Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]([F:36])([F:35])[C:15]1[C:20]([C:21]([O:23][CH2:24]C)=[O:22])=[CH:19][C:18]([C:26]([O:28][CH2:29]C)=[O:27])=[C:17]([C:31]([F:34])([F:33])[F:32])[N:16]=1.Cl[Si:38]([CH3:41])([CH3:40])[CH3:39]>CCCCCC.C1COCC1.O>[F:13][C:14]([F:36])([F:35])[C:15]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([Si:38]([CH3:41])([CH3:40])[CH3:39])[C:18]([C:26]([O:28][CH3:29])=[O:27])=[C:17]([C:31]([F:34])([F:33])[F:32])[N:16]=1
Reactant: CCOC(=O)c1cc(C(=O)OCC)c(C(F)(F)F)nc1C(F)(F)F
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: O
Product: COC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
To 10 ml of dry THF at −78° C. was added 8.4 ml (0.012 mol) of 1.55 M n-butyllithium in hexane followed by 1.21 g (1.7 ml, 0.012 mol) of diisopropylamine. After stirring at −78° C. for 30 min, a solution of 3.59 g (0.01 mol) of diethyl 2,6-bis(trifluoromethyl)-3,5-pyridine-dicarboxylate (prepared by the procedure similar to example 1 of U.S. Pat. No. 4,692,184) in 10 ml of dry THF was added. The reaction turned dark red and after stirring at −78° C. for 10 min, 4.4 g (0.05 mol) of chlorotrimethylsilane was added. The reaction was warmed to room temperature, stirred for 30 min and then was poured into 0° C. water, extracted with ether, dried (MgSO4) and concentrated in vacuo. The residue was purified by HPLC (1:20 EtOAc:hexane) affording 2.09 g of the product as a light yellow oil which crystallized upon standing: mp 29-31° C.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].C1COCC1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH2:22][C:23]#[N:24])[C:18]([O:20]C)=O)=[CH:13][CH:12]=1.O>CCOCC.C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][C:23]3([CH2:2][CH2:1]3)[NH:24][C:18]2=[O:20])=[CH:15][CH:16]=1
Reactant: CC[Mg+]
Reactant: COC(=O)C(CC#N)c1ccc(Cl)cc1
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O=C1NC2(CC2)CC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
LHMDS (1.0 M solution in THF, 13.1 mL, 13.1 mmol) was added dropwise at −78° C. under nitrogen to a stirred solution of methyl 2-(4-chlorophenyl)acetate (2.20 g, 11.9 mmol) in THF (40 mL). The resulting solution was stirred at −78° C. for 1 hour. A solution of 2-bromoacetonitrile (2.50 g, 20.9 mmol) in THF (16 mL) was added dropwise. The reaction was stirred at −78° C. for 1 hour. The reaction was then warmed to room temperature and stirred overnight. The reaction was then quenched with 1N HCl. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexanes: EtOAc, 4:1) to give methyl 2-(4-chlorophenyl)-3-cyanopropanoate (2.60 g, 98%) as a white solid. A solution of EtMgBr in THF (1.0 M, 8.0 mL, 8.0 mmol) was added dropwise at room temperature to a stirred solution of this methyl 2-(4-chlorophenyl)-3-cyanopropanoate (0.894 g, 4.00 mmol) and Ti(i-PrO)4 (1.30 mL, 4.40 mmol) in Et2O (20 mL). After the mixture was stirred at room temperature for 1 hour, water (4 mL) was added, followed by DCM (100 mL). The resulting precipitate was filtered and washed with DCM. The combined filtrates were dried and concentrated. The residue was purified by column chromatography (hexanes:EtOAc, 1:1) to give 6-(4-chlorophenyl)-4-azaspiro[2.4]heptan-5-one (0.330 g, 37%) as a white solid. LCMS (APCI+) [M-Boc+H]+ 222.2; Rf: 2.44 min.
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH2:5][CH2:6]O)#[N:2].N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[I-:37].[Na+]>C(#N)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:1]([C:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH2:5][CH2:6][I:37])#[N:2]
Reactant: [I-]
Reactant: N#CC(CCCO)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#CC(CCCI)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
To a solution of 4-cyano-4,4-diphenylbutan-1-ol (2.2 g, 8.7 mmol.) and pyridine (2.69 ml, 33 mmol.) in acetonitrile (20 ml) was added p-toluenesulfonyl chloride (1.66 g, 8.7 mmol.). To the mixture was added 4-dimethylaminopyridine (a catalytic amount), and the mixture was stirred for two hours at room temperature. To the reaction mixture was added ethyl acetate, which was washed with a 1N HCl and a saturated aqueous saline solution, and, then, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was dissolved in acetone (30 ml), to which was added sodium iodide (1.96 g, 13 mmol.). The mixture was refluxed for one hour. The solvent was distilled off under reduced pressure. To the residue was added water, which was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution and a dilute aqueous solution of sodium thiosulfate, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography, eluting with ethyl acetate, to afford the title compound (1.3 g).
Reaction SMILES: [C:1]1([O:7][C:8]2[C:13]3[CH:14]=[N:15][C:16]4[NH:20][N:19]=[CH:18][C:17]=4[C:12]=3[N:11]3[N:21]=[CH:22][N:23]=[C:10]3[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:24]([N:20]1[C:16]2[N:15]=[CH:14][C:13]3[C:8]([O:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:9][C:10]4[N:11]([N:21]=[CH:22][N:23]=4)[C:12]=3[C:17]=2[CH:18]=[N:19]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(Oc2nc3ncnn3c3c2cnc2[nH]ncc23)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)n1ncc2c1ncc1c(Oc3ccccc3)nc3ncnn3c12

Procedure:
0.01 mol. of 5-phenyloxy-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine and 0.02 mol. of benzoyl chloride are stirred overnight in 50 ml. of dry pyridine at room temperature. On addition of 50 ml. of water, 8-benzoyl-5-phenyloxy-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine is filtered off.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].B.CSC.Cl.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1c(F)cc(F)cc1Cl
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CSC
Product: NCc1c(F)cc(F)cc1Cl
Temperature: 0 °C

Procedure:
To a solution of 2-chloro-4,6-difluorobenzonitrile (210 mg, 1.2 mmol) in 2.4 mL THF was added a 2M solution of borane-DMS in THF (0.6 mL). This reaction mixture was allowed to stir at refluxing temperature for 18 hours resulting in a loss of all solvent. The residue was re-dissolved in 3 mL THF, cooled to 0° C., a 6M solution of HCl(aq) was carefully added, and the mixture returned to reflux for 30 minutes. The reaction mixture was once again cooled to 0° C. and treated with 4M NaOH(aq). The aqueous phase was extracted with DCM, combined organic phases dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by flash chromatography (0-10% MeOH/DCM) to afford (2-chloro-4,6-difluorophenyl)methanamine. 1H-NMR (400 MHz, Chloroform-d) δ 6.95 (dt, J=8.3, 2.1 Hz, 1H), 6.76 (td, J=9.4, 2.5 Hz, 1H), 3.94 (d, J=1.9 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](I)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrCCBr.C[Si](Cl)(C)C.Br[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[Zn].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]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Product: CC(C)(C)OC(=O)N1CC(c2ccc([N+](=O)[O-])cc2)C1
Yield: 51.6 %

Procedure:
Following the same procedure as described in 46.3, the organozinc species was prepared using 3-iodo-azetidine-1-carboxylic acid tert-butyl ester (1.74 g, 6.14 mmol), Zn dust (520 mg, 7.95 mmol), 1,2 dibromoethane (84 μl, 0.97 mmol) and trimethylsilyl chloride (115 μl, 0.92 mmol). It was then coupled with 1-bromo-4-nitrobenzene (1.24 g, 6.13 mmol) using Pd2(dba)3 (90 mg, 0.10 mmol) and P(2-furyl)3 (85 mg, 0.36 mmol). Purification of the crude product by flash column chromatography (heptane:ethyl acetate, 4:1) provides the title compound (880 mg, 52%) as a light yellow oil.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:20]([CH2:22][NH2:23])[OH:21]>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([NH:23][CH2:22][CH2:20][OH:21])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Reactant: NCCO
Solvent: CS(C)=O
Product: OCCNc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 120 °C

Procedure:
210 mg of product obtained in stage 1 above are mixed with 2 ml of DMSO and 0.3 ml of ethanolamine, and the mixture is then heated at 120° C. for approximately 48 hours with stirring. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 90-9-1 mixture for eluent. Evaporation is carried out and a paste is formed in methylene chloride-methanol (5-5). Partial drying and drying under vacuum at 50° C. are carried out. 118 mg of expected product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=C)=[CH:4][CH:3]=1.C(Cl)Cl.CSC.C[OH:23]>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[O:23])=[CH:4][CH:3]=1
Reactant: C=CCn1c(=O)ccc2ccc(F)cc21
Reactant: CO
Solvent: ClCCl
Solvent: CSC
Product: O=CCn1c(=O)ccc2ccc(F)cc21
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
A solution of 7-fluoro-1-(2-propen-1-yl)-2(1H)-quinolinone (5.0 g, 0.025 mmol) in 3:1 CH2Cl2:MeOH (500 mL) was cooled to −70° and 03 was bubbled through the solution for 20 min. Dimethyl sulfide (19 mL, 0.25 mol) were added and the reaction was stirred for 90 min at −70° C., then allowed to warm to room temperature overnight. The solvents were removed under reduced pressure yielding a thick orange oil. Purification by column chromatography on silica gel (1% to 100% hexane:ethyl acetate gradient) yielded a dark yellow solid (4.2 g, 82%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([C:15]1[C@@H:20]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[N:19]2[N:29]=[C:30]([NH:32][C:33](=[O:42])[O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:31]=[C:18]2[N:17]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=2)[C:16]=1[CH3:53])#[N:14]>N1C=CC=CC=1.C1COCC1>[C:13]([C:15]1[C@@H:20]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[N:19]2[N:29]=[C:30]([N:32]([S:9]([CH3:8])(=[O:11])=[O:10])[C:33](=[O:42])[O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:31]=[C:18]2[N:17]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=2)[C:16]=1[CH3:53])#[N:14]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(C(=O)OCc3ccccc3)S(C)(=O)=O)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas and at room temperature, triethylamine (11.1 mg, 140 μmol, 2.6 eq.) and methanesulfonyl chloride (41 mg, 360 μmol, 10 eq.) were added to a solution of benzyl {(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}carbamate (20 mg, 36 μmol; Example 38) in dry pyridine (2 ml) and THF (2 ml), and the mixture was stirred for 12 h. The reaction mixture was then concentrated under reduced pressure and directly purified by preparative HPLC (Reprosil C18 column, 30×200 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (17.4 mg, 72% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:21][CH:22]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NCCCCSc2ccc(N)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NCCCCSc2ccc(NS(C)(=O)=O)cc2)cc1

Procedure:
A solution of 2.4 g of 4-methyl-N-[4-(4-aminophenylthio)butyl]benzenesulfonamide (Example 72) in 50 ml of pyridine is treated with 1.05 g of methane-sulfonyl chloride, and the solution stirred and heated on the steam bath for 6 hours. The pyridine is then removed in vacuo. The residue is shaken with 100 ml of water, and the mixture acidified below pH=2 with concentrated hydrochloric acid. The precipitate is collected, washed with water and dried. Recrystallization from 50% aqueous ethanol gives shiny white crystals after drying, m.p. 95°-96° C.; yield, 1.2 g.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[C:2]1([CH2:1][N:8]([CH3:9])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CCc1ccc([N+](=O)[O-])cc1)Cc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CN(CCc1ccc(N)cc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To a solution of N-benzyl-N-methyl[2-(4-nitrophenyl)ethyl]amine (3.9 g, 14.4 mmol) in 85% acetic acid (250 ml) was added in one portion zinc dust (9.4 g, 144 mmol). The reaction was stirred for 30 minutes, filtered, and concentrated. The residue was dissolved in water (50 ml), the solution basified with 2.5N aqueous sodium hydroxide and the mixture extracted with several portions of methylene chloride. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to yield 4-(2-((phenylmethyl)(methyl)amino)ethyl)phenylamine (3.41 g, 98%). The dihydrochloride salt, from methanol-ethyl acetate, melted at 275° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[CH2:10][CH2:9][CH:8]2[NH:18][C:19](=[O:23])[O:20][CH2:21][CH3:22])=[CH:4][CH:3]=1.[H-].[Na+].C(S(O[CH2:35][CH2:36][N:37]([CH3:44])[S:38]([CH2:41][CH2:42][CH3:43])(=[O:40])=[O:39])(=O)=O)CC.C(OCC)(=O)C>CN(C=O)C.C(OCC)(=O)C.C1CCCCC1.O>[CH2:21]([O:20][C:19](=[O:23])[NH:18][CH:8]1[CH2:9][CH2:10][C:11]2[C:16](=[CH:15][C:14]([O:17][CH2:35][CH2:36][N:37]([CH3:44])[S:38]([CH2:41][CH2:42][CH3:43])(=[O:40])=[O:39])=[CH:13][CH:12]=2)[CH:7]1[CH2:6][C:5]1[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:22]
Reactant: CCOC(=O)NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)cc1
Reactant: CCCS(=O)(=O)OCCN(C)S(=O)(=O)CCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)N(C)CCOc1ccc2c(c1)C(Cc1ccc(Cl)cc1)C(NC(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 1-(4-chlorobenzyl)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.128 g, 0.355 mmol) in DMF under N2 was treated with sodium hydride (0.014 g, 0.568 mmol) and the reaction was stirred for 30 minutes at room temperature. A solution of 2-(N-methylpropylsulfonamido)ethyl propane-1-sulfonate (0.102 g, 0.355 mmol) (see step 1) in DMF was added and the reaction mixture was stirred at ambient temperature over night. The mixture was portioned between ethyl acetate and water. The organic layer was washed with water, dried (MgSO4), filtrated and evaporated to afford brown/white crystals. After addition of a few drops of ethyl acetate/cyclohexane (1:4) a white precipitate formed. Yield 43 mg
Reaction SMILES: C([O-])(=O)C.[C:5]([O:9][C@@H:10]([C:16]1[C:31]([CH3:32])=[CH:30][C:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=3)[S:22][C:18]=2[C:17]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:11]([O:13]CC)=[O:12])([CH3:8])([CH3:7])[CH3:6].[CH3:40][O:41][C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][C:47]=1[O:48][CH3:49].C([O-])([O-])=O.[K+].[K+]>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>[C:5]([O:9][C@@H:10]([C:16]1[C:31]([CH3:32])=[CH:30][C:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:45]4[CH:44]=[CH:43][C:42]([O:41][CH3:40])=[C:47]([O:48][CH3:49])[CH:46]=4)[N:24]=3)[S:22][C:18]=2[C:17]=1[C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C:11]([OH:13])=[O:12])([CH3:7])([CH3:6])[CH3:8]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: COc1ccc(-c2nccc(-c3nc4cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(-c5ccc(Cl)cc5)c4s3)n2)cc1OC
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
Preparation of (S)-ethyl 2-tert-butoxy-247-(4-chlorophenyl)-2-(2-(3,4-dimethoxyphenyl)pyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate: (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (50.0 mg, 0.094 mmol), 3,4-dimethoxyphenylboronic acid (20.6 mg, 0.113 mmol), tetrakis(triphenylphosphine)palladium(0) (16.4 mg, 0.014 mmol), and K2CO3 (39.2 mg, 0.283 mmol) were taken in a microwave vial, and the vial was vacuum pumped and flushed with argon three times. To this mixture was added degassed 1,4-dioxane (1 mL) and degassed water (0.25 mL). The reaction mixture was stirred at 110° C. for 1.5 h, filtered through Celite (ethyl acetate eluent), and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the product. LCMS-ESI+ calc'd for C34H35ClN3O5S (M+H+): 632.2; Found: 632.2 (M+H+).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Cl.Br[C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[CH2:40][NH:39][CH2:38]2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[CH2:38]1[C:37]2[C:41](=[CH:42][C:43]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]3)=[CH:35][CH:36]=2)[CH2:40][NH:39]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Reactant: Brc1ccc2c(c1)CNC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CNC5)cc23)CC1
Yield: 7.5 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (150 mg, 0.325 mmol) in dioxane (0.75 mL) and water (0.25 mL), was added 5-bromo-2,3-dihydro-1H-isoindole hydrochloride (130 mg, 0.651 mmol), and cesium carbonate (636 mg, 1.952 mmol). The reaction mixture was kept under argon for 10 min before addition of tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol). The resultant mixture was heated in a microwave for 20 min at 150° C. Mixture was then purified by HPLC to give 11 mg of the title compound.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[Br:30][C:31]1[CH:38]=[C:37]([F:39])[C:34]([CH:35]=O)=[C:33]([F:40])[CH:32]=1>O1CCCC1>[CH3:2][O:3][CH:4]=[CH:35][C:34]1[C:37]([F:39])=[CH:38][C:31]([Br:30])=[CH:32][C:33]=1[F:40]
Reactant: O=Cc1c(F)cc(Br)cc1F
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (1133 g, 3.7 mol) was suspended in tetrahydrofuran (7.0 L) under argon atmosphere, and stirred with ice-water cooling. t-BuOK (397 g, 3.54 mol) was added in portions. Then a solution of 4-bromo-2,6-difluorobenzaldehyde (340 g, 1.54 mol) in tetrahydrofuran (2.7 L) was added and the reaction was stirred at room temperature for 6 hours. The solution was then poured into ice-water and extracted with ethyl acetate (2×). The combined organic phases were dried and concentrated in vacuo. This material was purified by flash chromatography to afford the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:12]=[C:11]([Cl:23])[C:10]=1[F:24])(C)(C)C.Cl>O1CCOCC1>[Cl:23][C:11]1[C:10]([F:24])=[C:9]([CH:14]=[C:13]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:12]=1)[CH2:8][NH2:7]
Reactant: CN1CCN(Cc2cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(Cc2cc(Cl)c(F)c(CN)c2)CC1

Procedure:
was prepared according to Scheme C2 (step D) from [3-chloro-2-fluoro-5-(4-methyl-piperazin-1-ylmethyl)-benzyl]-carbamic acid tert-butyl ester (225 mg, 0.61 mmol) and 4N HCl in dioxane. MS (LC-MS): 272.0 [M]+; tR (HPLC conditions c): 2.07 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([F:32])[F:31])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([F:32])[F:31])=[CH:26][CH:25]=2)[C@@H:12]2[CH2:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: FC(F)c1ccc(CBr)cc1
Product: O=C1NCCC(F)(F)C[C@H]1N(Cc1ccc(C(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
4-Chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 1-bromomethyl-4-difluoromethyl-benzene analogous to Example 1 to afford 4-chloro-N-(4-difluoromethyl-benzyl)-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide: