Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([C@@H:18]2[C@H:25]3[C@H:21]([CH2:22][NH:23][CH2:24]3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=O)=[CH:29][CH:28]=1.C(O)(=O)C.C([BH3-])#N>ClCCl>[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH:33]([C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N:23]2[CH2:24][C@H:25]3[C@@H:18]([N:4]([CH:1]4[CH2:2][CH2:3]4)[S:5]([C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=4)(=[O:6])=[O:7])[CH2:19][CH2:20][C@H:21]3[CH2:22]2)=[CH:31][CH:32]=1
Reactant: O=CCCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CC1)[C@H]1CC[C@H]2CNC[C@H]21
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CC1)[C@H]1CC[C@H]2CN(CCCCCC(c3ccc(F)cc3)c3ccc(F)cc3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N-Cyclopropyl-N-[(3aS*,4S*,6aR*)-octahydrocyclopenta[c]pyrrol-4-yl]-3-(trifluoromethyl)benzenesulfonamide from Example 201 (140 mg, 0.374 mmol) and 6,6-bis(4-fluorophenyl)hexanal (108 mg, 0.374 mmol) were combined in dichloromethane (2 mL) and then acetic acid (1 mL) was added. The reaction was stirred at room temperature for 20 minutes, then PS-cyanoborohydride (306 mg, 0.748 mmol) was added. The reaction was stirred at room temperature overnight, then filtered and the resin washed with dichloromethane. The solvent was removed in vacuo and the crude material purified using a silica gel cartridge (Analogix®, Burlington, Wis., RS-12) eluting with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.50 (s, 1H), 8.36 (d, J=7.9, 1H), 7.95 (d, J=7.9, 1H), 7.76 (dd, J=6.4, 14.2, 1H), 7.33 (dd, J=5.6, 8.3, 4H), 7.18-7.11 (m, 4H), 3.96 (dd, J=8.0, 16.3, 2H), 3.18-3.10 (m, 1H), 2.82 (dd, J=3.5, 9.5, 1H), 2.50-2.44 (m, 2H), 2.39 (t, J=8.0, 1H), 2.31-2.21 (m, 4H), 2.03 (dd, J=7.8, 15.3, 2H), 1.91 (dt, J=3.5, 10.4, 1H), 1.59 (dt, J=5.6, 11.5, 1H), 1.51 (dd, J=10.6, 16.2, 1H), 1.46-1.33 (m, 6H), 1.28 (dd, J=7.4, 15.1, 2H), 1.08 (td, J=5.0, 10.5, 1H), 0.84 (dt, J=6.9, 12.6, 1H), 0.75-0.66 (m, 1H); MS (ESI+) m/z 647 (M+H)+.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.O.[CH2:7]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])[CH3:8]>CO>[NH2:11][C:10]1[CH:12]=[CH:13][C:14]([CH:2]([C:14]2[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([CH2:7][CH3:8])[CH:15]=2)[C:1]([OH:5])=[O:4])=[CH:15][C:9]=1[CH2:7][CH3:8]
Reactant: CCc1ccccc1N
Reactant: O=CC(=O)O
Solvent: CO
Solvent: O
Product: CCc1cc(C(C(=O)O)c2ccc(N)c(CC)c2)ccc1N
Temperature: 25 °C

Procedure:
A mixture of glyoxylic acid 50% w/v (3.05 parts), water (20 parts) and methanol (10 parts) was stirred at ambient temperature. 2-ethylaniline (5.0 parts) was added and the mixture was stirred under reflux for 2 hours. After cooling to ambient temperature, the product was isolated by filtration, washed with a little water (50 parts) and dried to yield di(4-amino-3-ethylphenyl)acetic acid (5.5 parts).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.CC(C)([O-])C.[K+].[CH3:19][C:20]1[C:21]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:25][C:22]=2[S:23][CH:24]=1.[C:36](=[O:38])=[O:37]>CCOCC>[CH3:19][C:20]1[C:21]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:25][C:22]=2[S:23][C:24]=1[C:36]([OH:38])=[O:37]
Reactant: O=C=O
Reactant: Cc1csc2cc(Cc3cccnc3)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: Cc1c(C(=O)O)sc2cc(Cc3cccnc3)ccc12
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
n-Butyl lithium (0.65 ml. of 1.55M solution in hexane) was added dropwise to a stirred mixture of diisopropylamine (0.10 g.) and potassium t-butoxide (0.11 g.) in dry ether (10 ml.) at -78° C. under an atmosphere of dry nitrogen. The mixture was stirred at -78° C. for 45 minutes and then a solution of 3-methyl-6-(3-pyridylmethyl)benzo[b]thiophene (0.20 g.) in dry ether (5 ml.) was added. The solution was stirred at -78° C. for 45 minues and then an excess of crushed solid carbon dioxide was added. When all the carbon dioxide had evaporated, water (5 ml.) was added and the mixture was shaken. The aqueous layer was then separated and washed with ether. It was then acidified with acetic acid and the solid was filtered off and dissolved in 2N sodium hydroxide. The solution was decolorized by warming with charcoal and then filtered. Acidification of the filtrate with acetic acid gave a solid which was filtered off, washed with water and dried to give 3-methyl-6-(3-pyridylmethyl)benzo[b]thiophene-2-carboxylic acid (0.10 g.), m.p. 250°-252° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[F:25][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([F:24])[CH:21]=1)[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[N:9]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)cc(F)c4)cc3)c3c(N)ncnc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3cc(F)cc(F)c3)cc1)nn2[C@@H]1CCCNC1
Yield: 76.5 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of tert-butyl (3R)-3-[4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (340 mg, 0.65 mmol, 1.00 equiv) in dichloromethane (50 mL), followed by the addition of trifluoroacetic acid (10 mL) dropwise with stirring. The resulting solution was stirred for 12 h at room temperature and then concentrated under vacuum. The resulting solution was diluted with 20 of water. The pH value of the solution was adjusted to >7 with sodium carbonate and then extracted with dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 210 mg (76%) of 3-[4-(3,5-difluorophenoxy)phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4](I)[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:14][S:15]([C:18]1[CH:19]=[N:20][CH:21]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:23]=1)(=[O:17])=[O:16]>>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([C:22]2[CH:21]=[N:20][CH:19]=[C:18]([S:15]([CH3:14])(=[O:17])=[O:16])[CH:23]=2)[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC1(C)OB(c2cncc(S(C)(=O)=O)c2)OC1(C)C
Reactant: CC(=O)c1cc(Cl)c(F)c(I)c1O
Product: CC(=O)c1cc(Cl)c(F)c(-c2cncc(S(C)(=O)=O)c2)c1O
Yield: 87 %

Procedure:
The desired compound was prepared according to the procedure of Example 127, step A, using 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone (See, Example 172, Step 2) and 3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (PepTech Corp., Cat. No. BE358) as the starting materials in 87% yield. LCMS for C14H12ClFNO4S (M+H)+: m/z=344.0. Found: 343.9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl[CH2:22][CH2:23][N:24]([CH2:34][CH2:35]Cl)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:35][CH2:34][N:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:2]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Reactant: COc1ccc(CN(CCCl)CCCl)cc1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(OC)cc3)CC2)cc1

Procedure:
4-(4-but-2-ynyloxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1. Starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (2 g, 6.73 mmol) and bis-(2-chloro-ethyl)-(4-methoxy-benzyl)-amine (2.61 g, 8.75 mmol) and following the procedure as outlined in Example 1 (Step 6) 2.5 g of the product was isolated. Yield 2.5 g (77%); yellow oil; MS: 486 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]2)=[C:4]([CH3:12])[C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F-].[K+].[CH:26]1([NH2:29])[CH2:28][CH2:27]1>CS(C)=O>[CH:26]1([NH:29][C:5]2[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([F:1])=[C:3]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:4]=2[CH3:12])[CH2:28][CH2:27]1
Reactant: NC1CC1
Reactant: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2C)CC1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(NC3CC3)c2C)CC1
Temperature: 60 °C
Yield: 93.7 %

Procedure:
To 3,6-difluoro-2-(4-ethoxycarbonyl-1-piperazinyl)-5-nitrotoluene (7.1 g) are added anhydrous dimethylsulfoxide (23 ml), potassium fluoride (2.0 g) and cyclopropylamine (1.5 g), and the mixture is heated at 60° C. for 6 hours. The reaction mixture is poured into ice water, and extracted with dichloromethane. The solvent is distilled off and the residue is recrystallized from ethanol to give N-cyclopropyl-2-methyl-3-(4-ethoxycarbonyl-1-piperazinyl)-4-fluoro-6-nitroaniline (7.4 g), as orange red prisms, m.p. 97°-98° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]3[N:15]([CH3:16])[C:14]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:13]=4[N:12]=3)=[N:7][C:6]=2[CH:24]=1.[CH3:25][O:26][CH2:27][CH2:28][NH2:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:25][O:26][CH2:27][CH2:28][NH:29][C:21]([C:19]1[CH:18]=[CH:17][C:14]2[N:15]([CH3:16])[C:11]([NH:10][C:8]3[S:9][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:24][C:6]=4[N:7]=3)=[N:12][C:13]=2[CH:20]=1)=[O:23]
Reactant: COCCN
Reactant: Cn1c(Nc2nc3cc(F)ccc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3cc(F)ccc3s1)n2C

Procedure:
2-(5-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (32 mg) was prepared by following General Procedure F using 2-(5-fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (34 mg), 2-methoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 401; and 1H NMR (DMSO-d6, 400 MHz): δ 8.46 (t, 1H), 8.05 (d, 1H), 7.95 (s, 1H), 7.79-7.71 (m, 2H), 7.42 (d, 1H), 7.30 (d, 1H), 6.99 (t, 1H), 3.65 (s, 3H), 3.51-3.42 (m, 2H), 3.36 (d, 2H), and 2.73 (s, 3H).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6](#[N:9])[CH:7]=[CH2:8]>>[C:6]([C@H:7]1[CH2:1][CH2:2][C:3]([CH3:5])=[CH:4][CH2:8]1)#[N:9]
Reactant: C=CC(=C)C
Reactant: C=CC#N
Product: CC1=CC[C@@H](C#N)CC1

Procedure:
363 g of 4(5)-cyano-1-methyl cyclohexene (isomer mixture obtained by the cyclo addition of isoprene and acrylonitrile) were incrementally added to a mixture of 5.4 moles of 88% sulphuric acid and 891 g of hydrocyanic acid at 27° C. to 29° C. over a period of 75 minutes, with stirring, wherein the heat of reaction was removed by refluxing the boiling hydrocyanic acid. Ten minutes after completion of the addition, 900 g of water were added and the excess hydrocyanic acid was distilled off. 735 g of a 25% aqueous ammonia solution were then added at 20° C. to 30° C. The neutralized reaction solution obtained was then extracted five times, in each case with 150 g of isobutanol. After removing the extracting agent, 525 g of crude 1-formamido-1-methyl-3(4)-cyano cyclohexane (isomer mixture) (88.5% yield, determined by gas chromatography) was obtained. The isobutanol dissolved in the aqueous ammonium sulphate solution obtained following extraction was removed by distillation. The aqueous ammonium sulphate solution (1800 g, sulphur content: 9.5%, corresponding to 39.5% ammonium sulphate), which remained and from which isobutanol had been removed, had a chemical oxygen demand (COD) of 3500 mg/l.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:15][C:16]1[CH:17]=[N:18][NH:19][CH:20]=1.O[CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([CH3:28])[CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:15][C:16]1[CH:17]=[N:18][N:19]([CH:22]2[CH2:27][CH2:26][CH2:25][N:24]([CH3:28])[CH2:23]2)[CH:20]=1
Reactant: Brc1cn[nH]c1
Reactant: CN1CCCC(O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCCC(n2cc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DIAD (3.21 ml, 16.3 ml) was added dropwise to a solution of 4-bromopyrazole (2.0 g, 13.6 mmol), 3-hydroxy-1-methylpiperidine (1.57 ml, 13.6 ml) and triphenylphosphine (4.3 g, 16.3 mmol) in THF (50 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was partitioned between water and ethyl acetate and the organic layers were extracted into 2N HCl. The aqueous fraction was basified with sodium bicarbonate and extracted into ethyl acetate. The organic fractions were dried (MgSO4), filtered and concentrated under reduced pressure to give the product (1.64 g), which was used without purification. MS: [M+H]+=244.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11]([CH:14]=[CH:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1cnc(-c2ccc(F)cc2)nc1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cnc(-c2ccc(F)cc2)nc1

Procedure:
945 mg (4.67 mmol) of 2-(4-fluoro-phenyl)-pyrimidine-5-carbaldehyde, 1544 mg (14.84 mmol) of malonic acid and 4197 mg (49.29 mmol) of piperidine in 50 ml of pyridine were stirred at 125° C. for 17 h. After concentration, water and hydrochloric acid were added, and the solid product was filtered off with suction and dried. Yield: 1.01 g.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:13]=[C:14]([O:18][NH2:19])[CH:15]=[CH:16][CH:17]=1)([OH:11])=[O:10]>>[C:9]([C:12]1[CH:13]=[C:14]([O:18][N:19]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:16][CH:17]=1)([OH:11])=[O:10]
Reactant: NOc1cccc(C(=O)O)c1
Reactant: O=Cc1ccccc1
Product: O=C(O)c1cccc(ON=Cc2ccccc2)c1
Yield: 58.1 %

Procedure:
Benzaldehyde (21.0 μL, 0.207 mmol) was subjected to the representative coupling procedure with 3 (31.8 mg, 0.208 mmol) as outlined above (method 2), yielding 3a as a white solid (29.0 mg, 58%). 1H-NMR (500 MHz, 1:1 CD3OD:d6-DMSO) δ 7.39-7.45 (m, 5H), 7.59-7.64 (m, 1H), 7.71-7.78 (m, 3H), 8.58 (s, 1H); 13C-NMR (125 MHz, d6-DMSO) δ 114.5, 118.8, 123.3, 127.7, 129.1, 129.3, 130.8, 131.1, 132.3, 153.3, 158.9, 166.9; MALDI-FTMS (DHB) 242.0812 m/z [MH]+, C14H12NO3 requires 242.0812. RP-HPLC: 98% pure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].[F:11][C:12]([F:19])([F:18])[CH:13]([OH:17])[C:14](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:14]([CH:13]([OH:17])[C:12]([F:19])([F:18])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C(O)C(O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: OC(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 108 °C

Procedure:
4,5-Dichloro-benzene-1,2-diamine (8.50 g; 48.0 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (10.59 g; 73.52 mmoles) were suspended in 6N HCl (19 mL; 114 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (200 mL) and with ethyl acetate (200 mL), then sodium bicarbonate (6.05 g; 72.0 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×80 mL). The extracts were combined, washed with water (60 mL) and brine (60 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid which was then purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as a brown solid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]1([C:18]2[C:19]3[S:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[C:20]=3[NH:21][N:22]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[C:12]1([C:18]2[C:19]3[S:25](=[O:6])[C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[C:20]=3[NH:21][N:22]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(-c2n[nH]c3c2sc2ccccc23)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S1c2ccccc2-c2[nH]nc(-c3ccccc3)c21
Temperature: 10 °C
Reaction time: 4 h

Procedure:
A solution of 3-chloroperoxybenzoic acid (450 mg, 60% pure) in dichloromethane (30 ml) was added dropwise with stirring over 15 minutes to a solution of 3-phenyl-1H-[1]benzothieno[3,2-c]pyrazole (400 mg) in dichloromethane (50 ml) at 0-5° C. The mixture was stirred at 5-15° C. for 4 hours, then washed with water, dried and evaporated to give a solid which was purified by chromatography on silica using petroleum ether/ethyl acetate (1:3) as the mobile phase. Appropriate fractions were collected, combined and evaporated to give a solid which was triturated with ether, and filtered to give 3-phenyl-1H-[1]benzothieno[3,2-c]pyrazole 4-oxide, m.p. 222-224° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][O:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1)=[O:17]>ClCCl>[CH3:14][O:15][C:16]([C:18]1[NH:19][CH:20]=[C:21]([S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])[CH:22]=1)=[O:17]
Reactant: COC(=O)c1ccc[nH]1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1cc(S(=O)(=O)c2cccs2)c[nH]1
Reaction time: 24 h

Procedure:
To a solution of thiophene-2-sulfonyl chloride in dichloromethane was added aluminum chloride at 0-5° C., 1H-pyrrole-2-carboxylic acid methyl ester in dichloromethane was added slowly. Reaction mixture was stirred from room temperature to 60° C. for 24 hrs. On completion of reaction; reaction mixture was poured over crushed ice and extracted with dichloromethane, organic layer was washed with 1 N NaOH solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 4-(thiophene-2-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester (D1-I).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:11](Cl)(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH-].[NH4+:16]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([S:11]([NH2:16])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: NS(=O)(=O)c1ccc([N+](=O)[O-])c(F)c1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 5.00 g 3-fluoro-4-nitrobenzenesulfonyl chloride in 20 mL acetonitrile cooled in an ice bath was added dropwise 4.40 mL of a 30% ammonium hydroxide solution. After removal of the ice bath, stirring was continued for 30 min. at room temperature. Water was added and the mixture was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated to dryness to give 4.65 g (99%) of a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 2H), 7.89 (d, J=9.33 Hz, 1H), 7.92 (dd, J=10.23, 1.81 Hz, 1H), 8.14-8.21 (m, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[O:17])=[CH:19][CH:20]=1)([O-:11])=[O:10]
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1
Yield: 65.7 %

Procedure:
Using 4-fluoroaniline (1.0 ml, 9.93 mmol) and 4-nitrobenzoic acid (1.58 g, 9.36 mmol), the procedure of Reference Example 16 was repeated to obtain 1.60 g (65.8%) of the title compound in the form of light yellow needle crystals.
Reaction SMILES: [BrH:1].C(O)(=O)C.[N:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])[C:14]2[CH:19]=[CH:18][C:17]([C@H:20]([NH:22]C(OCC3C=CC=CC=3)=O)[CH3:21])=[C:16]([Cl:33])[CH:15]=2)=[CH:8][CH:7]=1>>[BrH:1].[BrH:1].[N:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])[C:14]2[CH:19]=[CH:18][C:17]([C@H:20]([NH2:22])[CH3:21])=[C:16]([Cl:33])[CH:15]=2)=[CH:8][CH:7]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Nc2ccncc2)cc1Cl
Agent: Br
Solvent: CC(=O)O
Product: C[C@@H](N)c1ccc(C(=O)Nc2ccncc2)cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 25% hydrogen bromide-acetic acid solution (7 ml) was added to (R)-N-(4-pyridyl)-4-(1benzyloxycarbonylaminoethyl)-3-chlorobenzamide (630 mg), and the mixture was stirred at room temperature for 6 hours. After the reaction, the solvent was evaporated under reduced pressure. The obtained crystals were washed with ether, and recrystallized from methanol to give 243 mg of (R)-(+)-N-(4-pyridyl)-4-(1aminoethyl)-3-chlorobenzamide dihydrobromide having a melting point of more than 300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:17]=[C:16](F)[CH:15]=[CH:14][C:13]=2[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:17]=[C:16]([N:28]3[CH2:27][CH2:26][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29]3)[CH:15]=[CH:14][C:13]=2[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(Nc1cc(F)ccc1C(=O)C(F)(F)F)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)C(F)(F)F)c1cc(Cl)cc(Cl)c1
Yield: 48.6 %

Procedure:
1-(2-(1-(3,5-Dichlorophenyl)ethylamino)-4-fluorophenyl)-2,2,2-trifluoroethanone (600 mg, 1.62 mmol), t-butyl piperazine-1-carboxylate (110 mg, 0.29 mmol), N,N-diisopropylethylamine (74.6 mg, 0.58 mmol) were stirred at 60° C. in dry acetonitrile (20 mL) for 3 days. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 20% ethyl acetate in hexanes to afford the title compound (77.0 mg, 49% yield). 1H NMR (400 MHz, CDCl3): δ 9.31 (d, 1H), 7.63 (d, 1H), 7.25 (s, 1H), 7.22 (s, 2H), 6.18 (d, 1H), 5.53 (s, 1H), 4.48 (m, 1H), 3.48 (m, 4H), 3.25 (m, 4H), 1.60 (d, 3H), 1.47 (s, 9H); MS (ESI) m/z: Calculated for C25H28Cl2F3N3O3: 545.15; Observed: 568.4 (M++Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)#[CH:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:20]#[C:19][C:21]4[CH:22]=[CH:23][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:25][CH:26]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Product: Cc1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(S(N)(=O)=O)cc3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-iodo-7-methyl-pyrazolo[1,5-a]pyrimidine (92 mg, 0.25 mmol) and 4-ethynyl-benzenesulfonamide (45 mg, 0.25 mmol) according to general procedure II. Obtained as an orange solid (52 mg, 49%). MS (ISP) 423.3 [(M+H)+]; mp 230-233° C.