Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]([CH3:33])([CH3:32])[CH2:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([C:29]([OH:31])=O)=[CH:17]2)=[O:12].C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:33][C:9]([CH3:8])([CH3:32])[CH2:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([C:29]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:31])=[CH:17]2)=[O:12]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)O)n2-c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.9 mg (0.09 mmol) of aniline are added to a solution of 27 mg (0.08 mmol) of 5-[(3,3-dimethylbutanoyl)amino]-1-phenyl-1H-indole-2-carboxylic acid (Example LIX), 4.7 mg (0.09 mmol) of DMAP and 22.2 mg (0.12 mmol) of EDC in 2 ml of dichloromethane, and the mixture is stirred at RT for 3 h. For work-up, 1-molar hydrochloric acid is added and the mixture is extracted repeatedly with dichloromethane. The combined organic phases are washed with saturated sodium bicarbonate solution and water, dried over sodium sulphate and filtered. Removal of the solvent under reduced pressure gives 35 mg (99% of theory) of the product.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@H:7]1[CH2:15][CH2:14][CH2:13][C@@:12]2([CH3:16])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[C@@H:17](O)[CH3:18])([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@H:7]1[CH2:15][CH2:14][CH2:13][C@@:12]2([CH3:16])[C@H:8]1[CH2:9][CH2:10]/[C:11]/2=[CH:17]\[CH3:18])([CH3:3])([CH3:4])[CH3:2].[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@H:7]1[CH2:15][CH2:14][CH2:13][C@@:12]2([CH3:16])[C@H:8]1[CH2:9][CH2:10]/[C:11]/2=[CH:17]\[CH3:18])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@H](O)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C/C=C1\CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Temperature: 0 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
1.43 g (4.58 mmol) of (S)-1-[(1S,3aR,4S,7aR)-4-(tert-Butyldimethyl-silanyloxy)7a-methyl-octahydro-inden-1-yl]ethanol was dissolved in 15 ml pyridine and cooled to 0° C. 420 μl of POCl3 were added slowly. The reaction mixture was stirred at room temperature overnight then poured into a buffer at pH 4, extracted with n-hexane. The organic solution was washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by column chromatography (eluent: n-hexane) to yield 516 mg (39%) of (E)-(3aR,4S,7aS)-4-(tert-Butyl-dimethyl-silanyloxy)-1-ethylidene-7a-methyl-octahydro-indene (E)-(3aR,4S,7aS)-4-(tert-Butyldimethyl-silanyloxy)-1-ethylidene-7a-methyl-octahydro-indene as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:27])([CH3:26])[CH2:9][N:10]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.B.[OH-:29].[Na+].OO>[Cl-].[Na+].O.C(O)C.C1COCC1.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:27])([CH3:26])[CH2:9][N:10]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:29])=[CH:20][N:19]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: C=Cc1ccc(N(CC(C)(C)c2ccc(F)cc2)C(=O)OC(C)(C)C)nc1
Agent: B
Agent: OO
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(CC(C)(C)c1ccc(F)cc1)c1ccc(CCO)cn1
Temperature: 35 °C
Reaction time: 0.75 h
Yield: 16.7 %

Procedure:
To a 20 dram vial was added tert-butyl 2-(4-fluorophenyl)-2-methylpropyl(5-vinylpyridin-2-yl)carbamate (2.4 g, 6.4 mmol, 1.0 equiv) and THF (20 mL). Borane (7.7 mL, 7.7 mmol, 4.0 equiv) was added slowly, and the reaction was heated to 35° C. and stirred for 45 min. The reaction was then cooled to 0° C. followed by the addition of a 50% ethanol/THF mixture (25 mL), 2N sodium hydroxide (13 mL, 25.8 mmol, 4.0 equiv), and 30% hydrogen peroxide (15 mL). The reaction was stirred for 1 h, diluted with brine (10 mL), and extracted with ethyl acetate (20 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and then purified by reverse phase column chromatography to give 414 mg (17%) of tert-butyl 2-(4-fluorophenyl)-2-methylpropyl(5-(2-hydroxyethyl)pyridin-2-yl)carbamate.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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:26][C:27]1[C:32]([C:2]2[N:6]([S:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: OB(O)c1cccnc1F
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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+]
Solvent: COCCOC
Solvent: O
Product: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 105 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A suspension of tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (2-fluoropyridin-3-yl)boronic acid (221 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (173 mg) in 1,2-dimethoxyethane (10 mL) and water (5 mL) was stirred at 105° C. for 1 hr. The reaction mixture was cooled to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→1:1) to give the title compound as a pale-yellow oil (yield 310 mg, 69%).
Reaction SMILES: [S:1]1[C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[C:21](Cl)(=[O:23])[CH3:22].Cl[Sn](Cl)(Cl)Cl.CCOC(C)=O>C(Cl)Cl>[C:21]([C:4]1[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[S:1][C:5]=1[NH:6][S:7]([C:10]1[CH:11]=[CH:12][C:13]([Br:16])=[CH:14][CH:15]=1)(=[O:9])=[O:8])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: O=S(=O)(Nc1cc2ccccc2s1)c1ccc(Br)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)c1c(NS(=O)(=O)c2ccc(Br)cc2)sc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
To a suspension of compound 361-A (9.21 g, 25.0 mmol) in DCM (50 mL), cooled in an ice-bath, was added an ice-cold solution of acetyl chloride (2.30 mL, 32.3 mmol), followed by SnCl4 (27.9 mmol) in DCM (200 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was quenched with saturated NH4Cl solution (125 mL), filtered over a pad of celite, dried over MgSO4, filtered and concentrated under vacuum. The residue was dissolved in refluxing EtOAc (75 mL), filtered hot and the filtrate allowed to cool. The solid was filtered and washed EtOAc (10 mL). Another batch of product was obtained by evaporation of the mother liquor, dissolving the residue in refluxing EtOAc (25 mL), filtering hot and allowing the filtrate to cool. The solid was filtered and washed with EtOAc (2 mL). The combined batches of solid were air-dried to afford 8.54 g of compound 361-B as a tan-orange powder. 1H-NMR (DMSO-d6) δ: 2.57 (s, 3H), 7.40-7.24 (m, 2H), 7.83-7.70 (m, 5H), 8.14 (d, 1H); MS: m/z 408.1 (M-H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6](/[CH:7]=[N:8]/[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>ClCCl>[CH:9]([N:8]1[CH:7]([C:6]2[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:32]1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc(/C=N/C(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(C2ON2C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
(E)-N-(4-methoxybenzylidene)-1,1-diphenylmethanamine 39 (3.62 g, 12.0 mmol) was dissolved in dichloromethane (130 mL) at 0° C., followed by the portionwise addition of mCPBA (2.96 g, 13.2 mmol). The resulting solution was warmed to room temperature, and stirred for 16 h prior to being transferred to a separatory funnel, and being washed 3 times with 50 mL of saturated sodium bicarbonate solution. The organic layer was then dried with anhydrous sodium sulfate, filtered, and concentrated to afford 40 as a light yellow oil (3.52 g, 92%). LRMS (ESI): (calc.) 317.4 (found) 318.2 (MH)+.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].CN(C)C1C=CC=CC=1.O[C:16]1[N:21]=[C:20]([S:22][CH3:23])[N:19]=[C:18]2[NH:24][N:25]=[C:26]([CH3:27])[C:17]=12>>[Cl:3][C:16]1[N:21]=[C:20]([S:22][CH3:23])[N:19]=[C:18]2[NH:24][N:25]=[C:26]([CH3:27])[C:17]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc(O)c2c(C)n[nH]c2n1
Solvent: CN(C)c1ccccc1
Product: CSc1nc(Cl)c2c(C)n[nH]c2n1
Reaction time: 0.17 h

Procedure:
To a mixture of POCl3 (26 mL) and of dimethylaniline (2 mL) was added crude 4-hydroxy-3-methyl-6-methylmercaptopyrazolo[3,4-d]pyrimidine (A-2) (1.46 g, 7.45 mmol). The solution was heated to reflux for 60 min until all solid dissolved. The excess of POCl3 was removed under reduced pressure. The residue was poured into ice water with vigorous stirring, it is stirred for 10 min, and the aqueous solution was extracted with ether. The ether layer was washed with cold water, dried with anhydrous Na2SO4 and concentrated to give the title compound (A-3) (1.21 g, 5.63 mmol). MS-ESI (m/z): 215.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Brc1ccc(-c2ccccn2)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc(-c3ccccn3)s1)O2
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
A mixture of 2.3 g of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 3.6 g (15 mmol) of 2-(5-bromo-2-thienyl)pyridine, 0.39 g of triphenylphosphine, 95 mg of cuprous iodide. 3 ml of triethylamine and 100 ml of acetnitrile was degassed with argon for 10 minutes. Palladium acetate, 110 mg. was then added and the mixture was stirred at room temperature for 18 hrs. After evaporation under reduced pressure, the residue was partitioned between methylene chloride and water. The organic layer was dried and evaporated and the residue was chromatographed over 140 g of silica gel using 5% of ethyl acetate in methylene chloride. The combined clean fractions were evaporated and the residue was crystallized from ether/hexane to yield 2 g of colorless crystals with m.p. 159°-162° . The analytical sample was recrystallized from ethanol and had m.p. 160°-162°.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][C:9](=O)[CH2:8][CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4].[BH4-].[Na+].C(N(CC)CC)C.[CH2:28]([O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO.C(OCC)(=O)C.Cl>[CH2:28]([O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([N:6]2[CH2:7][CH:8]3[CH2:9][CH2:10][CH:5]2[C:3](=[O:2])[O:4]3)(=[O:44])=[O:43])=[CH:38][CH:37]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)C1CC(=O)CCN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1OC2CCC1N(S(=O)(=O)c1ccc(OCc3ccccc3)cc1)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 29.5 %

Procedure:
To a solution of 4-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.1 g, 3.9 mmol) in 20 mL of methanol was added sodium borohydride (0.14 9, 3.9 mmol) at 0° C. After stirring for 2 h at 0° C., the mixture was diluted with ethyl acetate, washed with 1M HCl, 1M NaOH, and brine, dried over Na2SO4, filtered and concentrated. The residue was taken up in 10 mL of 6M aqueous HCl and was refluxed for 4 h. After cooling to room temperature, the mixture was concentrated in vacuo, and the residue was dissolved in 5.5 mL of anhydrous DMF. The solution was cooled to 0° C. and was treated with triethylamine (4.8 mL, 34 mmol) and 4-benzyloxy-benzenesulfonyl chloride (2.5 g, 8.8 mmol). After stirring for 2 h, the mixture was diluted with 1M HCl, extracted 3× with ethyl acetate, and the organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was filtered through a small pad of silica gel eluting with 1:1 ethyl acetate-hexane, affording 0.43 g of 5-(4-benzyloxy-benzenesulfonyl)-2-oxa-5-aza-bicyclo[2.2.2]octan-3one as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17].O.O.Cl[Sn]Cl.CCOC(C)=O.CCCCCC>CCO>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(Br)cnn1C
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: COc1ccc(N)cc1-c1c(Br)cnn1C
Yield: 88 %

Procedure:
To a stirred solution of 4-bromo-5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (1.799 g, 5.76 mmol) in EtOH (20 mL) was added SnCl2.2H2O (5.306 g, 23.05 mmol, 4.0 eq.), the mixture was stirred at reflux for 2 hrs and EtOH was removed under vacuum. The resulting solid was dissolved in EtOAc, 1N NaOH (30 mL) was added, and the mixture was stirred overnight. The white precipitate was filtered off through celite, and the aqueous phase was extracted with EtOAc (3×80 mL). The combined organic phase was dried over anhydrous MgSO4, filtered and evaporated. The crude reaction mixture was purified by SiO2 column chromatography (Eluent: EtOAc/Hexane=1/3 then 1/1) to give 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (1.430 g, 5.07 mmol, 88%) as a white solid: LCMS m/z (%)=282 (M+H79Br, 98), 284 (M+H81Br, 100). 1H NMR (400 MHz, CDCl3) δ: 7.52 (s, 1H), 6.86 (d, J=8.8 Hz, 1H), 6.80 (dd, J=2.8, 8.8 Hz, 1H), 6.22 (d, J=2.4 Hz, 1H), 4.25 (broad s, 2H), 3.72 (s, 3H), 3.71 (s, 3H).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([Cl:19])[C:13]=1[CH2:20][C:21]([NH:23][C:24]1[C:25]([C:30]([OH:32])=O)=[N:26][CH:27]=[CH:28][N:29]=1)=[O:22].O([CH2:41][CH:42]([F:44])[F:43])S(C(F)(F)F)(=O)=O.Cl>O1CCCC1>[F:43][CH:42]([F:44])[CH2:41][N:23]1[C:24]2=[N:29][CH:28]=[CH:27][N:26]=[C:25]2[C:30]([OH:32])=[C:20]([C:13]2[C:14]([Cl:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=2[Cl:11])[C:21]1=[O:22]
Reactant: O=C(Cc1c(Cl)ccc(Cl)c1Cl)Nc1nccnc1C(=O)O
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c(-c2c(Cl)ccc(Cl)c2Cl)c(O)c2nccnc2n1CC(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hexamethyldisilazide (“NaHMDS”) (1M in THF) (1.4 ml) was added dropwise to a solution of 3-[2-(2,3,6-trichloro-phenyl)-acetylamino]-pyrazine-2-carboxylic acid (Example 3.1) (0.225 g) in anhydrous tetrahydrofuran (10 ml) over a period of 10 minutes. Then difluoroethyl triflate (0.270 g) was added dropwise and the reaction mixture was allowed to stir at ambient temperature for 30 minutes. Then the reaction mixture was heated to reflux for 6 hours. The reaction mixture was allowed to cool to ambient temperature and acidified by addition of aqueous hydrochloric acid (1M). The mixture was concentrated. The residue was dissolved in diethyl ether and washed with aqueous hydrochloric acid (1M). The acid solution was extracted with ethyl acetate. The combined organic fractions were dried over magnesium sulfate and concentrated. The residue was purified by reverse phase HPLC to give Compound No. B11 of Table B (0.034 g).
Reaction SMILES: [CH:1]1([S:6][C:7]2[CH:8]=[C:9]([CH2:13][OH:14])[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:35][C@@H:34]([C:36]2[CH:47]=[CH:46][C:39]3[O:40][C:41]([CH3:45])([CH3:44])[O:42][CH2:43][C:38]=3[CH:37]=2)[O:33][C:32]1=[O:48])(=O)=O.P([O-])([O-])([O-])=O>CN(C=O)C>[CH:1]1([S:6][C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[CH2:13][O:14][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]2[CH2:35][C@@H:34]([C:36]3[CH:47]=[CH:46][C:39]4[O:40][C:41]([CH3:44])([CH3:45])[O:42][CH2:43][C:38]=4[CH:37]=3)[O:33][C:32]2=[O:48])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOS(C)(=O)=O)C(=O)O3)ccc2O1
Reactant: OCc1cccc(SC2CCCC2)c1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(SC5CCCC5)c4)C(=O)O3)ccc2O1
Reaction time: 1 h
Yield: 46.4 %

Procedure:
A solution of [3-(cyclopentylthio)phenyl]methanol (270 mg) in dry DMF (10 ml) under nitrogen was treated with sodium hydride (60% dispersion on mineral oil, 57 mg) and the mixture stirred for 1 h. 2-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethyl methanesulfonate (0.4 g) in dry DMF (2 ml) was then added and the mixture stirred for 18 h. Phosphate buffer solution (pH6.5) was added and the mixture extracted with ethyl acetate. The combined extracts were washed with water and dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified on a 10 g silica SPE cartridge, eluting with 10% to 20% ethyl acetate-cyclohexane to give the title compound (0.23 g). LCMS RT=4.08 min.
Reaction SMILES: [N:1]([C:4]1[C:9]([CH3:10])=[CH:8][N:7]=[CH:6][C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[C:9]([CH3:10])=[CH:8][N:7]=[CH:6][C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: [H][H]
Reactant: CCOC(=O)c1cncc(C)c1N=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cncc(C)c1N
Yield: 98.4 %

Procedure:
0.50 g of material prepared in Step A was dissolved in 15 mL of ethanol. 0.15 g of 10% palladium on carbon was added. The reaction mixture was placed under one atmosphere of hydrogen for 2 hours. The catalyst was removed by filtration. The solvent was removed with a rotary evaporator to afford 0.43 g of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=1[F:34])=O>O>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([F:34])[C:27]=1[C:25]1[N:12]=[C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=2)[S:13][CH:24]=1
Reactant: O=C(CBr)c1c(F)cccc1F
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Solvent: O
Product: O=C(O)c1cc(-c2nc(-c3c(F)cccc3F)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 16 %

Procedure:
4-[4-(2,6-Difluoro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (45 mg, 16%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-2′,6′-difluoroacetophenone (available from SynQuest Laboratories, Inc.) using the procedure described for the preparation of Example 18 except that the entire 4 mL of water was added at the beginning of the hydrolysis step rather than being added in two portions. 1H NMR (300 MHz, DMSO-d6) δ 8.45 (d, J=1.9 Hz, 1H), 7.94-8.04 (m, 3H), 7.50-7.70 (m, 3H), 7.19-7.32 (m, 4H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[N:27]=[C:26]3[N:28](C4CCCCO4)[N:29]=[CH:30][C:25]3=[C:24]([C:37]3[CH:38]=[C:39]([NH:43][C:44](=[O:47])[CH:45]=[CH2:46])[CH:40]=[CH:41][CH:42]=3)[N:23]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[N:27]=[C:26]3[NH:28][N:29]=[CH:30][C:25]3=[C:24]([C:37]3[CH:38]=[C:39]([NH:43][C:44](=[O:47])[CH:45]=[CH2:46])[CH:40]=[CH:41][CH:42]=3)[N:23]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)c(F)c3)nc3c2cnn3C2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)c(F)c3)nc3[nH]ncc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2,2-Trifluoroacetic acid (0.283 mL, 3.68 mmol) was added to a solution of N-(3-(6-((3-fluoro-4-morpholinophenyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide (20 mg, 0.037 mmol) in CH2Cl2 (5 mL), and the reaction mixture was stirred overnight at room temperature, after which the solvent was removed by vacuum. The residue was purified by flash column chromatography (5% CH3OH/CH2Cl2) to yield the title compound as a solid. 1H NMR (400 MHz, CD3OD): δ 8.72 (s, 1H), 8.34 (s, 1H), 8.01 (d, 1H, J=8.4 Hz), 7.94 (m, 1H), 7.73 (m, 1H), 7.54 (t, 1H, J=8.0 Hz), 7.41 (m, 1H), 7.01 (t, 1H, J=9.6 Hz), 6.44 (m, 2H), 5.81 (dd, 1H, J=2.4 & 9.6 Hz), 3.85 (m, 4H), 3.05 (m, 4H); ESI-MS: [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>COCCOC>[CH2:1]([O:8][CH2:9][C@H:10]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@H](CO)COCc1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 91.8 %

Procedure:
(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoic acid (7.2 g, 24.4 mmole) was dissolved in ethylene glycol dimethyl ether (50 mL). N-Methylmorpholine (2.7 ml, 24.4 mmole) was added, and the resulting clear solution was cooled to −20° C. Isobutyl chloroformate (3.19 ml, 24.4 mmole) was added dropwise to cause N-methylmorpholine HCl salt precipitation. Stirring was continued for 15 min and the supernatant was then transferred via a filter-tipped funnel into a rapidly stirred solution of NaBH4 (2.93 g, 73.2 mmole) in ice water and washed with dry DME. After the mixture was stirred for 30 min, it was extracted with EtOAc and washed with H2O. The organic layers were combined, dried over Na2SO4, and concentrated in vacuo. Purification by chromatography (silica, 4/1: Hexane/EtOAc, Rf=0.2) afforded tert-butyl N-[(1R)-2-(benzyloxy)-1-(hydroxymethyl)ethyl]carbamate as a white solid (6.3 g, 92%).