Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3([OH:21])[CH2:19][CH2:18][CH2:17][C:16]4[N:15]([CH3:20])[N:14]=[CH:13][C:12]3=4)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C.O>[Br:29][C:10]1[N:9]=[C:8]([C:11]2([OH:21])[CH2:19][CH2:18][CH2:17][C:16]3[N:15]([CH3:20])[N:14]=[CH:13][C:12]2=3)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1ncc2c1CCCC2(O)c1ncc2c(Cl)nccn12
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c1CCCC2(O)c1nc(Br)c2c(Cl)nccn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a solution of 4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-ol (1 g, 3.3 mmol) in DMF (8 ml) was added NBS (584 mg, 3.3 mmol) portionwise at 0° C. After the addition was complete, the reaction mixture was stirred at 0° C. for 30 minutes. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC to give 4-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-ol (860 mg, 68%). MS-ESI (m/z): 382 (M+1)+ (Acq Method: 10-80AB_2 min; Rt: 1.01 min)
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].C(N(CC)CC)C.Cl.[CH2:16]([O:18][C:19]([NH:21][C:22]1([CH2:28][N:29]2[CH2:34][CH2:33][N:32]([S:35]([C:38]3[CH:47]=[CH:46][C:45]4[C:40](=[CH:41][CH:42]=[C:43]([Cl:48])[CH:44]=4)[CH:39]=3)(=[O:37])=[O:36])[CH2:31][C:30]2=[O:49])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:20])[CH3:17]>CO>[ClH:48].[C:2]([N:25]1[CH2:26][CH2:27][C:22]([CH2:28][N:29]2[CH2:34][CH2:33][N:32]([S:35]([C:38]3[CH:47]=[CH:46][C:45]4[C:40](=[CH:41][CH:42]=[C:43]([Cl:48])[CH:44]=4)[CH:39]=3)(=[O:36])=[O:37])[CH2:31][C:30]2=[O:49])([NH:21][C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH2:23][CH2:24]1)(=[NH:7])[CH3:3]
Reactant: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCNCC1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(C(C)=N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 162.1 %

Procedure:
A 4N hydrochloric acid solution in ethyl acetate (30 ml) and ethanol (6 ml) were added to 1-[1-(tert-butoxycarbonyl)-4-ethoxycarbonylamino-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (5.21 g), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, the precipitated crystals were filtered, washed with ethyl acetate-ethanol, and dried to obtain 1-[4-ethoxycarbonylamino-4-piperidinylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone hydrochloride (3.71 g). Ethyl acetimidate hydrochloride(148 mg) and triethylamine (0.337 ml) were added to a solution of 1-[4-ethoxycarbonylamino-4-piperidinylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone hydrochloride (218 mg) in methanol (10 ml) under ice-cooling, and the mixture was stirred at room temperature overnight. After distillation of the solvent, purification by CHP20 column chromatography (water:acetonitrile:1N hydrochloric acid=100:0:0→60:40:0.5) afforded the colorless amorphous title compound (190 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[C:13]([NH:21][NH2:22])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[N:22][NH:21][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=2)=[CH:3][CH:2]=1
Reactant: NNC(=O)c1cccnc1
Reactant: O=Cc1ccnc2ccccc12
Solvent: CCO
Product: O=C(NN=Cc1ccnc2ccccc12)c1cccnc1
Temperature: 25 °C

Procedure:
A mixture of 7.86 gm (0.05 mole) of 4-quinolinecarboxaldehyde, 6.86 gm (0.05 mole) of nicotinic acid hydrazide and 100 ml of ethanol is refluxed 2 hr. The reaction mixture is cooled to room temperature. The solid which sepatates is collected, washed with water and dried; 14.4 gm (quantitative) to give the title compound; mp. 99.6° C. The product is recrystallized from ethanol to give 11.54 gm (83%) of the title compound, having a melting point of 192.7° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].C(O)(=O)C.[C:11]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH:20]=O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO>[C:14]([O:13][C:11]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH2:20][NH:1][CH2:2][C:3]([OH:5])([CH3:6])[CH3:4])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: CC(C)(O)CN
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(O)CNC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.4 %

Procedure:
4.34 g of 1-amino-2-methylpropan-2-ol (48.68 mmol) are placed in 50 ml of MeOH. 2.79 ml of acetic acid (48.68 mmol) and then 4.72 ml of N-Boc-L-prolinal (24.34 mmol), diluted beforehand in 20 ml of MeOH, are successively added dropwise. The reaction mixture is stirred at room temperature for 30 minutes and 3.22 g of sodium cyanoborohydride (48.68 mmol) are then added portionwise. After stirring at room temperature for 18 hours, the medium is poured into 400 ml of saturated aqueous NaHCO3 solution. The aqueous phase is extracted with 3 times 150 ml of DCM. The organic phases are combined, washed with 200 ml of water, with 200 ml of brine, dried over MgSO4, filtered and evaporated. 7.19 g of (S)-2-[(2-hydroxy-2-methyl propylamino)methyl]pyrrolidine-1-carboxylic acid tert-butyl ester are obtained.
Reaction SMILES: Cl.[F:2][C:3]([F:26])([F:25])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:33][CH2:34][CH:35]1[CH2:39][CH2:38][CH2:37][N:36]1[CH2:40][CH3:41]>C(Cl)(Cl)Cl>[F:2][C:3]([F:26])([F:25])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([S:21]([NH:33][CH2:34][CH:35]4[CH2:39][CH2:38][CH2:37][N:36]4[CH2:40][CH3:41])(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Reactant: CCN1CCCC1CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCN1CCCC1CNS(=O)(=O)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Temperature: 0 °C
Yield: 28.2 %

Procedure:
4-(7-Trifluoromethyl-4-quinolinylamino)benzenesulphonyl chloride hydrochloride (4.3 g, 0.01 mol) was added portionwise to a well stirred mixture of aqueous sodium carbonate (12.3 g in 70 ml of water) and 2-aminomethyl-1-ethylpyrrolidine (1.3 g, 0.01 mol) in chloroform (70 ml) at about 10° C. The ice bath used for cooling was removed and, after 11/2 hours, the mixture was filtered. The solid was washed with water and then air-dried. Recrystallisation from ethanol-water, followed by drying, gave the title compound (1.35 g), melting point 194°-5° C.
Reaction SMILES: [CH2:1](Br)[CH:2]([CH3:4])[CH3:3].[Mg].[CH2:7]([Cl:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]>[Na]>[CH3:3][CH:2]([CH2:1][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:7][Cl:16])[CH3:4]
Reactant: CC(C)CBr
Reactant: O=C(CCl)c1ccccc1
Agent: [Mg]
Agent: [Na]
Product: CC(C)CC(O)(CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
The Grignard reagent generated from isobutyl bromide (0.1 mol, 13.7 g) in sodium dry diethyl ether (50 ml) and magnesium turnings (0.11 g atoms; 2.6 g) was added dropwise to a solution of phenacyl chloride (0.05 mol, 7.7 g) in sodium dry diethyl ether (100 ml) so that gentle reflux was maintained. The solution was then stirred at room temperature for 1 hour and the magnesium complex destroyed by pouring into a saturated ammonium chloride solution (200 ml). The ethereal extract was washed with water (3×150 ml) and dried (Na2SO4). Removal of the solvent gave a colourless liquid which distilled at reduced pressure to give 2-methyl-4-phenyl-5-chloro-pentan-4-ol (70%), b.p. 86°-88°/0.01 mm Hg.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][N:19]=[C:18]4[O:23][CH2:24][O:25][C:17]=34)=[N:10][CH:11]=[N:12]2)=[C:7]([O:26][CH:27]([CH3:29])[CH3:28])[CH:6]=1.[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31].[I-].[K+]>CC(N(C)C)=O>[C:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([NH:15][C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18]5[O:23][CH2:24][O:25][C:17]=45)=[N:10][CH:11]=[N:12]3)=[C:7]([O:26][CH:27]([CH3:28])[CH3:29])[CH:6]=2)[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(C)Oc1cc(OCCCl)cc2ncnc(Nc3c(Cl)cnc4c3OCO4)c12
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(=O)N1CCN(CCOc2cc(OC(C)C)c3c(Nc4c(Cl)cnc5c4OCO5)ncnc3c2)CC1
Temperature: 100 °C
Yield: 90.2 %

Procedure:
A mixture of 7-(2-chloroethoxy)-4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxyquinazoline (24 g), 1-acetylpiperazine (21 g), potassium iodide (18 g) and DMA (500 ml) was stirred and heated to 100° C. for 4 hours. The solvent was evaporated and the residue was partitioned between methylene chloride (1 liter) and water (500 ml). The aqueous layer was extracted with methylene chloride. The organic solutions were combined, washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol (from a 20:1 mixture to a 10:1 mixture) as eluent. After evaporation of the solvent, the material so obtained was triturated under diethyl ether. There was thus obtained the title compound as a white solid (26.2 g); m.p. 208-210° C.
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([CH:20]3[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCCN(C(=O)OC(C)(C)C)C2)nc(N2CCOCC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCCNC2)nc(N2CCOCC2)n1

Procedure:
Reaction of tert-butyl 3-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidinecarboxylate (0.22 g, 0.40 mmol) with TFA (0.5 mL) in CH2Cl2 (8 mL) gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(3-piperidinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole, which was dissolved in a mixture of CH2Cl2 (4 mL) and NEt3 (0.29 mL, 2.1 mmol) and cooled to 0° C. Methane sulfonyl chloride (0.05 mL, 0.65 mmol) was added, and the resulting mixture was allowed to warm to room temperature over 2 hrs. The reaction mixture was then diluted with water, extracted with CH2Cl2, and dried. Chromatography on silica eluting first with hexanes/EtOAc (4:1), followed by hexanes/EtOAc (1:1), and then CH2Cl2/MeOH (99:1), gave 0.19 g (91% yield) of 2-(difluoromethyl)-4-methoxy-1-[4-[1-(methylsulfonyl)-3-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: mp 237-239° C.; 1H NMR (CDCl3) δ 7.98 (dd, J=8.4, 0.7 Hz, 1H), 7.54 (t, JHF=53.5 Hz, 1H), 7.40 (t, J=8.3 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 4.08-3.92 (m, 8H), 3.86-3.72 (m, 5H), 3.14 (dd, J=11.5, 10.2 Hz, 1H), 3.07-2.99 (m, 1H), 2.86-2.77 (m, 4H), 2.30-2.22 (m, 1H), 2.00-1.71 (m, 3H); Anal. Calcd. for C22H27F2N7O4S.0.5 H2O: C, 49.6; H, 5.3; N, 18.4. Found: C, 49.7; H, 5.2; N, 18.3%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[NH:23]1[CH2:26][CH2:25][CH2:24]1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]4[CH2:26][CH2:25][CH2:24]4)=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: C1CNC1
Reactant: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1
Product: Fc1ccc(-c2csc3cc(OCCCCN4CCC4)ccc23)cc1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and azetidine were converted to yield 1-{4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-azetidine as colorless oil, MS: 356 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1.Cl.[OH:21][C:22]1[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:15]([C:17]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:31]([CH3:32])[C:22]=4[OH:21])[CH2:27]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1
Reactant: O=C(O)c1nc(-c2cccnc2)nc2ccccc12
Reactant: Cc1ccc2c(c1O)CCNC2
Agent: Cl
Product: Cc1ccc2c(c1O)CCN(C(=O)c1nc(-c3cccnc3)nc3ccccc13)C2
Yield: 13 %

Procedure:
Reaction of 2-(3-pyridinyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 88 (13% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.13 and 2.17 (2s, 3H), 2.66 and 2.92 (2t, 2H), 3.52 and 4.05 (2t, 2H), 4.43 and 4.94 (2s, 2H), 6.30 and 6.75 (2d, 1H), 6.80 and 7.00 (2d, 1H), 7.61-8.23 (m, 5H), 8.39-8.45 (2s, 1H), 8.75-8.83 (m, 2H), 9.60 and 9.65 (2s, 1H); MS (ESI) m/z 397 ([M+H]+).
Reaction SMILES: C(O[C:4](=[O:20])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([NH2:18])[C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:22][NH2:23]>CCO>[NH2:18][C:14]1[CH:13]=[C:12]2[C:11](=[CH:16][C:15]=1[F:17])[O:10][CH2:9][C:8]1[N:7]2[CH:5]([CH3:6])[C:4](=[O:20])[NH:22][N:23]=1
Reactant: CCOC(=O)C(C)N1C(=S)COc2cc(F)c(N)cc21
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC1C(=O)NN=C2COc3cc(F)c(N)cc3N21
Temperature: 90 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of 2-(6-amino-7-fluoro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (0.400 g, 1.34 mmol) in EtOH (15 mL) was added hydrazine hydrate (98%, 0.430 g, 13.4 mmol) and the reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was cooled to ambient temperature then concentrated in vacuo and the residue was purified by column on silica gel (basified by treatment with triethyl amine, eluting with 10-20% MeOH in DCM) to give 6-amino-7-fluoro-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as a light yellow solid (0.316 g, 94%). 1H NMR (DMSO-d6, 400 MHz): δ 10.73 (s, 1H), 6.78 (d, J=11.6 Hz, 1H), 6.62 (d, J=8.8 Hz 1H), 4.84 (brs, 2H), 4.44-4.53 (m, 3H), 1.29 (d, J=6.8 Hz, 3H).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH2:13][O:14][CH3:15])[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd].[C]>[C:21]([O:20][C:18]([NH:17][CH2:16][C:10]1([CH2:13][O:14][CH3:15])[CH2:11][CH2:12][NH:8][CH2:9]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COCC1(CNC(=O)OC(C)(C)C)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: COCC1(CNC(=O)OC(C)(C)C)CCNC1

Procedure:
12 g (37.4 mmol) 1-benzyl-3-(tert.butoxy-carbonylamino-methyl)-3-methoxymethylpyrrolidine is desolved in 150 ml ethanol. This solution is hydrogenated at 4 g Pd-carbon (10%) at 100° C./100 bar H2. The catalyst is removed by filtration, and the organic solvents are removed in vacuo. The residue is distilled.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH:11]=2)=[CH:6][CH:5]=1)=[O:3].[ClH:29]>O1CCOCC1.ClCCl>[ClH:29].[NH:19]1[CH2:20][CH2:21][CH:16]([C:12]2[CH:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:2]([NH2:1])=[O:3])=[CH:5][CH:6]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(-c3ccc(C(N)=O)cc3)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)c1ccc(-c2cccc(C3CCNCC3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1,1-dimethylethyl 4-[4′-(aminocarbonyl)-3-biphenylyl]-1-piperidine carboxylate (0.95 g, 0.0025 mol; I-VII-3) and 4N HCl in dioxane (5 mL) in dichloromethane (5 mL) was stirred at ambient temperature for 3 hr. The resulting solid was collected by filtration, washed with dichloromethane, diethyl ether and air-dried to give the title compound as a white solid, used without further purification. LC/MS (method A) 1.17 min; m/z 281 (M+H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[C:25]([O:32][CH3:33])[CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)=[C:25]([O:32][CH3:33])[CH:24]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Product: COc1cc(F)ccc1-c1ccc(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)s1
Yield: 38.5 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, starting from 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol) and 4-fluoro-2-methoxyphenylboronic acid (10 mg, 0.06 mmol) giving 8.3 mg (37%) of the title compound. MS (ESI+) calcd for C18H14FN5O3S2 431.052209, found 431.052249.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].CI.[C:12](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:9][CH3:12])[C:2]=1[F:1]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(F)c1F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 2,3-difluorophenol 21a (2.08 g, 14.5 mmol, purchased from Beijing yu xiang hui da chemical Co., Ltd) in acetone (50 mL) were added methyl iodide (1.24 mL, 19.98 mmol) and potassium carbonate (3.18 g, 23.06 mmol) in turn at room temperature. The mixture was stirred at room temperature for 16 hours and then filtered. To the filtrate was added ethyl acetate (40 mL). The resulting mixture was washed with water (40 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 21b as yellow oil (2.09 g, 100%). This material was not further purified. The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.01 (m, 1H), 6.83-6.71 (m, 2H), 3.92 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13](F)[C:12]=1[F:21]>C1COCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]=1[F:21]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
Sodium hydride (60% oil dispersion) (2.125 g, 53.1 mmol) was added in portions to a solution of phenol (5.00 g, 53.1 mmol) in THF (100 mL) while cooling in an ice bath. After 30 min, 1,2,3-trifluoro-4-nitrobenzene (6.11 mL, 53.1 mmol) was added. The mixture was stirred at RT overnight. The reaction mixture was poured on to ice/10% aqueous HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated. Chromatography of the residue (ethyl acetate:hexane) gave the crude product (10.78 g, 43%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:15])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:5].FC(F)(F)C(O[I:21](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.II.OS([O-])=O.[Na+]>C(Cl)Cl>[I:21][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:4]([N:3]([O:2][CH3:1])[CH3:15])=[O:5]
Reactant: CON(C)C(=O)c1n[nH]c2ccccc12
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CON(C)C(=O)c1n[nH]c2ccc(I)cc12
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To N-methoxy-N-methyl-1H-indazole-3-carboxamide (CXI) (20 g, 97.4 mmol) in DCM (1 L) was added (Bis(trifluoroacetoxy)iodo)benzene (46 g, 107 mmol) followed by portionwise addition of iodine (14.84 g, 58.5 mmol) at room temperature. After 1 h, saturated aqueous NaHSO3 (600 mL) was added and a solid began to precipitate which was filtered and rinsed with excess DCM. The filtrate was washed with brine, dried over MgSO4, concentrated and the remaining solid was triturated with a minimal amount of DCM. The combined solids were dried under vacuum over KOH to produce 5-iodo-N-methoxy-N-methyl-1H-indazole-3-carboxamide (CXII) as a white solid (23.2 g, 70 mmol, 72% yield). 1H NMR (DMSO-d6) δ ppm 3.45 (s, 3H), 3.77 (s, 3H), 7.45-7.54 (m, 1H), 7.66 (dd, J=8.81, 1.51 Hz, 1H), 8.40 (d, J=1.01 Hz, 1H); ESIMS found for C10H10IN3O2 m/z 331 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([CH3:12])[CH2:8][CH:7]1O)=[O:5])[CH3:2].C1(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([CH3:12])[CH2:8][CH:7]1[N:28]=[N+:29]=[N-:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(C)CC1O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(C)CC1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 65 %

Procedure:
2-Hydroxy-4-methyl-cyclohexanecarboxylic acid ethyl ester (495 mg, 2.66 mmol) was dissolved in THF (13 ml) and then diphenylphosphoryl azide (680 ul, 3.19 mmol) and triphenylphosphine (837 mg, 3.19 mmol) were added. The resulting solution was cooled in an ice bath and diethyl azodicarboxylate (502 ul, 3.19 mmol) was added. After stirring at room temperature for 20 hours, the solvents were removed and the residue was purified by flash chromatography (0% to 3% EtOAc/Hexane) to obtain 365 mg (65%) of 2-Azido-4-methyl-cyclohexanecarboxylic acid ethyl ester.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([CH3:9])=[CH:7][NH:6][C:5]2=[O:10])[CH2:3][CH2:2]1.[H-].[Na+].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH2:17]Br>CN(C=O)C.[Cl-].[Na+].O>[CH:1]1([N:4]2[C:8]([CH3:9])=[CH:7][N:6]([CH2:17][C:16]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[C:14]([F:24])([F:13])[F:25])[C:5]2=[O:10])[CH2:3][CH2:2]1
Reactant: Fc1ccc(C(F)(F)F)c(CBr)c1
Reactant: Cc1c[nH]c(=O)n1C1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(Cc2cc(F)ccc2C(F)(F)F)c(=O)n1C1CC1
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Cyclopropyl-5-methyl-1,3-dihydro-imidazol-2-one (150 mg) was dissolved in DMF (5 mL) under argon and sodium hydride (55% in mineral oil, 71 mg) was added in one portion. The mixture was stirred until gas evolution stopped (approx. 20 minutes) and then a solution of 2-trifluoromethyl-5-fluorobenzyl bromide (307 mg) in DMF (2 mL) was added over 5 minutes. Stirring was continued for 1 hour and then the reaction mixture was poured into brine. The aqueous solution was extracted with ethyl acetate and the organic layer was separated and washed with brine. The combined organic extracts were dried over Na2SO4 and evaporated. Residual DMF was removed by co-evaporation with toluene. The crude material was purified by flash chromatography using a gradient of 20 to 50% ethyl acetate in heptane as an eluent. Fractions containing the desired product were combined and evaporated to give 3-cyclopropyl-1-(5-fluoro-2-trifluoromethyl-benzyl)-4-methyl-1,3-dihydro-imidazol-2-one as a colorless oil (201 mg). MS (ESI): 315.1 (MH+).