, 0.31 mmol). Purification by flash silica gel chromatography using a step wise gradient of CHCl3/MeOH (40:1-30:1-20:1) and preparative HPLC gave the title compound (67 mg, 61% yield).
Reaction SMILES: O[N:2]=[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=3)[CH2:21][CH2:20]2)=[CH:11][CH:10]=1)[CH2:4][CH2:5][C:6](O)=[O:7].[H][H]>[Ni].CO>[CH3:31][C:27]1[CH:26]=[C:25]([N:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][CH2:15][C:12]3[CH:11]=[CH:10][C:9]([CH:3]4[NH:2][C:6](=[O:7])[CH2:5][CH2:4]4)=[CH:14][CH:13]=3)[CH2:24][CH2:23]2)[CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cccc(N2CCN(CCCCc3ccc(C(CCC(=O)O)=NO)cc3)CC2)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Cc1cccc(N2CCN(CCCCc3ccc(C4CCC(=O)N4)cc3)CC2)c1
Yield: 71.4 %

Procedure:
To 9.7 g of 4-hydroxyimino-4-[4-(4-(4-(3-methylphenyl)piperazin-1-yl)butyl)phenyl]butyric acid and 5 g of Raney nickel, 300 ml of methanol is added, and stirred for 9 hours in 70 atm hydrogen gas at 120° C. in an autoclave. After the completion of the reaction, the catalyst is removed by filtration, and the solvent is distilled off under reduced pressure. The resulting oily substance is purified by silica gel column chromatography and recrystallized from ethyl acetate to give 6.4 g of 5-[4-(4-(4-(3-methylphenyl)piperazin-1-yl)butyl)phenyl]pyrrolidin-2-one having a melting point of 114° to 116° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[CH:14][CH:15]=[N:16]2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)([Br:22])=O>C(#N)C>[CH2:1]([S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Br:22])=[CH:14][CH:15]=[N:16]2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccnc2cc(SCc3ccccc3)ncc12
Reactant: O=P(Br)(Br)Br
Solvent: CC#N
Product: Brc1ccnc2cc(SCc3ccccc3)ncc12
Temperature: 65 °C
Yield: 73.4 %

Procedure:
To a flask fitted with a reflux condenser was added 7-(benzylthio)-1,6-naphthyridin-4-ol (0.160 g, 0.596 mmol) followed by acetonitrile (2 mL) and phosphorous oxybromide (0.121 mL, 1.193 mmol). The reaction was heated to 65° C. for 1 hour. The reaction was cooled to room temperature and quenched with aqueous sodium bicarbonate (20 mL) and was washed with DCM (20 mL×3). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting material was purified via silica gel MPLC (40 g), eluting with 0% to 100% ethyl acetate in heptanes. The fractions were collected and the solvent was removed under reduced pressure to provide 0.145 g of 7-(benzylthio)-4-bromo-1,6-naphthyridine as a yellow solid. m/z (ESI) 333.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][NH:11][CH:10]1[C:22]#[N:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CC(C)=O>[CH2:32]([N:11]1[CH2:12][C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]1[C:22]#[N:23])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: N#CC1NC[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CC1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)CN1Cc1ccccc1

Procedure:
A mixture of (3R,4R)-3,4-dibenzyloxy-pyrrolidine-2-carbonitrile (13 g, 42.2 mmol), potassium carbonate (8.7 g, 63 mmol), potassium iodide (0.1 g), benzyl bromide (7.5 ml, 63.2 mmol) and acetone (200 ml) were heated at reflux temperature for 4 hours. The mixture was cooled, filtered and the filtrate evaporated to dryness in vacuo to give the title compound as an oil. Purification of the crude product on a silica gel column (Eluent: From 100% heptane to 100% ethyl acetate) afforded (3R,4R)-1-benzyl-3,4-dibenzyloxy-pyrrolidine-2-carbonitrile (8.2 g, yield: 49%) as an oil.
Reaction SMILES: II.Br[CH:4]=[CH:5][CH3:6].[CH3:7][O:8][C:9](=[O:26])[CH2:10][CH:11]1[C:15]2=[CH:16][C:17]3[C:18](Br)=[CH:19][C:20]([O:23][CH3:24])=[CH:21][C:22]=3[N:14]2[CH2:13][CH2:12]1>C1COCC1.[Zn+2].[Br-].[Br-].[Pd].[Cu]I>[CH3:7][O:8][C:9](=[O:26])[CH2:10][CH:11]1[C:15]2=[CH:16][C:17]3[C:18]([C:5]([CH3:6])=[CH2:4])=[CH:19][C:20]([O:23][CH3:24])=[CH:21][C:22]=3[N:14]2[CH2:13][CH2:12]1
Reactant: CC=CBr
Reactant: COC(=O)CC1CCn2c1cc1c(Br)cc(OC)cc12
Agent: [Cu]I
Agent: [Pd]
Agent: II
Solvent: C1CCOC1
Product: C=C(C)c1cc(OC)cc2c1cc1n2CCC1CC(=O)OC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To Mg (143 mg, 5.8 mmol) in THF (4 mL) with trace of I2 was added α-bromopropene (583 μL) in order to maintain a 60° C. exotherm. After 30 minutes, a solution of ZnBr2 (1.31 g, 5.8 mmol) in THF (4 mL) was added. The reaction mixture was heated at 55° C. for 1 hour, cooled to r.t. and (Pd (dppf) CH2Cl2 (50 mg) was added followed by CuI (18.5 mg). After 5 minutes a solution of methyl (8-bromo-6-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (Example 22, Step 5, 200 mg, 0.59 mmol) in THF (7 mL) was added and the mixture was refluxed for 1 hour, cooled, quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to give the title compound (50 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][C@@H:10]([OH:12])[CH2:11][C:5]=2[CH:4]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:12][C@@H:10]2[CH2:9][CH2:8][CH2:7][C:6]3[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH2:11]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: COc1ccc2c(c1)C[C@H](O)CCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C[C@H](OS(=O)(=O)c1ccc(C)cc1)CCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
To a solution of (R)-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol (108.96 g) in pyridine (550 ml) was added portionwise p-toluenesulfonyl chloride (129.66 g) at 10° C.~13° C. The reaction mixture was stirred at ambient temperature for 1 day. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (1600 ml) and water (1080 ml). The organic layer was washed successively with 1N hydrochloric acid solution (1080 ml), aqueous sodium hydrogen carbonate (1080 ml), and brine (500 ml), dried over magnesium sulfate, and evaporated in vacuo to give a colorless powder. The colorless powder was washed with n-hexane (twice) to give (R)-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl 4-methylbenzenesulfonate (182.23 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[CH2:10][CH2:11][OH:12]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[CH2:10][CH2:11][OH:12]
Reactant: OCCc1cc(CO)ccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(Cl)c(CCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Manganese (IV) dioxide (1.00 g) was added to a solution of 2-(2-chloro-5-(hydroxymethyl)phenyl)ethanol [Aromatic Intermediate 1, step b] (0.205 g) in DCM (10 mL), and the resulting suspension was stirred at room temperature overnight. The mixture was then filtered through Celite, washing the filter pad well with DCM. The filtrate and washings were concentrated under reduced pressure to afford the titled compound as a colourless oil. Yield 0.159 g.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][CH:7]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]=2[N:9]([CH3:24])[C:8]1=[O:25])=[O:5])[CH3:3].[Cl:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)Cl>[Cl:26][CH2:27][C:28]([NH:1][C@H:2]([C:4]([NH:6][CH:7]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]=2[N:9]([CH3:24])[C:8]1=[O:25])=[O:5])[CH3:3])=[O:29]
Reactant: C[C@H](N)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: C[C@H](NC(=O)CCl)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
A solution of 3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (20.0 mg, 0.0595 mmol), α-chloroacetyl chloride (5.9 uL, 0.0744 mmol) and piperidinylmethyl polystyrene (59.5 mg, 3.6 mmol/g (Fluka)) in 1 mL of methylene chloride were shaken for 20 min. Aminomethyl polystyrene (58 mg, 3.0 mmol/g (Advanced Chemtech)) was then added and the reaction mixture was shaken for an additional 15 min. and filtered. Removal of the solvent under reduced pressure provided 23.9 mg (98%) of the crude product which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:26])[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[O:13])=[C:3]1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1.[BH4-].[Na+]>C(O)C>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][CH2:27][C:3]2[N:2]([CH3:1])[C:10]3[C:5]([C:4]=2[CH:11]([OH:26])[C:12]([N:14]2[CH2:15][CH2:16][CH:17]([N:20]4[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:18][CH2:19]2)=[O:13])=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:30][CH:31]=1
Reactant: Cn1c(COc2ccc(Cl)cc2)c(C(=O)C(=O)N2CCC(N3CCCCC3)CC2)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cn1c(COc2ccc(Cl)cc2)c(C(O)C(=O)N2CCC(N3CCCCC3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask under a nitrogen atmosphere was charged with 1-methyl-2-(4-chlorophenoxymethyl)-3-[2-[4-(piperidin-1-yl)piperidin-1-yl]-1,2-ethanedionyl]-1H-indole (0.1414 g, 0.282 mmol) and 2.8 ml of denatured ethanol. To this mixture was added sodium borohydride (0.064 g, 1.69 mmol). The reaction mixture was then stirred at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography.