Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:13])[CH:5]=[C:6]([C:8]([Cl:12])=[C:9]([Cl:11])[Cl:10])[CH:7]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([Cl:12])=[C:9]([Cl:10])[Cl:11])[CH:7]=1)[CH2:13][Br:32]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)cc(C(Cl)=C(Cl)Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: ClC(Cl)=C(Cl)c1cc(Cl)cc(CBr)c1
Yield: 66.4 %

Procedure:
A solution of 3-chloro-5-(trichlorovinyl)toluene (7.56 g) and dibenzoyl peroxide (0.5 g) in 250 ml of benzene was heated at reflux. N-Bromosuccinimide (6.04 g) was added in portions and the reaction mixture stirred at reflux for 3 hours. The mixture was then evaporated and the residue titurated with hexane (200 ml). The precipitated succinimide was removed by filtration and washed with hexane (2 x 25 ml). The hexane was concentrated and the residual oil (10.1 g) chromatographed on silica with petroleum ether as eluant. The column afforded 1.39 g of starting toluene, 1.18 g of dibromide, and 6.57 g of the desired benzyl bromide.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][CH2:6][C:7](=O)[CH2:8][CH3:9].[NH2:11][C:12]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)=[CH:20][C:13]=1[C:14](OC(C)C)=[O:15].Cl>C1(C)C(C)=CC=CC=1.CO>[CH2:8]([C:7]1[NH:11][C:12]2[C:13]([C:14](=[O:15])[C:6]=1[CH3:5])=[CH:20][C:21]([O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:35])([F:34])[F:36])=[CH:28][CH:27]=1)=[C:22]([CH3:24])[CH:23]=2)[CH3:9]
Reactant: Cc1cc(N)c(C(=O)OC(C)C)cc1Oc1ccc(OC(F)(F)F)cc1
Reactant: CCC(=O)CC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Solvent: CO
Product: CCc1[nH]c2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(=O)c1C
Temperature: 25 °C
Yield: 83 %

Procedure:
Aluminum chloride (30.0 g) and 125 ml of xylene were added into a 1000-ml glass flask equipped with a stirring device, a thermometer, a reflux condenser, and Dean-Stark device under a nitrogen gas stream. 3-Pentanone (58.1 g) was added dropwise thereto with stirring at 10° C. or below. Subsequently, 60.55 g of isopropyl 2-amino-4-methyl-5-(4-(trifluoromethoxy)phenoxy)benzoate dissolved in 250 ml of xylene was added dropwise thereto at room temperature, and the mixture was heated under reflux for 6 hr. A mixture composed of 5.0 g of aluminum chloride, 65 ml of xylene, and 9.69 g of 3-pentanone was added into the reaction solution, and the mixture was further heated under reflux for 18 hr. After the completion of the reaction, the reaction solution was allowed to cool at room temperature. The reaction solution was added little by little to 150 ml of a 5% aqueous hydrochloric acid solution prepared in a separate 1000-ml glass flask. Further, 150 ml of methanol was added thereto, and the mixture was heated under reflux for about one hr. The reaction mixture was allowed to cool at room temperature and was collected on a suction filter. The reaction mixture was washed with an aqueous methanol solution and was dried to give 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4(1H)-one as a light brown solid (51.33 g, yield: 90.7%).
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C:17]([F:28])([CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH2:18]O.N1C=CC=CC=1>ClCCl>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][CH2:18][C:17]([F:28])([F:16])[CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)(=[O:10])=[O:11]
Reactant: OCC(F)(F)COC1CCCCO1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(OCC(F)(F)COC1CCCCO1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triflic anhydride (1.8 ml, 11 mmol) was added to a cold (0° C.) solution of 2,2-difluoro-3-tetrahydropyranyloxy-1-propanol 91.6 g, 10 mmol), pyridine (0.9 ml, 11 mmol) in anhydrous dichloromethane (50 ml). The mixture was stirred 1 h at 0° C. and, after usual work-up, the product was purified by flash chromatography on silica gel (ethyl acetate:hexane; 15:85) (2.6 g, 80%).
Reaction SMILES: [C:1](=[O:43])([O:12][C:13]1[C:14]([CH3:42])=[C:15]2[C:20](=[C:21]([CH3:24])[C:22]=1[CH3:23])[O:19][C:18]([CH3:41])([CH2:25][CH2:26][CH2:27][CH:28]([CH3:40])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:39])[CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:17][CH2:16]2)[O:2][CH2:3][CH2:4][CH:5]1[CH2:9][O:8]C(C)(C)[O:6]1.O1CCCC1.CO.Cl>CCOCC>[C:1](=[O:43])([O:12][C:13]1[C:14]([CH3:42])=[C:15]2[C:20](=[C:21]([CH3:24])[C:22]=1[CH3:23])[O:19][C:18]([CH3:41])([CH2:25][CH2:26][CH2:27][CH:28]([CH3:40])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:39])[CH2:33][CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38])[CH2:17][CH2:16]2)[O:2][CH2:3][CH2:4][CH:5]([OH:6])[CH2:9][OH:8]
Reactant: Cc1c(C)c2c(c(C)c1OC(=O)OCCC1COC(C)(C)O1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1OC(=O)OCCC(O)CO)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Yield: 90 %

Procedure:
A mixture comprising 5.0 g of 2,2-dimethyl-1,3-dioxolan-4-yiethyl 2,5,7,8-tetramethyl-2-(4',8', 12'-trimethyltridecyl)-6-chromanyl carbonate, 20 ml of tetrahydrofuran, 10 ml of methanol and 8 ml of 2N hydrochloric acid was heated under reflux for 3 hours with stirring. Then the reaction mixture was dissolved in ether, successively washed with water, an aqueous solution of sodium hydrogencarbonate and water, and dried. After distilling off the solvent, the obtained oily residue was purified by column chromatography (silica gel, hexane : ethyl acetate=3.5:1.5) to thereby give 4.2 g of the title compound as a pale yellow, viscous liquid.
Reaction SMILES: C([O:4][C:5]1([O:14][CH2:13][C@:11]([C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:12])[C@:9]([C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([OH:10])[C@@:7]1([C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[OH:8])O)CC.[BrH:39].C(O)(=O)C.ClCCl>O>[Br:39][C:5]1([O:14][CH2:13][C@:11]([C:15](=[O:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([OH:12])[C@:9]([C:23](=[O:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([OH:10])[C@@:7]1([C:31](=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[OH:8])[OH:4]
Reactant: CCCOC1(O)OC[C@@](O)(C(=O)c2ccccc2)[C@@](O)(C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Reactant: Br
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1ccccc1)[C@]1(O)[C@](O)(C(=O)c2ccccc2)COC(O)(Br)[C@@]1(O)C(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
While the internal temperature of the reactor containing 2.622 kg (5.20 mol) of 1-propoxy-2,3,4-tribenzoyl-L-arabinopyranose was maintained at 0-20° C., 4.21 kg of a 30-33% hydrogen bromide/acetic acid solution was added dropwise thereto, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, 1.296 liters of dichloromethane was added to the reaction solution, which was then stirred for 30 minutes. The stirred solution was added dropwise to a reactor containing 4.162 liters of purified water and stirred for 30 minutes. Then, the stirred solution was separated into layers. The water layer was back-extracted with 1.296 liters of dichloromethane. The oil layer was washed two times with 0.195 kg of aqueous saturated sodium chloride solution and one time with 0.248 kg of aqueous saturated sodium bicarbonate solution, and then dried with sodium sulfate, and the solvent was removed by concentration. To the concentrated residue, 1.30 liters of dichloromethane was added, and the solution was stirred for 2-3 hours. 6.50 liters of hexane was added to the stirred solution, which was then cooled to a temperature of 0-5° C., stirred for 3-4 hours, and filtered. The filtered solids were washed with 2.76 liters of hexane and dried in a vacuum, thus obtaining 2.185 kg (80% yield) of 1-bromo-2,3,4-tribenzoyl-L-arabinopyranose. 1H NMR (CDCl3): δ 8.20-7.90 (dd, 4H), 7.90-7.80 (d, 2H), 7.70-7.20 (m, 9H), 6.93 (d, 1H), 5.97 (dd, 1H), 5.82 (m, 1H), 5.70 (dd, 1H), 4.50 (d, 1H), 4.25 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[N:3]=1.[CH3:16][O:17][C:18](=[O:22])[C@@H:19]([CH3:21])[NH2:20]>>[CH3:16][O:17][C:18](=[O:22])[C@H:19]([NH:20][C:13]([C:4]1[N:3]=[C:2]([Cl:1])[C:11]2[C:6]([C:5]=1[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:15])[CH3:21]
Reactant: O=C(O)c1nc(Cl)c2ccccc2c1O
Reactant: COC(=O)[C@@H](C)N
Product: COC(=O)[C@@H](C)NC(=O)c1nc(Cl)c2ccccc2c1O

Procedure:
1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 0.55 g, was coupled with 0.40 g of D-Alanine methyl ester analogously to Example A-54 a) and 0.200 g of off-white, solid product were obtained: MS-(+)-icon, M+1=308.8 amu.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:32])[C@H:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:14]C(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].C(O)C>O1CCCC1>[C:1]([O:5][C:6](=[O:33])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:32])[C@H:13]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[NH2:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1ccccc1

Procedure:
223 g of N-carbobenzoxy-L-phenylalanyl-L-proline tert.-butyl ester is hydrogenated in analogous manner to step (b), using 2100 ml absolute tetrahydrofuran as solvent instead of ethanol, to give the heading compound as a colourless oil.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[NH:19]1[CH2:22][CH:21]([O:23][CH2:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH2:20]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[O:17]=[C:15]([N:19]1[CH2:22][CH:21]([O:23][CH2:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH2:20]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: c1csc(COC2CNC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(OCc4nccs4)C3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (60 mg, 0.24 mmol), DMF (5.8 mL), 2-[(azetidin-3-yloxy)methyl]-1,3-thiazole hydrochloride (99 mg, 0.48 mmol; which may be prepared as described in Step 3), DIPEA (119 μL, 0.72 mmol), DMAP (2.4 mg, 0.02 mmol) and EDAC (56 mg, 0.29 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was precipitated in methanol/water and then filtered. The resulting solid was purified on column chromatography (eluent: 96/4 dichloromethane/MeOH) then triturated in pentane and MeOH to give the title compound (21 mg, 24%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([CH3:23])[N:15]=[C:14]([S:24][CH3:25])[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>CN(C=O)C.C(Cl)Cl.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16](/[CH:23]=[CH:28]/[N:29]([CH3:31])[CH3:30])[N:15]=[C:14]([S:24][CH3:25])[N:13]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Nc1cc(OC)cc(OC)c1
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(/C=C/N(C)C)nc(SC)nc1Nc1cc(OC)cc(OC)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
To the solution of ethyl 4-(3,5-dimethoxyphenylamino)-6-methyl-2(methylthio)pyrimidine-5-carboxylate (2.7 g, 7.4 mmol) in 30 mL DMF was added N,N-dimethylformamide dimethylacetal (1.58 mL, 11.1 mmol). The reaction mixture was stirred at 130° C. for 2 hour. After monitoring the reaction by TLC was cooled to room temperature, then the mixture was diluted with DCM and water. After extracted three times by DCM from the aqueous layer, the combined organic layer was dried over MgSO4. The solution was condensed under reduced pressure yielding crude mixture (3.16 g). The mixture was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[O:17][C:18]1[C:23]([F:24])=[C:22]([N:25]([CH3:34])[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH3:28])[CH3:27])[C:21]([F:35])=[C:20](F)[N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][N:38]1[CH2:42][CH2:41][N:40]=[C:39]1[C:43]1[CH:44]=[C:45]([OH:49])[CH:46]=[CH:47][CH:48]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[O:17][C:18]1[C:23]([F:24])=[C:22]([N:25]([CH3:34])[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH3:27])[CH3:28])[C:21]([F:35])=[C:20]([O:49][C:45]2[CH:46]=[CH:47][CH:48]=[C:43]([C:39]3[N:38]([CH3:37])[CH2:42][CH2:41][N:40]=3)[CH:44]=2)[N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)N(C)c1c(F)c(F)nc(Oc2cc(C#N)ccc2OCc2ccccc2)c1F
Reactant: CN1CCN=C1c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C)N(C)c1c(F)c(Oc2cccc(C3=NCCN3C)c2)nc(Oc2cc(C#N)ccc2OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of 4-benzyloxy-3-[(4-(N-methyl-N-(1-ethoxycarbonyl-1-methylethyl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile (2.4 g, 4.5 mmol) in DMSO (50 mL) was added 3-((1-methyl)imidazolin-2-yl)phenol (0.8 g, 4.5 mmol) and cesium carbonate (1.9 g, 5.8 mmol). The resultant mixture was stirred at 35° C. After 13 hours, the mixture was then cooled to ambient temperature and poured into 200 mL of water and 200 mL of ethyl acetate. The aqueous layer was separated and extracted with 100 mL of ethyl acetate. The combined organic extracts were washed with 0.5 M aqueous KOH solution (200 mL) then brine (200 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford 4-benzyloxy-3-[(4-(N-methyl-N-(1-ethoxycarbonyl-1-methylethyl)amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile as a solid foam: NMR (CDCl3) 7.4-7.0 (m, 12), 5.0 (s, 2), 4.2 (q, 2), 3.9 (t, 2), 3.5 (t, 2), 3.1 (s, 3), 2.8 (s, 3), 1.6 (s, 6), 1.3 (t, 3) ppm.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5][N:4]=1.N1C2C(=CC=CC=2)C=N1.[CH3:23][CH2:24][OH:25]>CCOCC>[ClH:1].[Br:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](=[NH:13])[O:25][CH2:24][CH3:23])[CH:10]=2)[NH:5][N:4]=1
Reactant: CCO
Reactant: N#Cc1ccc2[nH]nc(Br)c2c1
Agent: Cl
Agent: c1ccc2[nH]ncc2c1
Solvent: CCOCC
Product: CCOC(=N)c1ccc2[nH]nc(Br)c2c1
Reaction time: 2 h

Procedure:
Passed HCl (g) slowly into a suspension of indazole 3-bromo-1H-indazole-5-carbonitrile (7 g) in EtOH (USP, 300 ml) at 0° C. Stirred at 0° C.-5° C. for approximately 2 hours until precipitation occurred, and stirred overnight at room temperature. Diluted with Ether (ca. 300 ml) and filtered out white solid, dried at room temperature to yield ethyl 3-bromo-1H-indazole-5-carbimidate hydrochloride (7.5 g).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:19])[C:15]([O:17]C)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].B(Br)(Br)Br>ClCCl>[F:20][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:19])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1cc2c(cc1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Cl)cc21
Reaction time: 8 h
Yield: 52 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (48 mg, 0.15 mmol) in dichloromethane (2 mL) was treated with BBr3 (0.30 mL of a 1.0M solution in CH2Cl2, 0.30 mmol) and stirred overnight at 20 C. The excess BBr3 was quenched with water and the resulting mixture diluted with ether (20 mL), washed with Na2CO3 (10 mL) and brine (10 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 24 mg of a white solid. MS calculated for C13H13ClF3NO2+H: 308, observed: 308.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[C:13]=1[C:20]([O:22][CH3:23])=[O:21].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>ClCCl>[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:13]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1cccc(CN)c1C(=O)OC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CNC(=O)OCc2ccccc2)c1C(=O)OC
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
Triethylamine (1.87 g, 18.5 mmol) was added to a stirred suspension of methyl-3-(aminomethyl)-2-(methoxycarbonyl)benzoate hydrochloride (2.0 g, 8 mmol) in dichloromethane (30 ml). The mixture was cooled in an ice bath to 4° C. Benzyl chloroformate (1.66 g, 10 mmol) was added slowly keeping the temperature between 4-7° C. After the addition was complete, the cooled mixture was stirred an additional 30 minutes and then warmed to room temperature for 4 hours. The mixture was washed with water (2×30 ml), brine (30 ml) and dried. Solvent was removed and the residue was purified by chromatography (dichloromethane/ethyl acetate 95 to 5) to give 2.1 g (76%) of the product as a solid; 1H NMR (CDCl3) δ 7.87 (d, J=7.8 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.36-7.26 (m, 5H), 5.41 (b, 1H), 5.09 (s, 2H), 4.36 (d, J=6.3 Hz, 2H), 3.91 (s, 3H), 3.88 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:3]=1[O:4][C@@H:5]([CH3:27])[C:6]([NH:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][CH3:23])=[CH:18][NH:17][C:16]2=[O:24])[C@@H:12]([F:25])[C@@H:11]1[OH:26])=[O:7].[C:35]([NH:42][C@@H:43]([C:47](O)=[O:48])[CH:44]([CH3:46])[CH3:45])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>>[C:38]([O:37][C:35]([NH:42][C@@H:43]([C:47]([O:26][C@@H:11]1[C@@H:10]([CH2:9][NH:8][C:6](=[O:7])[C@@H:5]([O:4][C:3]2[CH:28]=[C:29]([O:33][CH3:34])[C:30]([Cl:32])=[CH:31][C:2]=2[Cl:1])[CH3:27])[O:14][C@@H:13]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][CH3:23])=[CH:18][NH:17][C:16]2=[O:24])[C@H:12]1[F:25])=[O:48])[CH:44]([CH3:45])[CH3:46])=[O:36])([CH3:40])([CH3:41])[CH3:39]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCc1c[nH]c(=O)n([C@@H]2O[C@H](CNC(=O)[C@H](C)Oc3cc(OC)c(Cl)cc3Cl)[C@@H](O)[C@@H]2F)c1=O
Product: CCc1c[nH]c(=O)n([C@@H]2O[C@H](CNC(=O)[C@H](C)Oc3cc(OC)c(Cl)cc3Cl)[C@@H](OC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)[C@@H]2F)c1=O

Procedure:
Coupling of 1-[5-[2(S)-(2,4-dichloro-5-methoxyphenoxy)-propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl-5-ethyluracil with N-Boc-D-valine in a manner analogous to that described in Example 1(A) gave 1-[3-O-[N-(tert-butoxycarbonyl)-D-valyl]-5-[2(S)-(2,4-dichioro-5-methoxyphenoxy)-propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl-5-ethyluracil as a white solid, m.p. 101° C. (dec.).
Reaction SMILES: [S:1]1[C:5]2[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[Br:17]Br.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)(Cl)Cl.ClCCl>[Br:17][C:2]1[S:1][C:5]2[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccsc2C1
Reactant: BrBr
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2cc(Br)sc2C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.8 %

Procedure:
To tert-butyl 4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (2.0 g, 8.4 mmol) in chloroform (100 mL) at 0° C. was added dropwise bromine (430 μL, 8.4 mmol). The reaction was stirred 45 min with gradual warming to room temperature. The mixture was cooled to 0° C., and triethylamine (1.2 mL, 8.4 mmol) was added followed by di-tert-butyl dicarbonate (913 mg, 4.2 mmol). The reaction was stirred 1 hour, diluted with dichloromethane (50 mL), washed with 1.0 N HCl (1×50 mL), dried over MgSO4, and concentrated under reduced pressure. The resulting crude residue was purified via silica gel chromatography to afford 2 g (77% yield) of tert-butyl 2-bromo-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate as a colorless oil; 1H NMR (CDCl3) δ 6.78 (s, 1H), 4.50 (s, 2H), 3.67 (t, J=5.7 Hz, 2H), 2.65 (t, J=5.7 Hz, 2H), 1.50 (s, 9H); ES-MS: m/e=261.9 (M-55)+.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[S:29][CH:30]=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][C:34]=2[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:32]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22].NN>C1COCC1.CO>[NH2:3][CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[S:29][CH:30]=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][C:34]=2[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:32]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22]
Reactant: Cn1ncc(-c2ccccc2)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ncc(-c2ccccc2)c1-c1csc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)c1
Reaction time: 12 h

Procedure:
To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (crude from part a) in THF-MeOH (1:1, 10 mL) was added hydrazine (384 uL, 12 mmol). After 12 h, the solution was filtered and the filtrate was concentrated, dry loaded onto silica and purified via column chromatography (2% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[N:9]2)=[CH:4][C:3]=1[O:20][CH3:21].[C:22]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([N:13]([CH3:22])[C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])=[N:9]2)=[CH:4][C:3]=1[O:20][CH3:21]
Reactant: COc1cc(-n2ccc(NC(=O)C(F)(F)F)n2)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1cc(-n2ccc(N(C)C(=O)C(F)(F)F)n2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a mixture of N-(1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-3-yl)-2,2,2-trifluoroacetamide (320 mg, 0.879 mmol) and K2CO3 (146 mg, 1.055 mmol) in DMF (2 mL) was added MeI (202 mg, 1.055 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with Et2O. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to give N-(1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-3-yl)-2,2,2-trifluoro-N-methylacetamide (300 mg, MS: 380.0 [M+H+]).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[C:11]([Si:15]([CH3:30])([CH3:29])[O:16][CH2:17][CH2:18]OC1C=CC(I)=CC=1C=O)(C)(C)C.C[Si]([NH:35][Si](C)(C)C)(C)C.C([Li])CCC.C[Si](Cl)(C)C.C(N(CC)CC)C.C(Cl)(=O)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[N:35][C:17]([O:16][Si:15]([CH3:30])([CH3:29])[CH3:11])=[CH2:18])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(I)cc1C=O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: C=C(N=Cc1ccc(F)c(Br)c1)O[Si](C)(C)C

Procedure:
In a manner similar to the method described in example 190b, 3-bromo-4-fluorobenzaldehyde (4.6 g, 21 mmol) (Lancaster) was used as the starting material in place of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (4.36 mL, 21 mmol), n-butyllithium (2.5 M, 8.4 mL, 21 mmol), trimethylsilyl chloride (2.66 mL, 21 mmol), triethylamine (3.8 mL, 27.2 mmol) and acetyl chloride (1.94 mL, 27.2 mmol) to give crude 1-(3-bromo-4-fluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.