Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[F:21])=S)=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24].C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[N:23][OH:24])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[F:21])=[CH:4][CH:3]=1
Reactant: Fc1cc(C(F)(F)F)ccc1C(=S)Nc1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: ON=C(Nc1ccc(Br)cc1)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A mixture of N1-(4-bromophenyl)-2-fluoro-4-(trifluoromethyl)-1-benzenecarbothioamide (2.50 g, 0.00663 mol), hydroxylamine hydrochloride (0.65 g, 0.00928 mol) and sodium bicarbonate (0.78 g, 0.00928 mol) was heated in absolute ethanol (25 mL) at reflux under nitrogen atmosphere for 14 hours: The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure and the residue partitioned between saturated solution of sodium bicarbonate in water (50 mL) and ethyl acetate (50 mL). The organic phase was washed with brine, dried with magnesium sulfate and concentrated. The residue was suspended in cold n-heptane and the precipitate was collected by filtration and dried to yield N1-(4-bromophenyl)-2-fluoro-4-(trifluoromethyl)-1-benzeneamidoxime (2.35 g, 0.00625 mol) as an off-white solid.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[F:13][C:14](F)([F:17])[CH2:15][OH:16].[OH-].[Li+]>>[F:13][CH:14]([F:17])[CH2:15][O:16][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCC(F)F)nc1
Temperature: 25 °C
Yield: 79 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 79% yield starting from ethyl 6-chloronicotinate and 2,2,2-trifluoroethanol. The reduction was performed using 3 equiv of lithium hydroxide, the reaction mixture was stirred at ambient temperature over night; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (d, 1 H), 8.20 (dd, 1 H), 7.02 (d, 1 H), 6.21-6.57 (m, 1 H), 4.65 (dt, 2 H); MS (ESI) m/z 202[M−H+].
Reaction SMILES: C[O:2][P:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:4][CH3:5].[C:12]([C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[CH2:19]Cl)([CH3:15])([CH3:14])[CH3:13]>>[CH3:5][O:4][P:3]([CH2:19][C:18]1[CH:17]=[C:16]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:23]([OH:24])=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2]
Reactant: COP(OC)c1ccccc1
Reactant: CC(C)(C)c1cc(CCl)cc(C(C)(C)C)c1O
Product: COP(=O)(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)c1ccccc1
Temperature: 110 °C
Yield: 82.9 %

Procedure:
A mixture of 5 grams (29 mmol) of dimethylphenylphosphonite with 7.5 grams (29 mmol) of 3,5-di-tert-butyl-4-hydroxybenzyl chloride (CAS REG # 955-01-1) is heated at 110° C. for 1 hour and cooled to obtain a white solid. The resultant solid is crystallized from 100 mL of hexane to give 9 grams (83% yield) of (3,5-di-tert-butyl-4-hydroxy-benzyl)-phenyl-phosphinic acid methyl ester as a white solid mp 112-114° C.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:25])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C:14](=[O:16])[CH3:15])[CH2:5]1)=[N+:2]=[N-:3].C1C=C[NH+]=CC=1.[Br:32][Br-]Br>C(O)C.C(Cl)(Cl)Cl.ClCCl>[N:1]([C@@H:4]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:25])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C:14](=[O:16])[CH2:15][Br:32])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C[C@]12CC[C@@H](N=[N+]=[N-])C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]12
Temperature: 50 °C

Procedure:
To a solution of 3α-azido-5α-pregnan-20-one (51.5 mg, 0.15 mmol) in absolute ethanol (3 mL) and chloroform (3 mL) was added pyridinium bromide perbromide (143 mg, 0.44 mmol) and the resulting mixture was heated at 50° C. for 45 min. Subsequently the mixture was diluted with dichloromethane and the organic layer was washed with water, brine and dried (Na2SO4). Evaporation of the solvent in vacuo and purification of the residue using flash column chromatography and petroleum ether/ethyl acetate 90/10 as elution solvent afforded the compound named above.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[OH-].[Na+].Cl.Cl[CH:11]([CH3:14])[CH2:12][NH2:13].O>CN(C=O)C>[CH3:1][C:2]1[N:3]([CH2:14][CH2:11][CH2:12][NH2:13])[CH:4]=[CH:5][N:6]=1
Reactant: CC(Cl)CN
Reactant: Cc1ncc[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nccn1CCCN
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
A solution of 2-methylimidazole (0.820 g, 10.0 mmol) in DMF (10 mL) was cooled in an ice/water bath and sodium hydroxide (1.00 g, 25.0 mmol) added. The resulting mixture was stirred for 30 min, then 2-chloropropylamine hydrochloride (1.30 g, 10.0 mmol) added in one portion. The resulting suspension was then stirred for 16 h during which time the reaction slowly warmed to room temperature. After this time the mixture was poured into water (500 mL) and the mixture extracted with ether (3×100 mL). The combined ether extracts were dried over sodium bicarbonate, filtered and concentrated under reduced pressure to afford 0.726 g (52% yield) of 3-(2-methylimidazol-1-yl)propylamine as a yellow oil. 1H NMR (300 MHz, CD3OD) δ 7.00 (d, J=1.4 Hz, 1H), 6.79 (d, J=1.4 Hz, 1H), 3.97 (t, J=7.3 Hz, 2H), 2.63 (t, J=7.1 Hz, 2H), 2.35 (s, 3H), 1.87 (m, 2H).
Reaction SMILES: C([CH2:4][C@H:5]1[C@@H:9]([CH3:10])[O:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:6]1)(O)=O.[OH-:17].[Na+].C[OH:20].C(Cl)(Cl)Cl>CO>[CH3:10][C@H:9]1[O:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:6][C@@H:5]1[C:4]([OH:20])=[O:17]
Reactant: [OH-]
Reactant: CO
Reactant: C[C@H]1OC(c2ccccn2)=N[C@H]1CC(=O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C[C@H]1OC(c2ccccn2)=N[C@@H]1C(=O)O
Reaction time: 1 h
Yield: 39 %

Procedure:
To a solution of (4S, 5R)-4-carboxymethyl-4,5-dihydro-5-methyl-2-(2-pyridinyl)oxazole (0.22 g, 1.00 mmol, obtained as above) in MeOH (2 mL) was added aq NaOH (44.0 mg, 1.10 mmol in 0.20 mL of H2O ). After 1 h at room temperature, the solvent was removed under reduced pressure. The residue was partitioned between EtOAc (5 mL) and 1N HCl (1 mL). The aqueous layer was extracted with further EtOAc (2×10 mL). the combined organic extracts were dried over MgSO4 and concentrated to give a white residue. Flash chromatography (2% to 10% MeOH/CHCl3 +1% AcOH, silica gel) gave 80.0 mg (39%) of the desired compound as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:24][C:19]5(OCC[O:20]5)[CH2:18][CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:25])[CH2:3][CH2:2]1.C1COCC1.Cl.C(=O)([O-])O.[Na+]>O.CO>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:24][CH:19]([OH:20])[CH2:18][CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:25])[CH2:2][CH2:3]1
Reactant: Fc1cc(-c2nc3c(o2)CC2(CC3)OCCO2)ccc1OCC1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: OC1CCc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To 2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-4,7-dihydro-5H-spiro[1,3-benzoxazole-6,2′-[1,3]dioxolane] (3.75 g) in a mixed solvent of THF (25 mL)-methanol (12.5 mL)-water (12.5 mL) was added 6 M hydrochloric acid (10.8 mL), and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. To the organic layer was added sodium tetrahydroborate (411 mg), and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.58 g).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:33][CH2:34][OH:35])[CH2:20][C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18].CCN(CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:33][CH:34]=[O:35])[CH2:20][C:21]([N:23]([CH3:1])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: COc1cccc(CNC(=O)CC(CCO)c2ccc(Cl)c(Cl)c2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CN(C)C(=O)CC(CC=O)c2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 127 %

Procedure:
Oxalyl chloride (3.23 g) in CH2Cl2 (100 mL) was added to a -78° C. solution of DMSO (4.14 g) in CH2Cl2 (20 mL) over 15 mins. This mixture was stirred for 15 minutes whereupon a CH2Cl2 (30 mL) solution of 3,4-Dichloro-beta-(2-hydroxyethyl)-N-[(3-methoxyphenyl)methyl]benzenepropanamide (8.4 g) was added dropwise. The mixture was stirred for 30 minutes and then treated with a solution of Et3N (6.43 g) in CH2Cl2 (30 mL) and stirred for an additional 30 minutes at -78° C., then allowed to warm to ambient temperature. The reaction mixture was washed with water (100 mL), the organic fraction separated, dried over MgSO4, filtered and concentrated under reduced pressure to yield an oil (11 g). Silica gel chromatography eluting with 10% EtOAc/CH2Cl2 gave the title compound (7.75 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[CH:31]([C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[N:23]1([CH2:22][CH2:21][N:20]([CH2:31][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:19][CH2:18][O:17][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][C:9]3[CH:10]=[CH:11][C:6]([C:2]4[O:1][CH:5]=[CH:4][N:3]=4)=[CH:7][CH:8]=3)=[CH:30][CH:29]=2)[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: c1coc(-c2ccc(Cc3ccc(OCCNCCN4CCOCC4)cc3)cc2)n1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(CN(CCOc2ccc(Cc3ccc(-c4ncco4)cc3)cc2)CCN2CCOCC2)cc1
Reaction time: 17 h
Yield: 84 %

Procedure:
A solution of N-[2-[4-[[4-(2-oxazolyl)phenyl]methyl]phenoxy]ethyl]-4-morpholineethanamine (0.25 g, 0.6 mmol) and methyl 4-formylbenzoate (0.11 g, 0.66 mmol) in dichloroethane (5 mL) was stirred as sodium triacetoxyborohydride (0.16 g, 0.74 mmol) was added and stirred for 17 h. The reaction was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried and concentrated. Purification by chromatography on silica gel using a gradient of methanol in dichloromethane gave 0.28 g of methyl 4-[[[2-(4-morpholinyl)ethyl][2-[4-[[4-(2-oxazolyl)phenyl]methyl]phenoxy]ethyl]amino]-methyl]benzoate; 1H NMR (400 MHz, CDCl3) δ 7.97 (m, 4H), 7.68 (s, 1H), 7.42 (d, 2H), 7.27 (d, 2H), 7.21 (s, 1H), 7.08 (d, 2H), 6.78 (d, 2H), 4.03 (t, 2H), 3.96 (s, 2H), 3.92 (s, 3H), 3.79 (s, 2H), 3.66 (m, 4H), 2.92 (t, 2H), 2.73 (t, 2H), 2.47 (m, 2H), 2.42 (m, 4H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([NH:15][C:16]([NH2:18])=[S:17])[CH:12]=[CH:13][CH:14]=2)[CH:4]=1.[ClH:19].[C:20](OCC)(=O)C>CN(C)C=O.O1CCOCC1.IC>[ClH:19].[ClH:19].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([NH:15][C:16](=[NH:18])[S:17][CH3:20])[CH:12]=[CH:13][CH:14]=2)[CH:4]=1
Reactant: CCOC(C)=O
Reactant: COc1ccnc(-c2cccc(NC(N)=S)c2)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CI
Solvent: C1COCCO1
Product: COc1ccnc(-c2cccc(NC(=N)SC)c2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of N-(3-(4-methoxypyridin-2-yl)phenyl)thiourea (122 mg) in N,N-dimethylformamide (2.5 ml) were added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.25 ml) and iodomethane (0.156 ml), and the mixture was stirred at ambient temperature for 5 hours. Ethyl acetate (100 ml) was added to the mixture, and the mixture was cooled. The precipitate was collected by filtration. The precipitate was dissolved in water, and to the solution was added a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and to the solution was added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.5 ml). The precipitate was collected by filtration and dried under reduced pressure to give N-(3-(4-methoxypyridin-2-yl)phenyl)-S-methylisothiourea dihydrochloride (153 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N:15]1C=CC=CC=1.B.Cl.[CH3:23][OH:24]>>[CH3:23][O:24][NH:15][CH2:13][CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: c1ccncc1
Reactant: CO
Reactant: CC(=O)Nc1ccc(CCC=O)cc1
Agent: B
Agent: Cl
Product: CONCCCc1ccc(NC(C)=O)cc1
Temperature: 70 °C

Procedure:
A mixture of 3-(4-acetamidophenyl)propanal (96 mg, 0.50 mmol), methoxy]amine hydrochloride (92 mg, 1.1 mmol), and pyridine (110 μL) in methanol (0.7 mL) is heated in a 70° C. oil bath for 18 hours and then allowed to cool to room temperature. Methanol (1 mL) is added and the mixture is cooled to 0° C. in an ice-water bath. Borane.pyridine complex (0.11 mL, 1.1 mmol) is added, followed by the dropwise addition of 10% aqueous hydrochloric acid. The mixture is allowed to warm to room temperature and then concentrated under reduced pressure. The residue is purified by reverse-phase HPLC to give N-[4-(3-methoxyamino-propyl)-phenyl]-acetamide.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[N:8]([CH3:20])[C:9]([CH2:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)=[N:10][C:6]=2[CH:5]=1)([O-])=O.[N+](C1C=CC2N=C(CC3C=CC(C#N)=CC=3)N(C)C=2C=1)([O-])=O.C(Cl)Cl>CO.[Pd]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]2[N:8]([CH3:20])[C:9]([CH2:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)=[N:10][C:6]=2[CH:5]=1
Reactant: Cn1c(Cc2ccc(C#N)cc2)nc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: Cn1c(Cc2ccc(C#N)cc2)nc2ccc([N+](=O)[O-])cc21
Solvent: CO
Solvent: ClCCl
Product: Cn1c(Cc2ccc(C#N)cc2)nc2cc(N)ccc21
Reaction time: 1 h

Procedure:
1.1 g (37.6 mmol) of 4-[(5-nitro-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile and 4-[(6-nitro-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzonitrile are dissolved in 30 ml methanol and 40 ml methylene chloride and after the addition of 0.2 g palladium on activated charcoal (10%) hydrogenated for 60 minutes at ambient temperature. Then the catalyst is filtered off and the filtrate is concentrated by evaporation. The residue is chromatographed on silica gel and eluted with methylene chloride/methanol (30:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[I:10](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.C([O-])([O-])=O.[Ca+2]>C(Cl)Cl.CO.CCOCC>[Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][C:6]([I:10])=[C:4]([CH:3]=1)[NH2:5]
Reactant: O=I(=O)Cl
Reactant: Cc1ccc(N)cc1Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(I)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
3-Chloro-4-methylaniline (1.50 g, 10.6 mmol) and benzyltrimethylammonium dichloroiodate (4.60 g, 13.2 mmol) were dissolved in CH2Cl2 (50 mL) and MeOH (20 mL), then CaCO3 (3.10 g, 31.0 mmol) was added and the reaction stirred at room temperature overnight. The reaction was diluted with Et2O (200 mL), filtered through Celite®, and concentrated. The crude material was purified by column chromatography using 97.5/2.5 hexane/EtOAc, giving the product (1.80 g, 63%) as light tan solids. MS (DCI) m/e 268 and 270 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 7.48 (s, 1H), 6.76 (s, 1H), 4.00 (v br s, 2H), 2.22 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20](O)=[O:21])[CH:16]=1)[CH3:13])(=[O:11])=[O:10].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:35]1[CH2:39][CH2:38][N:37]=[C:36]1[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][NH2:47])=[CH:42][CH:41]=1.Cl.CCN(C(C)C)C(C)C>ClCCCl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20]([NH:47][CH2:46][C:43]2[CH:42]=[CH:41][C:40]([C:36]3[NH:37][CH2:38][CH2:39][N:35]=3)=[CH:45][CH:44]=2)=[O:21])[CH:16]=1)[CH3:13])(=[O:11])=[O:10]
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1c(Cl)cccc1Cl
Reactant: NCc1ccc(C2=NCCN2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cc(C(=O)NCc2ccc(C3=NCCN3)cc2)co1)S(=O)(=O)c1c(Cl)cccc1Cl

Procedure:
5-({[(2,6-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (51 mg, 0.14 mmol) was dissolved in DCE (0.5 mL) and CDI (34 mg, 0.21 mmol) was added. The mixture was stirred until acid activation was complete. 1-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methanamine.HCl (180 mg, 0.42 mmol) and DIPEA (0.22 mL, 1.26 mmol) were sonicated in DMF (3 mL) for 15 min, 0.25 mL of activated acid solution was added to 0.5 mL of amine solution and the reaction was diluted with DMF (1.5 mL) and stirred at ambient temperature for 18 h. The reaction was concentrated, dissolved in DCM and washed with water (3×1.5 mL) and saturated brine (1 mL)). The organic layer was dried over MgSO4, shaken with Ambersep and PL-MIA resins, and solvents were removed in vacuo. A portion of the crude product was purified using prep method C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][CH3:11].[NH2:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=2[N:17]=1.[C:27](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:27][N:1]1[C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N:10]=[C:11]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][C:23]([F:26])([F:24])[F:25])[CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CNc1cc(C#N)ccc1N
Solvent: ClCCCl
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C#N)ccc21
Yield: 78 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonitrile (2.27 g) was prepared by following General Procedure D starting from 4-amino-3-methylamino-benzonitrile (1.1 g), 2-amino-6-(trifluoromethoxy)benzothiazole (1.75 g), 1,1′-thiocarbonyldiimidazole (1.78 g), and EDC (1.9 g). This product was triturated with DCM-methanol (9:1) before being used in the next step.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH2:8][CH2:7]1)=[O:5].[N:31]1([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][C@H:32]1[C:41](O)=[O:42].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>>[CH3:21][N:20]([CH3:22])[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([C:4](=[O:5])[C@H:3]([NH:2][C:41]([C@@H:32]2[CH2:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:40][N:31]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:42])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:11][CH2:10]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: CN(C)C(=O)c1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl 3-[N-((1R)-2-{4-[2-(N,N-dimethylcarbamoyl)-phenyl]piperazinyl}-1-[(4-chlorophenyl)methyl]-2-oxoethyl)carbamoyl](3S)-1,2,3,4-tetrahydro-isoquinoline-2-carboxylate was prepared according to the procedure described in Preparation V by using (2-{4-[(2R)-2-amino-3-(4-chlorophenyl)-propanoyl]-piperazinyl}phenyl)-N,N-dimethylcarboxamide HCl salt (Step 5) (230 mg, 0.50 mmol), Boc-L-Tic-OH (Bachem Company) (150 mg, 0.55 mmol), HOAT (Aldrich) (68 mg, 0. 50 mmol), EDC (Aldrich) (190 mg, 1.00 mmol) and DIEA (Aldrich) (87 μL, 0.50 mmol). The compound was isolated and purified by column chromatography (CH2Cl2: 1.5% 2 M NH3 in MeOH). (255 mg). MS (ESI, pos. ion) m/z: 674 (M+H). Calc'd for C37H44ClN5O5: 674.23.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[C:16]([NH:19][C:20]1[S:21][CH:22]=[C:23]([CH:25]=O)[N:24]=1)(=[O:18])[CH3:17].C(N(CC)CC)C.[BH4-].[Na+]>CO>[C:16]([NH:19][C:20]1[S:21][CH:22]=[C:23]([CH2:25][NH:2][CH2:3][CH:4]([OH:15])[C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=2)[N:24]=1)(=[O:18])[CH3:17]
Reactant: COc1ccc(C(O)CN)cc1OC
Reactant: CC(=O)Nc1nc(C=O)cs1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(C(O)CNCc2csc(NC(C)=O)n2)cc1OC
Yield: 82 %

Procedure:
α-(aminomethyl)-3,4-dimethoxybenzyl alcohol hydrochloride (2.88 g) and 2-acetamido-4-formyl-thiazole (2.1 g) were suspended in 14 ml methanol, and 1.8 ml triethylamine was added dropwise to this suspension with stirring. The resulting solution was heated under reflux for 30 minutes, and 0.70 g sodium borohydride was added in small portions with stirring under ice cooling. The crystals which separated out were collected by filtration, washed with water and methanol in that order and vacuum-dried, giving 3.55 g of α-[[[(2-acetamido-4-thiazolyl)methyl]amino]methyl]-3,4-dimethoxybenzyl alcohol (m.p. 204°-206° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](F)(F)F)=[CH:4][CH:3]=1.[Al+3].[Cl-:13].[Cl-:14].[Cl-].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)([Cl:14])[Cl:13])=[CH:6][CH:7]=1
Reactant: Fc1ccccc1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: [Cl-]
Agent: [Al+3]
Product: Fc1ccc(C(Cl)(Cl)c2ccc(Cl)cc2)cc1

Procedure:
From 4-chlorobenzotrifluoride (180 mg, 1 mmol), AlCl3 (400 mg, 3 mmol) and fluorobenzene (96 mg, 1 mmol), light yellow oil (382 mg, 131% crude).
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][C:5]2[N:6]([CH2:10][CH3:11])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.Cl[CH2:16][CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20]>C1(OC)C=CC=CC=1>[Cl-:1].[Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][C:5]2[N+:6]([CH2:10][CH3:11])=[C:7]([CH3:9])[N:8]([CH2:16][CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:4]=2[CH:3]=1
Reactant: CCn1c(C)nc2cc(Cl)c(Cl)cc21
Reactant: CS(=O)(=O)NCCCl
Solvent: COc1ccccc1
Product: CC[n+]1c(C)n(CCNS(C)(=O)=O)c2cc(Cl)c(Cl)cc21
Product: [Cl-]
Temperature: 150 °C
Reaction time: 2 h

Procedure:
22.9 g (0.1 mol) of 5,6-dichloro-1-ethyl-2-methylbenzoimidazole and 23.6 g (0.15 mol) of N-(2-chloroethyl)methanesulfonamide were put into a 200-ml three-necked flask equipped with a stirrer and heated with stirring for 2 hours on an oil bath which had been heated to a temperature of 150° C. Then, 20 ml of anisole was added to the mixture. The mixture was then allowed to cool to room temperature with stirring. The resulting crystals were filtered off, washed with acetone and isopropanol, and dried.