Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([O:13][CH2:14][C@@H:15]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:16][CH2:17][C:18]([OH:20])=O)=[O:12].[C:35]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([O:13][CH2:14][C@@H:15]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:16][CH2:17][C:18]([N:45]1[CH2:44][CH2:43][N:42]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:47][CH2:46]1)=[O:20])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)O)COC(=O)Nc1nc2ccccc2s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)COC(=O)Nc1nc2ccccc2s1
Reaction time: 8 h

Procedure:
To a solution of (S)-5-(benzo[d]thiazol-2-ylcarbamoyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoic acid (˜4.41 mmol) in DMF (8 mL) at RT were added N-Boc-piperazine (820 mg, 1 equiv.), DIEA (1.2 mL, 1.5 equiv.), and HBTU (2.00 g, 1.2 equiv.) The reaction was allowed to stir overnight, and the crude was purified by RP-HPLC (5-100% ACN in H2O) to give (S)-tert-butyl 4-(5-(benzo[d]thiazol-2-ylcarbamoyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoyl)piperazine-1-carboxylate as a white solid (801 mg, 27% over 2 steps). LRMS (M+Na+)=699.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([SH:20])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:21]([O:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:33][S:20][C:15]2[C:12]3[CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10][C:11]=3[CH:18]=[CH:17][C:16]=2[Cl:19])=[CH:35][CH:36]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(S)c2CC1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(OCc4ccccc4)cc3)c2CC1
Yield: 67.3 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (706 mg, 1.84 mmol) in methanol (20 mL). Add potassium hydroxide (3.5 g, 55 mmol) and heat the mixture at reflux for 3 h. Cool to ambient temperature. Pour reaction in saturated aqueous NH4Cl solution. Extract three times with EtOAc. Combine organic extracts, dry over Na2SO4 and concentrate in vacuo to obtain crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (602 mg, 100%). Dissolve 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (282 mg, 0.9 mmol) in acetone (30 mL). Add 4-benzyloxybenzyl chloride (251 mg, 1.08 mmol), potassium carbonate (powder) (373 mg, 2.7 mmol) and potassium iodide (powder) (15 mg, 0.1 mmol) and reflux for 16 h. Cool the reaction to ambient temperature, dilute with acetone, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 17:3) to give 6-(4-benzyloxybenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (309 mg, 67%). MS (ES+) m/z: 510 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[CH:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH2:8][CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(c1O)CC(c1ccccc1)C(=O)N2Cc1ccccc1
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(c1O)CC(c1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2,3,4-tetrahydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (22 mg, 0.057 mmol), β-alanine (657 mg, 7.4 mmol) and NaOMe solution (11 mL, 5.7 mmol, 0.5 M in MeOH) was refluxed for 48 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH about 2. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4, and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH 2 with 4 M HCl, and the resulting precipitate was collected by filtration to give 12.4 mg of the title compound as a white solid. MS: (+) m/z 446.40 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH:25]=[C:24]([C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)[CH:23]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])C.[OH-].[Na+]>>[C:42]([CH2:41][CH2:40][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH:25]=[C:24]([C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:47])=[O:3])([OH:44])=[O:43]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3cccnc3)cc(-c3cccnc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(-c3cccnc3)cc(-c3cccnc3)c2)c1CCC(=O)O
Yield: 72.6 %

Procedure:
A similar procedure as described in Example 1, step 3 was used, starting from 4-{3-[6-(3,5-di-pyridin-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (150 mg, 0.26 mmol) and 1.0 N aqueous NaOH (2.5 mL) to afford 4-{2-(2-carboxy-ethyl)-3-[6-(3,5-di-pyridin-3-yl-phenoxy)-hexyl]-phenoxy}-butyric acid (110 mg, 80%) as an amorphous white solid: ES(+)-HRMS m/e calculated for C35H38N2O6 (M+H)+ 583.2803, found 583.2800.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH2:12])[CH:4]=1.[CH:13]([C:16]1[N:17]=[C:18]([C:21](O)=[O:22])[S:19][CH:20]=1)([CH3:15])[CH3:14].CCN=C=NCCCN(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:7]([C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[NH:12][C:21]([C:18]1[S:19][CH:20]=[C:16]([CH:13]([CH3:15])[CH3:14])[N:17]=1)=[O:22])(=[O:8])[NH2:9]
Reactant: COc1ccc(C(N)=O)c(N)c1
Reactant: CC(C)c1csc(C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(C(N)=O)c(NC(=O)c2nc(C(C)C)cs2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution of 4-methoxy-2-aminobenzamide (5.6 g, 33.7 mmol), 4-isopropylthiazole-2-carboxylic acid (7.1 g, 42 mmol) and Hobt-hydrate (6.4 g, 42 mmol) in DMF (150 ml) was added EDAC (8.6 g, 45 mmol) and TEA (6.4 ml, 45 mmol) and the mixture was stirred overnight at room temperature. A 2.5% aqueous solution of citric acid (600 ml) was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with brine and saturated sodium hydrogencarbonate. The solution was dried over sodium sulphate and evaporated under reduced pressure. Yield: 9.0 g, 91%.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH:11]1([Mg]Br)[CH2:13][CH2:12]1.O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[CH:11]1([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[OH:10])[CH2:13][CH2:12]1
Reactant: Br[Mg]C1CC1
Reactant: COc1ccccc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C(O)C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Magnesium (10.7 g) was suspended in tetrahydrofuran (80 ml), and to the suspension was added iodine (5 mg). Bromocyclopropane (32.0 ml) was added dropwise thereto over 1.5 hr and the mixture was heated under reflux for 1.5 hr. Thereto was added tetrahydrofuran to give a 1M cyclopropylmagnesium bromide-tetrahydrofuran solution. Subsequently, o-anisaldehyde (8.17 g) was dissolved in tetrahydrofuran (150 ml), the 1M cyclopropylmagnesium bromide-tetrahydrofuran solution (90 ml) was added dropwise thereto over 50 min under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was ice-cooled, a saturated aqueous ammonium chloride solution (9 ml) was added, and the reaction mixture was stirred at room temperature for 30 min. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1) to give the title compound (6.13 g).
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[N+:14]([C:11]1[CH:10]=[CH:9][C:8]([C:4]2[N:3]([O:2][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:7]=[CH:6][N:5]=2)=[CH:13][CH:12]=1)([O-:16])=[O:15]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(-c2nccn2O)cc1
Agent: Cl
Product: CN(C(=O)On1ccnc1-c1ccc([N+](=O)[O-])cc1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-2-(4-nitrophenyl)imidazole, hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (90%, yellow crystals).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6](#[N:9])[CH:7]=[CH2:8]>>[C:6]([CH2:7][CH2:8][NH:1][CH2:2][CH2:3][CH2:4][OH:5])#[N:9]
Reactant: C=CC#N
Reactant: NCCCO
Product: N#CCCNCCCO
Reaction time: 8 h

Procedure:
A solution of 75 g. (1 mole) of 3-aminopropanol is stirred while 54 g. (1 mole) of acrylonitrile is added dropwise. After being allowed to stand at room temperature for several hours and preferably overnight, the reaction mixture is concentrated under reduced pressure at 50° yielding 3-(2-cyanoethyl)aminopropanol.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].[Cl:18][C:19]1[N:24]2[CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[C:34]([CH2:36]Cl)[CH:33]=[CH:32][N:31]=3)[N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[Cl:18][C:19]1[N:24]2[CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[C:34]([CH2:36][N:8]4[CH:9]=[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([O:5][CH2:3][CH3:4])=[N:7]4)[CH:33]=[CH:32][N:31]=3)[N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: ClCc1ccnc(OCc2cn3c(Cl)cccc3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccnc(OCc3cn4c(Cl)cccc4n3)c2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
Sodium hydride (60%, oily, 160 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (849 mg) and 5-chloro-2-(4-chloromethyl-2-pyridyloxymethyl)imidazo[1,2-a]pyridine (1230 mg) in N,N-dimethylformamide (20 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[2-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)-4-pyridylmethyl]-3-ethoxy-1H-pyrazol-4-yl]propionate (1570 mg, yield: 81%) as a colorless oily substance from the fraction eluted with ethyl acetate.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[CH2:26](O)[CH3:27].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([O:24][CH2:26][CH3:27])=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [K]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reaction time: 3 h

Procedure:
52.4 g (0.15 mol) of 1-benzyl-3-(5-carboxy-2-furyl)indazole, potassium salt, were initially charged in 1250 ml of toluene, and after addition of 200 ml of abs. ethanol and 50 ml of conc. sulfuric acid the mixture was stirred under reflux on a water separator. After 3 hours, the mixture was concentrated using a rotary evaporator, the oil that remained was taken up in water/ethyl acetate and the aqueous phase was separated off. The organic phase was washed with water and 7.5% strength NaHCO3 solution, dried with sodium sulfate and concentrated. The residue was recrystallized from isopropanol. This gave 37.8 g (73%) of the title compound. m.p.: 98-99 ° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N:9]([CH3:11])[CH3:10])=[CH:4][N:3]=1.Cl.Cl.[NH:14]1[C:18]2[CH2:19][CH2:20][CH2:21][NH:22][C:17]=2[N:16]=[CH:15]1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.O>[Cl:1][C:2]1[N:7]=[C:6]([N:22]2[CH2:21][CH2:20][C:19]3[N:16]=[CH:15][NH:14][C:18]=3[CH2:17]2)[C:5]([N:9]([CH3:11])[CH3:10])=[CH:4][N:3]=1
Reactant: c1nc2c([nH]1)CCCN2
Reactant: CN(C)c1cnc(Cl)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CN(C)c1cnc(Cl)nc1N1CCc2nc[nH]c2C1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
5 g of 2,4-dichloro-5-dimethylamino-pyrimidine are dissolved in 30 mL isopropanol and combined with 5.82 g 4,5,6,7-tetrahydroimidazopyridine dihydrochloride and 6.06 g potassium carbonate. After 6 and 8 days in each case 1 g of 4,5,6,7-tetrahydroimidazopyridine dihydrochloride and 1 g potassium carbonate are added. In all, the mixture is stirred for 10 days at 25° C. The reaction mixture is diluted with 400 mL water and stirred for 1 h. The precipitate formed is suction filtered, washed and dried.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[N-:7]=[N+:8]=[N-:9].[Na+]>C1C=CC=CC=1.Cl>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]=[N+:8]=[N-:9])=[O:6]
Reactant: O=C=NCCCl
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Product: [N-]=[N+]=NC(=O)NCCCl
Temperature: 0 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A solution of 2-chloroethyl isocyanate (0.2 mole) in 100 ml of benzene was slowly added to a stirred solution of activated sodium azide (0.2 mole) in 100 ml of hydrochloric acid (13%) maintained at 0° C. The two-phase reaction mixture was stirred for 4 hours at 0° C. and the water phase was removed. 2-chloroethylcarbamoyl azide was crystallized from benzene/petroleum ether in the form of white needles. Yield: 88%. M.P. 49.6 to 50.2° C. NMR(CDCl3 -TMS)δ=3.4 to 3.9 ppm (unres., 4H, CH2 --CH2Cl); 6.12 ppm (br, s, iH, NH); MS(14 v):m/e 148(M+), m/e 106(M--N3)+, m/e 105 (M--HN3)+=base peak. An intensity ratio of m/e 148 / m/e 150 is typical for a monochlorinated compound.
Reaction SMILES: [BH4-].[Li+].[F:3][C:4]([F:15])([F:14])[C:5]1[S:9][CH:8]=[C:7]([C:10](OC)=[O:11])[CH:6]=1.Cl>O1CCCC1>[F:14][C:4]([F:3])([F:15])[C:5]1[S:9][CH:8]=[C:7]([CH2:10][OH:11])[CH:6]=1
Reactant: COC(=O)c1csc(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1csc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a suspension of lithium borohydride (15.9 g) in tetrahydrofuran (550 ml) was added dropwise a solution of methyl 5-(trifluoromethyl)thiophene-3-carboxylate (55.1 g) in tetrahydrofuran (50 ml) at 0° C., and the obtained mixture was stirred at 50° C. overnight. The reaction mixture was cooled to 0° C., poured into 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (37.3 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.Cl.[Cl:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[ClH:12].[N:20]1([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][N:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)[NH2:10])=[CH:15][CH:16]=2)[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: ClCc1ccc(-n2ccnc2)cc1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: NN(Cc1ccc(-n2ccnc2)cc1)c1ccc(F)cc1

Procedure:
The 1-[4-1H-imidazol-1-yl)benzyl]-1-(4-fluorophenyl)hydrazine hydrochloride used above is prepared as follows: a mixture of 1-(4-fluorophenyl)hydrazine hydrochloride (3.3 g), 1-[4-(chloromethyl)phenyl]-1H-imidazole hydrochloride (3.1 g), triethylamine (6.6 ml) and toluene (200 ml) is refluxed under nitrogen for 13 hours. After cooling the mixture is filtered and the solution is evaporated to dryness. The residue is purified through a silica gel column eluiting with methylene chloride/methanol (100/5) to give 2.0 g of 1-[(4-1H-imidazol-1-yl)benzyl]-1-(4-fluorophenyl)hydrazine hydrochloride, ms: m/e 282 (M+), 158,157.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=2)[CH:7]=1.C(O)(=O)C.[O-:27][C:28]#[N:29].[K+]>O>[CH2:17]([C:10]1[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([NH2:29])=[O:27])[CH:3]=[CH:4][C:5]=2[O:19][CH2:20][CH2:21][CH3:22])[NH:13][C:12](=[O:14])[C:11]=1[CH2:15][CH3:16])[CH3:18]
Reactant: N#C[O-]
Reactant: CCCOc1ccc(N)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCCOc1ccc(NC(N)=O)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Reaction time: 2 h
Yield: 101.6 %

Procedure:
The compound (200 mg, 0.6 mmol) of example 42 was suspended in a mixed solution of water (5 ml) and acetic acid (5 ml), added with potassium cyanate (81 mg, 1 mmol), and heated to reflux and stirred for 2 h. The cooled reaction mixture was poured into water to generate a white solid, which was washed with water (10 ml×3) and dried to give the title compound (210 mg, yield: 91%). 1H NMR (DMSO-d6) δ: 11.76 (1H, br), 8.56 (1H, br), 7.76 (1H, d), 7.59 (1H, dd), 7.06 (1H, d), 5.78 (1H, br), 4.00 (2H, t), 2.56 (2H, q), 2.46 (2H, q), 1.74 (2H, m), 1.19 (3H, t), 1.04 (3H, t), 0.97 (3H, t).
Reaction SMILES: F[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:22]1[S:26][CH:25]=[N:24][CH:23]=1.Cl.[OH:28][CH2:29][C@@H:30]1[CH2:34][NH:33][CH2:32][C@H:31]1[OH:35]>>[OH:35][C@H:31]1[C@H:30]([CH2:29][OH:28])[CH2:34][N:33]([C:2]2[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)=[O:7])=[CH:4][C:3]=2[C:22]2[S:26][CH:25]=[N:24][CH:23]=2)[CH2:32]1
Reactant: OC[C@@H]1CNC[C@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(-c2cncs2)c1
Agent: Cl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@@H](CO)[C@H](O)C2)c(-c2cncs2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 4 using 4-fluoro-3-(thiazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.1) and trans-4-(hydroxymethyl)pyrrolidin-3-ol hydrochloride to afford an off-white solid. UPLC-MS (Condition 3) tR=0.95 min, m/z=480.1 [M+H]+, m/z=478.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.04-2.18 (m, 1H) 2.78 (dd, J=10.39, 3.79 Hz, 1H) 2.97 (dd, J=9.90, 5.01 Hz, 1H) 3.18 (dd, J=10.51, 5.62 Hz, 1H) 3.23-3.28 (m, 1H) 3.32-3.37 (m, 1H) 3.37-3.47 (m, 1H) 3.91-4.03 (m, 1H) 4.63 (t, J=5.14 Hz, 1H) 4.94 (d, J=4.16 Hz, 1H) 6.99 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.83-7.98 (m, 5H) 9.16 (d, J=0.73 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[F:32][C:33]1[CH:34]=[C:35]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([F:32])[CH:34]=3)(=[O:41])=[O:40])=[O:24])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1cccc(F)c1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3cccc(F)c3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 3-fluorobenzenesulfonamide: 1H-NMR (CDCl3) δ 7.70-7.59 (2H, m), 7.45-7.17 (11H, m), 6.41 (1H, br.s), 3.47-3.37 (2H, m), 2.77-2.73 (2H, m), 2.27 (3H, s), 2.21 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[CH:18]=O)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1.N1CCCC1>CO>[C:1]([O:5][C:6](=[O:20])[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[CH:18]=[C:26]1[C:25]2[C:29](=[CH:30][C:22]([Cl:21])=[CH:23][CH:24]=2)[NH:28][C:27]1=[O:31])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(Cl)cc1C=C1C(=O)Nc2cc(Cl)ccc21
Yield: 46.1 %

Procedure:
In a manner similar to the method described in Example 227b, 2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid tert-butyl ester (9 g, 30 mmol) was reacted with 6-chlorooxindole (5.1 g, 30 mmol) and pyrrolidine (2.49 g, 35 mmol) in methanol to give E/Z 2-[4-chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid tert-butyl ester as a yellow oil (6.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C)=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)=[CH:15][C:14]=2[Cl:25])[CH:3]=1>Cl.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)=[CH:15][C:14]=2[Cl:25])[CH:3]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1Oc1ccc(-c2noc(C)n2)cc1Cl
Agent: Cl
Solvent: CCO
Product: Cc1nc(-c2ccc(Oc3cc(Cl)ccc3N)c(Cl)c2)no1

Procedure:
The subtitle compound was prepared using the product from step ii) (0.50 g) which was dissolved in 2M HCl (10 ml) and ethanol (10 ml). The mixture was heated at reflux for 3 hours and concentrated under reduced pressure to an solid. Yield 0.45 g.