Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(O)C.[Cl:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: OB(O)c1ccc(F)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: Cc1cc([N+](=O)[O-])cnc1-c1ccc(F)cc1Cl
Temperature: 90 °C
Reaction time: 4.5 h

Procedure:
To a stirred solution of 2-chloro-3-methyl-5-nitropyridine (prepared according to the procedure of Hawkins and Roe, J. Am. Chem. Soc., page 330, 1948) (5.3 g, 30.7 mmol, 1 eq.) in 1,2-dimethoxyethane (50 mL) and ethanol (25 mL) was added 2-chloro-4-fluorobenzeneboronic acid (5.9 g, 33.8 mmol, 1.1 eq.). The resulting mixture was degassed with argon. To the mixture was added a solution of Na2CO3 (11.4 g, 107.45 mmol, 3.5 eq) in water (50 mL). The mixture was degassed with argon, and tetrakis(triphenylphosphine)palladium(0) (1.1 g, 0.95 mmol, 0.03 eq) was added. The mixture was degassed with argon and heated to 90° C. under argon. After 4.5 h, the mixture was cooled. The solvent was removed under reduced pressure. The residue was diluted with water and extracted 3× with ethyl acetate. The aqueous layer was extracted several times with ethyl acetate. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated. The product was purified by flash column chromatography on silica gel eluting with 5% Et2O in hexanes giving 2-(2-chloro-4-fluorophenyl)-3-methyl-5-nitropyridine. Mass spectrum (EST) 267 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.CCN(C(C)C)C(C)C.[C:21]([OH:25])([CH3:24])([CH3:23])[CH3:22].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)n1
Reactant: CC(C)(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)n1
Reaction time: 8 h

Procedure:
To a solution of 2,6-dichloropyrimidine-4-carbonyl chloride (1.026 g, 4.85 mmol) in DCM (25 mL) was added iPr2NEt (1.01 mL, 5.80 mmol) and t-butanol (0.51 mL, 5.3 mmol). The mixture was stirred overnight then pyridine (0.39 mL, 4.8 mmol) was added and the stirring continued over another night. The reaction mixture was evaporated in vacuo and the resulting residue was chromatographed over silica gel with 0-40% EtOAc in hexanes. The product fractions were evaporated in vacuo to give tert-butyl 2,6-dichloropyrimidine-4-carboxylate as a yellow-orange waxy solid (0.310 g, 1.24 mmol, 26% yield). 1H NMR (400 MHz, DMSO-d6): 8.15 (1H, s), 1.56 (9H, s). LC/MS: m/z=271.1 [M+Na]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([NH:24][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:14])[CH:3]=2)[CH3:23])=[CH:18][CH:17]=1
Reactant: COc1cccc2c(Cl)cc(C)nc12
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Product: COc1cccc2c(N[C@H](C)c3ccc(Cl)cc3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 41. Starting materials were 4-chloro-8-methoxy-2-methylquinoline and (R)-1-(4-chloro-phenyl)ethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:13])=[C:7]([CH2:9][C:10](O)=[O:11])[CH:8]=1.CN(C=O)C.S(Cl)([Cl:21])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:13])=[C:7]([CH2:9][C:10]([Cl:21])=[O:11])[CH:8]=1
Reactant: COc1ccc(Br)c(CC(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(CC(=O)Cl)c1
Temperature: 0 °C

Procedure:
5-Methoxy-2-bromophenylacetic acid (56 g, 0.23 mol) is dissolved in CH2Cl2 (350 mL) and a catalytic amount of DMF is added and the solution stirred and cooled to 0° C. Thionyl chloride (41 mL, 0.34 mol) is added dropwise. The reaction mixture is heated at reflux temperature overnight and then cooled to room temperature. Solvents are removed by rotary evaporator. Twice benzene (500 mL) is added to the residual oil and the benzene solution is evaporated by rotary evaporator to remove any additional volatile components. The residual oil is crystallized from hexanes to give 5-methoxy-2-bromophenylacetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[O:10])=[C:4]([N+:33]([O-])=O)[CH:3]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl.CO.O>[NH2:33][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:10]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)cc4[N+](=O)[O-])cc3)c2cc1OC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)cc4N)cc3)c2cc1OC
Temperature: 60 °C
Reaction time: 0.62 h
Yield: 22.2 %

Procedure:
N-(4-Chloro-2-nitrophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea (158 mg) was dissolved in chloroform/methanol/water (10 ml/70 ml/5 ml), sodium thiosulfate (1.01 g) was added, and the admixture was stirred at 60° C. for 37 minutes. The reaction mixture was extracted 2 times with chloroform, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 33 mg of the title compound (yield: 22%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)=[CH:13][C:12]=1[N+:28]([O-:30])=[O:29])C(OCC)=O)[CH3:2].CS(C)=O.O>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)=[CH:13][C:12]=1[N+:28]([O-:30])=[O:29])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)Cc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 87.5 %

Procedure:
A 2 L, 3-necked round bottomed flask equipped with a heating mantle, condenser, overhead stirrer, thermocouple, and N2(g) inlet was charged with 2-[2-Nitro-4-(3-nitro-benzoyl)-phenyl]-malonic acid diethyl ester (105 g, 0.24 mol), DMSO (1 L) and H2O (87 mL) The reaction was heated at 110° C. for 11 h. Thin layer chromatographic analysis (Hexanes/ethylacetate 6:4) indicated completion of reaction. The reaction mixture was cooled to room temperature and was diluted with ethyl acetate (4 L). The organic layer was washed with brine (3×4 L), dried over Na2SO4 and concentrated. Methyl t-butyl ether (1 L) was added to the solids and stirred. The product was filtered and washed with Methyl t-butyl ether (2×250 mL). The solids collected were dried in the vacuum oven at 45° C. for 24 hours to yield 89% of pure [2-Nitro-4-(3-nitro-benzoyl)-phenyl]-acetic acid ethyl ester (77 g, 0.21 mol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.[C:31]([O:35][C:36]([N:38]1[CH2:42][C@H:41]([F:43])[CH2:40][C@H:39]1[C:44](O)=[O:45])=[O:37])([CH3:34])([CH3:33])[CH3:32].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:43][C@H:41]1[CH2:42][N:38]([C:36]([O:35][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:37])[C@H:39]([C:44](=[O:45])[NH:23][C@@:15]([C:4]2[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=[C:2]([F:1])[CH:3]=2)([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:40]1
Reactant: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a solution of (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (42 mg, 0.1 mmol), prepared as described in Procedure 3, 4, 5 and 6, and (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (23 mg, 0.1 mmol) in CH2Cl2 (1 mL) was added EDCI (25 mg, 0.1 mmol) and DMAP (16 mg, 0.1 mmol). The reaction mixture was stirred overnight and concentrated to dryness under a stream of argon. The resulting residue was dissolved in MeOH and purified by preparative HPLC (Phenoma Luna AXIA 10A, C18, eluting with 10-90% MeCN/H2O containing 0.1% TFA, monitoring at 220 nm) to provide (2S,4R)-tert-butyl 4-fluoro-2-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylcarbamoyl)pyrrolidine-1-carboxylate (40 mg, 64% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.30 (s, 1H), 7.13-7.03 (m, 5H), 6.95-6.90 (m, 2H), 6.80-6.78 (m, 2H), 6.70 (bs, 1H), 6.51-6.47 (m, 2H), 5.88-5.67 (m, 1H, —CF2H), 5.10 (app d, J=50 Hz, 1H, —CFH), 4.48-4.45 (m, 1H), 3.89-3.78 (m, 2H), 3.70 (d, J=10 Hz, 1H0, 3.29-3.18 (m, 1H), 2.79-2.55 (m, 2H), 2.25-2.11 (m, 1H), 1.32 (s, 9H); LC/MS: RT=3.746 min [M+H] 641.2 Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeCN/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([C:15]#[N:16])[CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[Cl-].[NH4+].C(OCC)(=O)C>CN(C)C=O>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:15]#[N:16])[C:9](=[O:14])[C:10]([F:13])([F:11])[F:12])[CH3:25]
Reactant: N#Cc1cc(Cl)ccc1NC(=O)C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C(=O)C(F)(F)F)c1ccc(Cl)cc1C#N
Yield: 92.8 %

Procedure:
Under nitrogen, stir and cool to 0° C. a solution of N-(4-chloro-2-cyano-phenyl)-2,2,2-trifluoroacetamide (4.80 g, 19.31 mmol) in dimethylformamide (50 mL), and add NaH (0.7 g, 29.1 mmol). Stir the reaction for 1 h at ambient temperature and add ethyl bromoacetate (4.3 mL, 38.77 mmol) by means of a syringe. Stir at 50° C. overnight and then pour the reaction into aqueous ammonium chloride-ethyl acetate. Wash the organic layer with brine (2×'s), dry over MgSO4, filter and evaporate to obtain an oil. Chromatograph the oil eluting with 20% ethyl acetate/heptane and then 30% ethyl acetate/heptane. Concentrate the appropriate fractions and obtain 6.0 g of a solid MS 335(M+H), m.p. 71–73° C.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([O:38][C:39]1[CH:40]=[CH:41][C:42]([O:50][CH2:51][C@@H:52]2[CH2:54][O:53]2)=[C:43]2[C:48]=1[NH:47][C:46](=[O:49])[CH2:45][CH2:44]2)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:21]([NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:54][C@H:52]([OH:53])[CH2:51][O:50][C:42]3[CH:41]=[CH:40][C:39]([OH:38])=[C:48]4[C:43]=3[CH2:44][CH2:45][C:46](=[O:49])[NH:47]4)=[CH:30][CH:29]=2)[CH2:13][CH2:14]1)=[O:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=C1CCc2c(OC[C@@H]3CO3)ccc(OCc3ccccc3)c2N1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)c4c3CCC(=O)N4)cc2)CC1
Yield: 27.1 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide formate (0.431 g, 1.0 mmol) was reacted with 8-(benzyloxy)-5-[(2S)oxiranylmethoxy]-3,4-dihydro-2(1H)-quinolinone (0.325 g, 1.0 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.19 g, 0.271 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](/[CH:9]=[C:10](\[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])/[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[CH3:25].C(Cl)Cl>[B-](F)(F)(F)F.CC[C@H]1P(C2C(P3[C@H](CC)CC[C@H]3CC)=CC=CC=2)[C@H](CC)CC1.C1[CH][CH]CC[CH][CH]C1.[Rh].CO>[NH2:1][C:2]1[C:3]([CH3:25])=[CH:4][C:5]([CH2:9][C@@H:10]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)/C(=C/c1cc(C)c(N)c(C)c1)C(=O)OCc1ccccc1
Agent: [Rh]
Agent: CC[C@@H]1CC[C@@H](CC)P1c1ccccc1P1[C@H](CC)CC[C@H]1CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H](Cc1cc(C)c(N)c(C)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(Z)-Methyl 3-(4-amino-3,5-dimethylphenyl)-2-(benzyloxycarbonyl)acrylate (84.5 g, 239 mmol) was weighed into a flame-dried 2 L Parr shaker, followed by the addition of methylene chloride (300 mL) and methanol (300 mL). The bottle was swirled to form a light brown suspension, and this suspension was degassed by a flow of nitrogen for 30 min. Following addition of (−)-1,2-bis((2R,5R)-2,5-diethylphospholano)bezene(cyclooctadiene)rhodium(I)tetrafluoroborate ([(2R,5R)-Et-DuPhosRh]BF4) (2.11 g, 3.20 mmol), the bottle was put onto a Parr Hydrogenator. After 5 cycles of purging with hydrogen (60 psi) and vacuum, the final hydrogen pressure was set at 65 psi and the suspension was agitated at room temperature for 16 h (after 3 h, the suspension became a clear solution), and the reaction was complete. Solvents were removed and the residue was subjected to flash chromatography on silica gel using ethyl acetate/methylene chloride (1:9) as the eluent to afford the title compound as a very light tan solid (82.9 g, 98% yield). 1H-NMR (DMSO-d6) δ 7.70 (d, J=7.9 Hz, 1H), 7.37-7.28 (m, 5H), 6.68 (s, 2H), 5.00 (s, 2H), 4.41 (s, 2H), 4.15-4.10 (m, 1H), 3.62 (s, 3H), 2.82 (dd, J=13.7, 5.2 Hz, 1H), 2.65 (dd, J=13.4, 9.8 Hz, 1H), 2.04 (s, 6H); 3C-NMR (DMSO-d6) δ 172.5, 155.9, 142.6, 136.9, 128.3, 128.2, 127.7, 127.5, 124.0, 120.4, 65.3, 56.1, 51.7, 35.9, 17.7.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([O:17][CH3:18])(=[O:16])[CH2:14][SH:15].[CH3:19][N:20]([CH3:38])[C:21]1[CH:37]=[CH:36][C:24]([CH:25](O)[C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:34][N:32]([CH3:33])[C:29]1[CH:28]=[CH:27][C:26]([CH:25]([C:24]2[CH:36]=[CH:37][C:21]([N:20]([CH3:38])[CH3:19])=[CH:22][CH:23]=2)[S:15][CH2:14][C:13]([O:17][CH3:18])=[O:16])=[CH:31][CH:30]=1
Reactant: CN(C)c1ccc(C(O)c2ccc(N(C)C)cc2)cc1
Reactant: COC(=O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)CSC(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Reaction time: 1 h
Yield: 53 %

Procedure:
A slurry of ρ-toluenesulfonic acid monohydrate (1.50 g, 7.89 mmol) and activated 3 Å molecular sieves (300-500 mg) in 7 mL of toluene is stirred for 15 minutes. Methyl thioglycolate (410 mg, 3.86 mmol) is then added followed by 4,4'-bis(dimethyamino)benzhydrol (Aldrich) (950 mg, 3.51 mmol) and stirred for 1 hour. The reaction is diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine and dried over magnesium sulfate. Chromatography on silica gel, eluting with a 1:4 mixture of ethyl acetate: hexane, provides methyl [[bis-(4-dimethylaminophenyl)methyl]thio]acetate as a greenish yellow solid in 53% yield.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=[C:10]([CH3:11])[C:5]2=[C:4]([CH2:18]OS(C)(=O)=O)[CH:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][CH2:33][C:32]1([CH2:41][CH3:42])[CH2:39][CH3:40])=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>C1COCC1.O>[C:24]([O:28][C:29]([N:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[N:34]([CH2:18][C:4]2[CH:3]=[C:2]([Br:1])[N:7]=[C:6]3[N:8]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][O:13]4)[N:9]=[C:10]([CH3:11])[C:5]=23)[CH2:33][C:32]1([CH2:41][CH3:42])[CH2:39][CH3:40])=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCC1(CC)CNC(C)(C)CN1C(=O)OC(C)(C)C
Reactant: Cc1nn(C2CCCCO2)c2nc(Br)cc(COS(C)(=O)=O)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCC1(CC)CN(Cc2cc(Br)nc3c2c(C)nn3C2CCCCO2)C(C)(C)CN1C(=O)OC(C)(C)C
Temperature: 160 °C
Yield: 51.6 %

Procedure:
A mixture of 500 mg of methanesulfonic acid 6-bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl ester, 400 mg of 2,2-diethyl-5,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester and 0.43 ml of DIPEA in 8 ml of dry THF was heated to 160° C. for 30 min in a microwave reactor. For workup the mixture was taken up in water and ethyl acetate, the phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtrated and concentrated in vacuo and the resulting residue was purified by flash chromatography (silica, heptane/ethyl acetate). 369 mg (50%) of the title compound were obtained.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[CH:11]([S:14](Cl)(=[O:16])=[O:15])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][S:14]([CH:11]([CH3:13])[CH3:12])(=[O:16])=[O:15]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NCc1cccc(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)NCc1cccc(Br)c1

Procedure:
In analogy to example 1, step 1, 3-bromobenzylamine hydrochloride was reacted with isopropylsulfonyl chloride and triethylamine in dichloromethane to give propane-2-sulfonic acid 3-bromo-benzylamide as a colorless solid. MS: 290.0 ([M−H]−)
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10]([SH:14])[CH2:11][CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:8][C:6]1[CH:7]=[C:2]([S:14][CH2:10][CH2:11][CH2:12][CH3:13])[CH:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: CCCCS
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: CCCCSc1cc(C)cc(C)c1
Yield: 94.7 %

Procedure:
The general procedure in example 39 was followed. 5-Iodo-m-xylene (144 μL, 1.0 mmol), 1-butanethiol (107 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the n-butyl 3,5-dimethylphenyl sulfide (184 mg, 95% yield) as colorless oil. Column chromatographic solvent (hexane). Rf=0.5 (hexane). 1H NMR (CDCl3, 300 MHz) δ 6.92 (s, 2 H), 6.77 (s, 1 H), 2.89 (t, 2 H, J=7.2 Hz), 2.27 (s, 6 H), 1.41-1.65 (m, 4 H), 0.92 (t, 3 H, J=7.5 Hz). 13C NMR (CDCl3, 75 MHz) δ 138.5, 136.7, 127.7, 126.6, 33.5, 31.6, 22.4, 21.7, 14.1. IR (neat, cm−1) 3083, 3050, 3011, 2965, 2867. MS (EI) m/z (relative intensity) 194 (70), 138 (100). Anal Cald for C12H18S, Cald. C, 74.16; H, 9.34. Found C, 73.89; H, 9.32.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[S:19]([NH2:22])(=[O:21])=[O:20])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[Cl:30].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:23][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]([S:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[S:19]([NH2:22])(=[O:21])=[O:20])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Cc1ccc(NS(=O)(=O)c2cccc(Br)c2)c(S(N)(=O)=O)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: Cc1ccc(NS(=O)(=O)c2cccc(-c3ccc(Cl)c(Cl)c3)c2)c(S(N)(=O)=O)c1
Temperature: 80 °C
Reaction time: 10 h
Yield: 51.6 %

Procedure:
To a solution of 2-(3-bromobenzenesulfonylamino)-5-methyl-benzensulfonamide (1.50 g, 3.70 mmol), 3,4-dichlorobenzeneboronic acid (0.84 g, 4.44 mmol), tricyclohexyl phosphine (0.45 g, 1.60 mmol) and potassium phosphate (3 g, 14.15 mmol) in DMF (10 mL), was added Pd(OAc)2 (0.17 g, 0.74 mmol). The reaction mixture was stirred at 80° C. for 10 h, diluted with 1N HCl and the product was extracted with ethyl acetate. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography using ethyl acetate/hexane (1:3) to afford the title compound (0.9 g, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:18]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=2[Cl:27])=[C:17]([F:28])[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH2:13][C:14](O)=[O:15])[C:7]=2[CH:6]=1)=[O:4].[CH:29]1[CH:30]=CC2N(O)N=[N:35][C:33]=2[CH:34]=1.O.CCN(CC)CC.N1CCCC1.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:18]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=2[Cl:27])=[C:17]([F:28])[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH2:13][C:14](=[O:15])[N:35]3[CH2:30][CH2:29][CH2:34][CH2:33]3)[C:7]=2[CH:6]=1)=[O:4]
Reactant: On1nnc2ccccc21
Reactant: COC(=O)c1cc2c(ncn2CCC(=O)O)c(F)c1Nc1ccc(Br)cc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(ncn2CCC(=O)N2CCCC2)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
To solution of 6-(4-bromo-2-chloro-phenylamino)-3-(2-carboxy-ethyl)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester (60 mg, 0.13 mmol) in DMF (1.8 mL) is added HOBt-H2O (24 mg, 0.16 mmol), Et3N (0.043 mL, 0.31 mmol), pyrrolidine (0.011 mL, 0.13 mmol), and EDCI (34 mg, 0.18 mmol) at room temperature. The resulting yellow solution is stirred 16 hours at room temperature. The reaction mixture is diluted with EtOAc and water, washed with sat'd aqueous NH4Cl, brine, sat'd aqueous NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give a crude material which is purified by flash chromatography (3% MeOH in CH2Cl2) to afford 45 mg (67%) of the desired product: MS APCI (+) m/z 523, 525 (M+, Br pattern) detected.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([F:17])[C:10]=1[F:16])[CH2:28]2
Reactant: COc1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1cccc2c1CN(c1c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 46 %

Procedure:
210 mg of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 115 mg of 4-methoxyisoindoline, 213 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 138 mg of the target compound.