Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:3]([C:5]1[N:6]=[C:7]([CH2:11][N:12]([CH3:14])[CH3:13])[S:8][C:9]=1[CH3:10])O)C.Cl.[NH2:16][CH2:17][CH2:18][SH:19].Br>>[CH3:14][N:12]([CH2:11][C:7]1[S:8][C:9]([CH3:10])=[C:5]([CH2:3][S:19][CH2:18][CH2:17][NH2:16])[N:6]=1)[CH3:13]
Reactant: NCCS
Reactant: CCC(O)c1nc(CN(C)C)sc1C
Agent: Br
Agent: Cl
Product: Cc1sc(CN(C)C)nc1CSCCN

Procedure:
Following the procedure of Example 3, a reaction mixture consisting of 6.4 g. of ethyl 2-dimethylaminomethyl-5-methyl-4-thiazolemethanol, 4.2 g. of cysteamine hydrochloride and 30 ml. of 48% aqueous hydrobromic acid was maintained at a temperature of about 100° C. under a nitrogen atmosphere for about 4 hours. The reaction mixture was cooled and the volatile constituents removed in vacuo. The resulting dark residue was twice trituated with ethanol and the ethanol removed by evaporation to remove residual HBr. The residue was then treated with 50 ml. of 5N aqueous sodium hydroxide. The alkaline layer was continuously extracted with ether over an 18 hour period. The ether extract was dried and the ether removed therefrom in vacuo to provide 2-(2-dimethylaminomethyl-5-methyl-4-thiazolylmethylthio)ethylamine prepared in the above reaction; yield=1.38 g. The compound was a brown oil having the following physical characteristics:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Cl:21]OC(C)(C)C>C(Cl)(Cl)(Cl)Cl>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:21])[CH:15]=2)([CH3:13])[CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OCl
Reactant: CC(C)Oc1ccc(C(C)(C)c2ccc(O)cc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)Oc1ccc(C(C)(C)c2ccc(O)c(Cl)c2)cc1
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To a solution of 4-(1-(4-isopropyloxyphenyl)-1-methylethyl)phenol (0.51 g) in carbon tetrachloriode (1.3 ml), a solution prepared by dissolving 0.23 g of tert-butyl hypochlorite in 0.5 ml of carbon tetrachloride was added dropwise with stirring under ice cooling. After 30 minutes, an ice bath was removed, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into water and extracted three times with 5 ml of carbon tetrachloride. Then, the carbon tetrachloride layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. This crude product was subjected to silica gel column chromatography to give 0.49 g of 4-(1-(4-isopropyloxyphenyl)-1-methylethyl)-2-chlorophenol (yield, 85%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[N:13]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17][NH:16][CH2:15][CH:14]1[C:19]([O:21][CH3:22])=[O:20].C(N(CC)C(C)C)(C)C>CC(C)CC(=O)C>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:16]2[CH2:17][CH2:18][N:13]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH:14]([C:19]([O:21][CH3:22])=[O:20])[CH2:15]2)=[N:3][N:4]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)CC(C)C
Product: COC(=O)C1CN(c2nnc(Cl)c3ccccc23)CCN1C(=O)OC(C)(C)C

Procedure:
1,4-dichlorophthalazine (741 mg, 3.72 mmol), 1-tert-butyl 2-methyl piperazine-1,2-dicarboxylate (1.00 g, 4.09 mmol), N,N-diisopropylethylamine (0.972 mL), and 4-methyl-2-pentanone (6 mL) were heated at 120° for 16 hours. The solvent was removed and the residue purified by chromatography over silica using a gradient of hexanes/0-70% ethyl acetate. The compound was obtained as a white solid. MS (M+H)+=407.1.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10]1)=[O:7])(=O)C.O>C(OCC)C>[OH:4][CH2:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10]1)=[O:7]
Reactant: CC(=O)OCC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Solvent: O
Solvent: CCOCC
Product: O=C(CO)N[C@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Yield: 99.1 %

Procedure:
Using essentially the technique of Example 74, starting from 3-(4-((3S)-3-acetoxyacetylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-one (140 mg, 0.3 mmol) gave the desired product (125 mg) after trituration with water, diethyl ether and drying.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:4](=[O:25])[CH2:5][CH2:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1)[CH3:2].[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([N:3]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:4](=[O:25])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([OH:17])=[O:16])=[CH:23][CH:24]=1)[CH3:2]
Reactant: CCN(CCc1ccccn1)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CCc1ccccn1)C(=O)CCc1ccc(OCc2ccccc2C(=O)O)cc1
Yield: 20.8 %

Procedure:
Methyl 2-[(4-{3-[ethyl(2-pyridin-2-ylethyl)amino]-3-oxopropyl}phenoxy)methyl]-benzoate (0.135 g, 0.30 mmol) was dissolved in a mixture of THF/water (7/1, 5 ml) and lithium hydroxide (29 mg, 1.2 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). The reaction mixture was acidified (HCl, 1 M, 1 ml) and the water phase was washed with two portions of EtOAc (2×5 ml). The organic phases were combined, dried (MgSO4) and the solvent was removed by evaporation. The crude product was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 27 mg of 2-[(4-{3-[ethyl(2-pyridin-2-ylethyl)amino]-3-oxopropyl}phenoxy)methyl]benzoic acid (yield 20.6%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C([O-])=O.[NH4+]>C1COCC1.CO.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CSc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CSc1ccc(N)cc1F
Yield: 71.9 %

Procedure:
10.0 g of 3-fluoro-4-methylsulfanylnitrobenzene prepared in the above example 1, 0.1 eq of Pd/C (5 wt %), 4 eq of amonium formate were dissolved in THF/MeOH (1:1) and refluxed for 3 hours. The solid, which was not dissolved in the solution, was filtered away, and the filtrate was distilled under reduced pressure to obtain oily compound, which was dissolved again in 80 ml of ethyl acetate. Solid amonium formate which was not dissolved in the solution, was filtered away, and the filtrate was distilled under reduced pressure to obtain oily filtrate, which was purified by column chromatography (ethyl acetate:n-Hexane=1:3) to give 6.04 g of the title compound as a yellow solid (yield 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([N+:16]([O-])=O)[CH:4]=1.Cl[Sn]Cl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:5]([NH2:16])[CH:4]=1
Reactant: COc1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: COc1ccc(Sc2ccccc2)c(N)c1
Yield: 96.6 %

Procedure:
The product from Example 9a (2.70 g, 10.2 mmol) was reacted with SnCl2 (9.40 g, 50.0 mmol) for 22 h following the procedure from Example 1f giving the title compound as a white solid (2.28 g, 96%).
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.CS([Cl:37])(=O)=O>C(Cl)Cl>[Cl:37][CH2:2][C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(CO)n2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(CCl)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl 4-(6-hydroxymethylpyridine-2-carbonyl)-piperazine-1-carboxylate (1.26 g) and diisopropylethylamine (1.0 g) were dissolved in 20 mL of methylene chloride, 0.1 mL of methanesulfonyl chloride was added dropwise into the above solution at ice temperature, and the mixture was stirred at room temperature overnight. After the solvent was removed under reduced pressure from the reaction mixture, the residue was purified by chromatography on silica gel (methylene chloride-ethanol=40:1) to give 1.07 g of t-butyl 4-(6-chloromethylpyridine-2-carbonyl)piperazine-1-carboxylate as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH2:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36](O)=[O:37])=[CH:30]2>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH:25][C:36]([C:31]2[NH:32][C:33]3[C:29]([CH:30]=2)=[CH:28][C:27]([Cl:26])=[CH:35][CH:34]=3)=[O:37])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(N)c2ccccc2Cl)CC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Product: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2cc3cc(Cl)ccc3[nH]2)c2ccccc2Cl)CC1

Procedure:
Using coupling method A, 4-[2-amino-2-(2-chlorophenyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.8 mmol) and 5-chloroindole-2-carboxylic acid (158 mg, 1.4 mmol) afforded, after purification (SiO2: 33% EtOAc in hexane), 407 mg (92%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH:25]=[CH2:26])(=[O:24])=[O:23])=[CH:17][CH:16]=3)=[CH:10][C:9]=2[CH3:27])=[O:7])=[CH:4][CH:3]=1.[CH2:30]([N:32](CC)[CH2:33]C)C.Cl.CNC.CN(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH2:25][CH2:26][N:32]([CH3:33])[CH3:30])(=[O:23])=[O:24])=[CH:17][CH:16]=3)=[CH:10][C:9]=2[CH3:27])=[O:7])=[CH:28][CH:29]=1
Reactant: C=CS(=O)(=O)Nc1ccc(Cc2cc(C)c(C(=O)c3ccc(Cl)cc3)n2C)cc1
Reactant: CCN(CC)CC
Agent: CN(C)C
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(Cc2ccc(NS(=O)(=O)CCN(C)C)cc2)n(C)c1C(=O)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 93 %

Procedure:
N-{4-[5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]phenyl}-ethenesulfonamide (250 mg, 0.583 mmol) [prepared as in Example 19], was dissolved in DMF (1.1 ml). Triethylamine (0.11 ml, 0.8 mmol), followed by dimethylamine hydrochloride (36 mg, 0.69 mmol), was added and the reaction mixture was stirred for 1 h. A second batch of trimethylamine and dimethyamine hydrochloride was added and the stirring was continued overnight. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was separated and dried over sodium sulfate. The solvent was removed in vacuo and the crude product was then dissolved in ethyl acetate, after which ethanolic HCl was added to give N-{4-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]phenyl}-2-(dimethyl-amino)ethanesulfonamide (257 mg, 86%) as the hydrochloride salt.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[C:10](=[O:11])[N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[S:7]1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[O:11]=[C:10]1[N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[S:7][CH:6]1[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:32]
Reactant: CCOC(=O)CC1SC2(CCN(C(=O)OC(C)(C)C)CC2)N(CCc2ccccc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC1SC2(CCNCC2)N(CCc2ccccc2)C1=O
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
In 56 ml of methylene chloride was dissolved 18.50 g of tert-butyl 2-(2-ethoxy-2-oxoethyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decane-8-carboxylate. After adding 56 ml of trifluoroacetic acid at 0-5° C., the resulting mixture was stirred at the same temperature as above for 30 minutes and then at ambient temperature for 5 hours. The solvent was distilled off under reduced pressure, the residue was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 8.0 with saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Thus, 7.26 g of ethyl 2-(3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-2-yl)-acetate was obtained as a yellow oily product.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[CH2:14]([S:21][C:22](=[O:35])[CH2:23][C@H:24]([NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH:32]=[CH2:33])[C:25]([OH:27])=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>CS(C)=O>[CH2:14]([S:21][C:22](=[O:35])[CH2:23][C@H:24]([NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH:32]=[CH2:33])[C:25]([O:27][CH2:2][C:3]#[N:4])=[O:26])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=CCCC(=O)N[C@@H](CC(=O)SCc1ccccc1)C(=O)O
Reactant: N#CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(=O)N[C@@H](CC(=O)SCc1ccccc1)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78.7 %

Procedure:
2-Bromoacetonitrile (4.35 ml, 62.4 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.651 ml, 3.74 mmol) were added to a solution of (S)-4-(benzylthio)-4-oxo-2-(pent-4-enamido)butanoic acid (Compound 1f-ID) (1.00 g, 3.12 mmol) in DMSO (4.35 ml), and the mixture was stirred at room temperature for 40 minutes. A saturated aqueous ammonium chloride solution (5 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→40/60) to afford (S)-cyanomethyl 4-(benzylthio)-4-oxo-2-(pent-4-enamido)butanoate (Compound 1g-ID) (885.2 mg, 79%).
Reaction SMILES: C([O:8][C@H:9]([CH2:36][O:37]CC1C=CC=CC=1)[CH2:10][O:11][C:12](=[O:35])[NH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[NH:20][C:21]2=[O:24])=[CH:16][CH:15]=1)C1C=CC=CC=1.C(O)(=O)C>C(O)C.[OH-].[Pd+2].[OH-]>[OH:8][C@H:9]([CH2:36][OH:37])[CH2:10][O:11][C:12](=[O:35])[NH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:32])([F:33])[F:34])[NH:20][C:21]2=[O:24])=[CH:16][CH:15]=1
Reactant: O=C(Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1)OC[C@@H](COCc1ccccc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1)OC[C@H](O)CO
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A mixture consisting of 26 mg (0.043 mmol) of (R)-2,3-bisbenzyloxypropyl[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]carbamate synthesized in Example 132; 5 mg (0.036 mmol) of palladium hydroxide; and 0.2 ml (3.49 mmol) of acetic acid, was suspended in 3 ml of ethanol, and the obtained suspension was then stirred under a hydrogen atmosphere for 2 hours. Thereafter, the reaction solution was filtrated with celite, and was then concentrated. The obtained residue was purified by silica gel chromatography (dichloromethane:methanol=10:1), so as to obtain 18 mg (100%) of (R)-2,3-dihydroxypropyl[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]carbamate in the form of a light yellow oily substance.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])(=[O:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:10]([CH2:11][Br:20])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)cccc1Oc1ccccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CC(=O)Oc1c(CBr)cccc1Oc1ccccc1Cl
Yield: 102.5 %

Procedure:
A mixture of 2-chlorophenyl 2-acetoxy-3-methylphenyl ether (17 g), N-bromosuccinimide (13 g) and 2,2'-azobisisobutyronitrile (1.7 g) in benzene (150 ml) was refluxed under heating for 3 hours. After cooling, the precipitate was filtered off. The filtrate was washed with water, aqueous sodium thiosulfate and water successively, dried over magnesium sulfate and then evaporated to give oily 2-chlorophenyl 2-acetoxy-3-bromomethylphenyl ether (22.4 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:37])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([N:21]5[CH2:25][CH2:24][CH:23]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:22]5)=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:34]([NH2:36])=[O:35])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([CH:48]=O)=[C:43]([CH:47]=1)[C:44]([OH:46])=[O:45].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O1CCCC1.O.CCOC(C)=O>[Si:27]([O:26][CH:23]1[CH2:24][CH2:25][N:21]([C:16]2[CH:15]=[C:14]3[C:19]([C:20]4[C:8]([C:4]5[C:3]([CH3:37])=[C:2]([NH:1][CH2:48][C:42]6[CH:41]=[CH:40][C:39]([Cl:38])=[CH:47][C:43]=6[C:44]([OH:46])=[O:45])[CH:7]=[CH:6][CH:5]=5)=[CH:9][N:10]=[C:11]([C:34](=[O:35])[NH2:36])[C:12]=4[NH:13]3)=[CH:18][CH:17]=2)[CH2:22]1)([C:30]([CH3:32])([CH3:33])[CH3:31])([CH3:28])[CH3:29]
Reactant: O=Cc1ccc(Cl)cc1C(=O)O
Reactant: Cc1c(N)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(N4CCC(O[Si](C)(C)C(C)(C)C)C4)ccc3c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(NCc2ccc(Cl)cc2C(=O)O)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(N4CCC(O[Si](C)(C)C(C)(C)C)C4)ccc3c12
Reaction time: 8 h

Procedure:
To a homogeneous, light orange solution of 4-(3-amino-2-methylphenyl)-7-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-9H-pyrido[3,4-b]indole-1-carboxamide (0.0782 g, 0.152 mmol), 5-chloro-2-formylbenzoic acid (0.070 g, 0.379 mmol), and acetic acid (0.022 mL, 0.379 mmol) in dichloromethane (3.03 mL) and tetrahydrofuran (2.022 mL) under nitrogen was added sodium triacetoxyborohydride (0.096 g, 0.455 mmol), and the mixture was stirred overnight. Water (3 mL) was added, and the reaction was stirred at rt for 10 min. EtOAc (50 mL) and water (20 mL) were added, and the layers were separated. The organic layer was washed with water (6×20 mL) and brine (20 mL), dried over MgSO4, and concentrated in vacuo to give a crude product which was used in the subsequent step.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[N:19]=[CH:18][C:17]([C:20]23[CH2:27][CH2:26][CH2:25][N:24]2[CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=1.[Br:28]C(F)(F)C(Br)(F)F>C1COCC1>[Br:28][C:15]1[CH:16]=[C:17]([C:20]23[CH2:27][CH2:26][CH2:25][N:24]2[CH2:23][CH2:22][CH2:21]3)[CH:18]=[N:19][C:14]=1[F:13]
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: Fc1ccc(C23CCCN2CCC3)cn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Fc1ncc(C23CCCN2CCC3)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.4 %

Procedure:
n-BuLi (2.5M in hexanes, 0.252 mL, 0.63 mmol) was added to di-isopropylamine (0.082 mL, 0.63 mmol) in THF and stirred at room temperature for 10 minutes, then cooled to -78° C. 7a-(6-Fluoro-3-pyridinyl)-hexahydro-1H-pyrrolizine (123 mg, 0.60 mmol, from Example 12d) and 1,2-dibromo-1,1,2,2-tetrafluoroethane (0.215 mL, 1.80 mmol) were added. The mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched with 2N HCl, and the mixture was washed with Et2O. The aqueous layer was basified with 15% NaOH and extracted with methylene chloride. The organic extracts were combined, dried, (MgSO4) and concentrated. The residue was chromatographed (silica gel; CHCl3 /MeOH, 99:1) to afford the title compound as an oil (64 mg, 37%). 1H NMR (CDCl3, 300 MHz) δ1.59-1.71 (m, 2H), 1.79-2.06 (m, 6H), 2.64-2.72 (m, 2H), 3.12-3.19 (m, 2H), 8.14 (dd, J=8.8, 2.2 Hz, 1H), 8.19 (dd, J=2.2, 1.2 Hz, 1H); MS (CI/NH3) m/z: 285/287 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.Cl[CH2:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[C:39]([O:41][CH3:42])=[O:40]>C(#N)C>[CH3:47][O:46][C:45]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][C:36]=1[CH2:35][N:22]1[CH2:23][CH2:24][N:19]([C:17](=[O:18])[C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])=[CH:12][CH:13]=2)[CH2:20][CH2:21]1
Reactant: COC(=O)c1ccc(OC)c(CCl)c1
Reactant: O=C(Nc1ccccc1)Nc1ccc(C(=O)N2CCNCC2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(OC)c(CN2CCN(C(=O)c3ccc(NC(=O)Nc4ccccc4)cc3)CC2)c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
1-Phenyl-3-(4-(piperazin-1-carbonyl)phenyl)urea (439 mg, 1.0 mmol) was stirred in acetonitrile (8 mL) at room temperature for 1 hour, N-Ethyl-N-isopropylpropan-2-amine (697 μl, 4 mmol) was added, followed by a solution of methyl 3-(chloromethyl)4-methoxy-benzoate (215 mg, 1.0 mmol) in acetonitrile (5 mL). The mixture was heated to 45° C. and stirred overnight. The mixture was concentrated under vacuum, diluted with dichloromethane (40 mL) and washed with saturated aqueous ammonium chloride (25 mL) and saturated aqueous sodium chloride (25 mL). The organic phase was dried on magnesium sulfate, filtered and concentrated under vacuum. The residue was submitted to silica chromatography (0-10% methanol in dichloromethane as eluant) to give the title compound (216 mg). MS (ESI) m/z 503.1 [M+H]+