Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[S:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:12].C(O)C>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11](=[O:12])[C:13]2[S:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: Cc1ccc(C(=O)CBr)s1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(C(=O)Cn2cc(Cl)cnc2=O)s1

Procedure:
A mixture of 5-chloropyrimidin-2-one (522 mg) and 2-bromoacetyl-5-methylthiophene (1.30) g) in triethylamine (0.84 ml) and ethanol (25 ml) was stirred at room temperature. After 2 h. the mixture was concentrated to ca. 10 ml, diluted with ethyl acetate (100 ml), washed with water (×3) and brine, dried (MgSO4) and evaporated to a gum. The gum was triturated with diethyl ether and the resulting solid dissolved in ethanol and treated with charcoal. Evaporation of the solvent followed by recrystallisation of the residue twice from ethyl acetate gave the title pyrimidinone (205 mg) m.p. 199°-203° C., εmax (EtOH) 226.5 nm (ε8,570), 261.5 nm (ε9,280), 297 nm (ε11,630).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH2:9][CH2:10][NH2:11].C(N(CC)CC)C.[F:26][C:27]([F:40])([F:39])[O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH2:9][CH2:10][NH:11][S:35]([C:32]1[CH:31]=[CH:30][C:29]([O:28][C:27]([F:26])([F:39])[F:40])=[CH:34][CH:33]=1)(=[O:37])=[O:36]
Reactant: NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(OC(F)(F)F)cc1
Yield: 59.6 %

Procedure:
To a solution of 0.20 g of 3,5-dichloro-4-(2-aminoethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene and 0.10 g of triethylamine dissolved in 5 ml of dichloromethane was added dropwise a solution of 0.16 g of 4-trifluoromethoxybenzenesulfonyl chloride dissolved in 5 ml of dichloromethane, while stirring under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.20 g of 3,5-dichloro-4-(2-(4-trifluoromethoxybenzenesulfonamido)ethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene (60% yield), nD23.0 1.5470.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH:17]=[C:16]2[C:21]2[O:22][C:23]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:25]=2)[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:26]1([C:24]2[N:25]=[C:21]([C:16]3[CH:15]([CH2:14][C:10]4[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][CH:11]=4)[CH2:20][CH2:19][CH2:18][CH:17]=3)[O:22][C:23]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.6 %

Procedure:
To a solution of {3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenyl}carbamic acid tert-butyl ester (2.34 g, 4.62 mmol) in methylene chloride (25 ml) was added trifluoroacetic acid (7 ml) at 5° C. and the mixture was stirred at room temperature for 1.5 hour. After evaporation, the residue was dissolved in EtOAc, and saturated sodium hydrogencarbonate solution was added thereto under ice-cooling. The mixture was extracted with EtOAc, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 3:1 elution) to give 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-y]methyl}phenylamine (1.74 g, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:6]Br.C(N(CC)CC)C.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([NH:28][CH2:6][C:5]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cc(CBr)ccc1[N+](=O)[O-]
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(CNCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
To a 150 mL round bottomed flask containing 1.97 g (8.0 mmol) of 3-methoxy-4-nitro-benzyl bromide in 20 mL THF was added, 2.4 g (24 mmol, 3 eq.) of triethylamine followed by 2.5 g (24 mmol, 3 eq.) of benzylamine. The mixture was stirred at room temperature for 2 h, and was then partitioned between 50 mL ethyl acetate and brine. The organic phase was dried over MgSO4 and concentrated. The residue was purified by flash chromatography, eluting with 14% MeOH in dichloromethane to give 1.6 g (73%) of the benzyl amine as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J=8.61 Hz, 1H), 7.34 (m, 5H), 7.16 (s, 1H), 6.99 (d, J=8.61 Hz, 1H), 3.97 (s, 3H), 3.86 (s, 2H), 3.81 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:31]=[CH:30][C:29]3[C:28]4[C:23](=[CH:24][C:25](Br)=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]([O:37][C:38]([N:40]1[CH:45]([C:46]2[NH:50][C:49]3[CH:51]=[C:52](B4OC(C)(C)C(C)(C)O4)[CH:53]=[CH:54][C:48]=3[N:47]=2)[CH:44]2[CH2:64][CH:41]1[CH2:42][CH2:43]2)=[O:39])([CH3:36])([CH3:35])[CH3:34].C([O-])(O)=O.[Na+]>COCCOC.O>[C:33]([O:37][C:38]([N:40]1[CH:45]([C:46]2[NH:50][C:49]3[CH:51]=[C:52]([C:25]4[CH:26]=[CH:27][C:28]5[C:29]6[C:20](=[CH:19][C:18]([C:15]7[NH:14][C:13]([CH:9]8[CH2:10][CH2:11][CH2:12][N:8]8[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:17][CH:16]=7)=[CH:31][CH:30]=6)[CH2:21][CH2:22][C:23]=5[CH:24]=4)[CH:53]=[CH:54][C:48]=3[N:47]=2)[CH:44]2[CH2:64][CH:41]1[CH2:42][CH2:43]2)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(Br)ccc2-3)[nH]1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]c5c4)ccc2-3)[nH]1
Temperature: 80 °C
Yield: 59 %

Procedure:
Pd(Ph3)4 (20 mg, 0.017 mmol) was added to a mixture 2-[5-(7-bromo-9,10-dihydro-phenanthren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (173 mg, 0.35 mmol), 3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (154 mg, 0.35 mmol), NaHCO3 (103 mg, 1.22 mmol) in 1,2-dimethoxyethane (5 mL) and water (1 mL). The reaction mixture was flushed with nitrogen, heated at 80° C. for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 3-(6-{7-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-9,10-dihydro-phenanthren-2-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a white solid (150 mg, 59%). m/z 727.4 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].C(=O)([O-])[O-].[K+].[K+].OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[F:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(#N)C>[F:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][OH:5])[CH2:31][CH2:30]1
Reactant: FCCN1CCNCC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: OCCCN1CCN(CCF)CC1
Temperature: 85 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
3-Bromopropan-1-ol (581 mg, 4.18 mmol) and potassium carbonate (2.88 g, 20.9 mmol) were added to a solution of 1-(2-fluoroethyl)-piperazine diTFA salt (1.5 g, 4.18 mmol) in acetonitrile (11 ml). The reaction mixture was stirred at 85° C. for 4 hours and then loaded directly onto a column and eluted with a mixture of methanol in methylene chloride (7/93) to give 3-[4-(2-fluoroethyl)piperazin-1-yl]propan-1-ol (721 mg, 91%).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[N:11][N:12]([CH3:13])[C:8]=2[CH:7]=1)=[O:5].O1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:13][N:12]1[C:8]2[CH:7]=[C:6]([C:4](=[O:5])[CH2:18][C:19]3[CH:20]=[CH:21][CH:8]=[C:9]([CH3:14])[N:10]=3)[CH:15]=[CH:14][C:9]=2[N:10]=[N:11]1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1ccc2nnn(C)c2c1
Product: Cc1cccc(CC(=O)c2ccc3nnn(C)c3c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
−30° C. for 1 hour. In a separate flask, a solution of 3-methyl-3H-benzotriazole-5-carboxylic acid methoxy-methyl-amide (500 mg, 2.27 mmol) in 3 ml anhydrous tetrahydrofuran was cooled to −30° C. The cold anion solution was slowly added dropwise to the cold amide solution. Once the addition was complete, the reaction was allowed to slowly warm to room temperature over several hours and stirred overnight. The reaction was quenched with water and the solvent removed by rotary evaporation. The residue was dissolved in saturated aqueous ammonium chloride and extracted three times with chloroform. The combined organics were washed once with water and then once with brine. The combined organics were dried over sodium sulfate, filtered and concentrated to dryness. Crude material was purified on Biotage Flash 40S silica gel column using hexanes/ethyl acetate gradient system (80:20 to 40:60, respectively) as eluent to afford 1-(3-Methyl-3H-benzotriazol-5-yl)-2-(6-methyl-pyridin-2-yl)-ethanone (320 mg, 53%).
Reaction SMILES: C[O-].[Na+].Cl.[N:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][CH:6]=1.[SH:13][CH:14]([CH3:18])[CH:15]([OH:17])[CH3:16]>C(O)C>[OH:17][CH:15]([CH3:16])[CH:14]([S:13][CH2:11][C:8]1[CH:9]=[CH:10][N:5]=[CH:6][CH:7]=1)[CH3:18]
Reactant: CC(O)C(C)S
Reactant: ClCc1ccncc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(O)C(C)SCc1ccncc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Sodium methoxide (3.40 g., 63 mmoles) was dissolved in 30 ml. of absolute ethanol under nitrogen and cooled in an ice bath. To the chilled solution there was added a suspension of finely ground 4- picolyl chloride hydrochloride (5.07 g., 30 mmoles) suspended in approximately 30 ml. of absolute ethanol over 15 minutes, followed by the addition of a solution of 3-mercapto-2-butanol [3.19 g., 30 mmoles, Price et al., J. Am. Chem. Soc. 75, 2396 (1953)]in 6 ml. of absolute ethanol over 5 minutes. The reaction mixture was warmed to room temperature and allowed to stir for 14 hours. The reaction mixture was filtered, the solids being extracted with additional ethanol. The ethanol solutions were combined and evaporated to an oil containing solids (6.31 g.), which was taken up in chloroform, solids removed by filtration and concentrated to an oil. The resulting oil was chromatographed on 200 g. of silica gel with chloroform as eluant. Product fractions were combined and stripped to an oil (5.03 g.). Dissolution in approximately 50 ml. of ethyl acetate, filtration through diatomaceous earth and removal of solvent gave purified 4-(3-hydroxy-2-butylthiomethyl)pyridine [oil; ir (film): 3.08, 3.40, 3.45, 6.24, 7.08, 9.20, 12.27 μ; m/e calcd: 197, found: 197; pnmr/CDCl3 /TMS/delta: 8.57 (m, 2H), 7.30 (m, 2H), 3.85 (m, 1H), 3.76 (s, 2H), 3.12 (s, broad, 1H, exchanges with D2O), 2.75 (m, 1H) and 1.20 (d, 6H)].
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12](S(C)(=O)=O)[N:11]=[C:10]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[N:25]([CH3:26])[C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[N:22]=3)[CH:9]=2)[N:3]=1.[OH-:31].[Na+].O.Cl>O1CCOCC1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:9]=[C:10]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[N:25]([CH3:26])[C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[N:22]=3)[N:11]=[C:12]([OH:31])[N:13]=2)[N:3]=1
Reactant: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)nc(S(C)(=O)=O)n2)n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)nc(O)n2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylsulfonyl)pyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (1-6, 33.0 mg, 0.077 mmol, 1.0 eq.) in 1,4-dioxane (0.8 mL) was added 2 M NaOH in H2O (0.39 mL, 0.78 mmol, 10 eq.), and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was neutralized by the addition of aqueous concentrated HCl and the resulting precipitate was filtered, washed with 1,4-dioxane (2.0 mL) and dried to afford trans-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-2-ol (20) as an amorphous white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.2 (br s, 1H), 7.54 (br d, 11-1, J=7.5 Hz), 7.51 (br d, 1H, J=7.5 Hz), 7.22 (br t, 1H, J=7.5 Hz), 7.17 (br t, 1H, J=7.5 Hz), 6.73 (br s, 1H), 3.85 (s, 3H), 3.04 (m, 1H), 2.76 (s, 3H), 2.64 (m, 1H), 2.30 (s, 3H), 1.94-1.80 (m, 2H). LRMS m/z (M+H) 362 found, 362 required.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[NH2:26][CH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:18])([CH3:19])[C:15]([NH:26][CH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30])=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Reactant: CC(C)(CN)CO
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NCC(C)(C)CO)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and 3-amino-2,2-dimethylpropan-1-ol as a brown solid (40%). MS 432 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:37][CH2:36][C:20]3([O:25][CH2:24][CH2:23][N:22]([C:26]([C:28]4[N:29]=[C:30]([CH:33]([CH3:35])[CH3:34])[S:31][CH:32]=4)=[O:27])[CH2:21]3)[CH2:19][CH2:18]2)=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9](O)=[O:10].[CH3:38][O:39][CH:40]([O:49][CH3:50])[CH2:41][NH:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[Cl:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:18][CH2:19][C:20]3([O:25][CH2:24][CH2:23][N:22]([C:26]([C:28]4[N:29]=[C:30]([CH:33]([CH3:34])[CH3:35])[S:31][CH:32]=4)=[O:27])[CH2:21]3)[CH2:36][CH2:37]2)=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]([N:42]([CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)[CH2:41][CH:40]([O:49][CH3:50])[O:39][CH3:38])=[O:10]
Reactant: COC(CNC1CCCCC1)OC
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4Cl)CC3)C2)cs1
Product: COC(CN(C(=O)CCOCCc1cccc(CN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)c1Cl)C1CCCCC1)OC

Procedure:
Prepared by the method of Example 7, step e using 3-(2-chloro-3-((4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoic acid [Example 27, step d] (0.28 g) in place of 3-(2-fluoro-3-((4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoic acid, and N-(2,2-dimethoxyethyl)cyclohexanamine [WO 2008075025] (0.10 g) in place of N-(2,2-dimethoxyethyl)cycloheptanamine. Yield 0.11 g.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)C(C(O)=O)=[CH:20][CH:19]=[CH:18]3)[CH:9]=1.CN(C=O)C>C(Cl)Cl>[Cl:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:1]([C:2]([Cl:4])=[O:3])=[CH:20][CH:19]=[CH:18]3)[CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc2cc(Oc3cc(Cl)ncn3)ccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc2cc(Oc3cc(Cl)ncn3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 571 μl (6.66 mMol) oxalyl chloride in 15 ml CH2Cl2 is added to an ice-cooled solution of 1 g (3.33 mMol) 6-(6-chloro-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (preparation see WO 2006/59234; Step 25.1) and 10 μl DMF in 30 ml CH2Cl2. The reaction mixture is stirred at room temperature for 1 h. The solvent is then evaporated off under reduced pressure to afford the title compound as a brown solid, which is used directly without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4]([CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)=[CH:3]1.[ClH:30]>O1CCOCC1>[ClH:30].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4]([CH2:20][CH2:21][NH2:22])=[CH:3]1
Reactant: Cn1cc(CCNC(=O)OC(C)(C)C)c2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(CCN)c2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 54 %

Procedure:
tert-Butyl 2-[1-methyl-5-(phenylsulfonyl)-1H-indol-3-yl]ethylcarbamate (0.048 g, 0.12 mmol) was dissolved in a 4.0 N HCl in dioxane (3.0 mL) and stirred at room temperature for 3.5 hours. The white precipitate was filtered and washed with ethyl acetate then recrystallized from MeOH/EtOAc to give 0.022 g (54%) of a white solid as the title compound: mp 285.3-292° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J=1.4 Hz, 1H), 8.02 (br, 3H), 7.96-7.94 (m, 2H), 7.69-7.56 (m, 5H), 7.47 (s, 1H), 3.79 (s, 3H), 3.06 (br, 4H); 13C NMR (100 MHz, DMSO-d6) δ 142.6, 138.4, 132.9, 130.9, 129.4, 126.8, 126.6, 119.9, 119.1, 111.0, 110.9, 32.6, 22.4; IR (diffuse reflectance) 3060, 2980, 2962, 2944, 2904, 1488, 1305, 1288, 1162, 1149, 799, 725, 691, 643, 619 cm−1; HRMS (FAB) calcd for C17H18N2O2S+H 315.1167, found 315.1168; Anal. Calcd for C17H18N2O2S.HCl.0.5H2O: C, 56.73; H, 5.60; N, 7.78. Found: C, 56.96; H, 5.60; N, 7.70.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:16])[CH:12]=2)[CH:7]=1)[CH3:2].[Cl:18]N1C(=O)CCC1=O.Cl.O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:16])[CH:12]=2)[C:7]=1[Cl:18])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Nc1ccc2cc(Cl)ccc2c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Nc1ccc2cc(Cl)ccc2c1Cl
Temperature: 50 °C

Procedure:
A mixture of N-(6-chloro-2-naphthyl)carbamic acid ethyl ester (725 mg, 2.90 mmol), N-chlorosuccinimide (387 mg, 2.90 mmol) and 1 M HCl in acetic acid (2.90 mL, 2.90 mmol) in acetic acid (20 mL) is heated at 50° C. under N2 atmosphere for 1 hour. After cooling to room temperature, water (10 mL) is added and extracted with EtOAc. The organic layer is washed with brine, dried (Na2SO4) and concentrated by rotary evaporator to give N-(1,6-dichloro-2-naphthyl)carbamic acid ethyl ester as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]3[C:25]4[CH:26]=[CH:27][C:28]([NH2:30])=[CH:29][C:24]=4[CH2:23][CH2:22][O:21]3)[C@@H:14]([CH3:31])[CH2:13]1)=[CH:7][CH:6]=[CH:5]2.N1C=CC=CC=1.Cl[C:39]([O:41][CH2:42][CH2:43]Cl)=[O:40]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]3[C:25]4[CH:26]=[CH:27][C:28]([N:30]5[CH2:43][CH2:42][O:41][C:39]5=[O:40])=[CH:29][C:24]=4[CH2:23][CH2:22][O:21]3)[C@H:14]([CH3:31])[CH2:13]1)=[CH:7][CH:6]=[CH:5]2
Reactant: O=C(Cl)OCCCl
Reactant: C[C@H]1CN(c2cccc3cc(F)ccc23)CCN1CC[C@@H]1OCCc2cc(N)ccc21
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1CC[C@@H]1OCCc2cc(N3CCOC3=O)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1S)-1-{2-[(2S)-4-(6-fluoro-1-naphthyl)-2-methyl-piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine (0.217 g, mmol) in dry DMF (5 mL) was added pyridine (0.05 mL, mmol) and 2-chloroethyl chloroformate (0.055 mL, mmol), and the reaction stirred at room temperature under nitrogen for 2 h. The reaction was quenched by addition of 2M sodium hydroxide (3 mL), diluted with water and extracted into dichloromethane. The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by prep LCMS to yield 3-((1S)-1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methylpiperazinyl]-ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-1,3-oxazolidin-2-one. M+H=490.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:9]=[CH:10][C:5]2=[C:4](Cl)[N:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:9]=[CH:10][C:5]2=[C:4]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)[N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CC(C)(C)OC(=O)n1ncc2c(Cl)nc(N)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ncc2c(-c3ccco3)nc(N)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
A solution of tert-butyl 6-amino-4-chloro-1H-pyrazolo[3,4-d]pyrimidine-1-carboxylate (269 mg, 1 mmol) in DMF (2 mL) was treated with PdCl2(PPh3)2 (35 mg, 0.05 mmol) and 2-(tributylstannyl)furan (315 μL, 1 mmol), stirred at room temperature for 16 h and the resulting solid filtered and washed with EtOAc to give the title compound (298 mg, 99%) as a cream solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[C@H:5]([OH:7])[CH3:6].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1>CN(C=O)C>[F:3][C:4]([F:9])([F:8])[C@@H:5]([CH3:6])[O:7][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C[C@@H](O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](Oc1ccc(N)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
Sodium hydride (55%, 3.22 g) was added to DMF (20 mL) and the mixture was cooled to 0° C. Then, (R)-1,1,1-trifluoro-2-propanol (8.5 g) [CAS 17628-73-8] was added over a period of 1 h and stirring was continued for 30 minutes at 0° C. A solution of 1-fluoro-4-nitro-benzene [CAS 350-46-9] (10 g) in DMF (15 mL) was added over a period of 1.5 h while the internal temperature was kept between 5 to 15° C. Following addition, the mixture was allowed to warm to RT and stirring was continued for another 12 h. The reaction mixture was acidified and partitioned between ethyl acetate and water. The organic layer was separated, dried over Na2SO4 and evaporated to dryness. The residue was dissolved in methanol (150 ml) and Pd on carbon (10% Pd, 1 g) was added. The mixture was then hydrogenated at RT for 12 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to provide crude 4-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine as a dark liquid (14.5 g). MS (m/e): 206.1 (MH+).