Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:7][C@H:6]([OH:8])[C@@H:5]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=2)[CH2:4][CH2:3]1>CCCCCC.C(O)(C)C>[F:23][C:2]1([F:1])[CH2:7][C@@H:6]([OH:8])[C@H:5]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(Cn2cc([C@H]3CCC(F)(F)C[C@@H]3O)cn2)cc1
Solvent: CCCCCC
Solvent: CC(C)O
Product: COc1ccc(Cn2cc([C@@H]3CCC(F)(F)C[C@H]3O)cn2)cc1

Procedure:
The (1S*,2R*)-5,5-difluoro-2-[1-(4-methoxybenzyl)-1H-pyrazol-4-yl]cyclohexanol prepared in Example 143d was optically resolved with CHIRALPAK IA (Daicel Corp.; hexane/isopropanol=8:2) to yield the title compound as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28](=[O:48])[CH2:29][C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:48])[CH2:29][C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)[CH3:26]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol (Enantiomer A) and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([F:10])[C:7](Cl)=[N:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][C:14]=1[F:23].[CH3:25][N:26](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([C:25]#[N:26])=[N:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][C:14]=1[F:23]
Reactant: COC(=O)c1cc(F)c(Cl)nc1Nc1ccc([Si](C)(C)C)cc1F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(F)c(C#N)nc1Nc1ccc([Si](C)(C)C)cc1F
Yield: 91 %

Procedure:
A degassed suspension of 6-chloro-5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinic acid methyl ester (7.8 g, 21.2 mmol), zinc (II) cyanide (1.84 g, 15.6 mmol), and Pd(PPh3)4 (2.43 g, 2.12 mmol) in DMF (40 mL) was subjected to microwave irradiation at 150° C. for 15 minutes. The reaction mixture was filtered through Celite® and the filtrate diluted with ethyl acetate. The organic phase was washed twice with water and once with brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was triturated with diethyl ether and pentane, and then dried under vacuum to afford the title compound as a yellow solid (6.9 g, 91%). LCMS (method B): RT=4.99 min, [M+H]+=362.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH:20]([S:23]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][N:27]=1)(=[O:25])=[O:24])([CH3:22])[CH3:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:7]([CH2:9][N:28]3[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:26]([S:23]([CH:20]([CH3:22])[CH3:21])(=[O:24])=[O:25])=[N:27]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)S(=O)(=O)c1n[nH]c2ccccc12
Reactant: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2CCCS(C)(=O)=O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
A mixture of 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole (72 mg, 0.22 mmol), 3-(isopropylsulfonyl)-1H-indazole (50 mg, 0.22 mmol), K2CO3 (61 mg, 0.44 mmol) and DMF (1.5 mL) was stirred at RT overnight. The resultant mixture was purified by pre-HPLC to give 1-({5-chloro-1-[3-(methylsulfonyl)propyl]-1H-benzimidazol-2-yl}methyl)-3-(propan-2-ylsulfonyl)-1H-indazole as white solid (31.0 mg, yield: 27.2%).
Reaction SMILES: [C:1]([CH:3]([C:8]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([CH3:19])=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:4]([O:6][CH3:7])=[O:5])#[N:2].IC.[C:29](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]([C:8]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([CH3:19])=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:29])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(C#N)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)C(C)(C#N)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(±)-tert-Butyl 4-(1-cyano-2-methoxy-2-oxoethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 155-C) (1.1 g, 3.07 mmol) was dissolved in acetone (6.14 ml) and then added iodomethane (0.576 ml, 9.21 mmol) followed by potassium carbonate (0.636 g, 4.60 mmol) and stirred at room temperature for 2.5 hours. The reaction was then cooled in an ice bath and quenched with a saturated aqueous solution of ammonium chloride and diluted with DCM. The layers were separated and the organic layer was dried and concentrated to obtain the title compound. MS (ESI+) m/z 373.4 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([Cl:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1)=[O:5])C.[OH-].[Na+]>O.C(O)C>[Cl:12][C:11]1[C:6]([C:4]([OH:5])=[O:3])=[N:7][CH:8]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:10]=1
Reactant: CCOC(=O)c1ncc(C(F)(F)F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 3 h
Yield: 84.5 %

Procedure:
423 g of 3-chloro-5-trifluoromethyl-2-pyridinecarboxylic acid ethyl ester (Example P2) is placed in a mixture of 800 ml of water and 160 ml of ethanol. 800 ml of a 2N sodium hydroxide solution are added dropwise at below 35° C. After 3 hours, the mixture is washed twice with dichloromethane and then rendered acidic with excess concentrated hydrochloric acid while cooling with an ice-bath. The resulting slurry is filtered, washed with water and dried in vacuo. 318 g of the desired product are obtained in the form of a white solid having a melting point of 135° C. (decomposition).
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:12]([C:14](=[C:19]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:15]=[CH:16][CH:17]=[O:18])[CH3:13]>O1CCCC1>[CH2:12]([C:14](=[C:19]([C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH:15]=[CH:16][CH:17]([OH:18])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH3:13]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: CCC(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: C1CCOC1
Product: CCC(C=CC(O)CC(=O)CC(=O)OC(C)(C)C)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 3 h
Yield: 71.9 %

Procedure:
The dianion of 1,1-dimethylethyl acetoacetate (20 mL of 0.5 M solution, 10 mmol) was added to a solution of 4-ethyl- 5,5-bis-(4-fluorophenyl)-2,4-pentadienal (2.0 g, 6.7 mmol) in 20 mL of tetrahydrofuran at -70° C. The mixture was stirred for 3 hours during which time the temperature was allowed to rise to -30° C. and quenched with saturated ammonium chloride solution. The mixture was extracted with diethyl ether, the extracts dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 10% ethyl acetate in hexane to give 2.2 g of the title compound as an oil. MS(CI): m/e =456 for M+ of C27H30F2O4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([NH2:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(=O)([O-])O.[K+].[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1.O>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([NH:11][C:26]([O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27])[C:4]([O:3][CH2:1][CH3:2])=[O:12])[CH3:10]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Reaction time: 1.5 h

Procedure:
To a solution of 2-aminomalonic acid diethyl ester (10.0 g) in dioxane (60 ml) and water (36 ml), potassium hydrogen carbonate (10.4 g) was added. After completion of the effervescence benzylchloroformate (7.4 ml) was added. The mixture was stirred at 23° for 1.5 h then it was concentrated under reduced pressure, taken up with diethyl ether (400 ml) and washed with 5% HCl (50 ml) and brine (50 ml). The organic layer was dried over sodium sulphate and concentrated in vacuo to give the title compound as a colorless oil (13.6 g). T.l.c. EA/CH 1:4 Rf=0.25.
Reaction SMILES: C=O.[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH3:12][CH2:13][O-].[Na+].Cl>CN(C=O)C>[CH:3]1([CH2:9][CH:8]2[C:12]3[C:13](=[CH:11][CH:3]=[CH:4][CH:5]=3)[CH:6]=[CH:7]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: C1=Cc2ccccc2C1
Reactant: CC[O-]
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1=CC(CC2C=Cc3ccccc32)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
3.5 g of formalin (37% solution, 43.1 mmol) was added to a mixture of 10.0 g of indene (86.2 mmol) and 2.9 g of EtONa (43.1 mmol) in 100 mL of DMF. The reaction mixture was stirred at room temperature for 12 hours. A solution of HCl (1 M, 50 mL) was added. The mixture was extracted with CH2Cl2 (2×100 mL) and the organic phases combined, washed with a saturated solution of NaCl and then with water, dried over MgSO4, filtered and finally concentrated to yield bis(1-indenyl)methane as a viscous brown liquid (89% yield by GC). Vacuum distillation yielded the pure product as a yellow viscous oil (b.p. 160-180° C. at 1.2 mmHg, 3.65 g, 35% yield), which can be recrystallized from pentane.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH-:12].[Na+].Cl>O>[N+:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[OH:12])([O-:11])=[O:10]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)cc1O
Reaction time: 6 h
Yield: 90.1 %

Procedure:
192.0 g (1 mol) of 2,4-dichloronitrobenzene, 600 g of water and 273.0 g (2.05 mol) of sodium hydroxide are heated to 140° C. in a VA steel autoclave with vigorous stirring for 6 hours. The reacted reaction mixture is removed from the autoclave at 70° C. The orange-brown solution produced is adjusted to pH 2 using 30% strength hydrochloric acid, and the product is distilled over using steam. On stirring the distillate (about 1.5 1) at 10° C, 2-nitro-5-chlorophenol (156.4 g, 90% of theory) is obtained in the form of yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CO[CH:12]=[C:13]1[C:18](=[O:19])[O:17][C:16]([CH3:21])([CH3:20])[O:15][C:14]1=[O:22]>CC(O)C>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][CH:12]=[C:13]2[C:14](=[O:22])[O:15][C:16]([CH3:20])([CH3:21])[O:17][C:18]2=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Br
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Solvent: CC(C)O
Product: Cc1c(Br)cccc1NC=C1C(=O)OC(C)(C)OC1=O
Temperature: 90 °C
Yield: 77.5 %

Procedure:
To a vial charged with 3-bromo-2-methylaniline (1.207 g, 6.49 mmol) was added IPA (12.98 ml) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.208 g, 6.49 mmol) respectively. The mixture was heated to 90° C. for 2 hr providing a brown solution which was cooled to room temp affording an orange precipitate which was collected by vacuum filtration affording 5-(((3-bromo-2-methylphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.71 g, 5.03 mmol, 77% yield). This solid was transferred to a 5-20 ml microwave vial and 10 ml (0.5M 1,2-dichlorobenzene) was added and the mixture irradiated at 225° C. for 15 mins affording conversion to desired product according to LC-MS. Much precipitate was present directly following irradiation and cooling. The solid was collected via vacuum filtration and washed with heptane and dried under reduced pressure affording product as a brown solid 7-bromo-8-methylquinolin-4-ol (1.008 g, 4.23 mmol, 65.3% yield). m/z (ESI) 238.1 (M+H)+.
Reaction SMILES: O=[N:2][C:3](=O)[C:4](=O)[C:5]1[NH:6]C2C(=CC=1)C=CC1=NC=CC=21.C1(C)[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1>C1(C)C=CC=CC=1>[N:2]12[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[CH:26]=[N:6][CH2:5][CH2:4][CH2:3]2
Reactant: O=NC(=O)C(=O)c1ccc2ccc3nccc3c2[nH]1
Reactant: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: C1=NCCCN2CCCCC12

Procedure:
The formula (XXXVI) 2-(2-imidazolin-2-yl)quinolinecarboxylate esters can also be prepared from a formula (XXXVIII) dioxopyrroloquinoline acetamide, wherein R1, R2, X, L, M, Q and R7 are as described above, by cyclization thereof with a strong base, such as 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU) in the presence of an inert organic solvent such as xylene or toluene to give the crude imidazopyrroloquinolinedione of formula (XXXVII). The reaction mixture is heated to a temperature between 100° C. and 150° C., and water removed from the reaction mixture using a Dean-Stark water separator. At least one equivalent of alcohol R3OH represented by formula (V); wherein R3 is a substituent as described above, but excluding hydrogen and salt-forming cations, is then added to the reaction mixture, and the thus prepared mixture heated to reflux at a temperature between 100° C. and 150° C. to yield the formula (XXXVI) ester. The reaction may be graphically illustrated as follows: ##STR37## wherein R1, R2, R3, X, L, M, Q and R7 are as described above.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[C:7]([CH:8]=O)[C:6]([OH:11])=[CH:5][CH:4]=1)#[N:2].[NH:12]1[C:19](=[O:20])[CH2:18][C:16](=O)[NH:15][C:13]1=[S:14].CS(O)(=O)=O>C(O)CCC>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:16]3[NH:15][C:13](=[S:14])[NH:12][C:19](=[O:20])[C:18]=3[CH2:8][C:7]=2[CH:10]=1)#[N:2]
Reactant: N#Cc1ccc(O)c(C=O)c1
Reactant: O=C1CC(=O)NC(=S)N1
Agent: CS(=O)(=O)O
Solvent: CCCCO
Product: N#Cc1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2

Procedure:
To n-butanol (100 ml.) add 5-cyano-salicylaldehyde (6 g.), 2-thiobarbituric acid (6 g.) and methanesulfonic acid (10 ml.) With stirring, heat the mixture to reflux for 11/2 hours. Cool, filter, and wash the solid with isopropanol and ether to yield 7-cyano-(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C:7]([C:11]#[N:12])([CH3:10])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]>CCO.[Ni]>[C:1]([O:5][C:6](=[O:13])[C:7]([CH2:11][NH2:12])([CH3:10])[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(C)(C#N)C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CCO
Product: CCC(C)(CN)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a slurry of Raney-Ni (2.9 g, 50% in H2O, rinsed 3 times with EtOH before use) in EtOH (40 mL) was added 2-cyano-2-methyl-butyric acid tert-butyl ester (650 mg, 3.55 mmol). The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. The liquid was then carefully decanted into another flask and the metal was washed twice with EtOH. The combined EtOH solution was concentrated in vacuo to give the title compound in 600 mg, which was used directly in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25]O.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OCc1cccs1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=S(=O)(c1ccc(Cl)cc1)C(Cc1cccs1)c1cc(F)ccc1F
Yield: 69.7 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene(100 mg, 0.330 mmol) obtained in Example 5 and 2-thiophenemethanol (0.065 ml, 0.69 mmol) were dissolved in toluene (3 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (0.160 ml). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. The reaction mixture was then allowed to cool down. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by flash silica gel chromatography (using a hexane/ethyl acetate solvent mixture) to give a white solid. The resulting white solid was washed with hexane, whereby the title compound (92 mg, 0.23 mmol, 70%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:7][CH:8]=1.[C:21](Cl)(=[O:23])[CH3:22].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21](=[O:23])[CH3:22])=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C=C2Oc3cc(O)ccc3C2=O)c1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cccc(C=C2Oc3cc(OC(C)=O)ccc3C2=O)c1
Temperature: 25 °C

Procedure:
After 2-[(3-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, acetyl chloride 0.172 ml was added, and the mixture was refluxed for 2.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml twice. After the ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, it was concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 371.6 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:16])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13]CC)=[O:12])=[CH:7]2.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([F:16])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(F)cc(Cl)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc2cc(F)cc(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of 250 mg of ethyl 7-chloro-5-fluoro-1H-indole-2-carboxylate in 2 mL of methanol was added 5 mL of 1M aqueous sodium hydroxide solution, followed by stirring at room temperature for 3 hours. The reaction liquid was adjusted to an acidic condition by adding a 1M aqueous hydrochloric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 210 mg of 7-chloro-5-fluoro-1H-indole-2-carboxylic acid as a white solid.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:18]=[CH:17][N:16]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[N:15]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.CN(C=O)C.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[CH2:49][C:50]([F:53])([F:52])[F:51])(=O)=O>>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:18]=[CH:17][N:16]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][N:21]([CH2:49][C:50]([F:53])([F:52])[F:51])[CH2:20]4)[N:15]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3ccn(C4(CC#N)CNC4)n3)n2)cn1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cc3nccn3c(-c3ccn(C4(CC#N)CN(CC(F)(F)F)C4)n3)n2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.3 %

Procedure:
2-(3-(3-(7-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 130; 13.0 mg, 0.0301 mmol) was suspended in DMF (301 μL, 0.0301 mmol) and treated with diisopropylethylamine (31.4 μL, 0.180 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (9.07 mg, 0.0391 mmol). The reaction mixture was stirred at ambient temperature for 15 hours. Another portion of 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.0 mg, 0.87 mmol) was added and stirred for another 24 hours. The reaction mixture was then purified by reverse phase HPLC using 0-100% acetonitrile/water gradient, followed by preparative TLC using 10% MeOH/EtOAc to afford 2-(3-(3-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)azetidin-3-yl)acetonitrile (9.6 mg, 72% yield). MS (apci) m/z=442.3 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N:10]2[N:14]=[C:13]3[CH:15]=[CH:16][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:18][C:12]3=[N:11]2)[C:4]=1[OH:23].C(N(CC)CC)C.[C:31](Cl)(=[O:35])[C:32]([CH3:34])=[CH2:33]>C1COCC1>[C:31]([O:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N:10]2[N:14]=[C:13]3[CH:15]=[CH:16][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:18][C:12]3=[N:11]2)[C:4]=1[OH:23])(=[O:35])[C:32]([CH3:34])=[CH2:33]
Reactant: C=C(C)C(=O)Cl
Reactant: Cc1cc(CO)c(O)c(-n2nc3ccc(C(F)(F)F)cc3n2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCc1cc(C)cc(-n2nc3ccc(C(F)(F)F)cc3n2)c1O
Temperature: -10 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
In a 100 ml round bottom 3-neck flask equipped with a magnetic stirrer and nitrogen inlet was dissolved 3.58 g (11.1 mmol) 2-(hydroxymethyl)-4-methyl-6-(5-(trifluoromethyl)-2H-benzo[d][1,2,3]triazol-2-yl)phenol in 60 ml anhydrous THF. Triethylamine (5.6 ml, 40 mmol) was added and the mixture was cooled to −10° C. Methacryloyl chloride (1.373 g, 13.1 mmol) was added dropwise and the mixture was stirred for 1 hour at −10° C. followed by 20 hours at ambient temperature. The solid was filtered off and rinsed with diethyl ether and the resultant filtrate was poured into 100 ml diethyl ether and washed with 0.5 N HCl and water. The organic layer was dried with magnesium sulfate, filtered, and recrystallized with diethyl ether to give 1.90 g (44%) of a white solid. 1H NMR (CDCl3) delta: 11.17 (s, 1H, Ar—OH), 8.29 (s, 1H, Ar—H benzotriazole 4-position), 8.21 (s, 1H, Ar—H phenol 6-position), 8.06 (d, 1H, Ar—H benzotriazole 6-position), 7.69 (d, 1H, Ar—H benzotriazole 7-position), 7.29 (s, 1H, Ar—H phenol 4-position), 6.20 (s, 1H, C═C—H trans), 5.61 (s, 1H, C═C—H cis), 5.39 (s, 2H, Ar—CH2), 2.42 (s, 3H, Ar—CH3), 2.00 (s, 3H, C═C—CH3).