Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cc(F)cc(F)c2)cn1
Yield: 30 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 3,5-difluorophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (51 mg, 30%) which was obtained as a white solid (ESI). MS: m/e=337.9 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.CCN(C(C)C)C(C)C.Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH2:44][CH2:45][NH:46][CH2:47][CH:48]=2)=[CH:39][CH:38]=1>C(#N)CC>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH2:48][CH2:47][N:46]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][S:15][CH2:16][C@H:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:45][CH:44]=2)=[CH:39][CH:38]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCSC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cc(CN3CC=C(c4ccc(Cl)cc4)CC3)cnc2N2CCSC[C@@H]12
Temperature: 90 °C

Procedure:
To a suspension of (R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (70 mg, 0.279 mmol) in propiononitrile (Volume: 696 μl) was added (cyanomethyl)trimethylphosphonium iodide (81 mg, 0.334 mmol), DIEA (146 μl, 0.836 mmol) and finally 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (64.1 mg, 0.279 mmol). The vial was heated to 90° C. for 12 hours. Cooled to rt and concentrated to a brown residue which was treated with MeOH (5 mL). The precipitate was filtered, the solids were collected, taken up in EtOH (15 mL) and refluxed 2 hours. Let sit at RT ON. Filtered, dried in vacuum and retrieved 75.6 mg (63.6%) of the title compound as a white solid. 1H NMR (CHLOROFORM-d) δ (ppm): 7.80 (d, J=1.8 Hz, 1H), 7.66 (br. s., 1H), 7.30 (d, J=3.8 Hz, 5H), 7.04 (br. s., 1H), 6.02-6.09 (m, 1H), 5.06 (ddd, J=13.5, 2.8, 2.7 Hz, 1H), 4.42 (dd, J=10.5, 3.2 Hz, 1H), 3.54 (br. s., 2H), 3.10-3.26 (m, 3H), 3.00 (td, J=12.8, 2.7 Hz, 1H), 2.85-2.92 (m, 1H), 2.75 (br. s., 2H), 2.56 (br. s., 2H), 2.35-2.44 (m, 1H). [M+H] calc'd for C22H23ClN4OS, 427. found, 427.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:53][OH:54])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:62][S:63](Cl)(=[O:65])=[O:64]>O1CCCC1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:53][O:54][S:63]([CH3:62])(=[O:65])=[O:64])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1nc2ccc(CO)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCc1nc2ccc(COS(C)(=O)=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 0.250 g of 2-butyl-6-(hydroxymethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone and 0.246 ml of triethylamine in 5.0 ml of tetrahydrofuran is cooled to -78° C. and 0.137 ml of methanesulfonyl chloride added. The reaction mixture is allowed to warm to room temperature and continue stirring for 18 hours. The reaction mixture is partitioned between chloroform and water. The organic layer is washed with aqueous 5% HCl, water and saturated aqueous sodium bicarbonate then dried with magnesium suflate and evaporated to afford 0.278 g of the desired product. FAB MASS SPEC 787 (M+H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[C:23]([F:31])=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=O>>[Cl:21][C:22]1[C:23]([F:31])=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cccc(Cl)c1F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(Cl)c3F)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-chloro-2-fluorobenzoic acid: MS (APCI) m/z 420 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[CH:23][N+:24]([O-])=O)[CH:17]=1>C(N)C1C=CC=CC=1>[CH2:22]([N:24]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)=[CH:23]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])C=Cc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: NCc1ccccc1
Product: Clc1cccc(-c2cn(Cc3ccccc3)c3c2CNCC3)c1
Yield: 48.9 %

Procedure:
The title compound (193.3 mg) was prepared from 0.50 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 260 μL of benzylamine, and 0.45 g of 1-chloro-3-(2-nitro-vinyl)-benzene as in Example 9. MS (ESI): exact mass calculated for C20H19ClN2, 322.12; found, m/z 323.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.36-7.20 (m, 6H), 7.14-7.07 (m, 3H), 6.81 (s, 1H), 5.01 (s, 2H), 4.04 (s, 2H), 3.14 (t, J=5.8 Hz, 2H), 2.51 (t, J=5.8 Hz, 2H).
Reaction SMILES: COC1C=CC2CC3C(=O)C(C)(C=2C=1)CCCC3.[CH3:19][C:20]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][C:21]1=[O:30].[H-].[Na+]>CN(C)C=O>[CH3:19][C:20]12[C:21](=[O:30])[CH:22]([CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=31)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2
Reactant: CC1(CCCCCBr)C(=O)CCc2ccccc21
Agent: COc1ccc2c(c1)C1(C)CCCCC(C2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC12CCCCCC(Cc3ccccc31)C2=O
Yield: 40.4 %

Procedure:
Using a procedure analogous to that described in Example X for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one there is prepared from 1-methyl-1-(5-bromopentyl)-2-tetralone (19.8 g., 0.0675 mole) and sodium hydride (3.57 g., 0.081 mole, of a 54.5% dispersion in mineral oil) in dimethylformamide (250 ml.); 6.2 g. (40.4%) of the title product, b.p. 126° to 135° C. (0.3 mm.).
Reaction SMILES: CO[C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[C:7]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:6]=1)=[O:4].[CH2:19]([N:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[CH2:27][NH2:28])[CH:20]=[CH2:21].C([O-])(=O)C>O>[CH2:19]([N:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[CH2:27][NH:28][C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[C:7]([S:15](=[O:17])(=[O:18])[NH2:16])[CH:6]=1)=[O:4])[CH:20]=[CH2:21]
Reactant: COC(=O)c1cc(S(N)(=O)=O)cc2c1OCCO2
Reactant: C=CCN1CCCC1CN
Agent: CC(=O)[O-]
Solvent: O
Product: C=CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)cc2c1OCCO2
Yield: 64.7 %

Procedure:
145 g of methyl-7-sulfamoyl-1,4-benzodioxane-5-carboxylate, 48 g of water and 89 g of 1-allyl-2-aminomethyl-pyrrolidine were introduced into a balloon flask provided with a condenser. The mixture was heated on a water bath until a test sample was soluble in dilute acids and then 1 liter of water was added. The precipitated carboxamide was redissolved by acetate formation. The solution formed was filtered on carbon black and then the base was precipitated by the addition of 20% ammonia. The resulting crystals were dried off, washed with water, dried and purified by passing over hydrochloride (M.P.: 228°-230° C.) followed by transformation into a base by treatment with 20% ammonia. 131 g of N-(1-allyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 143°-144° C.; yield: 64.8%). The structure was confirmed by nuclear magnetic resonance.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[N:34]1[O:35][C:36]([C:43](O)=[O:44])=[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=12.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:43]([C:36]3[O:35][N:34]=[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=34)=[O:44])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(O)c1onc2ccccc12
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4onc5ccccc45)c3C2=O)C(=O)N1
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.8 g, 5.7 mmol) in DMF (20 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.9 g, 6.8 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.9 g, 6.8 mmol) and benzo[c]isoxazole-3-carboxylic acid (1.0 g, 6.3 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.6 g, 8.5 mmol). The mixture was stirred at room temperature overnight and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (50 mL), washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. Solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 3% MeOH in CH2Cl2) to afford benzo[c]isoxazole-3-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a yellow solid (1.93 g, 78%): mp, 253-255° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient from 10/90 (CH3CN/H2O) to 95/5(CH3CN/H2O) in 10 minutes: tR=6.6 min (96%); 1H NMR (DMSO-d6): δ 2.08-2.13 (m, 1H), 2.53-2.65 (m, 2H), 2.86-2.94 (m, 1H), 5.02 (d, J=6.0 Hz, 2H), 5.19 (dd, J=6, 12 Hz, 1H), 7.27-7.97 (m, 5H), 9.90 (t, J=6 Hz, 1H), 11.16 (s, 1H). 13C NMR (DMSO-d6) δ: 21.98, 30.93, 40.33, 48.89, 115.15, 118.27, 120.74, 122.07, 127.24, 131.54, 131.96, 133.20, 134.88, 138.13, 156.43, 156.52, 156.97, 160.91, 166.93, 167.49, 169.82, 172.75. Anal Calcd for C22H16N4O6+0.2H2O: C, 60.61; H, 3.79; N, 12.85. Found: C, 60.38; H, 3.50; N, 12.80.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)O1.C1(C)C=CC=CC=1.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(O)C>[CH3:8][C:7]1[C:2]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[CH:3][C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[CH:5][CH:6]=1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Yield: 95.6 %

Procedure:
To N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide (400.0 mg, 0.99 mmol) was added 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (270 mg, 1.1 mmol) followed by toluene (8.2 mL), then ethanol (1.15 mL), and K2CO3 (270 mg, 2.0 mmol in 1.1 mL water). The reaction was degassed with N2, then tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol) was added. The reaction was degassed again, and then heated at reflux under N2 atmosphere at 90° C. until LCMS and TLC indicated complete reaction, about 16 hours. The reaction was then cooled to ambient temperature, transferred to a separatory funnel and partitioned between water and EtOAc. The phases were separated and the organic phase was washed with water, then saturated aqueous NaCl, dried (MgSO4) and then evaporated to dryness to leave the crude product, which was purified by column chromatography to give the product (379 mg, 95.79%). 1H NMR (400 MHz, CDCl3): δ 8.29 (m, 2H), 8.12 (s, 1H), 8.07 (d, 1H), 7.82 (m, 2H), 7.5-7.7 (m, 5H), 7.33 (d, 1H), 2.26 (s, 3H). MS (EI) m/z=401 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][C:9]2[CH:14]=[C:13]([NH:15]C(=O)C(F)(F)F)[CH:12]=[CH:11][C:10]=2[S:22](Cl)(=[O:24])=[O:23])=[N:5][N:4]=1)[CH3:2].[NH2:26][C:27]1[CH:28]=[CH:29][C:30]2[CH2:34][O:33][B:32]([OH:35])[C:31]=2[CH:36]=1.N1C=CC=CC=1>C(#N)C>[NH2:15][C:13]1[CH:12]=[CH:11][C:10]([S:22]([NH:26][C:27]2[CH:28]=[CH:29][C:30]3[CH2:34][O:33][B:32]([OH:35])[C:31]=3[CH:36]=2)(=[O:23])=[O:24])=[C:9]([CH2:8][C:6]2[O:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=2)[CH:14]=1
Reactant: CCc1nnc(Cc2cc(NC(=O)C(F)(F)F)ccc2S(=O)(=O)Cl)o1
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: CC#N
Solvent: c1ccncc1
Product: CCc1nnc(Cc2cc(N)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 112.1 %

Procedure:
To a stirred solution of 2-((5-ethyl-1,3,4-oxadiazol-2-yl)methyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (335 mg, 0.84 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (125 mg, 0.84 mmol) in 5 mL of ACN was added pyridine (205 uL, 2.53 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. After the mixture was concentrated, the residue was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated to give the desired compound as a yellow solid (390 mg, yield 91%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH2:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][C:18]=1[F:25])[CH3:16]>>[CH2:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:19][C:18]=1[F:25])[CH3:16]
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CCc1ccc(CO)cc1F
Product: CCc1ccc(COc2ccnn2-c2cc(C#N)ccn2)cc1F

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-ethyl-3-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.16 (3H, t, J=7.6 Hz), 2.60 (2H, t, J=7.6 Hz), 5.13 (2H, s), 5.66 (1H, d, J=1.2 Hz), 7.02-7.05 (2H, m), 7.14-7.18 (1H, m), 7.34 (1H, d, J=5.2 Hz), 7.50 (1H, d, J=1.2 Hz), 7.96 (1H, s), 8.64 (1H, d, J=4.8 Hz). [M+H] Calc'd for C18H15FN4O, 323. Found, 323.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:9]([NH:15][C:16]([NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[S:17])([CH2:11][C:12]([CH3:14])=[CH2:13])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[I:27]I>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:10])[CH2:11][C:12]([CH2:14][I:27])([CH3:13])[S:17][C:16]([NH:18][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:15]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C=C(C)C[C@](C)(NC(=S)NC(=O)c1ccccc1)c1ccc(F)c(Br)c1
Reactant: II
Solvent: ClCCl
Product: CC1(CI)C[C@@](C)(c2ccc(F)c(Br)c2)N=C(NC(=O)c2ccccc2)S1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a 0° C. solution of (S)-N-(2-(3-bromo-4-fluorophenyl)-4-methylpent-4-en-2-ylcarbamothioyl)benzamide (1.3 g, 3.0 mmoles, 1.0 equiv) in dichloromethane (40 mL) is added iodine (1.5 g, 5.9 mmoles, 2.0 equiv). The reaction is stirred at 0° C. for 1 h and gradually warmed to room temperature. The reaction mixture is quenched with saturated aqueous sodium thiosulfate. The aqueous layer is extracted with dichloromethane. The combined organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (82% yield): MS (m/z): 561, 563 (M+1).
Reaction SMILES: C1(C)C=CC=CC=1.[C:8](OC(=O)C)([CH3:11])([CH3:10])[CH3:9].CS(O)(=O)=O.[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([CH3:31])[CH:30]=1)[NH:27][N:26]=[CH:25]2>O>[Br:21][C:22]1[CH:30]=[C:29]([CH3:31])[C:28]2[C:24](=[CH:25][N:26]([C:8]([CH3:9])([CH3:10])[CH3:11])[N:27]=2)[CH:23]=1
Reactant: Cc1cc(Br)cc2cn[nH]c12
Reactant: CC(=O)OC(C)(C)C
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cc2cn(C(C)(C)C)nc12
Temperature: 80 °C
Reaction time: 28 h

Procedure:
Toluene (150 mL), acetic acid tert-butyl ester (360 mL), and methanesulfonic acid (22 mL) were added to 5-bromo-7-methyl-1H-indazole (35.9 g), and the reaction solution was stirred at 80° C. for 28 hours. The reaction solution was cooled to room temperature, water (500 mL) was added, and extracted with toluene (500 mL) and 200 mL toluene. After separation, the organic layer was washed with water twice. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. Hexane was added to the resultant residue and the insolubles were separated by filtration. The solvent was evaporated from the filtrate under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 5-bromo-2-(tert-butyl)-7-methyl-2H-indazole as a light red oily substance.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[C:14]([C:21]#[N:22])=[CH:13][C:12]=2[CH3:23])[N:9]=[N:8][N:7]=1)(=O)C.O.[OH-].[Li+]>O.O1CCCC1>[OH:4][CH2:5][C:6]1[N:10]([C:11]2[C:12]([CH3:23])=[CH:13][C:14]([C:21]#[N:22])=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[N:9]=[N:8][N:7]=1
Reactant: CC(=O)OCc1nnnn1-c1cc(C(F)(F)F)c(C#N)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C#N)c(C(F)(F)F)cc1-n1nnnc1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {1-[4-cyano-2-methyl-5-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl acetate (Intermediate 62, 433 mg, 1.33 mmol) in water (2 mL) and tetrahydrofuran (4 mL), cooled in an ice bath, was added lithium hydroxide monohydrate (56 mg, 1.33 mmol). The reaction was stirred at room temperature for 1 hour and 30 min.
Reaction SMILES: Cl.[CH2:2]([NH:6][CH2:7][CH2:8][Cl:9])[CH2:3][CH2:4][CH3:5].[N-:10]=[N+:11]=[N-:12].[Na+].[OH-].[Na+]>CN(C=O)C.CCOCC>[ClH:9].[CH2:2]([NH:6][CH2:7][CH2:8][N:10]=[N+:11]=[N-:12])[CH2:3][CH2:4][CH3:5]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCNCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCNCCN=[N+]=[N-]
Yield: 68.8 %

Procedure:
7.0 g of 2-butylamino-ethyl chloride hydrochloride (Org. Synth. IV 1963, 333) are stirred together with 7.9 g of sodium azide in 50 ml of DMF at 500. After cooling, 82 ml of 1N sodium hydroxide solution are added dropwise. The mixture is taken up in 700 ml of ether, washed with water and, after drying the ether phase, treated with 25 ml of hydrochloric acid (5 molar in dioxane). After evaporating the ether phase, the residue is suspended in ether. The crystals are filtered and washed with ether. There are obtained 5 g of 2-butylamino-ethyl azide hydrochloride, Rf=0.14.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:5]([OH:19])=[C:6]([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:7]=[C:8]([CH3:10])[CH:9]=1.[CH3:20]I>CN(C)C=O>[CH3:3][C:4]1[C:5]([O:19][CH3:20])=[C:6]([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: CI
Reactant: Cc1cc(C)c(O)c(C(=O)C2CCCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C)cc(C)cc1C(=O)C1CCCCC1
Temperature: 70 °C
Yield: 105 %

Procedure:
53 Grams of 60% sodium hydride was gradually added to a solution prepared by dissolving 256.2 g of cyclohexyl 3,5-dimethyl-2-hydroxyphenyl ketone in 1 liter of dimethylformamide with stirring, generating heat at 70° C. After continuation of stirring for 30 minutes, the reaction mixture was cooled to room temperature and thereto was added dropwise 233 g of methyl iodide. The reaction mixture was further stirred at the same temperature for 2 hours and then added to 1 liter of ice water and stirred. The organic layer was extracted with 3 liters of ethyl acetate. The extract was washed with water and then with a saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 285.2 g of cyclohexyl 3,5-dimethyl-2-methoxyphenyl ketone.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7]C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.[CH:15]1([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]4[CH:35]=[C:36]([C:38]5[CH:43]=[CH:42][C:41]([CH:44]=O)=[CH:40][N:39]=5)[S:37][C:30]=34)=[C:24]([F:46])[CH:23]=2)=[O:20])[CH2:17][CH2:16]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.CC(O)=O>[NH2:7][CH:4]1[CH2:3][CH2:2][N:1]([CH2:44][C:41]2[CH:42]=[CH:43][C:38]([C:36]3[S:37][C:30]4[C:31](=[N:32][CH:33]=[CH:34][C:29]=4[O:28][C:25]4[CH:26]=[CH:27][C:22]([NH:21][C:19]([NH:18][CH:15]5[CH2:16][CH2:17]5)=[O:20])=[CH:23][C:24]=4[F:46])[CH:35]=3)=[N:39][CH:40]=2)[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: NC1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Reaction time: 0.5 h
Yield: 61 %

Procedure:
tert-Butyl piperidin-4-ylcarbamate (1.34 g, 6.69 mmol) was added to a solution of the aldehyde 47 (2.0 g, 4.46 mmol) in a mixture of NMP (20 mL) and glacial AcOH (0.250 mL). The reaction mixture was stirred for 30 min. NaBH(OAc)3 was then added and the reaction mixture was stirred for an additional 2.5 hours. The reaction mixture was then poured into a saturated aqueous NaHCO3 solution. A precipitate was formed which was collected by filtration, washed with water and air-dried. The crude material was purified by column chromatography using a 5 to 20% gradient of MeOH in EtOAc as eluent to afford the title compound 343 (1.45 g, 51.4% yield). MS (m/z): 633.6 (M+1)+.