Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][C:17](=[O:41])[C@@H:18]([NH:22][C:23](=[O:40])[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[C:31][C:32]2[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)[C@H:19]([OH:21])[CH3:20].[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(Cl)Cl.CO>C1COCC1>[CH3:15][O:16][C:17](=[O:41])[C@@H:18]([NH:22][C:23](=[O:40])[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[C:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)[C@H:19]([OH:21])[CH3:20]
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1)[C@@H](C)O
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)c1ccc(C#Cc2ccc(CN3CCOCC3)cc2)cc1)[C@@H](C)O
Reaction time: 4 h
Yield: 65.1 %

Procedure:
Sodium triacetoxyborohydride (0.670 g, 3.16 mmol) was added to a solution of benzaldehyde 3 (0.822 g, 215 mmol) and morpholine (260 μL, 2.97 mmol) in THF (15 mL) under N2 atmosphere and the reaction monitored by TLC (25:1 DCM/MeOH, Rf=0.2). After stirring 4 h, the reaction mixture was quenched with saturated NaHCO3 (150 mL), extracted with EtOAc (3×100 mL), dried over MgSO4, filtered and concentrated to give a yellow syrup. Purification by silica gel chromatography (35:1 DCM/MeOH) afforded 0.844 g (86% yield) of 4 as a sticky white foam.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@@H:16]([C:28](=[O:51])[N:29]([C@H:31]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([CH2:40][N:41]([CH3:43])[CH3:42])[CH2:35]1)=[O:33])[CH3:30])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)C)(C)(C)C>ClCCl>[CH2:44]([C@@H:31]([N:29]([CH3:30])[C:28](=[O:51])[C@H:16]([NH:14][CH3:13])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([CH2:40][N:41]([CH3:42])[CH3:43])[CH2:35]1)=[O:33])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CN(C)C[C@@H]1CCCN(C(=O)[C@@H](Cc2ccccc2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N1CCC[C@@H](CN(C)C)C1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 79.7 %

Procedure:
At 0° C., trifluoroacetic acid (20 ml) was added to a solution of N-((1R)-1-{N-[(1R)-1-benzyl-2-((3S)-3-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester (1.18 g, 1.92 mmol) in dichloromethane (20 ml). The reaction mixture was stirred for 50 min at 0° C. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (80 ml) and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (40 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 788 mg of (2R)—N-[(1R)-1-benzyl-2-((3S)-3-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)-propionamide.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13]N=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].Br[C:19]1C=CC(N2CCC(O)CC2)=CC=1>>[C:1]([O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:19]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: OC1CCN(c2ccc(Br)cc2)CC1
Reactant: CC(=O)OC1CCN(c2ccc(Br)cn2)CC1
Product: CC(=O)OC1CCN(c2ccc(Br)cc2)CC1
Yield: 92 %

Procedure:
The title compound was synthesized according to the method described for the synthesis of 1-(5-bromopyridin-2-yl)piperidin-4-yl acetate, except substituting 1-(4-bromophenyl)piperidin-4-ol (606 mg, 2.37 mmol). Crude product was purified by flash chromatography using EtOAc/hexanes as eluent (1:9 to 1:4) to give the title compound as a white solid (648 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=9.0 Hz, 2H), 6.80 (d, J=9.0 Hz, 2H), 4.92-4.89 (m, 1H), 3.47-3.41 (m, 2H), 3.06-3.00 (m, 2H), 2.08 (s, 3H), 2.04-1.99 (m, 2H), 1.84-1.76 (m, 2H); MS ESI 297.9 [M+H]+, calcd for [C13H16BrNO2+H]+ 298.04.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=2)=[C:4]([N+:19]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:19][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[S:8][C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1cccc(Sc2ccc(C)cc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: CC(=O)Nc1cccc(Sc2ccc(C)cc2N)c1

Procedure:
The product from Example 199b was reduced with SnCl2 following the procedure from Example 14 to give the title compound.
Reaction SMILES: C[N:2]([C:4](/[C:6](/[Br:14])=[CH:7]/[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=O)[CH3:3].[CH2:15]([O:17][C:18]([C:20]1[C:21](N)=[N:22][NH:23]C=1)=[O:19])[CH3:16].Br>C(O)C.C(O)(=O)C>[CH2:15]([O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]2[C:7]([CH:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:6]([Br:14])[CH:4]=[N:2][C:3]=12)=[O:19])[CH3:16]
Reactant: CN(C)C(=O)/C(Br)=C/C1CCCCC1
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: Br
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(C3CCCCC3)c(Br)cnc12
Temperature: 25 °C
Yield: 27.1 %

Procedure:
To a mixture of 1.69 g (6.50 mmol) of 2-bromo-1-cyclohexyl-3-dimethylamino-propenone and 1.01 g (6.50 mmol) of 3-amino-1H-pyrazole-4-carboxylic acid ethyl ester in 6 mL of ethanol was added 1.0 mL of 30% hydrogen bromide in acetic acid solution, and the resulting mixture was heated at reflux for 1 h. Then the reaction mixture was cooled to rt and concentrated to give a residue which was chromatographed on silica gel (gradient elution with dichloromethane to 25% ethyl acetate in dichloromethane) to give 620 mg (27% over 2 steps) of 6-bromo-7-cyclohexyl-pyrazolo[1,5-α]pyrimidine-3-carboxylic acid ethyl ester as indicated by 1H NMR (δ 8.70 (s, 1H), 8.49 (s, 1H), 4.44 (q, J=6.8 Hz, 2H), 2.70–2.57 (b, 1H), 1.98–1.90 (m, 2H), 1.87–1.78 (m, 2H), 1.78–1.69 (m, 2H), 1.59–1.42 (m, 4H), 1.43 (t, J=6.8 Hz, 3H)); LC-MS—calcd for C15H18BrN3O2 [M++H]+: 352.06, found: 352.0.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].Br[C:10]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:10]([C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: O=C(Cl)c1cccs1
Product: COc1ccc(C(=O)c2cccs2)c(C(=O)O)c1

Procedure:
This compound is obtained according to the procedure described in 1.1. by reacting thiophene-2-carboxylic acid chloride and 2-bromo-5-methoxybenzoic acid after halogen-lithium exchange. It is used in crude form in the following reaction.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:38]=[CH:37][C:20]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[CH:25]=2)=[O:22])=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15]([C:17]1[CH:38]=[CH:37][C:20]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([C:33]([F:34])([F:35])[F:36])(=[O:31])=[O:32])[CH:25]=2)=[O:22])=[CH:19][CH:18]=1)=[O:16]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc(C(=O)Nc2cccc(S(=O)(=O)C(F)(F)F)c2)cc1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(C(=O)Nc2cccc(S(=O)(=O)C(F)(F)F)c2)cc1
Temperature: 100 °C
Yield: 76 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-(hydrazinocarbonyl)-N-{3-[(trifluoromethyl)sulfonyl]phenyl}benzamide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 80 mg of the title compound (76%) as a yellow solid in 76% purity by HPLC (Rt: 4.96, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[F:15][C:16]([F:27])([F:26])[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:23]([CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][C:16]([F:15])([F:26])[F:27])=[CH:19][CH:20]=1)[CH2:12]2
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 41.3 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester (1.54 g, 4.5 mmol), 4-trifluoromethoxy-benzylamine (0.916 mL, 6.0 mmol), and K2CO3 (1.24 g, 9.0 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-chloro-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.781 g, 41%). GC-MS: m/z 421 (M)+, 336 (M−85)+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([CH:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.IC>C(O)(C)(C)C.O>[CH3:1][C:13]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:17][CH2:16][CH2:15][C:14]1=[O:18]
Reactant: O=C1CCCC1c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CC(C)(C)O
Product: CC1(c2ccccc2)CCCC1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.9 %

Procedure:
2-Methyl-2-phenyl-cyclopentanone was prepared using the technique described by Ireland et al., J Org. Chem., 31, 2543 (1966). Potassium tert-butoxide (6.2 g, 55 mmol) was added to a solution of 2-phenylcyclopentanone (8.4 g, 53 mmol) in 100 mL of tert-butanol and the solution was stirred at room temperature for 45 min. Iodomethane (6 mL, 100 mmol) was added and after 2 hours the mixture was diluted with water and extracted twice with ether. The ether extract was washed with water and brine, dried (sodium sulfate) and evaporated. Purification of the residue by flash chromatography (5% ethyl acetate-hexane) afforded 8.3 g of 2-methyl-2-phenyl-cyclopentanone as an oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][OH:28])=[CH:22][CH:21]=1.C(N(CC)CC)C.C(OCC)(=O)C>O>[CH3:1][S:2]([O:28][CH2:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][C:8]2[N:9]=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:11][C:7]=2[CH3:6])=[CH:25][CH:24]=1)(=[O:4])=[O:3]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
Methanesulfonyl chloride (3.37 g) was added dropwise to a mixture of 2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethan-1-ol (7.0 g), triethylamine (2.97 g), and ethyl acetate (300 ml) at 0° C., and the mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate, 1N hydrochloric acid and then with saturated aqueous sodium chloride solution, then dried (MgSO4), and concentrated. The crystals obtained were collected by filtration to yield 2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl methanesulfonate (8.44 g, yield: 96%). This was recrystallized from ethyl acetate-hexane. Melting point: 66–67° C.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[C:11]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:12]=[CH:13][C:14]=2[O:15][CH2:16][CH3:17])[CH2:3]1.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].Cl>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(O)C.C1(C)C=CC=CC=1>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[C:11]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:30]4[S:29][CH:33]=[CH:32][CH:31]=4)=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:12]=[CH:13][C:14]=2[O:15][CH2:16][CH3:17])[CH2:3]1
Reactant: OB(O)c1cccs1
Reactant: CCOc1ccc(NS(=O)(=O)c2ccc(I)cc2)cc1N1C[C@@H](C)N[C@@H](C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOc1ccc(NS(=O)(=O)c2ccc(-c3cccs3)cc2)cc1N1C[C@@H](C)N[C@@H](C)C1
Temperature: 25 °C

Procedure:
A mixture of N-[3-(cis-3,5-dimethyl-1-piperazinyl)-4-(ethyloxy)phenyl]-4-iodobenzenesulfonamide (E94) (206 mg, 0.4 mmol), 2-thienylboronic acid (103 mg, 0.8 mmol), 2M aqueous sodium carbonate solution (1 ml, 2 mmol) and bis(triphenylphosphine)palladium(II) chloride (14 mg, 0.02 mmol) in 1:1 toluene:ethanol (3 ml) was stirred in a microwave reactor (set at high absorbance) at 125° C. for 15 minutes. After cooling to room temperature the reaction mixture was acidified with 5N hydrochloric acid the mixture applied to an SCX ion exchange cartridge (Varian bond-elute) and washed with methanol and 2M ammonia in methanol. The combined basic fractions were concentrated in vacuo and the residue purified by chromatography on silica gel to afford the desired product (E310). MS (ES+) m/e 472 [M+H]+.
Reaction SMILES: [CH2:1]1[C:5]2=[C:6]3[C:7]([CH2:10][CH2:11]/[C:12]/3=[CH:13]\[CH2:14][NH2:15])=[N:8][CH:9]=[C:4]2[O:3][CH2:2]1.[C:16](Cl)(=[O:18])[CH3:17]>N1C=CC=CC=1.C(=O)([O-])O.[Na+]>[CH2:1]1[C:5]2=[C:6]3[CH:12]([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10][C:7]3=[N:8][CH:9]=[C:4]2[O:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: NC/C=C1\CCc2ncc3c(c21)CCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)NCCC1CCc2ncc3c(c21)CCO3
Reaction time: 0.17 h
Yield: 21.7 %

Procedure:
To a solution of (2E)-2-(1,2,6,7-tetrahydro-8H-cyclopenta[b]furo[3,2-d]pyridin-8-ylidene)ethanamine (186 mg, 0.920 mmol) in pyridine (3.7 mL) was added acetyl chloride (78.5 μL, 1.10 mmol) under ice-cooling, and the mixture was stirred for 10 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0). The residue was dissolved in methanol (1.1 mL), palladium-carbon powder (11 mg) was added, and the mixture was stirred at 50° C. for 3 hr under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=90/10→100/0) to give the title compound (49.1 mg, yield 22%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][CH:3]=1.[CH3:13][O-:14].[Na+]>CO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:14][CH3:13])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Clc1nccc2ccc(Br)cc12
Agent: [Na+]
Solvent: CO
Product: COc1nccc2ccc(Br)cc12
Temperature: 130 °C
Yield: 91 %

Procedure:
7-Bromo-1-chloroisoquinoline (570 mg, 2.4 mmol) was combined with methanol (10 mL) and sodium methoxide (25 wt % in methanol, 1.5 mL, 24 mmol) in a microwave vial. The vial was sealed and heated to 130° C. for 3 hours in a microwave. The reaction was concentrated. The crude residue was taken up in ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The aqueous layer was extracted two times with hot ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated to give the title compound (520 mg, 93%). +ESI (M+H+1) 240.0; 1H NMR (400 MHz, DMSO-d6, δ): 8.25-8.28 (m, 1H), 8.04 (d, J=5.9 Hz, 1H), 7.86-7.89 (m, 2H), 7.40 (dd, J=6.0, 0.9 Hz, 1H), 4.03 (s, 3H).
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[CH2:30])[C:20]([O:22]CC2C=CC=CC=2)=[O:21])=[CH:15][C:14]=1[F:31])C1C=CC=CC=1>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[F:31][C:14]1[CH:15]=[C:16]([CH:19]([CH3:30])[C:20]([OH:22])=[O:21])[CH:17]=[CH:18][C:13]=1[CH2:12][O:11][CH2:10][CH2:9][OH:8]
Reactant: C=C(C(=O)OCc1ccccc1)c1ccc(COCCOCc2ccccc2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C(=O)O)c1ccc(COCCO)c(F)c1
Yield: 35.5 %

Procedure:
A suspension of benzyl 2-(4-((2-(benzyloxy)ethoxy)methyl)-3-fluorophenyl)acrylate (2.2 g, 5.23 mmol), 10% Pd(OH)2 (300 mg) in EtOAc (20 mL) was hydrogenated (balloon pressure) at RT for 2 h until complete consumption of benzyl 2-(4-((2-(benzyloxy)ethoxy)methyl)-3-fluorophenyl)acrylate, as evidenced by TLC analysis. The reaction mixture was filtered through Celite, washed with MeOH (2×15 mL). The combined filtrate was concentrated and the obtained crude compound was purified by dissolving in EtOAc (30 mL) and shaken with aq 10% NaHCO3 solution (12 mL). The EtOAc layer was separated; the aq layer was acidified with aq. citric acid solution (pH˜5) and extracted with EtOAc (2×30 mL). The combined EtOAc layer was washed with water (10 mL), brine (10 mL) dried over anhydrous NaSO4, filtered and concentrated to afford 2-(3-fluoro-4-((2-hydroxyethoxy)methyl)phenyl)propanoic acid (450 mg, 36%) as colorless oil (TLC solvent system: 100% EtOAc; Rf: 0.15).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:17][CH:18]1[O:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:17][CH:18]1[O:20][CH2:19]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cl)cc1Cc1ccccc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Clc1ccc(OCC2CO2)c(Cc2ccccc2)c1

Procedure:
A suspension containing 21.87 g of 2-benzyl-4-chlorophenol, 27.76 g of 1-chloro-2,3-epoxypropane and 27.64 g of potassium carbonate in 200 ml of butanone is refluxed for 12 hours. The inorganic salts formed are filtered off and drained. The solvent and excess 1-chloro-2,3-epoxypropane are evaporated off under vacuum and the residue is distilled at between 160° C. and 180° C. under 0.01 mm of mercury.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:10]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:8])=[O:7].[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CCOC(C)=O>[Br:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:9]2[S:6]([NH:5][CH2:4][CH2:3][NH:2][CH2:39][C:38]1[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=1)(=[O:8])=[O:7]
Reactant: CCOC(=O)c1c(S(=O)(=O)NCCN)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(S(=O)(=O)NCCNCc2ccc(OC)cc2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product from Example 89, Step A was combined with 1.2 equivalents of 4-methoxybenzaldehyde and 1.5 equivalent of sodium triacetoxyborohydride in dichloroethane. The reaction was stirred for 1.5 hours at room temperature, was diluted with EtOAc and washed with sat. NaHCO3 and brine. The solution was dried with Na2SO4 and concentrated in vacuo to give the titled compound. ESI+ MS: 651 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[NH:21][C:20]2=[O:28])[CH2:15][CH2:14]1.Cl.[CH:30](O)=O>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:30][N:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:17][CH2:18]3)[C:3]=2[CH:4]=1
Reactant: O=CO
Reactant: Nc1ccc(Cl)cc1NCCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: Cl
Product: O=c1[nH]c2ccccc2n1C1CCN(CCCn2cnc3ccc(Cl)cc32)CC1
Yield: 27 %

Procedure:
A mixture of 4 parts of 1-[1-{3-[N-(2-amino-5-chlorophenyl)amino]propyl}-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, 6 parts of a concentrated hydrochloric acid solution and 30 parts of formic acid is stirred and refluxed overnight. The reaction mixture is evaporated and water is added to the residue. The whole is alkalized with a diluted ammonium hydroxide solution and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and recrystallized from 2-propanol, yielding 1.1 parts (27%) of 1-{1-[3-(6-chloro-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 214.9° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1.Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C(N(CC)CC)C>C(#N)C.O>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:4]=[C:5]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: FC(F)(F)c1cccc(C(c2cccc(C(F)(F)F)c2)N2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCN(C(c2cccc(C(F)(F)F)c2)c2cccc(C(F)(F)F)c2)CC1
Reaction time: 4 h
Yield: 50 %

Procedure:
To a solution of bis(3-(trifluoromethyl)phenyl)methanol (1.1 g, 3.4 mmol) in CH2Cl2 (10 mL) was added dropwise thionyl chloride (0.50 ml, 6.9 mmol) at rt. The reaction was stirred at 50° C. for 4 h, concentrated under vacuum, azeotroped with toluene, and dried under vacuum to give crude chlorobis(3-(trifluoromethyl)phenyl)methane. The crude chlorobis(3-(trifluoromethyl)-phenyl)methane was added to a solution of piperazine (0.81 ml, 10 mmol) in acetonitrile (10 mL), heated to 100° C. for 18 h and concentrated under vacuum. The residue was dissolved in CH2Cl2 (150 mL) and washed with 1N NaOH (150 mL). The organic layer was dried with K2CO3, filtered, and concentrated to give 1-(bis(3-(trifluoromethyl)-phenyl)methyl)piperazine. The crude 1-(bis(3-(trifluoromethyl)phenyl)-methyl)piperazine was dissolved in acetonitrile (10 mL) and tert-butyl bromoacetate (0.55 mL, 3.4 mmol) and triethylamine (0.96 ml, 6.9 mmol) was added. The solution was stirred for 4 h, diluted with water, and extracted with CH2Cl2. The organic layer was washed with saturated NaCl solution, then dried over Na2SO4, and concentrated. The crude product was purified by ISCO using 0-50% EtOAc in haxanes to give tert-butyl 2-(4-(bis(3-(trifluoromethyl)-phenyl)methyl)piperazin-1-yl)acetate (0.86 g, 50% yield). MS (ESI, pos. ion) m/z: 503.1 (M+1), which was then converted to the title compound by proceeding as described in Example 4 above.