Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[CH2:15]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18]>>[ClH:1].[CH2:15]([C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:14])[CH:3]=2)=[CH:24][CH:25]=1)[CH2:16][CH2:17][CH3:18]
Reactant: COc1ccc2c(Cl)cc(C)nc2c1
Reactant: CCCCc1ccc(N)cc1
Product: CCCCc1ccc(Nc2cc(C)nc3cc(OC)ccc23)cc1
Product: Cl

Procedure:
In a manner similar to that described in Example 35, Part A, 4-chloro-7-methoxy-2-methylquinoline and 4-butylaniline were transformed into the title compound: m.p. 245°-246° C.
Reaction SMILES: [Br:1][CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1.[C:7]1([P:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCCCCC>C1(C)C=CC=CC=1>[Br-:1].[CH:3]1([CH2:2][P+:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: BrCC1CCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: [Br-]
Product: c1ccc([P+](CC2CCC2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A solution of (bromomethyl)cyclobutane (4.5 ml, 0.04 mol) in toluene (50 ml) was treated with triphenylphosphine (10.56 g, 0.04 mol) and the mixture stirred at reflux, under a nitrogen atmosphere, for 2 days. The mixture was allowed to cool to room temperature and treated with hexane (50 ml). The solvent was decanted off and further hexane added. The solvent was decanted off again. The solid was washed with diethyl ether (×2) and dried under reduced pressure to afford the title compound as a white solid (6.34 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([F:12])[CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:13][O:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([Br:1])=[CH:3][C:4]=1[F:12]
Reactant: O=[N+]([O-])c1cc(O)c(F)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc([N+](=O)[O-])c(Br)cc1F
Reaction time: 5 h
Yield: 96.6 %

Procedure:
A solution of 4-bromo-2-fluoro-5-nitrophenol (25 g, 106 mmol) in DMF (200 mL) was treated with potassium carbonate (28.9 g, 212 mmol) and methyl iodide (12.8 mL, 212 mmol). The reaction mixture was stirred at 60 C for 5 hours and evaporated in vacuo. The mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated under vacuum to afford the product (25.6 g, 97%) as a yellow solid. LC-MS (ES) (M+H)+ m/z=251.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Li]CCCC.[O:23]1[C@H:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24]1.Cl>O1CCCC1.CCCCCC.CN(P(N(C)C)(N(C)C)=O)C>[OH:23][C@H:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)[C:16]#[N:17]
Reactant: CCCCCC[C@@H]1CO1
Reactant: COc1ccc(-c2ccc(CC#N)cc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCC[C@@H](O)CC(C#N)c1ccc(-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a solution of 1.02 g (4.6 mmol) of 4-(4-methoxyphenyl)phenylacetonitrile in 40 ml of tetrahydrofuran (THF) was added, at -78° C., 1.5 M n-BuLi solution in hexane in an amount of 3.6 ml (5.5 mmol). This mixture was stirred for 1 hour. Thereto were added a solution of 705 mg (5.5 mmol) of (R)-1,2-epoxyoctane in 20 ml of THF and 5 ml of HMPA. The resulting mixture was warmed to room temperature, and then stirred overnight. The reaction mixture was neutralized with 3 M hydrochloric acid, and then subjected to extraction with 300 ml of ethyl acetate. The resulting ethyl acetate solution was washed with saturated sodium chloride aqueous solution, dried with anhydrous magnesium sulfate, filtered, and then concentrated. The residue was separated and purified by column chromatography (hexane/ethyl acetate=3/1), thereby obtaining 1.05 g (yield 65%) of (4R)-4-hydroxy-2-[4-(4-methoxyphenyl)phenyl]decanenitrile.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.Cl[S:14]([C:17]1[CH:18]=[C:19]([C:27]([OH:29])=[O:28])[C:20]2[O:25][CH2:24][CH2:23][O:22][C:21]=2[CH:26]=1)(=[O:16])=[O:15]>O>[CH2:1]([N:3]([CH2:4][CH3:5])[S:14]([C:17]1[CH:18]=[C:19]([C:27]([OH:29])=[O:28])[C:20]2[O:25][CH2:24][CH2:23][O:22][C:21]=2[CH:26]=1)(=[O:16])=[O:15])[CH3:2]
Reactant: CCNCC
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCO2
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(CC)S(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Temperature: 25 °C
Yield: 74 %

Procedure:
200 ml of water, 100 ml of diethylamine and 200 ml of triethylamine were introduced into a balloon flask provided with an agitator and a thermometer and then 140 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were added in portions, the temperature being maintained at from 20°-30° C. The mixture was agitated at ambient temperature and then 500 ml of water were added. The solution was filtered and treated with 300 ml of hydrochloric acid. The precipitate was dried off, washed and dried. 117 g of 7-diethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 149° C.; yield: 74%).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CO.[C:27]([O:34]C([O-])=O)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O>ClCCl.C(N(CC)CC)C>[C:30]([O:29][C:27]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13]1)=[O:34])([CH3:31])([CH3:32])[CH3:33]
Reactant: COC(=O)C1=CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 92.5 %

Procedure:
4.62 g of methyl 1-benzyl-1,2,3,6-tetrahydro-4-pyridinecarboxylate was dissolved in 30 ml of dichloromethane. Under ice-cooling, 4.29 g of 1-chloroethyl chloroformate was added thereto and the resulting mixture was heated under reflux for 2 hours. After adding 50 ml of methanol, the mixture was stirred at 70° C. for 1 hour and 20 minutes. Then triethylamine was added to the reaction mixture under ice-cooling until the pH value of the mixture exceeded 7. After further adding 4.37 g of tert-butyl dicarbonate, the resulting mixture was stirred at room temperature for 10 minutes. Then the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 4.46 g of the title compound as a yellow oily substance.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[O:31])[CH:6]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Br:32][CH2:33][CH2:34]Br>C(O)C>[CH3:3][O:4][C:5](=[O:31])[CH:6]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:34][CH2:33][Br:32])=[CH:12][CH:13]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccc(C)cc1
Reactant: BrCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C(Cc1ccc(OCCBr)cc1)Nc1ccccc1C(=O)c1ccc(C)cc1
Yield: 53.3 %

Procedure:
To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) is added 2-[(2-(4-methylbenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid methyl ester (1.15 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). Then the mixture is heated to reflux for 8 hours. After cooled, the reaction mixture is filtered to remove the solid formed, and then the filtrate is evaporated under a vacuum. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (0.78 g, 53%).
Reaction SMILES: [OH-].[Li+].[CH:3]([O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=1[CH3:17])([CH3:5])[CH3:4]>O1CCCC1.O>[CH:3]([O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[CH3:17])([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc(OC(C)C)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)ccc1OC(C)C
Temperature: 65 °C
Yield: 90.9 %

Procedure:
To methyl 4-hydroxy-3-methyl-benzoate (1.0 g, 59.8 mmol) in dry DMF (62 mL) was added finely ground potassium carbonate (33.1 g, 239.3 mmol) followed by 2-iodopropane (20.3 g, 12.0 mL, 119.6 mmol). The reaction mixture was heated at 60° C. for 2 hours. The reaction mixture was cooled and diluted with ether (350 mL), and filtered over celite. The filtrate was washed with water (3×100 mL) and brine (100 mL) solution. The layers were separated and organics were dried over MgSO4. The solvent was evaporated and resulting residue was purified by silica gel using 0-30% EtOAc/hexanes mixtures as eluent to give methyl 4-isopropoxy-3-methylbenzoate as a colorless oil (11.2 g, 89%). ESI-MS m/z calc. 208.25. found 209.2 (M+1)+; Retention time: 1.93 minutes (3 min run). Lithium hydroxide (4.4 g, 181.6 mmol) was added to a solution of methyl 4-isopropoxy-3-methylbenzoate (11.2 g, 53.8 mmol) in tetrahydrofuran (31 mL) and water (31 mL). The mixture was rapidly stirred and heated at 65° C. for 6 hours. The reaction mixture was cooled, diluted with water (75 mL) and extracted with ether (2×50 mL). The aqueous layer was acidified to pH 2 with 6N aq. HCl and extracted with ethyl acetate (4×75 mL). The combined organics were washed with water (75 mL) and brine solution (75 mL) and layers were separated. The organics were dried over MgSO4 and concentrated in vacuo to give 4-isopropoxy-3-methyl-benzoic acid (9.5 g, 82%) as colorless crystals. ESI-MS m/z calc. 194.2. found 195.3 (M+1)+; Retention time: 1.53 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.78-7.71 (m, 2H), 7.02 (d, J=8.6 Hz, 1H), 4.70 (dt, J=12.1, 6.0 Hz, 1H), 2.15 (s, 3H), 1.30 (d, J=6.0 Hz, 6H).
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([CH3:28])=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O>[CH3:20]/[C:21](/[CH2:28][O:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:11][CH:10]=1)=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C=C(C)CBr
Reactant: CCC(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C(/C)COc1ccc(OC(C)CC)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 4-(1-methylpropoxy)phenol (0.84 g, 5.06 mmol) and potassium carbonate (0.66 g, 0.48 mmol) in 10 ml of dimethylformamide (DMF) at 5° is added ethyl 4-bromo-3-methyl-2-butenoate (1.0 g, 0.48 mmol). The mixture is allowed to warm to RT and is stirred at RT for 20 hours. The reaction mixture is poured into water and extracted with ether. The organic layer is washed with 10% sodium hydroxide to remove any starting phenol, dried and the solvent removed. The product is purified by preparative thin layer chromatography (prep. TLC). The second main band is collected to give ethyl (Z)-3-methyl-4-[4-(1-methylpropoxy)phenoxyl]-2-butenoate, MS m/e 292 (M+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:3]1=[O:24].[C:25]1([CH2:31][CH2:32][C@@H:33](OS(C(F)(F)F)(=O)=O)[C:34]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:37]([O:36][C:34]([C@@H:33]([NH:1][CH:2]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:3]1=[O:24])[CH2:32][CH2:31][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:35])[CH2:38][CH2:39][CH3:40]
Reactant: CCCCOC(=O)[C@@H](CCc1ccccc1)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CN1C[C@H](c2ccc(F)cc2)CC[C@@H](N)C1=O
Product: CCCCOC(=O)[C@H](CCc1ccccc1)NC1CCC(c2ccc(F)cc2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
According to a similar procedure to that described in Example 1(l), t-butyl α-[3(S*)-amino-6(R*)-(p-fluorophenyl)-2-oxoperhydroazepin-1-yl]acetate [prepared as described in Example 6(e)] was reacted with butyl 4-phenyl-2(R)-trifluoromethanesulfonyloxybutyrate, to give a crude product, which was subjected to column chromatography through silica gel using a 3:1 by volume mixture of cyclohexane and ethyl acetate as eluent.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH3:15].Br[CH2:18][CH2:19][C:20]([OH:22])=[O:21]>ClC1C=CC=CC=1Cl>[CH3:1][C:2]1([CH3:16])[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[N:4]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:3]1[CH3:15]
Reactant: O=C(O)CCBr
Reactant: CC1=Nc2ccc3ccccc3c2C1(C)C
Solvent: Clc1ccccc1Cl
Product: CC1N(CCC(=O)O)c2ccc3ccccc3c2C1(C)C
Temperature: 110 °C
Reaction time: 18 h
Yield: 112.2 %

Procedure:
A mixture of 1,1,2-trimethyl[1H]-benz[e]indole (10.0 g, 47.8 mmol) and 3-bromopropanoic acid (7.3 g, 47.8 mmol) in 1,2-dichlorobenzene (50 mL) was heated with stirring at 110° C. for 18 h. After the resulting mixture was cooled to room temperature, the precipitated was collected by filtration, triturated with DCM thoroughly, and dried under vacuum to afford 15.2 g of light brown powder (88%). ESI-MS: observed for [MH]+281.31.
Reaction SMILES: [C:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([OH:3])=[O:2].[CH3:13]O>>[C:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([O:3][CH3:13])=[O:2]
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: CO
Product: COC(=O)C1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Dissolve 2-carboxy-indan (2.5 g, 15.4 mmol) in methanol and cool to 0° C. Saturate with hydrochloride gas then add 2,2-dimethoxypropane (2-3 mL). Stir overnight then evaporate the solvent in vacuo. Purify by silica gel chromatography (2:1 methylene chloride/hexane) to give 2-carbomethoxy-indan as a water white oil. (2.04 g, 75%). Dissolve diisopropylamine (1.90 mL, 7.8 mmol) in anhydrous tetrahydrofuran (8 mL), cool to -20° C. and place under an argon atmosphere. Add, by dropwise addition, n-butyllithium (3.12 mL of a 2.5N solution in hexanes, 7.8 mmol) and stir for 20 minutes while cooling to -70° C. Add, by dropwise addition, a solution of 2-carbomethoxy-indan (1.34 g, 7.8 mmol) in anhydrous tetrahydrofuran (8 mL). Stir at -70° C. for an additional 30 minutes then add trimethylsilyl chloride (freshly distilled from barium oxide, 1.0 mL, 7.8 mmol). Allow to warm to 10° C., evaporate the solvent in vacuo and dry the residue under vacuum for 30 minutes. Suspend the residue in methylene chloride (30 mL), add zinc bromide (300 mg, 1.3 mmol) followed by t-butyl chloromethylsulfide (1.08 g, 7.8 mmol). Stir for 15 minutes at room temperature and add additional zinc bromide (500 mg, 2.2 mmol). Pour onto excess saturated sodium hydrogen carbonate and shake vigorously. Separate the organic phase and extract the aqueous phase with methylene chloride (30 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo to give crude product as a brown oil (2.12 g, 98%). Purify by silica gel chromatography (30-70° C. methylene chloride/hexane) and recrystallize (methanol) to give 2-carbomethoxy-2-(t-butyl)thiomethylindan as a crystalline solid (1.3 g, 61%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[Na+].[I-].[C:8]([O-:11])([O-])=[O:9].[K+].[K+].[C:14]1([CH:20]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:21][NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:25]=2[Cl:34])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[ClH:34].[Cl:34][C:25]1[C:26]([C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:22]([CH2:21][CH:20]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:2][CH2:3][CH2:4][O:5][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:14]=1[CH3:20])[C:8]([OH:11])=[O:9]
Reactant: FC(F)(F)c1cccc(CNCC(c2ccccc2)c2ccccc2)c1Cl
Reactant: O=C([O-])[O-]
Reactant: OCCCBr
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(C(=O)O)cc1OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Product: Cl
Temperature: 85 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a stirring solution of 3-bromo-propanol (77 ul, 0.84 mmol) in acetonitrile (10 ml) was added NaI (0.25 g, 1.7 mmol) and K2CO3 (0.23 g, 1.7 mmol). The mixture was stirred at 85° C. for 1 h, and then N-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine (0.43 g, 1.12 mmol) was added. The reaction mixture was heated at 85° C. overnight. Solvent was removed, the residue was washed with H2O, and extracted twice with EtOAc. The EtOAc extracts were dried over Na2SO4, filtered, and concentrated. The crude mixture was purified by preparative HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile:H2O, UV detection at 254 nm) to give 225 mg (60%) of the title compound as a white solid. MS (ESI) 448.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14](F)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)=[C:4]([CH3:22])[CH:3]=1.[C-:23]#[N:24].[Na+].O.C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([C:23]#[N:24])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)=[C:4]([CH3:22])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1NC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Br)cc(C)c1NC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.3 %

Procedure:
To a solution of N-(4-bromo-2,6-dimethyl-phenyl)-4-fluoro-3-nitro-benzamide (18.3 g, 49.8 mmol) (Example I1) in N,N-dimethylformamide (115 ml) was added sodium cyanide (2.7 g, 54.8 mmol). The reaction mixture was stirred at ambient temperature for 4 hours, then heated to 60° C. for 16 hours. More sodium cyanide (0.73 g, 14.8 mmol) was added and the reaction mixture was heated to 60° C. for a further 8 hours. The reaction mixture was cooled to ambient temperature before the addition of water (200 ml) and ethyl acetate (100 ml). The organic extract was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 3:1), yielding N-(4-bromo-2,6-dimethyl-phenyl)-4-cyano-3-nitro-benzamide (11.8 g, 63% yield). LC/MS (Method A): 374 (MH+). 1H-NMR (400 MHz, DMSO-d6): 8.91 (s, 1H), 8.53 (d, 1H), 8.4 (d, 1H), 7.4 (s, 2H), 2.2 (s, 6H) ppm.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][S:4](Cl)(=[O:6])=[O:5].C(O[C:13]([C:15]1([CH2:21][CH2:22]OC)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14])C.[F:25][C:26]([F:38])([F:37])[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1>>[CH2:3]([S:4]([N:18]1[CH2:17][CH2:16][C:15]2([C:13](=[O:14])[N:36]([C:33]3[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][C:26]([F:25])([F:37])[F:38])=[CH:31][CH:32]=3)[CH2:22][CH2:21]2)[CH2:20][CH2:19]1)(=[O:6])=[O:5])[C:2]([CH3:9])([CH3:8])[CH3:1]
Reactant: Nc1ccc(OCCC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CC(C)(C)CS(=O)(=O)Cl
Product: CC(C)(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(OCCC(F)(F)F)cc3)C2=O)CC1

Procedure:
This material was prepared according to example 1 steps C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester 2,2-dimethyl-propane-1-sulfonyl chloride, 4-(3,3,3-trifluoro-propoxy)-phenylamine as white solid. MS (ESI): 477.2 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:26]4[CH:27]=[CH:22][CH:23]=[C:24]([N:28]5[CH2:29][CH2:30][CH:31]([N:34]6[CH2:35][CH2:36][O:37][CH2:38][CH2:39]6)[CH2:32][CH2:33]5)[CH:25]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: Brc1cccc(N2CCC(N3CCOCC3)CC2)c1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(N5CCC(N6CCOCC6)CC5)c4)nc23)cc1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-[1-(3-bromo-phenyl)-piperidin-4-yl]-morpholine (100.0 mg, 0.3075 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.035 g, 25%). MP=230-236° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.4 Hz, 1H), 8.26 (d, J=8.0 Hz, 2H), 8.08 (d, J=7.1 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H), 7.35 (s, 1H), 7.24-7.18 (m, 1H), 7.01 (d, J=6.7 Hz, 1H), 6.96 (d, J=7.9 Hz, 1H), 6.84 (s, 1H), 6.60 (d, J=8.4 Hz, 1H), 3.81 (d, J=11.7 Hz, 2H), 3.77-3.72 (m, 4H), 3.10 (s, 3H), 2.78 (t, J=11.8 Hz, 2H), 2.63-2.58 (m, 4H), 2.40-2.30 (m, 1H), 1.97 (d, J=12.7 Hz, 2H), 1.74-1.62 (m, 2H). MS=533 (MH)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8].F[C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]>>[F:1][C:2]([F:12])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH:8][C:20]1[CH:21]=[N:22][CH:23]=[CH:15][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: NCc1cccc(OC(F)(F)F)c1
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1cccc(OC(F)(F)F)c1
Yield: 4 %

Procedure:
The title compound was prepared in 4% yield from 3-trifluoromethoxy-benzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.47 (br s, 1H), 8.11 (br s, 1H), 7.84 (br s, 1H), 7.59 (s, 1H), 7.24-7.51 (m, 4H), 4.64 (s, 2H). [M+H] calc'd for C14H11F3N2O3, 313; found 313.