Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:12]1[C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[N:17][C:9]=2[S:8][C:7]1=[N:6][C:5]1[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Li+]
Product: Cc1ccc(N=c2sc3ncccc3c(=O)n2Cc2ccccc2)cc1
Yield: 52.6 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (3.34 mmol) of 2-(4-methylanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 27 mg of lithium hydride and 572 mg of benzyl bromide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 631 mg of 3-benzyl-2,3-dihydro-2-[(4-methylphenyl)imino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (52%, recrystallized from a mixture of ether and hexane) as a low polarity substance and 238 mg of 2-[N-benzyl-N-(4-methylphenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from ether) as a high polarity substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[F:15][C:16]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:17]=1[NH2:18]>>[F:15][C:16]1[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cc(C(F)(F)F)ccc1F

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-fluoro-5-trifluoromethylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[F:51][C:52]([F:63])([F:62])[C:53]1[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=1)[CH:56]([OH:58])[CH3:57]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:58][CH:56]([C:55]2[CH:59]=[CH:60][CH:61]=[C:53]([C:52]([F:62])([F:63])[F:51])[CH:54]=2)[CH3:57])=[C:18]([CH3:24])[CH:17]=1
Reactant: CC(O)c1cccc(C(F)(F)F)c1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OC(C)c4cccc(C(F)(F)F)c4)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 61.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (76 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (110 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-trifluoromethyl-α-methylbenzyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (78 mg, yield 58%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([B:18]2[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]2)[CH:17]=1)[NH2:14].CS(O)(=O)=O>O1CCOCC1.C(OCC)(=O)C>[CH2:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:14][C:13]2[CH:15]=[C:16]([B:18]3[O:22][C:21]([CH3:23])([CH3:24])[C:20]([CH3:26])([CH3:25])[O:19]3)[CH:17]=[C:11]([CH3:10])[CH:12]=2)[N:7]=1)[CH3:9]
Reactant: CCc1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1ccnc(Nc2cc(C)cc(B3OC(C)(C)C(C)(C)O3)c2)n1
Temperature: 110 °C

Procedure:
A solution of 2-chloro-4-ethyl pyrimidine (0.98 g, 7.00 mmol), the product of Step 1 (1.794 g, 7.70 mmol), and methanesulfonic acid (0.50 mL, 7.70 mmol) in 1,4-dioxane (30 mL) was sealed in a 100 mL screw-top pressure flask and heated at 110° C. for 15 hours. The flask was cooled, an additional portion of 2-chloro-4-ethyl pyrimidine (0.145 g, 1.05 mmol) was added, and the flask was resealed and heated for another 6.5 hours. The reaction mixture was cooled, diluted with ethyl acetate (70 mL), washed with saturated aqueous sodium bicarbonate solution (25 mL) and brine (25 mL), dried over sodium sulfate, filtered, and concentrated. The resulting reddish brown solid 4-ethyl-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (3.44 g as a 80:20 w/w mixture with 1,4-dioxane) was used without further purification. MS ESI: [M+H]+ m/z 340.1
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH2:31][C:32]#N)=[CH:17][CH:16]=1.O1CCCC1.[OH-:41].[Na+].Cl.[OH2:44]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH2:31][C:32]([OH:44])=[O:41])=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc3ccccc3c2CC#N)cc1
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc3ccccc3c2CC(=O)O)cc1
Yield: 51 %

Procedure:
To a mixture of 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]acetonitrile (0.96 g), tetrahydrofuran (5 mL) and ethanol (15 mL) was added a 4N aqueous sodium hydroxide solution (7 mL), and the mixture was stirred with heating under reflux for 4.5 days. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.52 g, 51%) of 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]acetic acid from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 187-188° C.
Reaction SMILES: [C:1]([C:4](=[CH:10][NH:11][C:12]1[CH:13]=[N:14][NH:15][CH:16]=1)[C:5]([O:7]CC)=O)(=[O:3])[CH3:2].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[C:1]([C:4]1[C:5](=[O:7])[C:13]2[NH:14][N:15]=[CH:16][C:12]=2[NH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=CNc1cn[nH]c1)C(C)=O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)c1c[nH]c2cn[nH]c2c1=O
Yield: 74 %

Procedure:
Ethyl 2-acetyl-3-(4-pyrazolylamino)acrylate (D13, 1.0 g, 4.5 mmol) was added to boiling Dowtherm A, and the solution was heated under reflux for 20 min. The mixture was allowed to cool and 60°-80° petroleum ether (100 ml) was added. The solid was filtered off and washed well with petroleum ether to give the title compound (590 mg, 74%), m.p.>320° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH3:15]>C1COCC1>[Br-:13].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]2[CH:12]=[CH:11][N:10]([CH2:14][CH3:15])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCBr
Reactant: Cc1ccc(-n2ccnc2)cc1
Solvent: C1CCOC1
Product: CCn1cc[n+](-c2ccc(C)cc2)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure 6.32 mmol (1.00 g) 1-(4-Methylphenyl)imidazole and 7.58 mmol (0.826 g, 0.60 ml) bromoethane are dissolved in 5 ml THF and heated for 7 h to 90° C.
Reaction SMILES: [OH2:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([CH:18]=O)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20][O:21][C:22]1[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25][NH2:26]>CS(C)=O>[CH3:20][O:21][C:22]1[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25][N:26]=[C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][CH:18]=1)=[O:1]
Reactant: COc1ccc(CCN)c(OC)c1OC
Reactant: O
Reactant: O=CC(=O)c1ccccc1OCc1ccccc1
Solvent: CS(C)=O
Product: COc1ccc(CCN=C(OCc2ccccc2)C(=O)c2ccccc2)c(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10.5 g of 2-benzyloxyphenylglyoxal hydrate (crude oil) are dissolved in 30 ml of dimethylsulfoxide, and 9 g of 2,3,4-trimethoxyphenethylamine are added thereto. The mixture is stirred at room temperature for 30 minutes, whereby a solution of α-(2,3,4-trimethoxyphenethylimino)-2-benzyloxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: [NH2:1][C:2]([NH2:24])=[N:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16](Cl)[CH:17]=2)=[C:7]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:6]=1.[CH3:25]S(C1C=C(C=CC=1OC1C=NC=CC=1O)C(OC)=O)(=O)=O>>[NH2:1][C:2]([NH2:24])=[N:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[CH3:25])=[C:7]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:6]=1
Reactant: COC(=O)c1ccc(Oc2cnccc2O)c(S(C)(=O)=O)c1
Reactant: CS(=O)(=O)c1cc(C(=O)N=C(N)N)ccc1Oc1cncc(Cl)c1
Product: Cc1ccncc1Oc1ccc(C(=O)N=C(N)N)cc1S(C)(=O)=O

Procedure:
N-diaminomethylene-3-methylsulfonyl-4-(5-chloro-3-pyridyloxy)benzamide, m.p. 233°; with methyl 3-methylsulfonyl-4-(4-hydroxy-3-pyridyloxy)benzoate,
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12].[C:20]([O:23][C:24](=O)C)(=[O:22])C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:19][N:16]1[CH2:17][CH2:18][N:13]([C:11]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[NH:1][C:20](=[O:22])[O:23][CH3:24])=[O:12])[CH2:14][CH2:15]1
Reactant: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2N)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)N1CCN(C)CC1
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of Intermediate 69B (540 mg, 2.04 mmol) in DCM (20 mL) was added TEA (0.570 mL, 4.09 mmol), acetic anhydride (0.289 mL, 3.06 mmol), and DMAP (2 mg, 0.016 mmol). The reaction mixture was stirred overnight, then washed with saturated aqueous NaHCO3, dried, and concentrated. The reaction mixture was purified by flash chromatography, (SiO2, 24 g, 0-10% MeOH/DCM) to give Intermediate 69C (600 mg, 96%) as a yellow solid. HPLC: Rt=0.517 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm). MS (ES): m/z=307 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7](=O)[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15].O>N1C=CC=CC=1>[CH3:1][CH:2]1[CH2:8][C:7](=[S:15])[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC1CC(=O)Nc2ccccc2N1
Solvent: c1ccncc1
Solvent: O
Product: CC1CC(=S)Nc2ccccc2N1
Yield: 83.2 %

Procedure:
A solution of 4-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (220 mg, 1.25 mmol) and P2S5 (444 mg, 2.0 mmol) in pyridine (10 mL) was heated at 120° C. for 30 min. To the mixture, water (10 mL) was added, and then extracted with ethyl acetate (20 mL), dried with Na2SO4, concentrated and purified by CombiFlash (PE:EA=10:1) to give 4-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione (200 mg, 83%). LRMS (M+H)+: 192 m/z.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH2:17])=[S:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.Br[CH:19]1[C:24](=O)[CH:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[S:16][C:21]3[CH2:20][CH2:19][CH2:24][CH:23]([C:26]4[CH:27]=[CH:28][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:30][CH:31]=4)[C:22]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2F)cn1
Reactant: O=C1C(Br)CCCC1c1ccc(OC(F)(F)F)cc1
Product: Cc1cn(-c2ccc(Nc3nc4c(s3)CCCC4c3ccc(OC(F)(F)F)cc3)cc2F)cn1

Procedure:
The title compound was prepared from [3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (45 mg, 0.18 mmol) and crude 6-bromo-2-(4-trifluoromethoxy-phenyl)-cyclohexanone (170 mg, ca. 0.5 mmol) using in analogous manner the procedure described in example 1b). Obtained as a light-brown solid (57 mg, 65%). MS ISP (m/e): 489.0 [(M+H)+]. mp 148-151° C.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([O:16][C@H:17]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:18]3)[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:3]=1.[CH:33]([Sn](CCCC)(CCCC)CCCC)=[CH2:34]>C1(C)C=CC=CC=1.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>[CH:33]([C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([O:16][C@H:17]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:18]3)[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:3]=1)=[CH2:34]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2nc3ccccc3c3ccc(Br)cc23)CN1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)c(O[C@@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1)nc1ccccc12

Procedure:
To a degassed solution of the product mixture from Step 3 (320 mg, 0.64 mmol) in PhMe (5 mL) was added vinyltributyltin (0.225 mL, 0.77 mmol) and tetrakis(triphenylphosphine)palladium (74 mg, 0.06 mmol). The mixture was then heated to reflux for 18 h. The solvent was then removed in vacuo and the crude material was purified on silica (gradient elution, 5-50% EtOAc/hex) to provide the title compound as a 1:1 mixture with the expected regioisomer. LRMS ((M-Boc)+H)+=349.3.
Reaction SMILES: O=[C:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[F:9][C:10]([F:19])([F:18])[C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].C(O)(=O)C>C1C=CC=CC=1>[F:9][C:10]([F:18])([F:19])[C:11]1[CH:12]=[C:13]([NH:14][C:2]([CH3:8])=[CH:3][C:4]([O:6][CH3:7])=[O:5])[CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)CC(C)=O
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(=O)C=C(C)Nc1cccc(C(F)(F)F)c1

Procedure:
To a solution of 3.48 g (30 mmol) methyl 3-oxobutanoate in 90 ml benzene are added 4.83 g (30 mmol) 3-(trifluoromethyl)aniline and 1.80 g (30 mmol) acetic acid. The mixture is stirred at reflux for four hours using a Dean-Stark trap to remove water. After removal of the solvent in vacuo, the residue is purified by preparative HPLC (column: YMC C18 ODS-AQ 250 mm×30 mm, 11 μm; solvent A: acetonitrile, solvent B: water; gradient: 0 min 10% A, 3 min 10% A, 11 min 90% A, 13 min 90% A, 13.2 min 10% A, 15 min 10% A; wavelength: 220 nm; injection volume: ca. 900 μl ethanol solution; number of injections: 8). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[S:12]1[C:16]([C:17]2[CH:18]=[C:19]([NH2:26])[CH:20]=[C:21]3[C:25]=2[NH:24][N:23]=[CH:22]3)=[CH:15][C:14]2[CH:27]=[CH:28][CH:29]=[CH:30][C:13]1=2.C(N(CC)CC)C.C[O:39]CCOC>>[S:12]1[C:16]([C:17]2[CH:18]=[C:19]([NH:26][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([OH:39])[N:3]=3)[CH:20]=[C:21]3[C:25]=2[NH:24][N:23]=[CH:22]3)=[CH:15][C:14]2[CH:27]=[CH:28][CH:29]=[CH:30][C:13]1=2
Reactant: Nc1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Reactant: CS(=O)(=O)c1nccc(Cl)n1
Reactant: COCCOC
Solvent: CCN(CC)CC
Product: Oc1nccc(Nc2cc(-c3cc4ccccc4s3)c3[nH]ncc3c2)n1
Yield: 0.1 %

Procedure:
To a mixture of 4-chloro-2-methanesulfonyl-pyrimidine (Preparation #1, 1.35 g, 7.0 mmol) in DME (10 mL) was added a mixture of 7-benzo[b]thiophen-2-yl-1H-indazol-5-ylamine (Example #F.8.1, 1.03 g, 3.9 mmol) and triethylamine (0.76 mL, 5.4 mmol) in DME (70 mL). After about 16 hours at ambient temperature the mixture was filtered, and the solid was purified by reverse phase preparative HPLC (Thermo Hypersil-Keystone 250×21.2 mm 8μ Hypersil® HS C18 column; 5% CH3CN/50 mM aqueous ammonium acetate hold for 5 min; 5-50% CH3CN/50 mM aqueous ammonium acetate over 20 min; 50-100% CH3CN/50 mM aqueous ammonium acetate over 1 min; hold at 100% CH3CN for 5 minutes, 21 mL/min) to yield 4-(7-Benzo[b]thiophen-2-yl-1H-indazol-5-ylamino)-pyrimidin-2-ol (2 mg, 0.006 mmol, 0.1% yield): LC/MS Rt (Method e) 1.3 min; m/z (M−H)− 358.3.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]2=[O:12].N([O-])=O.[Na+].CS(C)=O.[IH:29].C([O-])([O-])=O.[Na+].[Na+]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[I:29])[C:7]2=[O:12])=[CH:15][CH:16]=1
Reactant: Nc1cccc2c(=O)n(Cc3ccc(F)cc3)ccc12
Reactant: I
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=c1c2cccc(I)c2ccn1Cc1ccc(F)cc1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
5-Amino-2-(4-fluorobenzyl)isoquinolin-1(2H)-one (0.6 g, 0.002 mol) was added to a solution of sodium nitrite (0.5 g, 0.008 mol) in dimethyl sulfoxide (10 mL, 0.1 mol) at 35° C. Aqueous hydrogen iodide (2 mL, 0.02 mol) in dimethyl sulfoxide (10 mL, 0.1 mol) was added. The reaction mixture was stirred at 35° C. for 1 hour. The cooled reaction mixture was neutralized with saturated aq. Na2CO3 and extracted with methylene chloride (3×20 mL). The combined methylene chloride extracts were washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was chromatographed on 12 g of silica gel column (0-50% EtOAc/Hexane) gave the desired product as a brown solid. MS m/z (M+H) 379.7.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[N:11]1([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:30])[CH:28]=[CH2:29])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C1COCC1.CN(C=O)C>[N:5]1([C:1]([N:14]2[CH2:13][CH2:12][N:11]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:30])[CH:28]=[CH2:29])=[CH:24][CH:25]=3)(=[O:18])=[O:19])[CH2:16][CH2:15]2)=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C1CCNCC1
Reactant: O=C(Cl)Cl
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)N3CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 14 %

Procedure:
Phosgene (0.5 ml, 20% solution in toluene) was added in one portion to a stirred solution of piperidine (0.1 g, 0.7 mmol) in THF (2 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the reaction mixture was concentrated under vacuum and the resulting residue was diluted with DMF (2 ml) and added drop wise to a stirred solution of N-[4-(Piperazine-1-sulfonyl)-phenyl]-acrylamide (0.16 g, 0.54 mmol) and diisopropylethylamine (0.19 ml, 1.1 mmol) in DMF (4 ml). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. After this time the reaction mixture was concentrated under vacuum and the residue was purified by Prep HPLC to give the title compound (0.032 g, 14% yield) as a white powder.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:32]([O:34][CH3:35])=[O:33])([CH2:30][CH3:31])[CH2:28][CH3:29])/[C:9]1=[O:36])=O)(C)(C)C.[F:37][C:38]1[CH:39]=[CH:40][C:41]([CH3:53])=[C:42]([CH:44]=[N:45][C:46]([O:48][Si](C)(C)C)=[CH2:47])[CH:43]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:36])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([CH2:28][CH3:29])([C:32]([O:34][CH3:35])=[O:33])[CH2:30][CH3:31])[CH2:47][C:46](=[O:48])[NH:45][CH:44]3[C:42]3[CH:43]=[C:38]([F:37])[CH:39]=[CH:40][C:41]=3[CH3:53])[C:11]2=[CH:12][CH:13]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21)C(=O)OC
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OC
Yield: 23.9 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-3-[5-chloro-2-(1-methoxycarbonyl-1-ethyl-propoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (7.6 g, 15 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (60 mmol) in toluene to give the title compound as a white solid (2.2 g).
Reaction SMILES: [Cl:1][SiH:2](Cl)[Cl:3].[CH2:5]([N:7]([CH2:15][CH3:16])[CH2:8][CH2:9][N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH3:6]>C(Cl)Cl>[Cl:1][SiH2:2][Cl:3].[CH2:13]([N:10]([CH2:11][CH3:12])[CH2:9][CH2:8][N:7]([CH2:15][CH3:16])[CH2:5][CH3:6])[CH3:14]
Reactant: Cl[SiH](Cl)Cl
Agent: CCN(CC)CCN(CC)CC
Solvent: ClCCl
Product: Cl[SiH2]Cl

Procedure:
The ability of trichlorosilane to redistribute in the presence of tetraethylethylenediamine (TEEDA) and methylene chloride to form a complex comprising dichlorosilane and TEEDA was evaluated. All reactions were performed in a glass flask under a blanket of dry nitrogen. Trichlorosilane was distilled before use. TEEDA was dried by refluxing over CaH2 and then distilled. Dichloromethane was distilled from P2O5 just prior to use. The volumes of materials placed in the flask are provided in Table 1. Materials were added to the flask through a rubber septum by means of a syringe.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[C:12]([CH3:17])[CH:13]=[CH:14][C:15]=1[F:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CCOCC.O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([O:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:17][Br:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)c(OC(=O)c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Oc1cc(CBr)ccc1F)c1ccccc1
Yield: 58.2 %

Procedure:
Commercial N-bromosuccinimide (NBS) was recrystallised from water and thoroughly dried in vacuo (24 h) prior to use (mp. 180-182° C., lit. 180-183° C.). To a solution of 3-benzoyloxy-4-fluorotoluene (2.47 g, 10 mmol) in anhydrous carbon tetrachloride (25 mL) was added finely powdered NBS (1.96 g, 11 mmol) and benzoylperoxide (0.01 g). The mixture heated at reflux for 2 h, cooled and diluted with Et2O (100 mL) and water (50 mL). The ethereal layer was washed with brine (20 mL) and dried (Na2SO4). Concetration in vacuo and subsequent purification by flash column chromatography [SiO2, EtOAc/n-hexane (1:25)] gave 3-benzoyloxy-4-fluorobenzyl bromide as a white solid (1.80 g, 58%); δH (400 MHz, CDCl3) 4.48 (s, 2H), 7.18 (dd, J=9.8, 8.6, 1H), 7.28 (ddd, J=8.6, 4.3, 2.3, 1H), 7.34 (dd, J=7.0, 2.3, 1H), 7.50-7.55 (m, 2H), 7.64-7.69 (m, 1H), 8.18-8.23 (m, 2H); LRMS (FAB+) m/z (rel. intensity) 229.1 (95), 309.0 (100, [M+H]+). Found: C, 54.1, H, 3.22; C14H10BrFO2 requires C, 54.39, H, 3.26%.