Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([NH2:18])[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([CH2:25][CH2:26][C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([CH2:25][CH2:26][C:27]([NH:29][CH2:30][C:31](=[O:32])[NH:18][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][CH:9]=2)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(c1ccccc1)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)CNC(=O)CCc1ccccc1
Product: O=C(CCc1ccccc1)NCC(=O)NC(c1ccccc1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared in analogy to example 1.1 from rac-C-phenyl-C-(4-trifluoromethyl-phenyl)-methylamine (CA [154238-38-2]) and (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-])=O)=[CH:16][C:15]=3[CH3:24])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]>CO.C(O)C.[Pd]>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:15]([CH3:24])=[CH:16][C:17]([NH2:21])=[CH:18][C:19]=3[CH3:20])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Cc1cc(N)cc(C)c1Oc1ccc2[nH]cc(C(C)C)c2c1

Procedure:
11.95 g (36.85 mmol) of nitro compound from Example XIV are hydrogenated in 500 ml of methanol/ethanol mixture using 550 mg of palladium/active carbon (10%) at 3 bar. The mixture is filtered through kieselguhr, the solvent is removed in vacuo and the product is purified by chromatography (toluene/ethyl acetate).
Reaction SMILES: O([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][N:23]4[CH2:28][CH:27]5[CH:25]([CH:26]5[CH2:29][OH:30])[CH2:24]4)=[CH:20][CH:19]=3)[CH:16]=2)[N:11]=[CH:10][N:9]=1)C1C=CC=CC=1.[CH:33]1([CH2:36][N:37]2[C:45]3[C:40](=[CH:41][C:42]([NH2:46])=[CH:43][CH:44]=3)[CH:39]=[CH:38]2)[CH2:35][CH2:34]1.Cl.[NH+]1C=CC=CC=1.C1(O)C=CC=CC=1>C(Cl)(Cl)Cl>[CH:33]1([CH2:36][N:37]2[C:45]3[C:40](=[CH:41][C:42]([NH:46][C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[C:15]([C:18]6[CH:19]=[CH:20][C:21]([CH2:22][N:23]7[CH2:28][CH:27]8[CH:25]([CH:26]8[CH2:29][OH:30])[CH2:24]7)=[CH:31][CH:32]=6)[CH:16]=5)[N:11]=[CH:10][N:9]=4)=[CH:43][CH:44]=3)[CH:39]=[CH:38]2)[CH2:34][CH2:35]1
Reactant: OCC1C2CN(Cc3ccc(-c4ccc5ncnc(Oc6ccccc6)c5c4)cc3)CC12
Reactant: Nc1ccc2c(ccn2CC2CC2)c1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: Oc1ccccc1
Solvent: ClC(Cl)Cl
Product: OCC1C2CN(Cc3ccc(-c4ccc5ncnc(Nc6ccc7c(ccn7CC7CC7)c6)c5c4)cc3)CC12
Temperature: 110 °C
Yield: 66.3 %

Procedure:
To a 3 mL Wheaton vial was, added {3-[4-(4-phenoxy-quinazolin-6-yl)-benzyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol 16 (100 mg, 0.24 mmol), 1-cyclopropylmethyl-1H-indol-5-ylamine 19 (48 mg, 0.26 mmol), pyridinium hydrochloride (33 mg, 0.284 mmol), and phenol (155 mg, 1.652 mmol). The vial was capped and heated overnight at 110° C. The vial was cooled to room temperature and the residue taken up in CHCl3 and washed with 15% aqueous NaOH, water, brine, and dried (MgSO4). The solvent was removed and the residue purified by flash chromatography (silica gel, EtOAc:MeOH, 95:5) to provide compound 18 (88 mg, 0.159 mmol) as a light brown solid in 67% yield. For compound 18: MS (Cl) m/e 515 (M++1, 100); HPLC, rt=4.83 min.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7](O)=[O:8])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:15])=O>CN(C=O)C.C1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7]([Cl:15])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)OCC(C)(C)C(=O)O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)OCC(C)(C)C(=O)Cl

Procedure:
A benzene solution (25 ml) of crude 3-acetoxy-2,2-dimethyl propionic acid from Example 3(a) (7.4 g, 46.5 mmol), oxalyl chloride (6.45 g, 51 ml) and DMF (2 drops) was stirred at ambient temperature for 3 hours. The pale yellow solution was distilled to provide the title compound as a colorless liquid, b.p.15 85°-88° C. NMR (CDCl3) δ4.18 (2H, s), 2.08 (3H, s), 1.35 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].C(OC1C=C(C2ON=C(C3C=CC=C4C=3C=CN4)N=2)C=CC=1OCCC)CC>>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH2:18][CH2:19][NH:20]4)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1Cl
Agent: CCCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1OCCC
Product: CCOc1ccc(-c2nc(-c3cccc4c3CCN4)no2)cc1Cl
Yield: 100 %

Procedure:
When the product of Step B was substituted for 5-(3,4-dipropoxyphenyl)-3-(1H-indol-4-yl)-1,2,4-oxadiazole in Example 43 Step D, the similar process afforded the title compound in 100% yield, as a creamy solid. 1H-NMR (CDCl3) 1.52 (tr, 3H, J=6.95 Hz); 3.69 (tr, 2H, J=7.53 Hz); 3.92 (tr, 2H, J=7.43 Hz); 4.18 (q, 2H, J=6.98 Hz); 7.03 (d, 1H, J=8.67 Hz); 7.39-7.45 (m, 2H), 7.94-8.10 (m, 2H), 8.21 (d, 1H, J=2.07 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[N+:24]([O-])=O)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.[Cl-].[NH4+].C(O)C.O1CCCC1>O>[NH2:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[CH:11]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: O=C(Nc1cn2cc(Oc3ccc([N+](=O)[O-])c(Cl)c3)ccc2n1)C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1Cl
Yield: 60.2 %

Procedure:
Using N-[6-(3-chloro-4-nitrophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (300 mg, 0.805 mmol), reduced iron (237 mg, 4.02 mmol), ammonium chloride (430 mg, 8.05 mmol), ethanol (2 mL), tetrahydrofuran (2 mL) and water (0.5 mL), and in the same manner as in Reference Example 105, the title compound (166 mg, 60%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([C:15](=[O:28])[CH2:16][CH2:17][C:18]2[S:19][C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[C:22]=2[CH3:23])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].O.O.[OH-].[Li+].Cl>C(O)C>[CH3:1][C:2]1[CH:14]=[C:13]([C:15](=[O:28])[CH2:16][CH2:17][C:18]2[S:19][C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[C:22]=2[CH3:23])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(C(=O)CCc2sc3ccccc3c2C)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=O)CCc2sc3ccccc3c2C)ccc1OCC(=O)O
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of ethyl 2-methyl-4-[3-(3-methylbenzothiophen-2-yl)propionyl]phenoxyacetate in ethanol (2 mL)/water (1 mL) was added lithium hydroxide monohydrate (70 mg, 1.7 mmol). The mixture was heated under reflux for 1 hour, cooled at room temperature. After addition of ice, the resultant mixture was acidified with 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from ethyl acetate/hexane to give the titled compound as a pale yellow crystal (120 mg, 59%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(OCl)(C)(C)C.[CH3:23][S:24][CH2:25][C:26]([NH2:28])=[O:27].C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:12][C:13]([Cl:16])=[CH:14][C:15]=1[CH:25]([S:24][CH3:23])[C:26]([NH2:28])=[O:27]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CSCC(N)=O
Agent: CC(C)(C)OCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC(C(N)=O)c1cc(Cl)cc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cold (-70° C.) solution of 12.77 g (0.055 mole) of 2-amino-5-chlorobenzophenone in 300 mL of methylene chloride, under nitrogen atmosphere, was added 6.0 g (0.552 mole) of t-butylhypochlorite in 20 mL of methylene chloride. After the reaction was stirred for an additional 15 min, a suspension of 5.8 g (0.055 mole) of α-(methylthio)acetamide in 150 mL of methylene chloride was added. The mixture was stirred at -65° C. for 1 h. Triethylamine (5.6 g, 0.055 mole) was added and the solution was allowed to warm to room temperature. The reaction mixture was extracted with water and the organic layer dried over magnesium sulfate. The volume of the solution was reduced in vacuo to about 200 mL and the product crystallized as a yellow solid, m.p. 173.5°-174.5° C. Yield was 6.86 g (37.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:22](OCC)=[O:23])[N:11]([CH3:21])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:4][CH:3]=1.[NH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([NH:27][C:22]([C:10]2[N:11]([CH3:21])[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=2)=[O:23])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1C
Reactant: NN1CCCCC1
Product: Cn1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl
Temperature: 90 °C

Procedure:
A mixture of ethyl 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-methylimidazole-2-carboxylate (50 mg, 0.125 mmol) from Step D in neat 1-aminopiperidine (1 mL) was heated at 90° C. for 72 hr. Most of the amine was evaporated under a stream of nitrogen and the residue was purified by Prep TLC (2×1 mm, silica) (40% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([CH:11]([C:13]3[N:14]=[C:15]([C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=[CH:22][CH:21]=4)[N:16]([CH2:18][CH3:19])[CH:17]=3)[OH:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:32]I>CN(C=O)C.CCOC(C)=O>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([CH:11]([C:13]3[N:14]=[C:15]([C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=[CH:22][CH:21]=4)[N:16]([CH2:18][CH3:19])[CH:17]=3)[O:12][CH3:32])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCn1cc(C(O)C2CCN(C3CCC3)CC2)nc1-c1cccc2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1cc(C(OC)C2CCN(C3CCC3)CC2)nc1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1-cyclobutyl-piperidin-4-yl)-(1-ethyl-2-naphthalen-1-yl-1H-imidazol-4-yl)-methanol (20 mg) in DMF (2 ml) is added NaH (6 mg, 60%), followed by CH3I (15 mg). The resulting mixture is stirred at rt for 30 min, and then diluted with EtOAc, washed with water and brine, dried and solvent removed. The crude product is purified by column (2% Et3N, 3% MeOH in EtOAc) to afford the title compound as an oil. LCMS 404.1 (M+1). 1H NMR (CDCl3) δ ppm 1.25 (t, 3H), 1.40-2.05 (m, 11H), 2.60 (m, 1H), 2.90 (m, 2H), 3.36 (s, 3H), 3.75 (q, 214), 4.05 (d, 1H), 7.02 (s, 1H), 7.42-7.60 (m, 5H), 7.86-7.96 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].CS(C)=O.ClCCl.[F:14][C:15]1[C:20]2[CH:21]=C(O)O[C:19]=2[C:18]([F:25])=[CH:17][CH:16]=1>O.C(N(CC)CC)C>[F:14][C:15]1[C:20]2[CH:21]=[C:2]([CH:1]=[O:5])[O:3][C:19]=2[C:18]([F:25])=[CH:17][CH:16]=1
Reactant: Oc1cc2c(F)ccc(F)c2o1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=Cc1cc2c(F)ccc(F)c2o1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
At a temperature of −78° C., 0.26 ml of oxalyl chloride was added to a mixture of 0.42 ml of dimethyl sulfoxide with 7 ml of dichloromethane, and the resulting solution was stirred at the same temperature for 3 minutes. At the same temperature, 272 mg of 4,7-difluoro-2-hydroxybenzofuran was added to the resulting mixture, and the resulting mixture was stirred for 40 minutes. After the addition of 1.2 ml of triethylamine to the reaction mixture, the temperature of the resulting mixture was raised to room temperature. The resulting mixture was further stirred at room temperature for 30 minutes, followed by the addition of water. The resulting mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The resulting residue was subjected to silica gel chromatography (developer: 5% ethyl acetate/n-hexane) to give 169 mg of the title compound as a colorless solid.
Reaction SMILES: [Si]([SiH2][O:19][CH2:20][CH2:21][CH:22]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)[CH2:23][C:24]#[N:25])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:19][CH2:20][CH2:21][CH:22]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=1)[CH2:23][C:24]#[N:25]
Reactant: CC(C)(C)[Si]([SiH2]OCCC(CC#N)c1ccc(C(F)(F)F)cc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#CCC(CCO)c1ccc(C(F)(F)F)cc1
Reaction time: 2 h
Yield: 107.3 %

Procedure:
5-(tert-Butyldiphenylsilanylsilanyloxy)-3-(4-trifluoromethylphenyl)pentanenitrile (600 mg) was dissolved in tetrahydrofuran (6 mL), and tetrabutylammonium fluoride (1.5 mL) was added at room temperature. After two hours, the mixture was partitioned with water and ethyl acetate. The organic layer was washed with brine and then dried over magnesium sulfate. Concentration under reduced pressure gave an oil. The oil was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=70%) to obtain the title compound (306 mg).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[CH:6][CH:5]=1.[Cl-].[NH4+].C(Cl)Cl>C(O)C.O.[Fe]>[F:1][C:2]([F:20])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccccc1Oc1ccc(OC(F)(F)F)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccccc1Oc1ccc(OC(F)(F)F)cc1

Procedure:
1-Trifluoromethoxy-4-(2-nitro-phenoxy)-benzene (HVB01037, 2.1 g, 7.02 mmol) was added to a solution of iron powder (2.15 g, 38.61 mmol) and ammonium chloride (0.27 g, 4.9 mmol) in ethanol (40 ml) and water (4 ml) at reflux. Stirred at reflux for 3 h. Ethanol removed in-vacuo and the residue was extracted with sodium hydrogen carbonate. Organic layers dried over anhydrous magnesium sulphate and evaporated to dryness, to afford a brown oil, 1.57 g, 95%. Rf: 0.6 (DCM) 1HNMR (CDCl3, 270 MHz) δ 3.81 (2H, s, NH2), 6.76 (1H, m, Ar HB), 6.84 (1H, dd, J=1.2, 7.9 Hz, Ar HA), 6.91 (1H, dd, J=1.0, 7.9 Hz, Ar HD), 6.98 (2H, d, J=9.1 Hz, Ar HF), 7.04 (1H, m, Ar HC), 7.18 (2H, d, J=8.7 Hz, Ar HE).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[S:11][C:12]([S:34][CH3:35])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30](=[O:32])[NH2:31])=[CH:26][C:25]=3[CH3:33])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])(C)(C)C.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[C:8]([C:10]1[S:11][C:12]([S:34][CH3:35])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([NH2:31])=[O:32])=[CH:26][C:25]=3[CH3:33])[CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH:14]=1)(=[NH:7])[NH2:9]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ccc(C(N)=O)cc2C)c1
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2ccc(C(N)=O)cc2C)c1
Yield: 59 %

Procedure:
Following the same procedure as in Example 220, step a, reaction of 4-bromo-3-methyl-benzamide (200 mg, 0.93 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.41 mL, 2.8 mmol, Aldrich Chemical Company), PdCl2(PPh3)2 (65 mg, 0.093 mmol, Strem Chemicals Inc, Newburyport, Mass.), Et3N (700 μL, 46 mmol), and dioxane (5 mL) afforded 140 mg of a brown oil (58%) after purification (SiO2, flash elution: 30% EtOAc in hexanes. The above boronate ester (140 mg, 0.54 mmol) was reacted according to the procedure used in Example 1, step c, with {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (88 mg, 0.18 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosine)palladium(0) (52 mg, 0.05 mmol, Strem Chemicals Inc, Newburyport, Mass.), Na2CO3 (0.7 mL, 2 M), and toluene/EtOH mixture (2:1, 2.1 mL) to afford {[4-(4′-Carbamoyl-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester after purification (preparative TLC, 1:3 EtOAc/hexanes, 3×1000μ SiO2 plate). ESI-MS (m/z): Calcd. for C25H27N3O5S3: 545.7; found: 446.1 (M−Boc). The above benzamide (44 mg. 0.08 mmol) was subjected to TFA treatment followed by C18-HPLC purification as described in Example 220, step c to afford 26 mg (59%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz) δ 8.33 (s, 1H), 8.04–8.08 (m, 1H), 7.99–8.01 (m, 1H), 7.85 (m, 1H), 7.78 (m, 1H), 7.70–7.73 (m, 2H), 7.32 (d, 1H, J=7.9 Hz), 2.72 (s, 3H), 2.29 (s, 3H). ESI-MS (m/z): Calcd. for C20H19N3O3S3: 446.1 (M+H); found: 446.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][CH:9]=3.[C:19](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.Cl>C1(C)C=CC=CC=1.COCCOCCN(CCOCCOC)CCOCCOC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH3:19])[C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][CH:9]=3
Reactant: COc1ccc2c(c1)Sc1cc(OC)ccc1N2
Reactant: O=C([O-])[O-]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: COS(=O)(=O)OC
Product: COc1ccc2c(c1)Sc1cc(OC)ccc1N2C
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A suspension of 21.75 g (83.9 mmol) of 3,7-dimethoxyphenothiazine, 43.36 g (0.34 mmol) of dried, powdered potassium carbonate, 25.22 g (0.20 mol) of dimethyl sulphate and 1.35 g (4.19 mmol) of tris-[2-(2-methoxyethoxy)ethyl]amine in 300 ml of toluene was stirred at 110° for 1 hour, then cooled and poured into 1 l of ice-water. The mixture was acidified slightly with 2N hydrochloric acid solution and extracted with ethyl acetate. The combined organic phases were extracted with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue was crystallized from ethanol/acetone, whereupon, after drying, 18.4 g (80.2%) of 3,7-dimethoxy-10-methylphenothiazine were obtained as a white solid of m.p. 166°-167°.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.C([O:11][C:12]([C:14]1[S:18][C:17]([O:19][CH2:20][C:21]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:23][O:24][C:25]=2[CH3:26])=[N:16][CH:15]=1)=O)C>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([NH:4][C:12]([C:14]1[S:18][C:17]([O:19][CH2:20][C:21]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:23][O:24][C:25]=2[CH3:26])=[N:16][CH:15]=1)=[O:11])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)s1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)NC(C)C)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a stirred solution of isopropylamine (66 mg, 1.12 mmol) in dioxane (5 mL) under argon and at room temperature was added trimethylaluminium (0.60 mL of a 2M solution in toluene, 1.20 mmol). After 1 h, a solution of 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-thiazole-5-carboxylic acid ethyl ester (100 mg, 0.28 mmol) in dioxane (5 mL) was added and the reaction mixture warmed to 90° C. After 3 h, the reaction mixture was cooled, quenched with Seignettes's salt solution and water, then extracted with dichloromethane. The combined organic extracts were dried, filtered and concentrated. Purification by chromatography (silica, 0 to 3% methanol in dichloromethane) gave the title compound (68 mg, 69%) as a white solid. MS: m/e=358.1 [M+H]+.
Reaction SMILES: [N+](C1C=C(C(N=[N+]=[N-])=O)C=C([N+]([O-])=O)C=1)([O-])=O.C(#N)C.[N+:21]([C:24]1[CH:25]=[C:26]([N:33]=[C:34]=[O:35])[CH:27]=[C:28]([N+:30]([O-:32])=[O:31])[CH:29]=1)([O-:23])=[O:22].[CH3:36][CH:37]([CH3:44])[C:38]([O:40][CH2:41][CH2:42][OH:43])=[O:39]>ClCCl.O>[C:38]([O:40][CH2:41][CH2:42][O:43][C:34](=[O:35])[NH:33][C:26]1[CH:25]=[C:24]([N+:21]([O-:23])=[O:22])[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=1)(=[O:39])[CH:37]([CH3:44])[CH3:36]
Reactant: CC(C)C(=O)OCCO
Reactant: O=C=Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [N-]=[N+]=NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CC(C)C(=O)OCCOC(=O)Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
19.5 g (0.0822 mol) of 3,5-dinitrophenyl carbonyl azide was placed, in a nitrogen current, in a 0.3-l four-necked flask equipped with a nitrogen inlet tube, a dropping funnel, a reflux condenser, a thermometer and a mixing blade. Thereto was added acetonitrile for dissolution and the total amount was made 50 ml. The flask contents were heated for refluxing to obtain 50 ml of an acetonitrile solution containing 3,5-dinitrophenyl isocyanate (compound 7). While the flask was being cooled with ice water, 12.0 g (0.0909 mol) of 2-hydroxyethyl 2-methylpropionate was dropwise added to the flask contents with stirring. After the dropwise addition, stirring was conducted at room temperature for 2 hours; 50 ml of water was added; and stirring was conducted for several minutes. Then, dichloromethane was added. All the flask contents were transferred into a separating funnel for separation of the aqueous layer. The organic layer taken out was returned to the separating funnel. Thereto was added a 5% aqueous sodium carbonate solution, followed by mixing. The lower layer (organic layer) was taken out and dried over anhydrous magnesium sulfate. From the dried solution was removed dichloromethane by distillation by the use of an evaporator, whereby a solid was separated. The solid was recrystallized from butanol to obtain 2-(3,5-dinitrophenylcarbamoyloxy)ethyl isobutyrate (compound 8) as a yellow powder. Yield: 14.4 g (50%) Melting point: 94-95° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:35]=[C:36]([O:38][CH3:39])[CH:37]=1)[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:27]3[CH:35]=[C:36]([O:38][CH3:39])[CH:37]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(COCCCCBr)cc(OC)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(COCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc(OC)c1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 4-(3,5-dimethoxybenzyloxy)butyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(4-(3,5-dimethoxybenzyloxy)-butyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][S:8]([CH2:11][CH2:12][C:13]([CH3:20])([CH3:19])[C:14](OCC)=[O:15])(=[O:10])=[O:9].Cl>O1CCCC1>[OH:15][CH2:14][C:13]([CH3:20])([CH3:19])[CH2:12][CH2:11][S:8]([NH2:7])(=[O:9])=[O:10]
Reactant: CCOC(=O)C(C)(C)CCS(N)(=O)=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(CO)CCS(N)(=O)=O
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
While a suspension of 0.35 g of lithium aluminum hydride in 30 ml of tetrahydrofuran was stirred with ice-cooling, a solution of 1.5 g of ethyl 4-aminosulfonyl-2,2-dimethylbutyrate in 8 ml of tetrahydrofuran was added dropwise. After completion of dropwise addition, the mixture was stirred at 0° C. for 30 minutes and, then, at room temperature for 30 minutes. To this reaction mixture was added aqueous tetrahydrofuran for decomposition of excess lithium aluminum hydride and the mixture was neutralized with 2N-hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried (MgSO4) and the solvent was distilled off. The residue was subjected to silica gel column chromatography and elution was carried out with hexane-ethyl acetate (1:1) to provide 0.94 g of the title compound. m.p.: 75°-76° C.