Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH2:10]([Sn](CCCC)(CCCC)C=C)[CH2:11]CC.[F-].[K+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH:10]=[CH2:11])[N:5]=[CH:4][N:3]=1
Reactant: Fc1c(Cl)ncnc1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: C=Cc1ncnc(Cl)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
A mixture of 4,6-dichloro-5-fluoropyrimidine (5.0 g, 30.0 mmol, 1.0 equiv) and tributyl(vinyl)tin (10.4 g, 33.0 mmol, 1.1 equiv) in dichloromethane (50 mL) was degassed with a stream of with nitrogen for 10 minutes. Bis(triphenylphosphine) palladium(II) chloride (0.53 g, 0.75 mmol, 0.025 equiv) was added. The resulting mixture was degassed with a stream of nitrogen for an additional 15 minutes and heated at reflux for 72 hours. The reaction mixture was cooled to room temperature and quenched with an aqueous potassium fluoride solution (2 M, 75 mL, 5 equiv). The resulting mixture was allowed to stir for 2 hours and filtered through Celite®. The filtrate was poured into a separatory funnel and separated. The organic layer was washed with water (20 mL) and saturated brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure at 20° C. The resulting crude product was purified on an AnaLogix® (SF40-115 g) column. The gradient utilized for the purification was 10 minutes isocratic pentane, followed by a 20 minutes ramp to 5% diethyl ether in pentane. The pure fractions were combined and concentrated under reduced pressure at 20° C. to give 4-chloro-5-fluoro-6-vinylpyrimidine (3.0 g, 63% yield).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:33])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][CH:10]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26](Cl)[C:27](OCC)=[O:28])=[CH:21][CH:20]=1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[NH2:34][C:35]([NH2:37])=[S:36].S1(CCCC1)(=O)=O>>[C:1]([O:4][C:5]1[C:6]([CH3:33])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][CH:10]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]3[S:36][C:35](=[NH:34])[NH:37][C:27]3=[O:28])=[CH:21][CH:20]=1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Solvent: O=S1(=O)CCCC1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(COc1ccc(CC3SC(=N)NC3=O)cc1)O2

Procedure:
The procedure described in Example 1(a) was repeated, except that 490 mg of ethyl 3-[4-(6-acetoxy-5,7,8-trimethylchroman-2-ylmethoxy)phenyl]-2-chloropropionate, 100 mg of thiourea and 2 ml of sulfolane were heated at 110°-120° C. for 5 hours. The product was then treated as described in Example 1(a), except that the crude product (in the form of crystals) was washed with ethyl acetate, to give the title compound, softening at 228°-236° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:10])=[C:4]([F:9])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(Br)ccc1CBr
Yield: 94.3 %

Procedure:
1-Bromo-3-fluoro-4-methylbenzene (28.37 g, 0.15 mol, 1 eq), N-bromosuccinimide (26.72 g, 0.15 mol, 1 eq), azobisisobutyronitrile (1.44 g) and carbon tetrachloride (500 mL) were mixed and refluxed overnight. The mixture was filtered and washed with water (3×300 mL). The organic layer was dried (MgSO4), and the solvent removed in vacuo to yield 37.88 g of an oil (75% product by NMR). NMR (CDCl3) δ 4.45 (s, 2H). This material was used in the subsequent step without further purification. ##STR47##
Reaction SMILES: [C:1]1([S:7][CH:8]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9][C:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClN1C(=O)CCC1=O>C1(C)C=CC=CC=1>[C:26]1([S:25][C:8]([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][C:10]([S:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(N=C(CC(Sc2ccccc2)Sc2ccccc2)Sc2ccccc2)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: Cc1ccccc1
Product: C(=C(Sc1ccccc1)Sc1ccccc1)C(=Nc1ccccc1)Sc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.6 %

Procedure:
To a solution of 0.50 g (1.1 mmol) of phenyl 3,3-bis(phenylthio)-N-(phenyl)propanimidothioate in toluene (5 mL) was added 0.16 g (1.2 mmol) of N-chlorosuccinimide under ice cooling and stirred at room temperature for 3 hours. After dilution with t-butyl methyl ether (50 mL), the mixture was washed with saturated NaCl solution, dried over MgSO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 38 mg of phenyl 3,3-bis(phenylthio)-N-phenyl-2-propenimidothioate (hereinafter referred to as the present compound 45).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[C:23]2[C:30]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[CH3:20][C:17]1[CH:18]=[CH:19][N:6]2[C:7]=1[C:8](=[O:16])[N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([C@@H:2]([NH:1][C:22]1[C:23]3[C:30]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])=[CH:29][NH:28][C:24]=3[N:25]=[CH:26][N:27]=1)[CH3:3])=[N:5]2
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: O=C(OCc1ccccc1)c1c[nH]c2ncnc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)OCc5ccccc5)c34)n(-c3ccccc3)c(=O)c12
Temperature: 80 °C
Reaction time: 12 h
Yield: 69.1 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (418 mg, 1.56 mmol) and benzyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (500 mg, 1.74 mmol) were dissolved in tert-butanol (8 ml) and DIEA (2 ml, 11.45 mmol) was added. After stirring the mixture at 80° C. for 12 h, the solvent was evaporated under reduced pressure and the residue was suspended in water, basified with sodium carbonate and extracted with AcOEt (×3). The organic phase was successively washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to obtain 560 mg (66% yield) of the title compound as a white solid. Purity 96%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:24]([C:33]([F:36])([F:35])[F:34])[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:28]1([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][O:1][C:2]3[CH:10]=[CH:9][C:8]4[NH:7][C:6]5[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=5[C:4]=4[CH:3]=3)=[CH:23][C:24]=2[C:33]([F:34])([F:35])[F:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a solution of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (50.0 mg, 0.193 mmol) and 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (152.0 mg, 0.578 mmol) in DMF (3 mL) was added cesium carbonate (75.0 mg, 0.231 mmol). The mixture was stirred at room temperature overnight, filtered through Celite®, and concentrated under reduced pressure. The residue was purified by HPLC to give the title compound as a light pink oil (38.7 mg). LCMS m/z=486.5 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][CH2:10][CH2:11][CH:12]([N:19]1[CH:23]=[C:22]([C:24]2[C:25]3[CH:32]=[CH:31][N:30](COCC[Si](C)(C)C)[C:26]=3[N:27]=[CH:28][N:29]=2)[CH:21]=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)Cl.CO.C(N)CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][CH2:10][CH2:11][CH:12]([N:19]1[CH:23]=[C:22]([C:24]2[C:25]3[CH:32]=[CH:31][NH:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH:21]=[N:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COCCC(c1ccccc1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: ClCCl
Solvent: NCCN
Solvent: CO
Product: COCCC(c1ccccc1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 2 h
Yield: 48.1 %

Procedure:
Trifluoroacetic Acid (2 mL, 0.02 mol) was added to a mixture of 4-[1-(3-methoxy-1-phenylpropyl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (80 mg, 0.0002 mol) in DCM (3 mL, 0.05 mol) at room temperature. The starting material was consumed after stirring for 2 hrs and the reaction solution was concentrated to remove the TFA. The crude reaction was diluted with methanol (3 mL, 0.07 mol) and was treated with ethylenediamine (0.3 mL, 0.004 mol) at room temperature. The reaction mixture was stirred for 18 hs and was concentrated and purified using HPLC on a C-18 column eluting with an ACN:water gradient containing 0.2% TFA, to give the title compound (43 mg, 60%) as a white amorphous solid. 1H NMR (400 MHz, CDCl3): δ□8.9 (s, 1H), 8.8 (s, 1H), 8.4 (s, 1H), 7.8 (s, 1H), 7.4 (m, 1H), 7.3 (m, 5H), 7.2 (b, 1H), 5.7 (m, 1H), 3.3 (m, 1H), 3.2 (s, 3H), 2.7 (m, 1H), 2.4 (m, 1H). m/z=334 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])[CH:11]=1.[NH3:21]>>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[CH:11]=[C:6]([CH2:5][CH2:4][C:3]([NH2:21])=[O:2])[CH:7]=[N:8][CH:9]=1
Reactant: COC(=O)CCc1cncc(-c2cccc(Cl)c2Cl)c1
Reactant: N
Product: NC(=O)CCc1cncc(-c2cccc(Cl)c2Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-[5-(2,3-dichloro-phenyl)-pyridin-3-yl]-propionic acid methyl ester and ammonia (7N in MeOH, 2 ml, 14.00 mmol) was stirred at room temperature for 24 hours. Ammonia (7N in MeOH, 1 ml, 7.00 mmol) was added, and the reaction mixture was stirred for another 24 hours. Solvent was removed in vacuo. The crude product was used in the next step without purification. ESI-MS m/z: 295 [M+1]+.
Reaction SMILES: CN(C)C=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:25])[F:24])=[O:16].[CH2:27](I)[CH3:28].[H-].[Na+]>O>[CH2:27]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:24])[F:25])=[O:16])[CH3:28]
Reactant: CCI
Reactant: CC(CCCCOC(=O)c1cc2ccccc2[nH]1)=C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(C(=O)OCCCCC(C)=C(F)F)cc2ccccc21
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.32 g (1.1 mmol) of 6,6-difluoro-5-methyl-5-hexenyl 1H-indole-2-carboxylate and 0.34 g (2.2 mmol) of ethyl iodide, followed by the addition of 0.06 g (1.5 mmol) of sodium hydride at room temperature and stirring at the same temperature for 1 hour. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:5) to obtain 0.31 g (yield: 88%) of 6,6-difluoro-5-methyl-5-hexenyl 1-ethyl-1H-indole-2-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19](=[C:24]([F:26])[F:25])[CH2:20][C:21](Cl)=[O:22]>ClCCl.O>[F:18][C:19](=[C:24]([F:26])[F:25])[CH2:20][C:21]([NH:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[N:7]=1)=[O:22]
Reactant: O=C(Cl)CC(F)=C(F)F
Reactant: COc1cc(OC)nc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)nc(NC(=O)CC(F)=C(F)F)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 10.7 %

Procedure:
To an ice-cooled stirred suspension of 2-amino-4,6-dimethoxypyrimidine (1.55 g, 10 mmol) in dichloromethane (50 mL) and potassium carbonate (2.76 g, 20 mmol) in water (20 mL) was added 3,4,4-trifluoro-3-butenoyl chloride (3.17 g, 20 mmol). The reaction mixture was stirred in cold for 10 min and at r.t. for 15 min. The organic layer was washed with 3N HCl (2×25 mL), saturated sodium bicarbonate (25 mL) and brine, and dried. Evaporation of the solvent gave 0.296 g (10%) of the title compound as a white solid. m.p. 127°-130° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH:13]([N:26]1[CH2:29][C:28](=[CH:30][S:31]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:42][CH2:43][CH2:44][CH2:45]Br)[CH:36]=2)(=[O:33])=[O:32])[CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C.C(OCC)(=O)C.O>[CH:13]([N:26]1[CH2:29][C:28](=[CH:30][S:31]([CH2:34][C:35]2[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=2)[O:41][CH2:42][CH2:43][CH2:44][CH2:45][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)(=[O:33])=[O:32])[CH2:27]1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(C=C1CN(C(c2ccccc2)c2ccccc2)C1)Cc1cccc(OCCCCBr)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=S(=O)(C=C1CN(C(c2ccccc2)c2ccccc2)C1)Cc1cccc(OCCCCN2CCOCC2)c1
Reaction time: 17 h

Procedure:
25 mg of potassium carbonate and then 0.016 cm3 of morpholine are successively added, at a temperature close to 20° C., under an inert atmosphere of argon, to a solution of 33 mg of 1-benzhydryl-3-{[3-(4-bromobutoxy)phenyl]methanesulfonylmethylene}azetidine in 2 cm3 of anhydrous acetonitrile. After stirring for 17 hours at a temperature close to 20° C., the reaction medium is diluted with 10 cm3 of ethyl acetate and 4 cm3 of water. The separated organic phase is washed with 4 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered on sintered glass and then concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. The residue obtained is purified by depositing, in solution in a minimum of dichloromethane, on chromatography on silica gel deposited on a plate [(gel 0.5 mm thick, 2 plates of 20 20 cm, eluent: dichloromethane-methanol (92.5-7.5 by volume)]. The zone corresponding to the desired product adsorbed, located with UV rays, is scraped and the silica recovered is washed on sintered glass with a dichloromethane-methanol mixture (80-20 by volume). The filtrates are combined and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 25.2 mg of 4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]phenoxy}butyl)morpholine are obtained in the form of a pale yellow foam [1H NMR spectrum (400 MHz, CDCl3, δ in ppm): 1.66 (mt, 2H), 1.81 (mt, 2H), 2.40 (t, J=7.5 Hz, 2H), 2.46 (mt, 4H), 2.77 (s, 3H), 3.72 (t, J=5 Hz, 4H), 3.84 (mt, 2H), 3.96 (t, J=6.5 Hz, 2H), 4.36 (mt, 2H), 4.53 (s, 1H), 6.87 (dd, J=8 and 2 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 6.96 (d, J=2 Hz, 1H), from 7.10 to 7.35 (mt, 7H), 7.42 (d, J=8 Hz, 4H)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:7]2[C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][C:16]=1[CH3:23].B(Br)(Br)Br.C1CCCCC=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:7]2[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=1[CH3:23]
Reactant: COc1ccc(-c2nn(CC(C)C)c3c(F)cccc23)c(C)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Cc1cc(O)ccc1-c1nn(CC(C)C)c2c(F)cccc12
Yield: 96.1 %

Procedure:
Prepared according to Method D step C from 7-fluoro-1-isobutyl-3-(4-methoxy-2-methyl-phenyl)-1H-indazole (0.364 g, 1.2 mmol), boron tribromide (0.450 mL, 4.6 mmol) and 1.0 mL of cyclohexene to give the product (0.344 g) as a white solid.
Reaction SMILES: C([O:3][C:4]1[C:5](=[O:17])[C:6](=O)[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>CS(C)=O>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:6]1[C:5](=[O:17])[C:4](=[O:3])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: COc1ccccc1N
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Solvent: CS(C)=O
Product: COc1ccccc1Nc1c(Nc2ccccc2O)c(=O)c1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 2-methoxyaniline (0.024 mL, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 311.4 (M+).
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:19][CH2:20][CH3:21])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Br:22]N1C(=O)CCC1=O.COC(C)(C)CC(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:22][CH:19]([C:7]1[NH:8][C:9]2[C:14]([C:6]=1[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)[CH2:20][CH3:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCc1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Agent: COC(C)(C)CC(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(Br)c1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Yield: 69.9 %

Procedure:
To a solution of methyl 3-isobutyryl-2-propylindole-6-carboxylate (201 mg) in carbon tetrachloride (7 ml) was added N-bromosuccinimide (187 mg) and 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile; (20 mg) and refluxed for 30 minutes. The resulting mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (2:1) to give methyl 2-(1-bromopropyl)-3-isobutyrylindole-6-carboxylate (179 mg).
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[C:27]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:36])=[O:3])[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1cccc(OC(C)(C)C(=O)O)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Under nitrogen, 2-{3-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the product in 99% yield as a white solid: 1H NMR (400 MHz, CDCl3) o 8.05-8.03 (m, 2H), 7.68-7.66 (m, 2H), 7.65-7.63 (m, 2H), 7.47 (t, J=7.6 Hz, 2H), 7.38 (tt, J=7.2, 1.6 Hz, 1H), 7.14 (t, J=8.4 Hz, 1H), 6.69 (t, J=2.4 Hz, 1H), 6.61 (dd, J=8.0, 2.8 Hz, 1H), 6.54 (dd, J=7.6, 2.4 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 2.95 (t, J=7.2 Hz, 2H), 2.37 (s, 3H), 1.56 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OC(O)C)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: Nc1ccccc1
Agent: CCOC(C)O
Product: CCOC(=O)c1ccc(Nc2ccccc2)nc1
Yield: 87.9 %

Procedure:
A mixture of 6-chloronicotinic acid ethyl ester (0.2 g, 0.00108 mole) and aniline (0.119 g, 0.00129 mole) in ethoxyethanol (10 mL) was heated to reflux for overnight. The mixture was then concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (5% ethyl acetate in hexane) to afford 0.23 g (88%) of 6-phenylamino-nicotinic acid ethyl ester. To a stirred solution 6-phenylamino-nicotinic acid ethyl ester (0.23 g, 0.00095 mol) in a mixture of THF (4 mL), methanol (4 mL) and H2O (2 mL) was added LiOH.H2O (0.159 g, 0.0038 mol) at ambient temperature and the resulting mixture was stirred overnight. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous citric acid solution. The resulting precipitate was isolated by filtration and dried to afford 0.174 g (85%) of 6-Phenylamino-nicotinic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.Cl.[CH3:15][C:16]1([CH3:35])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([C:23]2[CH:24]=[N:25][N:26]([C:28]3([CH2:32][C:33]#[N:34])[CH2:31][NH:30][CH2:29]3)[CH:27]=2)[O:17]1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[C:33]([CH2:32][C:28]1([N:26]2[CH:27]=[C:23]([B:18]3[O:19][C:20]([CH3:22])([CH3:21])[C:16]([CH3:35])([CH3:15])[O:17]3)[CH:24]=[N:25]2)[CH2:31][N:30]([C:2]2[N:3]=[CH:4][C:5]([C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=2)[CH2:29]1)#[N:34]
Reactant: CC(C)NC(=O)c1cnc(Cl)cn1
Reactant: CC1(C)OB(c2cnn(C3(CC#N)CNC3)c2)OC1(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)NC(=O)c1cnc(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cn1
Temperature: 100 °C
Yield: 57.6 %

Procedure:
A mixture of 5-chloro-N-isopropylpyrazine-2-carboxamide (200 mg, 1.00 mmol), {3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile HCl salt (325 mg, 1.00 mmol, from Example 1, step 3) and N,N-diisopropylethylamine (401 μL, 2.30 mmol) in 1,4-dioxane (5.0 mL) was heated at 100° C. for 2 h. After cooling, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexane (gradient: 20-80%) to afford the desired product (0.26 g, 58%). LCMS cacld. for C22H31BN7O3 (M+1)+: m/z=452.3. Found: 452.2.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([C:8]1[CH:9]=[C:10]([NH:14][C:15]([C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:20]=[CH:21]C=2O)=[O:16])[CH:11]=[CH:12][CH:13]=1)#[N:7]>O1CCCC1.N1C=CC=CC=1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][C:5]2[O:4][C:2](=[O:3])[N:14]([C:10]3[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=3)[C:6]#[N:7])[C:15](=[O:16])[C:17]=2[CH:18]=1
Reactant: COC(=O)Cl
Reactant: N#Cc1cccc(NC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#Cc1cccc(-n2c(=O)oc3ccc(-c4ccc(F)cc4F)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 49 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 9 (1.4 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% 1HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 21.