Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.Br[C:4]([F:13])([F:12])[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[CH2:14]([Sn](CCCC)(CCCC)CCCC)[CH:15]=[CH2:16].CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[F:12][C:4]([F:13])([CH2:16][CH:15]=[CH2:14])[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6]
Reactant: O=C(N1CCCC1)C(F)(F)Br
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: N#N
Solvent: Cc1ccccc1
Product: C=CCC(F)(F)C(=O)N1CCCC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2-bromo-2,2-difluoro-1-(pyrrolidin-1-yl)ethanone (600 mg, 2.63 mmol) in dry toluene (18 mL) was added allyltributyltin (0.84 mL, 2.63 mmol) and AIBN (9 mg, 0.05 mmol) at rt. The reaction mixture was stirred at 100° C. for 1 h. AIBN (9 mg, 0.05 mmol) was then added again and the reaction mixture further stirred at 100° C. for 30 h. The solvent was removed under reduced pressure and the crude residue purified by FC (SiO2 containing 10% KF, hept-EA, 1:0→4:1) to give the title compound as a colorless oil. LC-MS-conditions 08: tR=0.73 min; [M+H]+=190.30.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([Br:20])[CH:15]=2)=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].C1(C=CC=C(O)C=1)[OH:23].Cl[O-].[Na+].Cl>O1CCOCC1.C([O-])(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([Br:20])[CH:15]=2)=[CH:9][C:10]=1[O:11][CH3:12])[C:6]([OH:23])=[O:7]
Reactant: COc1cc(C=O)c(C(=O)c2ccnc(Br)c2)cc1OC
Reactant: Oc1cccc(O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)c(C(=O)c2ccnc(Br)c2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 3,4-dimethoxy-6-(2-bromoisonicotinoyl)benzaldehyde (8.61 g) in dioxane (120 ml) is added dropwise a solution of resorcinol (3.25 g) in acetate buffer (pH 3.8, 60 ml) at room temperature. To the mixture is Gradually added dropwise an aqueous solution of sodium hypochlorite (3.1 g) in water (30 ml), and the mixture is stirred at room temperature for two hours. The pH value of the reaction mixture is adjusted to about pH 1 with conc. hydrochloric acid, and then extracted with chloroform. The extract is washed, dried, and concentrated to give 3,4-dimethoxy-6-(2-bromoisonicotinoyl)benzoic acid (8.07 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][CH:14]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C@@H:30]([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[N:13][C:12]([C:15]([F:17])([F:18])[F:16])=[N:11][CH:10]=1)[CH2:19][O:20][C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C@@H:30]([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1ccc(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4cnc(C(F)(F)F)nc4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)=[C:10]([CH2:29][NH:30][CH3:31])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:20]([C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:9][C:10]=2[CH2:29][NH:30][CH3:31])[CH2:15][CH2:16]1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NCc2ccc(F)cc2)CC1
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](N(Cc2ccc(F)cc2)C(C)=O)CC1

Procedure:
from trans-4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-N-(4-fluorobenzyl)-cyclohexylamine and acetylchloride. Colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([O:24][C@H:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[CH:18]=1>>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([F:16])=[CH:18][C:19]=3[O:24][C@H:25]3[CH2:29][CH2:28][O:27][CH2:26]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: Nc1ccc(F)cc1O[C@H]1CCOC1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCOC3)c2c1C

Procedure:
Prepared analogously to example 100.1. from 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and (S)-4-fluoro-2-(tetrahydrofuran-3-yloxy)aniline (Intermediate XIX)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH2:12].[CH:13](=O)[CH2:14][CH2:15][CH3:16]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCC=O
Reactant: NCc1ccc2ccccc2c1
Product: CCCCNCc1ccc2ccccc2c1
Yield: 14.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 2-naphthalenemethanamine (500 mg, 3.18 mmol) and butyraldehyde (315 μL, 3.50 mmol) were converted to the title compound (100 mg, 15%). 1H NMR (CDCl3) δ 7.87-7.78 (m, 4H), 7.78-7.69 (br s, 1H), 7.56 (dd, J=8.4, 1.5 Hz, 1H), 7.52-7.43 (m, 2H), 4.06 (s, 2H), 2.78-2.69 (m, 2H), 1.65 (dt, J=15.4, 7.6 Hz, 2H), 1.38-1.23 (m, 2H), 0.88 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 214.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](OCC)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reaction time: 2 h

Procedure:
To a solution of ethyl N-t-butyloxycarbonylpiperidine-4-carboxylate (32.34 g, 0.1257 mol) in THF (100 mL) at 0° C. was added dropwise 1M LAH in THF (87.9 mL, 0.0879 mol). After 2 hours, excess hydride was quenched by the addition of water (3.2 mL), 2M NaOH (3.2 mL) and water (10 mL). The mixture was filtered, washed with EtOAc and the filtrate washed with water, sat. NaCl, dried (MgSO4) and concentrated. Pumping to constant weight gave 22.72 g (84%); mp: 79.2°-81.1° C.; 1H NMR (300 MHz, CDCl3) δ 4.12 (bd, J=12.8 Hz 2H), 3.49 (d, J=6.2 Hz, 2H), 2.68 (dt, J=13.2, 1.8 Hz, 2H), 1.69 (m, 3H), 1.44 (s, 9H, overlapped with m, 1H), 1.14 (m, 2H).
Reaction SMILES: ClC(Cl)(Cl)C([C:5]1[N:9]2[C:10]([CH2:14][N:15]([C:32](OC(C)(C)C)=[O:33])[C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[CH:18][CH:17]=3)=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)=O.C[Si](I)(C)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:29][C:28]([F:31])([F:30])[S:25]([NH:24][CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([N:15]2[CH2:14][C:10]3[N:9]4[C:5](=[CH:6][N:7]=[C:8]4[CH:13]=[CH:12][CH:11]=3)[C:32]2=[O:33])=[CH:21][CH:20]=1)(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12)c1ccc(CCNS(=O)(=O)C(F)(F)F)cc1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1c2cnc3cccc(n23)CN1c1ccc(CCNS(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
To a solution of 644 mg (1.00 mmol) of 3-trichloroacetyl-5-[N-tert-butoxycarbonyl-N-[4-(2-trifluoromethanesulfonamidoethan-1-yl)phenyl]aminomethyl]imidazo[1,2-a] pyridine in 5 ml of chloroform was added dropwise 0.29 ml (2.00 mmol) of trimethylsilyl iodide at room temperature. The reaction mixture was stirred for 30 minutes at room temperature, and poured into ice-water. The mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. To the mixture was added 50 ml of chloroform for extraction of the desired compound. The organic layer was washed with 50 ml of a saturated aqueous saline solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol=20:1) to afford 195.7 mg of the desired compound (46.1%, a pale yellow solid).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[C:9]([Br:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:5]=1[CH2:21]Br.[SH:24][CH2:25][C@H:26]([NH:33][C:34](=[O:36])[CH3:35])[C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1>>[CH3:1][O:2][C:3](=[O:23])[C:4]1[C:9]([Br:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:5]=1[CH2:21][S:24][CH2:25][C@H:26]([NH:33][C:34](=[O:36])[CH3:35])[C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1
Reactant: CC(=O)N[C@@H](CS)c1nc(C)no1
Reactant: COC(=O)c1c(Br)c(OC)cc(O[Si](C)(C)C(C)(C)C)c1CBr
Product: COC(=O)c1c(Br)c(OC)cc(O[Si](C)(C)C(C)(C)C)c1CSC[C@H](NC(C)=O)c1nc(C)no1

Procedure:
6-Bromo-2-bromomethyl-3-(tert-butyl-dimethylsilanyloxy)-5-methoxy-benzoic acid methyl ester and (R)-N-[2-mercapto-1-(3-methyl-1,2,4-oxadiazol-5-yl)-ethyl]-acetamide were subjected in an analogous manner to the procedure described in Example 6(b) to yield (R)-2-[2-acetylamino-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanylmethyl]-6-bromo-3-(tert-butyl-dimethyl-silanyloxy)-5-methoxybenzoic acid methyl ester as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH:23]([O:43][CH3:44])[C:24]2[N:28](COCC[Si](C)(C)C)[C:27]3[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:26]=3[N:25]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:7]=[CH:6]2)[CH3:2].C(C1C(C(OC)C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2)C.CC#N.C([O-])(O)=O.[Na+]>O>[CH2:1]([C:3]1[C:4]([CH:23]([O:43][CH3:44])[C:24]2[NH:28][C:27]3[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:26]=3[N:25]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:14])=[O:15])[CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(OC)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(OC)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(OC)c1nc2cc(C#N)ccc2[nH]1
Temperature: 75 °C
Reaction time: 14 h

Procedure:
A mixture of (±)-2-((5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile, (±)-2-((5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (mixture, 650 mg, 1.03 mmol) and LiBF4 in CH3CN (1M, 10 mL, 10 mmol)/H2O (1 mL) was stirred at 75° C. for 14 h. The mixture was cooled to room temperature and poured into 5% NaHCO3. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic phase was successively washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel flash column chromatography (heptanes/EtOAc=55/45) to give the title compound. MS (ESI+) m/z 499.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1.Cl[CH2:30][C:31]([O:33]C(C)(C)C)=[O:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([C:10](=[O:11])[NH:12][CH:13]3[CH2:14][CH2:15]3)[CH:16]=[CH:17][C:18]=2[CH3:19])[N:5]=[CH:4][C:3]=1[C:20]([C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[O:27][CH2:30][C:31]([OH:33])=[O:32])=[O:28]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(O)c2)c1N
Reactant: CC(C)(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(OCC(=O)O)c2)c1N
Temperature: 100 °C
Yield: 30.4 %

Procedure:
To a stirred solution of 3-[5-amino-4-(3-hydroxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide (400 mg, 1.06 mmol) and t-butyl chloroacetate (319 mg, 2.12 mmol) in DMF (20 mL) was added K2CO3 (292 mg, 2.12 mmol) and the mixture was heated at 100° C. overnight. The solvent was removed, and the residue was suspended in EtOAc, washed by water, brine, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography on silica gel (EtOAc:Hexane=3:1) to provide the product as a light yellow oil (140 mg, 27%).
Reaction SMILES: C(=O)(O)[O-].[Na+].[Br:6]N1C(=O)CCC1=O.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[C:32]3[N:33]([CH2:38][C:39]#[C:40][CH3:41])[C:34](=[O:37])[N:35]([CH3:36])[C:31]=3[CH:30]=[CH:29][N:28]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(OCC)(=O)C>CN(C)C=O.O>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27]2[C:32]3[N:33]([CH2:38][C:39]#[C:40][CH3:41])[C:34](=[O:37])[N:35]([CH3:36])[C:31]=3[C:30]([Br:6])=[CH:29][N:28]=2)[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC#CCn1c(=O)n(C)c2ccnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(=O)n(C)c2c(Br)cnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 60 h
Yield: 37.3 %

Procedure:
Sodium bicarbonate (0.146 g) and N-bromosuccinimide (0.288 g) were added to a solution of 4-[3-(2-butynyl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4.5-c]pyridin-4-yl]-piperazine-1-carboxylic acid t-butyl ester (0.447 g) in N,N-dimethylformamide (20 mL). This was then stirred at room temperature for 60 hours. Sodium bicarbonate (0.219 g) and N-bromosuccinimide (0.432 g) were added again, and this was stirred at room temperature for 15 hours. Ethyl acetate (100 mL) and water (50 mL) were then added, and the organic layer was washed twice with 50 mL of water and then once with 50 mL of saturated aqueous sodium chloride solution, then was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, and the hexane:ethyl acetate 1:1 fraction gave the title compound (0.201 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][OH:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.CCOC(C)=O.C1(C)C=CC=CC=1>CCOC(C)=O.O=[Mn]=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH:29]=[O:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: OCc1ccccc1CC=Cc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=Cc1ccccc1CC=Cc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1

Procedure:
To a solution of the benzylic alcohol of Step 5 (2.899 g, 6.20 mmol) in EtOAc (120 mL) was added portionwise activated MnO2 (10.15 g, 114 mmol) and the reaction was followed by TLC (EtOAc:toluene 7.5:92.5). When the reaction was completed (approximately 2 h), the mixture was filtered through silica, concentrated, and the title product was purified by flash chromatography on silica using EtOAc:toluene 2.5:97.5. Yield 2.18 g, 85%.
Reaction SMILES: ClC1C=CC(OC2C=C(F)C(S(=O)(=O)N(CC3C=CC(OC)=CC=3OC)C3SN=CN=3)=CC=2F)=C(C2C=CC3ON=C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)C=3C=2)C=1.[Cl:61][C:62]1[CH:96]=[CH:95][C:65]([O:66][C:67]2[CH:72]=[CH:71][C:70]([S:73]([N:76](CC3C=CC(OC)=CC=3OC)[C:77]3[N:82]=[CH:81][CH:80]=[CH:79][N:78]=3)(=[O:75])=[O:74])=[CH:69][C:68]=2[F:94])=[C:64]([C:97]2[CH:98]=[CH:99][C:100]3[O:104][C:103](=[O:105])[NH:102][C:101]=3[CH:106]=2)[CH:63]=1>>[Cl:61][C:62]1[CH:96]=[CH:95][C:65]([O:66][C:67]2[CH:72]=[CH:71][C:70]([S:73]([NH:76][C:77]3[N:82]=[CH:81][CH:80]=[CH:79][N:78]=3)(=[O:74])=[O:75])=[CH:69][C:68]=2[F:94])=[C:64]([C:97]2[CH:98]=[CH:99][C:100]3[O:104][C:103](=[O:105])[NH:102][C:101]=3[CH:106]=2)[CH:63]=1
Reactant: COc1ccc(CN(c2ncccn2)S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3-c3ccc4oc(=O)[nH]c4c3)c(F)c2)c(OC)c1
Agent: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c4c3)cc2F)c(OC)c1
Product: O=c1[nH]c2cc(-c3cc(Cl)ccc3Oc3ccc(S(=O)(=O)Nc4ncccn4)cc3F)ccc2o1
Yield: 50 %

Procedure:
Following the procedure as described in EXAMPLE 44, making non-critical variations to replace di-tert-butyl [5-(5-chloro-2-{4-[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)sulfamoyl]-2,5-difluorophenoxy}phenyl)-1,2-benzoxazol-3-yl]imidodicarbonate with 4-(4-chloro-2-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenoxy)-N-(2,4-dimethoxybenzyl)-3-fluoro-N-(pyrimidin-2-yl)benzenesulfonamide, 4-(4-chloro-2-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenoxy)-3-fluoro-N-(pyrimidin-2-yl)benzenesulfonamide was obtained a beige solid in 50% yield over two steps (0.054 g): 1H NMR (300 MHz, DMSO-d6) δ11.93 (br s, 1H), 11.69 (s, 1H), 8.50 (d, J=2.9 Hz, 2H), 7.83 (d, J=9.8 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.59 (s, 1H), 7.49 (d, J=7.7 Hz, 1H), 7.29-7.01 (m, 6H); MS (ES+) m/z 512.8 (M+1), 514.8 (M+1).
Reaction SMILES: FC(F)(F)C1C=C([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)C=CC=1.C[C@H]1N[C@@H](C)CN(C(C2C=C(C)NC=2C=O)=O)C1>C(O)C.N1CCCCC1>[NH:13]1[C:14]2[C:10](=[CH:9][CH:17]=[CH:16][CH:15]=2)[CH2:11][C:12]1=[O:18]
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Agent: Cc1cc(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 278.5 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-[(cis)3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (62.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-2-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (92.7 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([F:35])=[C:15]([C:17]3([CH3:34])[C:23]([F:25])([F:24])[CH2:22][O:21][CH2:20][C:19]([NH:26]C(=O)OC(C)(C)C)=[N:18]3)[CH:16]=2)=[O:9])=[N:6][CH:7]=1>O1CCOCC1.Cl>[NH2:26][C:19]1[CH2:20][O:21][CH2:22][C:23]([F:24])([F:25])[C:17]([C:15]2[CH:16]=[C:11]([NH:10][C:8](=[O:9])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[CH:12]=[CH:13][C:14]=2[F:35])([CH3:34])[N:18]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)C(F)(F)COC1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)N=C(N)COCC1(F)F

Procedure:
A solution of tert-butyl 5-(5-(5-chloropicolinamido)-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-ylcarbamate (0.210 g, 0.41 mmol) in 10% dioxane in HCl was heated in a sealed tube at 55° C. for 5 h. Reaction mixture was concentrated under reduced pressure, basified with 2% methanolic ammonia and purified by column chromatography on silica gel with MeOH/DCM (3:97) to obtain the title compound as an off white solid. Yield=0.08 g (50%). TLC (20% methanol in chloroform): Rf=0.35, m.p.=190-193° C.,
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][C:6]=2[CH:17]=1.B([O-])([O-])O[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(CCO)=CC=CC=1.O.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>[F:28][C:27]([F:29])([F:30])[O:26][C:23]1[CH:24]=[CH:25][C:20]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][C:6]=3[CH:17]=2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)C1=Cc2cc(Br)ccc2OCC1
Reactant: [O-]B([O-])Oc1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: O
Product: CCOC(=O)C1=Cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2OCC1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
Under argon atmosphere, to a solution of 4-trifluoromethoxybromobenzene (10.0 g) in tetrahydrofuran (75 ml) was dropwise added n-butyllithium (1.6M, hexane solution) (28.5 ml) at −78° C. for 20 minutes, and the mixture was stirred for 40 minutes. To the reaction mixture was dropwise added a solution of trimethyl borate (12.9 g) in tetrahydrofuran (12 ml) for 15 minutes, and the mixture was stirred at −78° C. for 30 minutes and at room temperature for 1 hour. To the reaction mixture was added was dropwise added 10% sulfuric acid (57.6 ml) for 15 minutes, and the mixture was stirred for 2 hours, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane to give 4-trifluoromethoxyphenyl borate (2.7 g) as colorless crystals. Under argon atmosphere, a solution of ethyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (500 mg), the above 4-trifluoromethoxyphenyl borate (380 mg) and potassium carbonate (0.46 g) in toluene-ethanol-water (20-2-2 ml) was stirred at room temperature for 1 hour. To the reaction mixture was added tetrakistriphenylphosphinepalladium (0.06 g), and the mixture was refluxed for 18 hours and cooled to room temperature. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:10) to give ethyl 7-(4-trifluoromethoxyphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (379 mg) as colorless crystals.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11]>C(Cl)(Cl)Cl>[CH:1]1([NH:7][C:10](=[O:11])[CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[Br:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(Br)c1ccccc1
Reactant: NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCCCC1)C(Br)c1ccccc1
Yield: 41.3 %

Procedure:
To a mixture of cyclohexylamine (10.9 g), triethylemine (11.1 g) and chloroform (200 ml), α-bromophenylacetyl chloride (23.3 g) was added dropwise over 10 minutes under cooling with ice and stirring, and the mixture was refluxed for 10 hours. After cooling by allowing to stand, the reaction mixture was washed with 0.5N hydrochloric acid (100 ml), with 0.5N aqueous solution of sodium hydroxide (100 ml) and with saturated saline solution (100 ml), and then concentrated. The residue was recrystallized from ethyl acetate-ethanol to obtain 12.2 g of title compound as colorless crystals. The mother liquor from recrystallization was concentrated and the residue was purified by means of column chromatography (developing solvent, chloroform:ethanol=20 : 1) to obtain 13.0 g of additional. title compound as colorless crystals (overall yield 85.4%).