Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][C:4]=1[S:13][CH3:14].CO[CH:17]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:18][NH2:19].[BH4-].[Na+].[CH3:29][OH:30]>>[CH3:29][O:30][C:26]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:20][CH2:17][CH2:18][NH:19][CH:10]([CH3:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([S:13][CH3:14])[CH:5]=1
Reactant: COc1ccc(CC(C)=O)cc1SC
Reactant: CO
Reactant: COC(CN)Oc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccccc1OCCNC(C)Cc1ccc(OC)c(SC)c1

Procedure:
A mixture of 8.4 g of 4-methoxy-3-methylthiophenylacetone, 6.7 g of 2-methoxyphenoxyethylamine, and 150 ml of methanol was refluxed for 2 hours. The reaction mixture was cooled to a temperature below 10° C. and after adding 2.5 g of sodium borohydride to the reaction mixture with stirring at temperatures below 10° C., the mixture was further stirred for 3 hours at room temperature. Then, the solvent was distilled off under reduced pressure and after adding water to the residue, the product was extracted with ethyl acetate. The extract was washed with water, dried by anhydrous magnesium sulfate, and then the solvent was distilled off to provide an oily product. The product was purified by a silica gel column chromatography (eluate: chloroform) to provide 8.5 g of 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisole. The product (750 mg) was dissolved in 10 ml of methanol and after adding thereto a solution of 90 mg of anhydrous oxalic acid dissolved in 1 ml of methanol, the mixture was allowed to stand overnight at room temperature. The crystals thus formed were recovered by filtration and recrystallized from ethanol to provide 600 mg of 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisole oxalate having a melting point of 173°-174° C.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][CH:4]=1.BrCC1CCCCO1.[F:20][C:21]([F:44])([F:43])[C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:30]=1[NH:29][C:28](=[O:31])[C:27]12[C:35]2=[CH:36][C:37]3[O:41][CH2:40][O:39][C:38]=3[CH:42]=[C:34]2[O:33][CH2:32]1>>[F:44][C:21]([F:20])([F:43])[C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:30]=1[N:29]([CH2:2][C:3]1[O:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][CH:4]=1)[C:28](=[O:31])[C:27]12[C:35]2=[CH:36][C:37]3[O:41][CH2:40][O:39][C:38]=3[CH:42]=[C:34]2[O:33][CH2:32]1
Reactant: O=C1Nc2c(C(F)(F)F)cccc2C12COc1cc3c(cc12)OCO3
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2c(C(F)(F)F)cccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-bromomethyl-2-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 7′-(trifluoromethyl)-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (43%) as a colorless solid: mp 95-98° C.; 1H NMR (300 MHz, CDCl3) δ7.59 (d, J=8.1 Hz, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.15 (dd, J=7.8, 7.8 Hz, 1H), 6.69 (d, J=3.2 Hz, 1H), 6.50 (s, 1H), 6.23 (d, J=3.0 Hz, 1H), 6.10 (s, 1H), 5.86 (d, J=3.0 Hz, 2H), 5.23 (ABq, 2H), 4.78 (ABq, 2H); 13C NMR (75 MHz, CDCl3) δ178.6, 156.0, 152.2, 149.3, 142.7, 141.4 (q), 139.1, 135.1, 127.9, 127.0 (m), 122.9 (d), 121.1 (d), 119.3 (d), 118.7, 113.4 (q), 112.5, 108.2, 102.8, 101.7, 93.7, 80.8, 56.9, 39.4; MS (ES+) m/z 498.4 (M+1).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[NH:9])[NH2:8].[Cl:10][C:11]([SH:14])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:10][C:11]1[S:14][N:8]=[C:7]([C:3]2[S:2][CH:6]=[CH:5][CH:4]=2)[N:9]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(-c2cccs2)ns1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
To a solution of thiophene-2-carboximidamide hydrochloride (1.62 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 ml, 10.0 mmol) in dichloromethane (10 ml) was added dropwise a solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.40 g (69.3%) of the desired product as an oil.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[CH:16]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[OH:27])[CH2:20][CH2:19][CH2:18][CH2:17]1.C[O:29][C:30](=[O:39])[CH:31](Br)[CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH:33]1([CH2:32][CH:31]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH:6]=[N:5]2)[C:30]([OH:29])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Oc1ccccc1C1CCCC1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)CC1CCCC1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2C2CCCC2)cc1=O
Yield: 88 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2-cyclopentyl-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(2-cyclopentyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (12.89 g, 88%) as a white solid; LC-MS [M+H+]=397; HPLC (0.1% trifluoroacetic acid in acetonitrile/water, 50%-100% acetonitrile, gradient, 1 mL/min, Venusil MP-C18, C18-150 cm×4.6 mm-5 μm), 214 nm, 97.39%, 254 nm, 96.72%. 1H-NMR (300 MHz, CDCl3) δ 7.88 (s, 1H), 7.29-7.41 (m, 1H), 7.22-7.26 (m, 2H), 6.98-7.01 (m, 1H), 5.91-5.92 (d, J=3, 1H), 5.49-5.54 (m, 1H), 3.03-3.12 (m, 1H), 2.28-2.38 (m, 1H), 2.09-2.18 (m, 1H), 1.95-1.98 (d, J=9 Hz, 2H), 1.50-1.79 (m, 13H), 1.09-1.26 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C=O)C.C(OCC)(=O)C>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH3:35]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C

Procedure:
To a stirred solution of tert-butyl 4-(2-hydroxyphenyl)-piperazine 20 (1 g, 0.0035 mol.) and cesium carbonate (2.34 g, 0.0071 mol.) in 5 mL of DMF anhydrous was added a solution of ethyl 4-bromobutanoate (6a) at rt. The resulting mixture was heated at 70° C. overnight (12 h). The progress of the reaction was monitored by thin layer chromatography (TLC). After the reaction was complete, the reaction mixture was diluted with 25 mL of ethyl acetate and filtered to remove cesium carbonate. The filtrate was washed with saturated aqueous NaHCO3 solution, dried over Na2SO4 and evaporated to give tert-butyl 4-(2-(4-ethoxy-4-oxobutoxy)phenyl)-piperazine-1carboxylate 21a which was purified by silica gel chromatography using a gradient elution of ethyl acetate and hexane. Colorless oil (1.1 g, 78%). 1H NMR (400 MHz, CDCl3): δ 1.25 (t, J=6.4 Hz, 3H); 1.45 (s, 9H); 2.14 (q, J=7.2 Hz, 2H); 2.53 (t, J=7.2Hz, 2H); 3.00 (br s, 4H); 3.58 (br s, 4H); 4.04 (t, J=6.4 Hz, 2H); 4.12 (q, J=6.4 Hz, 2H); 6.84-6.97 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:12][NH:13][CH3:14])=[CH:5][N:6]2[CH3:11].CNCC1C2C=CC=CC=2N2CCCC=12.[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([OH:41])=O)=[CH:33][CH:32]=1.Cl.O=C1NC2N=CC(/C=C/C(O)=O)=CC=2CC1>>[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([N:13]([CH2:12][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[N:6]([CH3:11])[CH:5]=2)[CH3:14])=[O:41])=[CH:33][CH:32]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1cn(C)c2cccc(F)c12
Agent: CNCc1c2n(c3ccccc13)CCC2
Agent: Cl
Agent: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Product: CN(Cc1cn(C)c2cccc(F)c12)C(=O)/C=C/c1ccc(N)nc1
Yield: 31.3 %

Procedure:
According to the procedure of Example 24, except substituting 4-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.2 g, 1.04 mmole) for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, and substituting (E)-3-(6-amino-pyridin-3-yl)acrylic acid (0.17 g, 1.04 mmole) for the (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt, the title compound (0.11 g, 37%) was prepared as an off-white powder: MS (ES) m/e 339 (M+H)+.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][C:5]([CH2:21][OH:22])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[CH2:4][CH2:3]1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl.CCOC(C)=O>[O:14]([C:10]1[CH:9]=[C:8]([C:5]2([CH2:21][OH:22])[CH2:4][CH2:3][C:2]3([O:31][CH2:1]3)[CH2:7][CH2:6]2)[CH:13]=[CH:12][CH:11]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=C1CCC(CO)(c2cccc(Oc3ccccc3)c2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: OCC1(c2cccc(Oc3ccccc3)c2)CCC2(CC1)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of (4-methylene-1-(3-phenoxyphenyl)cyclohexyl)methanol (53 mg, 0.180 mmol) in CH2Cl2 (0.9 mL) at 0° C. was added m-chloroperbenzoic acid (43.5 mg, 0.252 mmol). The solution was warmed to rt and stirred for 1 h. The reaction mixture was diluted with EtOAc, washed successively with 1 N aqueous NaOH, water, and brine, dried (MgSO4), filtered, and concentrated in vacuo to afford the title compound (56 mg, 100% yield) as a colorless oil. LCMS, [M+H]+=311.1.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([Cl:39])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([Cl:39])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C(=O)O)cc1Cl
Yield: 97.5 %

Procedure:
To a mixture of ethyl 1-benzyl-3-[(3-chloro-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate (0.40 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was heated under reflux for 1 hr. The reaction mixture was neutralized by adding 1N hydrochloric acid and water, and the precipitated crystals were collected by filtration to give 1-benzyl-3-[(3-chloro-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylic acid as crystals (0.37 g, yield 97%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 191-192° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2([CH3:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:24])=O.C(Cl)Cl>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2([CH3:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:7][C:3]=1[C:4]([Cl:24])=[O:5]
Reactant: Cc1ccc(CNC(=O)C2(C)CCCCC2)cc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(CNC(=O)C2(C)CCCCC2)cc1C(=O)Cl

Procedure:
A mixture of 2-methyl-5-[(1-methylcyclohexylcarbonylamino)methyl]benzoic acid (0.250 g, 0.864 mmol), 0.16 mL thionyl chloride, 15 mL DCM and 10 μL DMF were heated at reflux for 2 h and concentrated. The crude acid chloride was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:28])[C:9]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][N:23]=[C:24]([O:25][CH2:26][CH3:27])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1)[C:5]#[N:6].C(N(CC)CC)C.[Cl-].[OH:37][NH3+:38]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[N:38][OH:37])[NH2:6])[CH:7]=[C:8]([Cl:28])[C:9]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][N:23]=[C:24]([O:25][CH2:26][CH3:27])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1
Reactant: [NH3+]O
Reactant: CCOc1nccc2c(Nc3c(Cl)cc(C#N)cc3Cl)nc3ccncc3c12
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOc1nccc2c(Nc3c(Cl)cc(C(N)=NO)cc3Cl)nc3ccncc3c12
Temperature: 80 °C

Procedure:
To a solution of 3,5-dichloro-4-[(10-ethoxypyrido[4,3-c]-1,6-naphthyridin-6-yl)amino]benzonitrile (Example 160, Step 1) (200 mg, 0.49 mmol) in ethanol (6 mL) was added triethylamine (0.285 mL, 2.04 mmol) and hydroxyammonium chloride (105 mg, 1.51 mmol). The reaction mixture was heated to 80° C. for 3 h in a sealed tube. After cooling to room temperature, the solid was filtered, washed with ethanol and water and dried under vacuum to afford the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:53][N:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[NH2:55]>CN(C=O)C.O1CCCC1>[CH3:53][N:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[NH:55][C:12](=[O:14])[C:11]1[CH:15]=[C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCOCC2)c1
Reactant: CN(N)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(NC(=O)c1cnc(OCC(F)(F)F)c(C2CCOCC2)c1)c1ccccc1
Reaction time: 8 h

Procedure:
In a 10 mL two-necked flask, the above prepared 5-(tetrahydro-pyran-4-yl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (50 mg, 164 μmol, Eq: 1.00) was combined with tetrahydrofuran (1.0 mL) and DMF (1 mL) to give a colorless solution. TBTU (78.9 mg, 246 μmol, Eq: 1.5) and N,N-diisopropylethylamine (106 mg, 143 μl, 819 μmol, Eq: 5) were added and the reaction mixture stirred for 10 min at rt before 1-methyl-1-phenylhydrazine (24.0 mg, 23.1 μl, 197 μmol, Eq: 1.2, CAN 618-40-6) was added and the reaction mixture kept overnight at rt. Work up: The reaction mixture was quenched with 1 M HCl (10 mL) and extracted with EtOAc (2×20 mL). The organic layers were washed with 1 M NaOH, then with H2O/NaCl sol., the combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (silica gel, 10 g, 15% to 50% EtOAc in heptane) delivered eventually 62 mg of the title compound as white foam; MS (EI) 410.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[Cl:21][C:22]1[CH:31]=[CH:30][C:25]2[C:26](=O)[CH2:27][O:28][C:24]=2[CH:23]=1.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:26]3[C:25]4[CH:30]=[CH:31][C:22]([Cl:21])=[CH:23][C:24]=4[O:28][CH2:27]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: O=C1COc2cc(Cl)ccc21
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3COc4cc(Cl)ccc43)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 6-chloro-benzofuran-3-one using decaborane yielded a mixture of epimers of the title compound as a white foam. MS (ESI): m/z=431.3 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4]Br.[Mg:7].[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Br:21]>O1CCCC1>[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][Mg:7][Br:8].[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Br:21]
Reactant: [Mg]
Reactant: CC(C)CCBr
Reactant: BrCCCCCCCCCCCCBr
Solvent: C1CCOC1
Product: CC(C)CCCCCCCCCCCCCCBr
Product: CC(C)CC[Mg]Br
Reaction time: 1 h

Procedure:
A solution of 3-methylbutylmagnesium bromide is prepared by treating 15.1 g. of 3-methylbutyl bromide with 2.7 g. of magnesium turnings in 50 ml. dry tetrahydrofuran. The resultant Grignard reagent is dropwise added to a cold (-10° C.) solution of 36.1 g. of 1,12-dibromododecane and 0.2 g. of Li2CuCl4 in 75 ml. dry tetrahydrofuran. The solution is stirred for 1 hour, evaporated, and fractionally distilled in vacuo to yield 15-methylhexadecyl bromide as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1.O=P(Cl)(Cl)Cl.CN([CH:32]=[O:33])C>>[CH2:17]([O:16][C:4]1[CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[C:2]([Cl:1])[C:3]=1[CH:32]=[O:33])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(Cl)cc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 63 %

Procedure:
12 g of chloro-3,5-dibenzyloxybenzene are dissolved in 40 ml of DMF. 12 ml of POCl3 are slowly added dropwise at 5-10°. The mixture is allowed to react further for 90 min at room temperature, then overnight at 80° C. The solution is evaporated in a Rotavapor, then added to 200 ml of icewater. The mixture is extracted 3× with EtOAc, washed with water, dried and evaporated. Silica gel chromatography gives 8.2 g (63%) of 2,4-bisbenzyloxy-6-chlorobenzaldehyde, which crystallises from (Me2C)2O, m.p. 85-86°.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[OH:16]OS([O-])=O.[K+].CO.O1CCCC1.[OH2:29]>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][S:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)(=[O:16])=[O:29]
Reactant: O=S([O-])OO
Reactant: CN(C)CCSc1ccc([N+](=O)[O-])cc1
Reactant: O
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CCS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a 0° C. solution of give N,N-dimethyl-N-{2-[(4-nitrophenyl)thio]ethyl}amine (0.50 g, 2.2 mmol) in methanol/tetrahydrofuran/water (33 mL, 1:1:1) is added dropwise an aqueous solution of OXONE®, monopersulfate compound (2.7 g, 9.5 mL). The reaction mixture is stirred for one week at room temperature and then quenched by the addition of an aqueous sodium hydrogen sulfite solution (3 g, 20 mL). The mixture is then basified to pH 8 with concentrated ammonium hydroxide and extracted 3× with dichloromethane. The combined extracts were washed with aqueous 5% sodium thiosulfite solution (100 mL) and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a golden oil, which solidified upon standing. The crude solid (0.31 g) is purified by flash chromatography (Isco 12 g Redi-Sep column, MeOH/CHCl3) to give dimethyl-[2-(4-nitro-benzenesulfonyl)-ethyl]-amine.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>O=P(Cl)(Cl)Cl>[Cl:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc2nnc(-c3ccccc3)c(O)c12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cccc2nnc(-c3ccccc3)c(Cl)c12

Procedure:
27.3 g (0.116 mol) of the compound from Example VI are boiled under reflux with 18.3 g of PCl5 and 200 ml of POCl3 for 18 h. The mixture is added to ice with good stirring and extracted with methylene chloride, and the organic phase is washed with saturated NaHCO3 solution, dried and evaporated in vacuo. 12 g (41% crude yield) of a solid are obtained, which after chromatography has a m.p. of 128° C.
Reaction SMILES: [O:1]1[C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][C:3](C(CC)C#N)=[CH:2]1.[OH-].[NH4+:16]>[Rh].C(O)C>[O:1]1[C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][C:3]([NH:16][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:2]1
Reactant: [NH4+]
Reactant: CCC(C#N)c1coc2cccc-2c1
Agent: [Rh]
Agent: [OH-]
Solvent: CCO
Product: CCCCNc1coc2cccc-2c1
Yield: 72 %

Procedure:
This compound was prepared by the same method as for intermediate 30, using 4-benzofuran-3-yl-butyronitrile (1.05 g, 5.67 mmol), 420 mg of 5% rhodium on alumina, 100 mL of ammonium hydroxide, and 150 mL of ethanol, to afford 770 mg (72%) of the title compound after chromatography: 1H NMR (CDCl3, 400 MHz) δ 7.52 (d, J=8.2 Hz, 1 H), 7.43 (d, J=8.1 Hz, 1 H), 7.38 (s, 1 H), 7.18-7.27 (m, 2 H), 2.72 (t, J=7.0 Hz, 2 H), 2.67 (t, J=7.3 Hz, 2 H), 1.73 (quint, J=7.9 Hz, 2 H).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:13][CH2:14][CH2:15][CH3:16])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:17][NH2:18].[BH4-].[Na+].O>CO>[C:1]([C:5]1[C:6]([O:13][CH2:14][CH2:15][CH3:16])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH:18][CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CCCOc1c(C=O)cccc1C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCOc1c(CNC)cccc1C(C)(C)C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
3-tert-Butyl-2-propoxy-benzaldehyde (1.15 g, 5.21 mmol) was dissolved in anhydrous methanol (25 ml). Methylamine (2.00 ml of 33% solution in ethanol, 16.1 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a yellow oil and then dissolved in anhydrous methanol (25 ml). Sodium borohydride (198 mg, 5.23 mmol) was added and the mixture was stirred overnight at room temperature. Water (10 ml) was added and the solution was concentrated. Sodium hydroxide (30 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×50 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford (3-tert-butyl-2-propoxy-benzyl)-methyl-amine (1.18 g, 96%) as a clear oil: 1H NMR (400 MHz, DMSO-d6) δ 7.28 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 6.97 (y J=8.0, y1H), 3.79 (t, J=4.0 Hz, 2H), 3.61 (s, 2H), 2.28 (s, 3H), 1.80-1.75 (m, 2H), 1.33 (s, 9H), 1.03 (t, J=8.0 Hz, 3H).
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:10])[N:4]=1.[CH3:11][N:12]([CH2:14][C:15]1[N:20]=[C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])[CH:18]=[CH:17][CH:16]=1)[CH3:13].[NH3:26]>>[NH2:26][C:3]1[C:7]([NH:25][CH2:24][CH2:23][S:22][CH2:21][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:14][N:12]([CH3:11])[CH3:13])[N:20]=2)=[N:6][S:5](=[O:10])[N:4]=1
Reactant: COC1=NS(=O)N=C1OC
Reactant: N
Reactant: CN(C)Cc1cccc(CSCCN)n1
Product: CN(C)Cc1cccc(CSCCNC2=NS(=O)N=C2N)n1

Procedure:
When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide is successively treated with an equimolar amount of 2-[(6-dimethylaminomethyl-2-pyridyl)methylthio]ethylamine [prepared in Step C] and excess ammonia, the title compound is thereby produced.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:23]3[CH:24]=[CH:25][S:21][CH:22]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: OB(O)c1ccsc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccsc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and thiophene-3-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-thiophen-3-yl-6-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 337(MH+).