Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])=O.[NH4+].[N+:5]([C:8]1[CH:9]=[C:10]([NH:14][C:15]([C:17]2[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:11]=[CH:12][CH:13]=1)([O-])=O.C1COCC1>[OH-].[OH-].[Pd+2].C(O)(C)C.C(OCC)(=O)C>[NH2:5][C:8]1[CH:9]=[C:10]([NH:14][C:15]([C:17]2[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Nc1cccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c1
Yield: 93.8 %

Procedure:
Ammonium formate (16.3 g, 258 mmol, 3 equiv), followed by Pearlman's catalyst [Pd(OH)2] (6.03 g, 4.30 mmol, 0.05 equiv) was added to a solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid (3-nitro-phenyl)-amide (33.2 g, 85.9 mmol, 1 equiv) in isopropanol (330 mL, 10 volumes) and ethyl acetate (170 mL, 5 volumes). The mixture was heated at reflux for 3 hours. After cooling, THF (500 mL) was added to the reaction mixture to help solubilize the product. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated to about 100 mL. Ethyl acetate (600 mL) and THF (200 mL) were added. The organic layer was washed with saturated sodium bicarbonate solution (300 mL), dried over sodium sulfate, filtered, and concentrated to afford 4′-trifluoromethyl-biphenyl-2-carboxylic acid (3-amino-phenyl)-amide (28.7 g, 94%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:16](=[O:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[H-].[Na+].[CH3:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28](OC)=[O:29].Cl>O1CCCC1.O>[CH3:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28](=[O:29])[CH2:17][C:16]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:2]([CH3:1])[CH:3]=1)=[O:18]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C)c1
Reactant: COCCOc1ccccc1C(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1ccccc1C(=O)CC(=O)c1ccc(OCc2ccccc2)c(C)c1
Temperature: 25 °C
Yield: 16.9 %

Procedure:
To a solution of 1-{3-methyl-4-[(phenylmethyl)oxy]phenyl}ethanone (0.81 g, 3.4 mmol) in tetrahydrofuran (11 mL) was added sodium hydride (0.27 g, 6.7 mmol) followed by methyl 2-{[2-(methyloxy)ethyl]oxy}benzoate (0.70 g, 3.4 mmol, Harkin, S. H.; Wells, N. S., GB Patent 2250511, 1992) and the resultant mixture was heated in a 60° C. oil bath for 12 h. The solution was allowed to cool to room temperature and was diluted with water then 1M aqueous hydrochloric acid. The mixture was extracted (3× ethyl acetate) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 5:1 hexanes/ethyl acetate) gave 0.24 g (17%) of 1-(2-{[2-(methyloxy)ethyl]oxy}phenyl)-3-{3-methyl-4-[(phenylmethyl)oxy]phenyl}propane-1,3-dione as a colorless oil. 1H NMR (400 MHz, CDCl3): 8.01 (dd, 1H), 7.89 (m, 2H), 7.34-7.45 (m, 7H), 7.08 (t, 1H), 6.97 (d, 1H), 6.92 (d, 1H), 5.17 (s, 2H), 4.24 (m, 2H), 3.85 (m, 2H), 3.42 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[C:10]([O:20][CH3:21])=[C:11]([CH:17]([NH2:19])[CH3:18])[CH:12]=[C:13]([F:16])[C:14]=1[CH3:15].Br[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.C(N(CC)C(C)C)(C)C.C(O)C>CO>[Br:8][C:9]1[C:10]([O:20][CH3:21])=[C:11]([CH:17]([NH:19][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3[CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH3:18])[CH:12]=[C:13]([F:16])[C:14]=1[CH3:15]
Reactant: COc1c(C(C)N)cc(F)c(C)c1Br
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(F)c(C)c1Br
Temperature: 95 °C
Yield: 24.6 %

Procedure:
A mixture of 1-(3-bromo-5-fluoro-2-methoxy-4-methylphenyl)ethanamine trifluoroacetate (130 mg, 0.35 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (150 mg, 0.53 mmol, from Example 108, Step 1), N,N-diisopropylethylamine (0.31 mL, 1.8 mmol) and ethanol (2.0 mL) was heated at 95° C. for 1 hour. The resulting mixture was diluted with methanol and purified by preparative LCMS (pH 10) RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 60 mL/min) to afford N-[1-(3-Bromo-5-fluoro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (40 mg, 47%). LCMS calculated for C20H24BrFN5O2 (M+H)+: m/z=464.0, 466.0. Found: 464.1, 466.1.
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2[CH:6]=[N:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:28].[CH:29]1([O:32][C:33]2[CH:34]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:36]=[CH:37][C:38]=2[O:39][CH:40]([F:42])[F:41])[CH2:31][CH2:30]1.C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.O>[CH:29]1([O:32][C:33]2[CH:34]=[C:35]([C:2]3[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:5]4[CH:6]=[N:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:16])[CH3:17])[C:9](=[O:10])[C:4]=4[C:3]=3[CH3:28])[CH:36]=[CH:37][C:38]=2[O:39][CH:40]([F:41])[F:42])[CH2:30][CH2:31]1
Reactant: Cc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Reactant: CC1(C)OB(c2ccc(OC(F)F)c(OC3CC3)c2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Yield: 84.5 %

Procedure:
To a mixture of 1.46 g (3.00 mmol) of 2-bromo-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the following Reference example 18-(d) and 1.47 g (4.50 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in the following Reference example 1-(a) were added 7 mg of palladium acetate, 22 mg of butyl-di-1-adamantylphosphine, 20 ml of toluene, 2.59 g of potassium phosphate and 1.2 ml of water, and the mixture was degassed under reduced pressure and replaced with argon. The reaction mixture was refluxed for 6 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=1:0→2:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 1.54 g of the title compound as a slightly yellowish oil. (Yield: 84%)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2].[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:29][CH:26]4[CH2:28][CH2:27]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: NC1CC1
Product: COc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NC3CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methoxyphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and cyclopropanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.61 (br. s., 2H) 0.67-0.80 (m, 2H) 2.78-2.93 (m, 1H) 3.96 (s, 3H) 7.37-7.55 (m, 2H) 8.38 (d, J=7.6 Hz, 1H) 8.46 (br. s., 1H) 8.59 (br. s., 1H) 8.68 (br. s., 1H) 8.75 (br. s., 1H) 8.89 (s, 1H) 13.40 (br. s., 1H). MS m/z [M+H]+ 376.4.
Reaction SMILES: ClC1C=C([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[C:32]1([CH2:38][CH2:39]CCC(O)=O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:31][C@H:28]1[CH2:27][CH2:26][C@H:25]([N:11]([CH2:10][CH2:9][CH2:8][CH2:39][CH2:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:30][CH2:29]1
Reactant: O=C(O)CCCCc1ccccc1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCCCc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 5-phenyl-pentanoic acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](Cl)=[N:12][CH:11]=1.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])=[N:12][CH:11]=1
Reactant: NCCCCCCN
Reactant: Nc1ccccc1NC(=O)c1ccc(Cl)nc1
Product: NCCCCCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Yield: 66.9 %

Procedure:
N-(2-Aminophenyl)-6-chloronicotinamide (248 mg, 1 mmol) and 1,6-diaminohexane (5.80 g, 50 mmol) were heated to 80° C. for 3 hours. The excess 1,6-diaminohexane was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (219 mg, 67% yield) as a brown solid. LC-MS (m/z) 328 (M+1).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br>C(O)C>[O:19]1[CH2:20][CH2:21][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:17][CH2:18]1
Reactant: BrCCOCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)CCOCC1
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
Diethyl malonate (32.0 g) was added to a solution of sodium ethoxide (1 equivalent) in ethanol and the solution was stirred for 30 min. 2-Bromoethyl ether (46.0 g) was then added and the mixture was stirred at reflux for 3 h. The mixture was then cooled, evaporated in vacuo and the residue partitioned between water and dichloromethane. The organic layer was separated and washed with water and brine, then dried (MgSO4) and evaporated. The residue was then purified by flash column chromatography on silica gel, eluting with 4:1 hexanes/ether, to give the title compound (28.0 g) as colourless liquid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>>[Cl:32][C:33]1[CH:38]=[C:37]([C:12]2[N:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1cccc(Cl)c1
Product: Clc1cccc(-c2c3c(nn2-c2ccccc2)CCNCC3)c1
Yield: 27.8 %

Procedure:
The title compound (37.5 mg) was prepared from 192.3 mg of 2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 176, Step B) and 84.7 mg of 3-chlorophenylboronic acid as in Example 199. MS (ESI): exact mass calculated for C19H18ClN3, 323.12; found, m/z 324.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.32-7.16 (m, 8H), 7.01-6.98 (m, 1H), 3.12-3.08 (m, 2H), 3.05-3.02 (m, 2H), 3.01-2.98 (m, 2H), 2.69-2.66 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([NH:6][CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:6]2[CH2:7][CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:9][C:28]2=[O:30])=[CH:16][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC(CNc1ccc(Br)cc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC(c2ccccc2)CN1c1ccc(Br)cc1
Temperature: 0 °C
Yield: 151.2 %

Procedure:
A solution containing 2-(4-bromoanilino)-1-phenyl-1-ethanol (0.74 g, 0.00253 mol), N,N-diisopropylethylamine (1.01 g, 0.00786 mol) and N,N-dimethylaminopyridine (0.092 g, 0.00076 mol) in anhydrous dichloromethane (32 mL) was cooled to 0° C. and a solution of triphosgene (0.38 g, 0.00127 mol) in anhydrous dichloromethane (8 mL) was added dropwise. The reaction mixture was slowly warmed up to ambient temperature while stirring under an atmosphere of nitrogen for eighteen hours. The organic phase was washed with a saturated solution of sodium bicarbonate in water (40 mL), brine (30 mL) and dried with magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography on silica using ethyl acetate/n-heptane (1:5) as mobile phase to yield 3-(4-bromophenyl)-5-phenyl-1,3-oxazolan-2-one (0.62 g, 0.00192 mol) as a white solid.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[Br:9][C:10]1[C:25]([F:26])=[CH:24][C:13]2[O:14][C:15]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=3[CH:17]=[N:18][C:12]=2[CH:11]=1.C(OCC)C>C1(C)C(C)=CC=CC=1>[Br:9][C:10]1[C:25]([F:26])=[CH:24][C:13]2[O:14][C:15]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=3[C@H:17]3[C@H:2]([C:1]([OH:7])=[O:8])[CH2:3][CH2:4][C:5](=[O:6])[N:18]3[C:12]=2[CH:11]=1
Reactant: O=C1CCCC(=O)O1
Reactant: Fc1ccc2c(c1)Oc1cc(F)c(Br)cc1N=C2
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: O=C(O)[C@@H]1CCC(=O)N2c3cc(Br)c(F)cc3Oc3cc(F)ccc3[C@@H]12
Temperature: 150 °C

Procedure:
Glutaric anhydride (7.93 g, 69.5 mmol) was added to a stirred solution of 8-bromo-3,7-difluoro-dibenz[b,f][1,4]oxazepine (14.4 g, 46.4 mmol) in xylene (30 mL) and the mixture was heated to 150° C. for 72 h. The reaction mixture was allowed to cool to ambient temperature, and diethyl ether was added. The product was collected by filtration and dried to yield the title compound which was used without further purification (16.2, 82%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]2[C:16]3([CH2:21][CH2:20][S:19][CH2:18][CH2:17]3)[C:15](=[O:22])[NH:14][C:11]2=[CH:12][CH:13]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:16]3([CH2:17][CH2:18][S:19][CH2:20][CH2:21]3)[C:15](=[O:22])[N:14]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:11]2=[CH:12][CH:13]=1
Reactant: O=C1Nc2ccc(Br)cc2C12CCSCC2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1C(=O)C2(CCSCC2)c2cc(Br)ccc21
Reaction time: 16 h

Procedure:
Cesium carbonate (610 mg, 1.87 mmol) was added to a solution of 5-bromo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-2(1H)-one from Step C (372 mg, 1.25 mmol) and ethyl bromoacetate (0.166 mL, 1.50 mmol) in DMF (2 mL). After 16 h, H2O (5 mL) was added to the reaction and the resulting precipitate was collected by filtration to give the title compound. MS: m/z=386 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[N:10][C:11]2[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][CH3:20])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH3:21][Al](C)C.[OH-].[K+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][CH3:20])([CH3:21])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: C[Al](C)C
Reactant: CCc1cccc(CC)c1N=C(C)c1cccc(Br)n1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1NC(C)(C)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
In argon atmosphere, to a mixture of 6.20 g (18.7 mmol) of N-[1-(6-bromopyridin-2-yl)ethylidene]-2,6-diethylaniline in 110 ml of dry toluene cooled to 0° C., a solution of 2.70 g (37.4 mmol) of AlMe3 in 40 ml of dry toluene was added dropwise for 10 min. The reaction mixture was slowly warmed to room temperature, stirred for 25 min at 40° C., and then cooled to 0° C. Further on, 150 ml of 5% KOH was added dropwise by vigorous stirring for 1 h at this temperature. The aqueous layer was separated, the organic layer was washed with 100 ml of water, 100 ml of brine, dried over Na2SO4, and then evaporated to dryness. Yield 6.40 g (98%) of yellow oil. Anal. Calc. for C18H23BrN2: C, 62.25; H, 6.68, N, 8.07. Found: C, 62.40; H, 6.82, N, 8.04. 1H NMR (CDCl3): δ 7.61 (dd, J=7.5 Hz, J=0.6 Hz, 1H, 5-H in pyridine), 7.51 (t, J=7.5 Hz, 1H, 4-H in pyridine), 7.34 (dd, J=7.5 Hz, J=0.6 Hz, 1H, 3-H in pyridine), 6.97-7.03 (m, 3H, 3, 4, 5-H in 2, 6-Et2C6H3), 3.97 (br.s, 1H, NH), 2.45 (q, J=7.5 Hz, 4H, CH2Me), 1.46 (s, 6H, Me2C), 1.11 (t, J=7.5 Hz, 6H, CH2Me).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH2:39][C:40]1[S:44][CH:43]=[N:42][C:41]=1[CH3:45])[CH2:24][NH:25][CH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:27]1=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:25]([CH2:24][C:23]2[CH:34]=[CH:35][C:36]([O:37][CH2:38][CH2:39][C:40]3[S:44][CH:43]=[N:42][C:41]=3[CH3:45])=[C:21]([O:20][CH3:19])[CH:22]=2)[CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:27]2=[O:33])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(CNC2CCCCNC2=O)ccc1OCCc1scnc1C
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)ccc1OCCc1scnc1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-chlorobenzenesulfonylchloride (0.26 mmol) was added to a methylene chloride (0.2 M) solution of triethylamine (1.0 mmol) and 3-{3-Methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzylamino}-azepan-2-one (7) (0.26 mmol), and stirred at room temperature for 12 h. The product (8) was obtained by purification upon reverse phase HPLC.
Reaction SMILES: [ClH:1].C([CH2:9][NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[OH:18])C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[ClH:1].[CH3:9][NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[OH:18]
Reactant: [H][H]
Reactant: OC1(c2cccnc2)CCCCC1CNCCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CNCC1CCCCC1(O)c1cccnc1
Reaction time: 8 h
Yield: 75.2 %

Procedure:
11.1 g 2-[(benzylmethylamino)methyl]-1-pyridin-3-yl-cyclohexanol hydrochloride were dissolved in 110 ml glacial acetic acid under nitrogen, 2.0 g palladium-on-active charcoal (10 percent by weight) were added as a catalyst and the mixture was stirred under a hydrogen pressure of 2.0 bar until the uptake of hydrogen had ended. The mixture was filtered with suction, the filtrate was concentrated, the residue was stirred overnight with 75 ml isopropanol and the precipitate obtained was filtered off with suction and dried. 6.18 g 2-methylaminomethyl-1-pyridin-3-yl-cyclohexanol hydrochloride were obtained.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C1(C)C=CC=CC=1.[CH2:14]([O:25][C:26]1[CH:27]=C([CH:32]=[CH:33][CH:34]=1)C(O)=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CN(C=O)C.C(Cl)Cl>[CH2:14]([O:25][C:26]1[CH:27]=[C:1]([CH:32]=[CH:33][CH:34]=1)[C:2]([Cl:4])=[O:3])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCOc1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCOc1cccc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
1 mL of oxalyl chloride (11.5 mmol) and two drops of anhydrous DMF are added under argon to 93 mg of toluene-dried acid 22 (318 μmol) dissolved in 20 mL of anhydrous DCM. The medium is stirred at room temperature for two hours, and then concentrated to give 99 mg of a yellow oil, i.e. a yield of 99%.
Reaction SMILES: N#N.Br[C:4]1[C:5]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([NH:16][CH3:17])=[O:15])=[CH:6][C:7]([Cl:10])=[N:8][CH:9]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:30]1(C)[CH:35]=CC=C[CH:31]=1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:10][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([NH:16][CH3:17])=[O:15])[C:4]([C:30]([CH3:35])=[CH2:31])=[CH:9][N:8]=1
Reactant: Cc1ccccc1
Reactant: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: C=C(C)c1cnc(Cl)cc1Nc1ccccc1C(=O)NC
Temperature: 110 °C

Procedure:
In a tube a solution of isopropenyboronic acid pinacol ester (3.31 mL, 17.6 mmole, 3 eq) in toluene (200 mL) was degassed with N2 at 50° C. for 15 min. To this was added Pd(PPh3)4 (0.68 g, 0.59 mmole, 0.1 eq) and 2-(5-bromo-2-chloro-pyridin-4-ylamino)-N-methyl-benzamide (2 g, 5.87 mmole, 1 eq). This mixture was again degassed with N2 for 30 min. A degassed solution of K3PO4 (4.98 g, 23.48 mmole, 4 eq) in H2O (8 mL) was added to the above mixture in one portion and the resulting mixture was heated at 110° C. for overnight. After completion of the reaction, it was allowed to cool to room temperature and solvent was removed under reduced pressure to yield crude product. It was purified by column chromatography over silica gel (60-120 mesh) using 0.5% MeOH-DCM as the eluant to give the title compound as an off white solid (0.8 g, 45%). 1H-NMR (400 MHz, DMSO-d6): δ 2.06 (s, 3H), 2.73-2.74 (d, 3H, J=4.52 Hz), 5.14 (s, 1H), 5.46 (s, 1H), 7.04-7.15 (m, 2H), 7.45-7.60 (m, 2H), 7.64-7.71 (m, 1H), 7.96 (s, 1H), 8.60-8.72 (brs, 1H), 9.87 (s, 1H). LC-MS [M+H]+=302.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]1.C(Cl)Cl.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>C(N(CC)CC)C>[CH3:22][S:23]([O:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:14][CH2:13]1)(=[O:25])=[O:24]
Reactant: COc1ccccc1N1CCN(CCCO)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCOS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-[4-(2-methoxyphenyl)piperazin-1-yl]-1-propanol (24 g, 95.87 mmol), prepared as in Example 10, in 25 mL of triethylamine and 300 mL of methylene chloride was cooled to approximately 0° C. and then methanesulfonyl chloride (8.8 mL) was added dropwise. The mixture was stirred at approximately 0° C. for 1 hour and then at room temperature for 0.5 hours. The mixture was poured into saturated sodium carbonate and stirred for 15 minutes. The organic phase was separated, washed with saturated sodium carbonate (2×150 mL), dried (MgSO4) and concentrated to give 3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl methanesulfonate (21 g, 63.63 mmol).