Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:20])[C:7](=[O:19])[N:8]2[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(OCC)(=O)C>CS(C)=O>[O:24]1[CH2:25][CH2:26][N:21]([C:2]2[CH:10]=[C:9]3[C:5]([C:6](=[O:20])[C:7](=[O:19])[N:8]3[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(=O)c2ccc(F)cc21
Reactant: C1COCCN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN1C(=O)C(=O)c2ccc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 2-(6-fluoro-2,3-dioxoindolin-1-yl)acetate (0.400 g, 1.432 mmol) in DMSO (10 ml), morpholine (1.248 ml, 14.32 mmol) was added drop wise at room temperature. The resulting orange mixture was stirred at room temperature for 24 hours. Ethyl acetate (50 ml) was added and the solution was washed with brine (3×30 ml); the organic phase was dried over sodium sulfate, filtered and concentrated under vacuum. The crude was purified by silica gel flash chromatography (DCM:MeOH=98:2) affording tert-butyl 2-(6-morpholino-2,3-dioxoindolin-1-yl)acetate (0.400 g, 1.155 mmol, 81% yield 0. MS/ESI+ 347.1 [MH]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH:13]=[O:14])[CH2:7][C:6]2([CH3:16])[CH3:15].COC1C2C(=CC=CC=2)C(C)(C)CN1C=O.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH:13]=[O:14])[CH2:7][C:6]2([CH3:16])[CH3:15]
Reactant: COc1ccc2c(c1)C(C)(C)CN(C=O)C2
Agent: BrB(Br)Br
Agent: COC1c2ccccc2C(C)(C)CN1C=O
Solvent: ClCCl
Product: CC1(C)CN(C=O)Cc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred, cooled (−78° C.) solution of 6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-2-carbaldehyde (Intermediate 19, 3.26 g, 15 mmol) in anhydrous dichloromethane (15 mL) was treated with 1M solution of boron tribromide in dichloromethane (50 mL) stirred at ambient temperature for 3 h. It was then cooled again to 78° C. and quenched carefully with saturated aqueous sodium carbonate solution, diluted with water and the aqueous phase was extracted with ethyl acetate (×2). The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a solid foam (3 g, 99%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>CS(C)=O>[CH3:22][CH:23]1[NH:24][CH2:25][CH2:26][N:27]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[N:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=[C:6]([C:19]([OH:21])=[O:20])[C:7](=[O:18])[C:8]3=[CH:9][C:10]=2[F:17])[CH2:28]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC1CNCCN1
Solvent: CS(C)=O
Product: COc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 55 °C
Yield: 76 %

Procedure:
Twenty grams of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid and 14.2 g (2.1 eq) of 2-methyl piperazine were suspended in DMSO (400 mL) under a blanket of nitrogen. The mixture was heated to 55° C. during 24 hours. Subsequently, the mixture was heated to 70° C. and half of the amount of DMSO was distilled-off at reduced pressure (1-5 mm Hg). At the end of the distillation, dimethylcarbonate (200 mL) was added, the reaction mixture was cooled to 5° C. and held at this temperature overnight. The mixture was then filtered under vacuum. The compound was then dried under vacuum to obtain 20.22 g after assay (76% yield) of gatifloxacin.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[CH2:2].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>[Pd].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.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.O1CCCC1>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH2:2]
Reactant: C=Cc1ccccc1B(O)O
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccccc1-c1ccccn1
Yield: 75 %

Procedure:
The reaction was performed with 2-vinyl-phenylboronic acid (10 g, 0.0676 mol), 2-bromopyridine (12.64 g, 0.08 mol), tetrahydrofuran (100 ml), 2M potassium carbonate aqueous solution (26 ml), and tetrakis(triphenylphosphine) palladium (Pd(Ph3)4, 0.06 g, 1 mol %) according to Example 1. The yield was 75%.
Reaction SMILES: [O:1]1[CH2:13][CH:2]1[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8](C=O)=[CH:7][CH:6]=1.O[C:15]1C=CC(C=O)=C[CH:16]=1.C(C1OC1)Cl.[OH-].[Na+].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.CS(C)=O>[CH2:3]([O:4][CH:5]=[CH:12][C:11]1[CH:8]=[CH:7][CH:6]=[CH:16][CH:15]=1)[CH:2]1[O:1][CH2:13]1
Reactant: O=Cc1ccc(OCC2CO2)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCC1CO1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: C(=Cc1ccccc1)OCC1CO1
Yield: 70 %

Procedure:
The application gives the manufacture of styryl glycidyl ether by first synthesizing 4-(2,3-epoxypropoxy)benzaldehyde from 4-hydroxy benzaldehyde and epichlorohydrin in the presence of NaOH, tetra-n-butyl ammonium iodide and dimethylsulfoxide. 4-(2,3-epoxypropoxy)benzaldehyde was then added to a dry tetrahydrofuran solution (0° C., argon atmosphere) containing suspended methyl-triphosphonium bromide, catalytic amounts of 18-crown-6-ether and potassium t-butoxide. From this mixture styryl glycidyl ether was then obtained in a yield of 70%.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[N:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=2)[CH:18]=1>ClCCl.CN(C)C=O>[N:29]([C:25]1[CH:24]=[C:23]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)[N:28]=[CH:27][N:26]=1)=[C:1]=[S:2]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Nc1cc(-c2cccnc2)ncn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: S=C=Nc1cc(-c2cccnc2)ncn1
Temperature: 60 °C

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.682 g, 2.94 mmol) in dichloromethane/N,N-dimethylformamide at room temperature was added 6-(pyridin-3-yl)pyrimidin-4-amine (0.337 g, 1.957 mmol). The mixture was heated at 60° C. for 18 hours. LC/MS showed the desired product peak as the major peak. The deep orange mixture was purified by silica gel chromatography (1-40% ethyl acetate-hexanes) to afford 4-isothiocyanato-6-methoxypyrimidine (0.12 g, 0.56 mmol, 28.6% yield) as an orange oil.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:40])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:40])([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1NC(CC(C)(C)c2ccccc2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)c1ccccc1
Yield: 91 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 82b (1.0 g, 1.7 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.0 g, 91%).
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[CH:4]=[CH:3]1.CN(C)[C:15]1[O:16][C:17](=[O:25])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=1.C(O)(=O)C>O>[CH3:12][O:11][C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][N:2]2[N:1]2[C:17](=[O:25])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[NH:20][C:15]2=[O:16])=[CH:6][CH:7]=1
Reactant: COc1ccc2ccn(N)c2c1
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2ccn(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2c1
Yield: 57.3 %

Procedure:
A mixture of 0.2 g 1A, 0.268 g 2-dimethylamino-4-trifluoromethyl-1,3-oxazin-6-one (obtained according to M.-A. Decock-Plancquaert et al., Bull. Soc. Chim. Belg. 101 (4) 313-321 (1992)) and 10 ml acetic acid is refluxed for 4 hours. The mixture is poured into water, extracted and chromatographed to yield 0.23 g of 1B as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17](=[O:29])[CH:18]([CH3:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Cl:27])[CH:21]=1)C>>[Cl:27][C:22]1[CH:21]=[C:20]([CH2:19][CH:18]([CH3:28])[C:17]([OH:29])=[O:16])[CH:25]=[CH:24][C:23]=1[O:26][CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: ClCc1cccnc1SC1CCC1
Reactant: CCOC(=O)C(C)Cc1ccc(O)c(Cl)c1
Product: CC(Cc1ccc(OCc2cccnc2SC2CCC2)c(Cl)c1)C(=O)O
Yield: 77.6 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (50 mg, 0.25 mmol) obtained in Step C of Preparation Example 23 and 3-(3-chloro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (60 mg, 0.28 mmol) obtained in Step B of Preparation Example 46 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (76 mg, 81%).
Reaction SMILES: O=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[C:8]1([S:14]([C:17]#[N:18])(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(C)C=CC=CC=1.B(OCCCC)(OCCCC)OCCCC>C(O)CCC>[C:8]1([S:14]([C:17]2[CH:6]=[C:5]([CH3:7])[CH:4]=[C:2]([CH3:3])[N:18]=2)(=[O:15])=[O:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)C=C(C)C
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(S(=O)(=O)c2ccccc2)c1
Temperature: 116 °C
Yield: 49.7 %

Procedure:
First, 9.80 g (100 mmol) of mesityl oxide (4-methyl-3-penten-2-one) and 8.35 g (50.0 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and 1.15 g (5.00 mmol) of tributyl borate was added. Then the mixture was heated under reflux for 10 hours while agitating at an internal temperature of 116° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 6.14 g of 2-benzenesulfonyl-4,6-dimethylpyridine with the following properties as colorless crystals (purity of 99%, yield of 49% based on benzenesulfonyl cyanide).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][C:40]1[CH:41]=[C:42]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH:43]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:39][C:40]1[CH:41]=[C:42]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH:43]=[C:44]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:45]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: Cc1cc(NS(C)(=O)=O)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(NS(C)(=O)=O)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (200 mg, 0.34 mmol) was treated N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methane sulfonamide (160 mg, 0.51 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol), aqueous solution 2M of sodium carbonate (260 μl, 0.5 mmol) and 4 ml N,N-dimethylformide according to the method described in Preparation 186 but stirring at 100° C. overnight. The crude was purified using SP1® Purification System (hexane-ethyl acetate) to give 110 mg (38% yield) of the title compound. Purity 80%.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].COC(/C=C/[C:16]1[CH:21]=[C:20](O)[C:19]2[O:23][CH:24](C3C=CC(O)=C(O)C=3)[CH:25](C(OC)=O)[C:18]=2[CH:17]=1)=O>C(Cl)Cl>[Cl:1][CH2:2][C:3]([C:16]1[CH:21]=[CH:20][C:19]2[O:23][CH2:24][CH2:25][C:18]=2[CH:17]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)/C=C/c1cc(O)c2c(c1)C(C(=O)OC)C(c1ccc(O)c(O)c1)O2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1ccc2c(c1)CCO2
Temperature: 25 °C

Procedure:
Chloroacetyl chloride (10.39 g) was dissolved in methylene chloride (25 ml) and the solution was added to a slurry of aluminium chloride (12.2 g) in methylene chloride (50 ml) at -15° C. A solution of dihydrobenzofuran (10 g) in methylene chloride (25 ml) was added and the solution was allowed to warm to room temperature over 20 hours. The reaction mixture was poured into ice (700 g) and the aqueous layer was back-washed with methylene chloride (2×200 ml). The combined organic extracts were washed with water (800 ml), dried with MgSO4 and concentrated in vacuo. The resulting solid (11 g) was heated in cyclohexane (110 ml) and the supernatant liquid decanted off and allowed to crystallise. Filtration produced the title compound as a white solid, yield 2.1 g, m.p. 85°-87° C.
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.FC(F)(F)C(O)=O.[F:13][C:14]1[CH:15]=[C:16]([C:24]2O[CH:27]=[N:26][CH:25]=2)[CH:17]=[CH:18][C:19]=1[C:20]([F:23])([F:22])[F:21]>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:15]=[C:16]([C:24]2[C:2]3[CH2:3][CH2:4][CH2:5][C:1]=3[CH:27]=[N:26][CH:25]=2)[CH:17]=[CH:18][C:19]=1[C:20]([F:22])([F:23])[F:21]
Reactant: C1=CCCC1
Reactant: Fc1cc(-c2cnco2)ccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Fc1cc(-c2cncc3c2CCC3)ccc1C(F)(F)F
Temperature: 230 °C
Yield: 50.1 %

Procedure:
The reaction was performed on a custom-made flow system consisting of a Dionex P580 pump and a HP 6890 Series Gas Chromatography oven used as a heating source. The GC oven was equipped with a stainless steel coil reactor (53 mL volume) made from Supelco stainless steel tube (ID=2.1 mm). After heating to 230° C. using toluene as a system solvent, a mixture of cyclopentene (1.77 g, 26.0 mmol) and trifluoroacetic acid (0.30 g, 2.60 mmol) in toluene (1.0 mL), a mixture of 5-(3-fluoro-4-(trifluoromethyl)phenyl)oxazole (0.30 g, 1.30 mmol), cyclopentene (1.77 g, 26.0 mmol) and trifluoroacetic acid (0.30 g, 2.60 mmol) in toluene (1.0 mL) and finally a mixture of cyclopentene (1.77 g, 26.0 mmol) and trifluoroacetic acid (0.30 g, 2.60 mmol) in toluene (1.0 mL) were injected onto the stainless steel coil reactor in sequential order. The system was run at a flow rate of 0.35 mL/min equaling to a nominal residence time of tR=150 min and an effective residence time of tR,eff=120 min taking the 25% volume expansion of toluene at 230° C. into account (R. E. Martin et al., Eur. J. Org. Chem. 2012, 47-52). A 750 psi back-pressure regulator with a protection guard (filled with sand/glass wool) was used at the exit of the reactor to maintain system pressure. The reaction mixture was collected in a round bottom flask, triethylamine (5 mL) was added and the solvent mixture removed under reduced pressure. Purification by flash chromatography (50 g SiO2, Telos-cartridge) eluting with a 0 to 50% EtOAc/n-heptane gradient provided the title compound (183 mg, 50%) as a slightly brown solid. MS: 282.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH:19]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)[C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]=2[CH3:32])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[S:43])[C:11]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH:19]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)[C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]=2[CH3:32])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCc1ccc(Cl)nc1
Solvent: Cc1ccccc1
Product: Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=S)NCc1ccc(Cl)nc1
Temperature: 25 °C
Yield: 48.4 %

Procedure:
To the stirred solution of (E)-N-((6-chloropyridin-3-yl)methyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzamide (0.06 g, 0.117 mmol) in toluene (3 mL) was added Lawesson's reagent (0.14 g, 0.351 mmol) and the reaction was irradiated at 100° C. for 1 h, then cooled to RT and concentrated under reduced pressure to provide crude compound. The crude product was purified by preparative HPLC to afford the product as yellow color solid (0.03 g, 49%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:10]=3[N:11](CC3C=CC(OC)=CC=3)[C:12](=[O:23])[CH:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:14]=2)=[CH:4][N:3]=1.C(#N)C>O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:10]=3[NH:11][C:12](=[O:23])[CH:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:14]=2)=[CH:6][N:7]=1
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(c3cnc(N)nc3)c3cc(Cl)ccc32)cc1
Solvent: CC#N
Solvent: O
Product: Nc1ncc(C2=NC(Cc3ccccc3Cl)C(=O)Nc3ccc(Cl)cc32)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
Ceric ammonium nitrate (201 mg, 2.6 eq) was added portionwise to a stirred solution of 5-(2-aminopyrimidin-5-yl)-7-chloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (75 mg) in 9:1 acetonitrile:water (9 mL:1 mL). The reaction was stirred at room temperature overnight, and then another 200 mg of ceric ammonium nitrate was added. The reaction was stirred another 3 h, and then concentrated in vacuo. The crude was partitioned between EtOH and saturated potassium carbonate. The aqueous layer was re-extracted with ethanol 4×. The combined extracts were then dried over sodium sulfate, then concentrated and purified by chromatography (Gradient: 3:1 hexanes:EtOAc to EtOAc) yielding product (44 mg, 76% yield). 1HNMR (300 MHz, DMSO-d6) δ10.78 (s, 1H), 8.18 (s, 2H), 7.62 (d, 1H), 7.50-7.13 (m, 8H), 3.70 (m, 1H), 3.50-3.32 (m, 2H). HRMS (ES+) m/z calcd for C20H15Cl2N5O [M+H]+, 412.0732. found, 412.0726.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([F:17])[CH:11]=2)[CH:7]=[CH:8][N:9]=1)[CH3:3].[Cl:18][C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])C=CC=1>C(Cl)Cl>[Cl:18][CH2:19][CH2:20][CH2:21][NH:25][C:26]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([N:6]2[CH:7]=[CH:8][N:9]=[C:5]2[CH2:4][N:2]([CH3:1])[CH3:3])=[CH:11][C:12]=1[F:17])=[O:27]
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CN(C)Cc1nccn1-c1ccc(N)c(F)c1
Solvent: ClCCl
Product: CN(C)Cc1nccn1-c1ccc(NC(=O)NCCCCl)c(F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 234.3 mg (1 mmol) of 4-(2-dimethylaminomethyl-imidazol-1-yl)-2-fluoro-phenylamine in 5 mL of anhydrous CH2Cl2 and under N2 atmosphere were added 179 mg (1.5 mmol) of 3-chlorophenylisocyanate. The mixture was stirred for 3 days at room temperature. The volatiles were concentrated to yield quantitatively 1-(3-chloro-propyl)-3-[4-(2-dimethylaminomethyl-imidazol-1-yl)-2-fluoro-phenyl]-urea as a viscous oil. This compound can be was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.25 (t, J=8.6 Hz, 1H), 7.44 (dd, J=9.7 Hz, and J=2.1 Hz, 1H), 7.25 (m, 1H), 7.13 (m, 1H), 7.065 (d, J=6.5 Hz, 1H), 5.65 (t, 1H), 3.65 (t, J=6.5 Hz, 2H), 3.47 (m, 2H), 3.38 (s, 2H), 2.24 (s, 6H), 2.05 (m, 2H), ppm. LC-MS (ESI) 354.0 [M+H]+, tR=2.51 min (Shimadzu Phenomenex S5 ODS 4.6×50 mm Luna flow rate 2.5 mL/mn; detection at 220 nM; Gradient elution 0% to 100% B over 8 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4& B=90% MeOH, 10% H2O, 0.2% H3PO4). HRMS (ESI) m/z calcd for C16H22ClFN5O [M+H]+ 354.1497, found 354.1491.
Reaction SMILES: [I-:1].[CH3:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:6]=2[NH+:7]=1.[C:17]1(C)C=CC(S(OCC)(=O)=O)=C[CH:18]=1.[I-]>CO.C(O)C>[I-:1].[CH2:17]([N+:7]1[C:6]2[CH:8]=[C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:11][C:5]=2[O:4][C:3]=1[CH3:2])[CH3:18]
Reactant: Cc1[nH+]c2cc(NS(C)(=O)=O)ccc2o1
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Agent: [I-]
Solvent: CO
Solvent: CCO
Product: CC[n+]1c(C)oc2ccc(NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 121.4 %

Procedure:
Intermediate D (4.52 g) and ethyl p-toluenesulfonate (4.4 g) were combined in a large test tube and heated over a hot air gun with manual stirring for 5 minutes. A brownish melt formed, which solidified to a glass on cooling to room temperature. The glas was dissolved in 50 ml hot methanol, diluted with an 100 ml hot ethanol, and 9.0 g tetrabutylamonnium iodide dissolved in 20 ml ethanol was added. The brown, clear solution was cooled to room temperature and then ice cooled for 4 hours. Filtration of the resulting crystalline product gave 5.92 g of 3-ethyl-2-methyl-5-methylsulfonamidobenzoxazolium iodide (Intermediate E).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([OH:11])=O)[CH:3]=1.BrC1C=CC=C2C=1C(O)=[N:16]N2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:7][CH:8]=1)[NH:6][N:16]=[C:9]2[OH:11]
Reactant: Oc1n[nH]c2cccc(Br)c12
Reactant: Nc1ccc(Br)cc1C(=O)O
Product: Oc1n[nH]c2ccc(Br)cc12

Procedure:
5-Bromo-1H-indazol-3-ol CCVII was prepared from 4-bromo-2-carboxyaniline using the procedure described for preparation of 4-Bromo-1H-indazol-3-ol CLXXXIII (Example 37).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH2:12](O)[C:13]([Cl:16])([Cl:15])[Cl:14].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:14][C:13]([Cl:16])([Cl:15])[CH2:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[CH2:2][Br:1]
Reactant: O=C(O)c1ccccc1CBr
Reactant: OCC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(OCC(Cl)(Cl)Cl)c1ccccc1CBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
To a suspension of 2-(bromomethyl)benzoic acid (1.0 g, 4.65 mmol), β-trichloroethanol (0.54 mL, 5.58 mmol) and DMAP (0.057 g, 0.465 mmol) in DCM (20 mL) was added EDCxHCl (1.34 g, 6.98 mmol) at 0° C. The solution was stirred at 0° C. for 0.5 h and thereafter allowed to reach rt and stirred overnight. Water was added and the phases were separated through a phase separator. The organic portion was concentrated and the crude was submitted to flash chromatography using heptane and EtOAc (90/10) as eluent to yield the titled compound (0.80 g, 50%) as an oil; 1H NMR (400 MHz, CDCl3): δ 4.99 (s, 2H), 5.08 (s, 2H), 7.46 (m, 1H), 7.60 (m, 2H), 8.13 (d, 1H).