Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OB(O)c1ccc(F)cc1
Solvent: C1COCCO1
Product: Fc1ccc(-c2cncc(Cl)n2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
A mixture of 2,6-dichloropyrazine (2.75 g, 18.3 mmol), 4-fluorophenyl boronic acid (2.3 g, 16.5 mmol) and palladium tetrakis triphenylphosphine (0.1 g) in dioxane (50 mL) was stirred at 60° C. for one hour. The mixture was cooled and partitioned between water and diethyl ether. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was recrystallized from diethyl ether and methanol to give 1.2 g of 2-chloro-6-(4-fluoro-phenyl)-pyrazine.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[F:10][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=Cc1ccc(Br)cc1F
Product: COc1ccc(-c2ccc(C=O)c(F)c2)cc1

Procedure:
The title compound was prepared by reacting 4-bromo-2-fluoro-benzaldehyde (3 g, 14.8 mmol) with 4-methoxyphenylboronic acid (2.70 g, 17.8 mmol) according to Method B to yield 3.2 g (94%) of white solid: mp 85-86° C.; 1H NMR (DMSO-d6): δ 3.83 (3H, s). 7.06-7.09 (2H, m), 7.70-7.75 (2H, m), 7.79-7.82 (2H, m), 7.88 (1H, t, J=7.96 Hz), 10.22 (1H, s); IR 1681 cm−1; MS (ESI) m/z 231 (M+H)+.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:10]([CH3:12])=[CH2:11])(C)(C)C.[BH4-].[Li+].O.Cl>CCOCC>[C:16]([O:15][C:13]([N:8]([CH2:7][CH2:6][OH:5])[CH2:9][C:10]([CH3:12])=[CH2:11])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: C=C(C)CN(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: C=C(C)CN(CCO)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
A solution of N-(tert-butoxycarbonyl)-N-(2-methylprop-2-enyl)glycine tert-butyl ester (0.26 g, 0.93 mmol) in Et2O (3 mL) was treated with lithium borohydride (0.011 g), then stirred at room temp. overnight. To the resulting mixture was added water (2 mL), then a 1N HCl was added dropwise until gas evolution stopped. The organic phase was washed with a saturated NaHCO3 solution (20 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, gradient from 10% EtOAc/hex to 50% EtOAc/hex) to give N-(tert-butoxycarbonyl)-N-(2-hydroxyethyl)-1-amino-2-methylprop-2-ene (0.113 g, 57%): TLC (10% EtOAc/hex) Rf0.66.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:4]([O:21][CH3:22])[CH:3]=1.FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:39](=[O:54])[C:40]1[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[C:42]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:41]=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[C:39](=[O:54])[C:40]2[CH:45]=[C:44]([C:46]([F:49])([F:47])[F:48])[CH:43]=[C:42]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:41]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: COc1cc(F)ccc1-c1ccncc1NCCS(C)(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(F)ccc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 4-(4-fluoro-2-methoxyphenyl)-N-(2-(methylsulfonyl)ethyl)pyridin-3-amine (0.08 g, 247 μmol, example 192, intermediate a) and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (177 mg, 617 μmol, example 223, intermediate d) in CH2Cl2 (2 mL) was added DIPEA (128 mg, 172 μL, 987 μmol) and the clear solution was stirred at room temperature for 19 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted twice with CH2Cl2. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown foam (0.075 g; 52%). MS (ESI): m/z=575.09 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:31]([F:34])([F:33])[F:32])=[N:4][CH:5]=[C:6](Cl)[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]2[C:27]3[C:22](=[C:23]([F:29])[CH:24]=[CH:25][C:26]=3[F:28])[N:21]=[CH:20][N:19]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C>CCO.[Pd]>[Cl:1][C:2]1[C:3]([C:31]([F:33])([F:34])[F:32])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:17][C:18]2[C:27]3[C:22](=[C:23]([F:29])[CH:24]=[CH:25][C:26]=3[F:28])[N:21]=[CH:20][N:19]=2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(F)c2c(NCCc3ccc(Oc4c(Cl)cnc(C(F)(F)F)c4Cl)cc3)ncnc12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Fc1ccc(F)c2c(NCCc3ccc(Oc4ccnc(C(F)(F)F)c4Cl)cc3)ncnc12
Reaction time: 0.17 h
Yield: 0 %

Procedure:
{2-[4-(3,5-dichloro-2-trifluoromethylpyridin-4-yloxy)-phenyl]-ethyl}-(5,8-difluoroquinazolin-4-yl)-amine (700 mg, 1.4 mol) was dissolved in 2B EtOH (100 mL) under nitrogen in a Parr shaker bottle. Triethylamine (130 mg) and 10% Pd/C (200 mg) were added and the bottle was charged with H2 to an initial pressure of 50 psi. After shaking for approx. 10 min (approx 1 psi H2 uptake), the reaction was filtered through Celite and concentrated in vacuo to provide a white solid. The solid was partitioned between water and EtOAc twice, and the pooled fractions were dried and concentrated in vacuo. The residue was triturated with Et2O, to afford 310 mg of {2-[4-(3-chloro-2-trifluoromethylpyridin-4-yloxy)-phenyl]-ethyl}-(5,8-difluoroquinazolin-4-yl)-amine as a white crystalline solid, M.P. 129-131°. 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1 H), 8.35 (d, J=5.4 Hz, 1 H), 7.40-7.31 (m, 3 H), 7.12-7.06 (m, 2 H), 7.05-6.97 (m, 1 H), 6.85-6.66 (m, 2 H), 4.01-3.92 (m, 2 H), 3.09 (t, J=7.1 Hz, 2 H); MS: m/z 480.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=1.[F:22][C:23]([F:41])([F:40])[C:24]1[CH:39]=[CH:38][C:27]([CH2:28][O:29][CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[CH2:9][O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:35]2[CH2:34][CH2:33][CH:32]([CH2:31][CH2:30][O:29][CH2:28][C:27]3[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:40])[F:41])=[CH:39][CH:38]=3)[CH2:37][CH2:36]2)[CH:7]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: FC(F)(F)c1ccc(COCCC2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CCC(CCOCc3ccc(C(F)(F)F)cc3)CC2)c1
Temperature: 99 °C
Yield: 111.6 %

Procedure:
To a solution of 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(R)-pyrrolidinyl]methoxy]pyridine (210 mg, 0.59 mmol) and 4-[2-[4-(trifluoromethyl)benzyloxy]ethyl]piperidine (186 mg, 0.65 mmol, 1.1 equiv.) in anhydrous toluene (2 mL) were added successively sodium tert-butoxide (93 mg, 0.97 mmol, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium(0) (11.8 mg, 13 μmol, 0.02 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 22.4 mg, 39 μmol, 0.06 equiv.). The mixture was degassed and purged with Ar (3 cycles), then warmed to 98-100° C. for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc, and the solution was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by CC on SiO2 with CH2Cl2/EtOAc 4:1, then 1:1. The product (371 mg, 100%) was obtained as a dark yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH3:20])=[C:15]([CH:17]4[CH2:19][CH2:18]4)[N:16]=3)[CH:13]=2)[C:4](=[O:21])[CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[S:25][CH:26]=[C:27]([CH2:29][OH:30])[N:28]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>O>[CH:17]1([C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:30][CH2:29][C:27]5[N:28]=[C:24]([C:23]([F:32])([F:31])[F:22])[S:25][CH:26]=5)=[CH:3][C:4]4=[O:21])=[CH:13][N:12]3[C:14]=2[CH3:20])[CH2:19][CH2:18]1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cn12
Reactant: OCc1csc(C(F)(F)F)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(C(F)(F)F)n4)cc3=O)cn12
Temperature: 100 °C
Yield: 15.6 %

Procedure:
A mixture of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (80 mg), (2-(trifluoromethyl)-1,3-thiazol-4-yl)methanol (51.1 mg), potassium tert-butoxide (78 mg) and toluene (2 ml) was heated at 100° C. for 1 h. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (16.2 mg) as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:6]([F:9])([F:8])[F:7])[C:3]([OH:5])=[O:4].[CH3:10]O.S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O>[OH:1][CH:2]([C:6]([F:9])([F:8])[F:7])[C:3]([O:5][CH3:10])=[O:4]
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: CO
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C(O)C(F)(F)F

Procedure:
A mixture of (±)-2-hydroxy-3,3,3-trifluoropropionic acid (7.8 g.), methanol (10 ml.) and concentrated sulphuric acid (0.5 ml.) is heated under reflux for 2 days. The cooled solution is poured into water (100 ml.), the mixture is saturated with sodium sulphate, and is extracted three times with ether. The extract is dried with sodium sulphate and evaporated. The residual oil (8.6 g.) is fractionally distilled to give (±)-methyl 2-hydroxy-3,3,3-trifluoropropionate b.p. 60°-64° C. at 12 mm. pressure, m.p. 50°-53° C. (3.9 g.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)NCCc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NCCc1ccccc1N

Procedure:
A solution of 0.95 g of N-[2-(2-nitrophenyl)ethyl]acetamide in 30 ml of ethanol is hydrogenated in the presence of 0.112 g of 10% Pd/C at room temperature over 3.5 hours. The reaction mixture is clarified by filtration and the filtrate is concentrated by evaporation. The crude title compound is obtained as a light brown solid from the residue. Rf=0.50 (9:1 dichloromethane-methanol); Rt=1.86.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:41])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Clc1ccccc1Sc1ccc(Br)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3ccccc3Cl)cc2)c1C
Temperature: 25 °C
Yield: 27.7 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.56 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)-palladium(0) (0.032 g, 0.028 mmol), impure 1-bromo-4-(2-chlorophenylsulfanyl)-benzene (0.334 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then cooled to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(2-chloro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.07 g, 28%) as a solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][N:20]=1>C1COCC1.O>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([CH2:14][O:15][C:19]2[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1=CCN(Cc2ccccc2)CC1
Reactant: Clc1ncccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1cccnc1OCC1=CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-methanol (0.675 g, 3.019 mmol) [C.A.S. 158984-76-0] in dry THF (40 ml) cooled at 0° C., was added NaH (0.138 g, 3.622 mmol; 60% mineral oil). The resulting reaction mixture was stirred at 0° C. for 30 min. Then, a solution of 2-chloro-3-bromopyridine (0.58 g, 3.019 mmol) in dry THF (10 ml) was added and the mixture was heated in a sealed tube at 85° C. for 2 h. After cooling, additional (1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-methanol (0.675 g, 3.019 mmol), NaH (0.138 g, 3.622 mmol; 60% mineral oil) were added to the reaction mixture, which was then heated at 85° C. overnight. Then, after cooling, the mixture was diluted with water and extracted with EtOAc. The organic phase was separated, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 2% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate D58 (0.55 g, 50%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:14]O)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:36]>C(Cl)Cl>[Br:36][CH2:14][C:6]1[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1cc(CO)cc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CBr)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 236.7 %

Procedure:
To a solution of [3-nitro-5-(trifluoromethyl)phenyl]methanol (13.15 g, 59.5 mmol) in DCM (200 mL) at 0° C. was added PPh3 (18.7 g, 71.4 inmol) and CBr4 (21.7 g, 65.4 mmol). The reaction mixture was allowed to stir and warm to rt overnight. The reaction mixture was poured directly onto a pad of silica and the eluant was concentrated to give 1-(bromomethyl)-3-nitro-5-(trifluoromethyl)benzene as a yellow oil (40 g, 689%).
Reaction SMILES: NC1C=CC(N2CCC[C@H](C(N3CCN(C)CC3)=O)C2)=CC=1OC.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([N:36]2[CH2:45][CH2:44][C:39]3([O:43][CH2:42][CH2:41][O:40]3)[CH2:38][CH2:37]2)[CH:30]=[CH:31][C:32]=1[N+:33]([O-])=O>>[O:40]1[C:39]2([CH2:44][CH2:45][N:36]([C:29]3[CH:30]=[CH:31][C:32]([NH2:33])=[C:27]([O:26][CH3:25])[CH:28]=3)[CH2:37][CH2:38]2)[O:43][CH2:42][CH2:41]1
Reactant: COc1cc(N2CCC3(CC2)OCCO3)ccc1[N+](=O)[O-]
Agent: COc1cc(N2CCC[C@H](C(=O)N3CCN(C)CC3)C2)ccc1N
Product: COc1cc(N2CCC3(CC2)OCCO3)ccc1N

Procedure:
4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-2-methoxy-phenylamine was prepared in an analogous fashion to [(S)-1-(4-Amino-3-methoxy-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone of Example 460c replacing [(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone with 8-(3-Methoxy-4-nitro-phenyl)-1,4-dioxa-8-aza-spiro[4.5]decane (1.25 g, 93%). LC/MS (E/I+) 265.08 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[CH3:14][N:15]([CH3:23])[CH2:16][CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20].[H-].[Na+]>>[CH3:14][N:15]([CH3:23])[CH2:16][CH2:17][N:18]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)CCNS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCN(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])S(C)(=O)=O

Procedure:
Prepared from 2,4-dinitro-chlorobenzene, N-(2-dimethylamino-ethyl)-methanesulphonamide and sodium hydride as base
Reaction SMILES: [C:1]([NH:4][CH2:5][C@H:6]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)(=[O:3])[CH3:2].C(OCC)(=O)C.Cl>C(O)C>[Cl:20][C:15]1[CH:14]=[C:13]([C@@H:12]2[O:11][CH2:10][CH2:9][NH:8][CH2:7][C@H:6]2[CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.4 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-[(acetylamino)methyl]-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (160 mg) in ethanol (0.5 mL) was added 4.0 M hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1.5 hr. The solvent was evaporated under reduced pressure. To the residue was added 1 N aqueous sodium hydroxide solution, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethanol, and a solution of fumaric acid (39.3 mg) in ethanol was added. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from ethanol-ethyl acetate to give the title compound (73.5 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: FC(F)(F)c1ccc(I)cc1
Product: FC(F)(F)c1ccc(Oc2ccc(N3CCN(Cc4ccccc4)CC3)cc2)cc1
Yield: 29.1 %

Procedure:
The title compound (120 mg, 25%) was prepared from 4-(4-benzyl-piperazin-1-yl)-phenol (268 mg, 1 mmol) and 1-iodo-4-trifluoromethyl-benzene (270 mg, 1 mmol) by the procedure described in step 2 of Example 17: MS (ESI) m/z 413 (M+H): 1H NMR (400 MHz, CDCl3) δ 2.63 (br, 4H), 3 18 (br, 4H), 3.58 (s, 2H), 6.92-6.98 (m, 6H), 7.32-7.35 (m, 5H), 7.52 (d, J=7.2 Hz, 2H).
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)[CH3:5])C.[NH:16]([C:18]1[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[NH2:17].O>ClCCl.CO>[Cl:14][C:10]1[CH:9]=[C:8]([C:7]2[N:16]([C:18]3[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[N:17]=[C:4]([CH3:5])[N:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NNc1ccc(S(N)(=O)=O)cn1
Reactant: CCOC(C)=NC(=O)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(-c2cccc(Cl)c2)n(-c2ccc(S(N)(=O)=O)cn2)n1
Reaction time: 8 h
Yield: 49 %

Procedure:
N-(1-ethoxy-ethylidene)-3-chloro-benzamide 472 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433 mg (2.23 mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-[5-(3-chloro-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-pyridine-3-sulfonic acid amide (358 mg, yield: 49%) was obtained as a solid phase.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].Cl.[CH3:13][C:14]1[S:15][CH:16]=[C:17]([C:19]([N:21]2[CH2:26][C:25]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[O:24][CH2:23][CH2:22]2)=[O:20])[N:18]=1>C(N(CC)CC)C.C(#N)C>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]1[CH2:30][CH2:31][C:25]2([O:24][CH2:23][CH2:22][N:21]([C:19]([C:17]3[N:18]=[C:14]([CH3:13])[S:15][CH:16]=3)=[O:20])[CH2:26]2)[CH2:27][CH2:28]1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: OCCCCCCCCCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCCCCCCCCO)CC3)C2)cs1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
9-Bromononan-1-ol (0.29 g) was added to a suspension of (2-methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone hydrochloride (example 1, step f) (0.4 g) in a mixture of triethylamine (0.41 mL) and acetonitrile (10 mL). The resulting mixture was stirred for 16 h at 50° C. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (30 mL) and saturated sodium bicarbonate solution (30 mL). The layers were separated and the aqueous extracted with ethyl acetate (2×30 mL). The combined organic solutions were washed with brine (30 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in methanol (10 mL) and applied to a SCX cartridge pre-wetted with methanol. The cartridge was washed with methanol (10 mL) and eluted with 3M ammonia in methanol solution (100 mL). The eluent was evaporated in vacuo to give the subtitled compound a yellow oil. Yield 0.32 g.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][O:6][CH3:7])[CH2:3][OH:4].[CH2:9]([Si:11](Cl)([CH3:13])[CH3:12])[CH3:10]>>[CH3:1][C:2]([CH3:8])([CH2:3][O:4][Si:11]([CH2:9][CH3:10])([CH3:13])[CH3:12])[CH2:5][O:6][CH3:7]
Reactant: CC[Si](C)(C)Cl
Reactant: COCC(C)(C)CO
Product: CC[Si](C)(C)OCC(C)(C)COC

Procedure:
According to the procedure as described in Example 1,2,2-dimethyl-1-methoxy-3-[(ethyldimethylsilyl)oxy]propane was prepared from intermediate 2,2-dimethyl-3-methoxy-1-propanol and reagent ethyldimethylsilyl chloride.