Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].CO.[H][H]>[C].[Pd].C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2ccccc2c(=O)n1Cc1ccccc1
Yield: 69.8 %

Procedure:
A mixture of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (400 mg), 10% palladium carbon (100 mg), methanol (5 ml) and THF (5 ml) was stirred at room temperature under 1 atm hydrogen pressure for 12 hrs. Palladium carbon was filtered off, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized (ethyl acetate-hexane) to give the title compound (230 mg).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[CH3:18][C:19](=[N:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](=[N:44][O:45][CH3:46])[C:40](OC)=[O:41])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1.ClCCl>CO>[CH3:18][C:19](=[N:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](=[N:44][O:45][CH3:46])[CH:40]=[O:41])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1
Reactant: CON=C(C(=O)OC)c1ccccc1CON=C(C)c1cccc(C(F)(F)F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CON=C(C=O)c1ccccc1CON=C(C)c1cccc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 47.3 %

Procedure:
1M diisobutylaluminum hydride/toluene solution (11 ml, 16.5 mmol) was added dropwise to a mixture of methyl 2-[(α-methyl-3-trifluoromethylbenzylidene)aminooxymethyl]-α-methoxyiminophenylacetate (4.83 g, 11.8 mmol) and dichloromethane (47 ml) at -65° C. or lower over 4 minutes, and the mixture was stirred at -78° C. to room temperature for 3 hours. Methanol (7 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The precipitated insoluble materials were removed, and the remaining mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-[(α-methyl-3-trifluoromethylbenzylidene)aminooxymethyl]-α-methoxyiminophenylacetaldehyde (2.11 g, 47.3%) as a colorless oil.
Reaction SMILES: C(C1[CH:4]=[C:5]2[C:9](=[N:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#N.Cl.[C:13]([O:16]CC)(=[O:15])[CH3:14]>C(O)C.[OH-].[K+]>[NH:8]1[C:9]2[C:5](=[CH:4][C:14]([C:13]([OH:16])=[O:15])=[CH:11][N:10]=2)[CH:6]=[CH:7]1
Reactant: N#Cc1cnc2[nH]ccc2c1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc2[nH]ccc2c1
Temperature: 90 °C

Procedure:
To a solution of 5-cyano-7-azaindole XXX (50 mg, 0.35 mmol) in ethanol (10 ml), 10% aqueous potassium hydroxide (15 ml) was added. The reaction was heated at 90° C. for two days after which the reaction was allowed to cool to room temperature. The pH was adjusted to 6 with 10% HCl and diluted with ethyl acetate (100 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (4×, 75 ml). The organic layers were combined and washed once with brine (100 ml) before drying over sodium sulfate. The organic layer was evaporated under reduced pressure to yield the titled product as an off-white solid. (52 mg, M−1, 161.2)
Reaction SMILES: [O:1]1[CH:5]=[C:4]([CH:6]=O)[N:3]=[CH:2]1.[CH3:8][C:9]([S:12]([NH2:14])=[O:13])([CH3:11])[CH3:10]>C1COCC1.C(OCC)(=O)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:1]1[CH:5]=[C:4](/[CH:6]=[N:14]/[S:12]([C:9]([CH3:11])([CH3:10])[CH3:8])=[O:13])[N:3]=[CH:2]1
Reactant: O=Cc1cocn1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)/N=C/c1cocn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
In a round-bottomed flask, oxazole-4-carbaldehyde (300 mg, 3.09 mmol) was dissolved in THF (7 ml) and 2-methylpropane-2-sulfinamide (450 mg, 3.71 mmol) and titanium(IV) ethoxide (1.3 ml, 6.18 mmol) were added. The reaction mixture was stirred at room temperature overnight then slowly quenched by dropwise addition of brine (2 ml) which resulted in the formation of a thick light yellow precipitate. The reaction mixture was diluted with ethyl acetate and stirred vigorously at room temperature for 30 min. The suspension was filtered over Celite and rinsed with ethyl acetate. The filtrate was concentrated and the residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-40% EtOAc) to afford 552 mg (89%) of 2-methyl-propane-2-sulfinic acid 1-oxazol-4-yl-meth-(E)-ylideneamide as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.[C-]#N.[K+].C[C:13]([OH:15])=[O:14]>CCO.O>[CH3:1][C:2]1([CH3:8])[CH2:6][C:5](=[O:7])[CH2:4][CH:3]1[C:13]([OH:15])=[O:14]
Reactant: CC(=O)O
Reactant: CC1(C)C=CC(=O)C1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(=O)CC1C(=O)O
Temperature: 40 °C

Procedure:
To a solution of 4,4-dimethylcyclopent-2-enone (2.0 g, 18 mmol) in EtOH (50 mL), water (7.5 mL) and AcOH (1.5 mL) was added potassium cyanide (2.36 g, 36.3 mmol). The reaction mixture was heated to about 40° C. and after about 15 h the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with brine. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in aqueous HCl (6N, 50 mL) and heated to reflux. After about 3 days the reaction mixture was cooled to room temperature and concentrated under reduced pressure to provide 2,2-dimethyl-4-oxocyclopentanecarboxylic acid (3.7 g, 90%, ˜70% purity by 1H NMR) that was carried on without additional purification: LC/MS (Table 2, Method a) Rt=1.30 min; MS m/z: 155 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:34][CH:33]=1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(CNC(=O)OC(C)(C)C)cc3)c(F)cn2c1=O
Yield: 108.9 %

Procedure:
Ethyl 8-(4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.31 mmol) and (4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-boronic acid (101 mg, 0.40 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (167 mg, 100%). ESI-MS m/z: 495 (M+Na)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:25]([O:27][CH3:28])=[O:26])=[C:9]([CH3:24])[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1F)[CH3:2].[CH2:30]([S-:32])[CH3:31].[Na+].IC>CS(C)=O.O>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:25]([O:27][CH3:28])=[O:26])=[C:9]([CH3:24])[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1[S:32][CH2:30][CH3:31])[CH3:2]
Reactant: CC[S-]
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)OC)c2cc1F
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Solvent: O
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)OC)c2cc1SCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 7-(ethyloxy)-6-fluoro-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (9.35 g, 22.95 mmol) in dimethyl sulfoxide (150 mL) was added sodium ethanethiolate (6.44 g, 68.9 mmol) and the resulting mixture was stirred at room temperature overnight. Iodomethane (7.18 mL, 115 mmol) was added, and the mixture was stirred for 2 h. The mixture was diluted with water and extracted with methylene chloride. The organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford methyl 7-(ethyloxy)-6-(ethylthio)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification. MS (m/z) 450.1 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[CH:10]=[C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[N:19]=2)[C:12]([C:15]#[N:16])=[N:13][CH:14]=1.C[Si](C)(C)[O-:28].[K+]>O1CCOCC1>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[CH:10]=[C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[N:19]=2)[C:12]([C:15]([NH2:16])=[O:28])=[N:13][CH:14]=1
Reactant: C[Si](C)(C)[O-]
Reactant: CCc1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)cnc2C#N)n1
Agent: [K+]
Solvent: C1COCCO1
Product: CCc1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)cnc2C(N)=O)n1
Temperature: 100 °C

Procedure:
A suspension of 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(6-ethylpyridin-2-yl)amino]pyridine-2-carbonitrile (51 mg, 0.152 mmol) and potassium trimethylsilanolate (486 mg, 3.79 mmol) in dioxane (3 mL) was heated to 100° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, filtered, and concentrated under reduced pressure. The residue was dissolved in DMSO, filtered, and purified via reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to afford 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(6-ethylpyridin-2-yl)amino]pyridine-2-carboxamide. MS ESI calc'd. for C19H27N6O[M+H]+ 355. found 355. 1H NMR (500 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.56 (s, 1H), 7.92 (s, 1H), 7.88-7.80 (m, 2H), 7.70 (d, J=2.5 Hz, 1H), 7.58-7.54 (m, 1H), 7.34 (s, 1H), 6.76 (d, J=7.3 Hz, 1H), 6.65 (d, J=8.2 Hz, 1H), 6.34 (d, J=8.4 Hz, 1H), 3.81 (br s, 1H), 2.68 (q, J=7.5 Hz, 2H), 1.86-1.79 (m, 2H), 1.73-1.67 (m, 1H), 1.67-1.54 (m, 3H), 1.45-1.35 (m, 2H), 1.24 (t, J=7.6 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]2=[CH:8][S:9][CH:10]=[C:6]2[S:5](=[O:12])(=[O:11])[N:4]([CH3:13])[C:3]=1[C:14]([O:16]C)=O.[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2=[CH:8][S:9][CH:10]=[C:6]2[S:5](=[O:11])(=[O:12])[N:4]([CH3:13])[C:3]=1[C:14]([NH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1)=[O:16]
Reactant: COC(=O)C1=C(O)c2cscc2S(=O)(=O)N1C
Reactant: Nc1nccs1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2cscc2S1(=O)=O

Procedure:
0.9 G. of 4-hydroxy-3-methoxycarbonyl-2-methyl-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide are suspended together with 0.4 g. of 2-aminothiazole in 100 ml. of absolute xylene and heated to reflux for 4 hours, 70 ml. of xylene being slowly distilled off. A crystalline precipitate separates from the cooled solution and is filtered off under suction. There is obtained 4-hydroxy-2-methyl-N-(2-thiazolyl)-2H-thieno[3,4-e]-1,2-thiazine-3-carboxamide 1,1-dioxide of melting point 243°-245° C. (decomposition).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>ClCCl>[C:1]1([C:7]2([CH2:13][O:14][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1(c2ccccc2)CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a stirred solution of (1-phenyl-cyclohexyl)-methanol (251) (43.0 g, 225.97 mmol) in dichloromethane (250.0 mL) was added Et3N (63.0 mL, 451.9 mmol), followed by drop-wise addition of mesyl chloride (21.0 mL, 271.16 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was quenched by the addition of water and extracted with dichloromethane. The organic layer was then washed with water and brine and dried over sodium sulfate and concentrated under reduced pressure to get a crude product. It was purified by normal silica gel column chromatography (using 5% ethyl acetate in hexane) to get methanesulfonic acid 1-phenyl-cyclohexylmethyl ester (252) (49.3 g, 81.0%) as a white solid.
Reaction SMILES: O.NN.[Si:4]([O:11][C:12]1[CH:30]=[CH:29][C:15]([CH2:16][O:17][N:18]2C(=O)C3=CC=CC=C3C2=O)=[CH:14][CH:13]=1)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Si:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][O:17][NH2:18])=[CH:29][CH:30]=1)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CON)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
Hydrazine monohydrate (1.25 ml) was added to a solution of N-[4-(tert-butyldimethylsilyloxy)benzyloxy]phthalimide (5.00 g) in ethanol (10 ml)-tetrahydrofuran (40 ml) and stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, an aqueous solution of potassium carbonate was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated to obtain 4-(tert-butyldimethylsilyloxy)benzyloxyamine (3.15 g, yield 95%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Cl[C:27]1[S:28][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:30][N:31]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[S:28][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:30][N:31]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1cnc(Cl)s1
Product: NS(=O)(=O)c1cnc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (300 mg, 1.0 mmol) and 2-Chloro-thiazole-5-sulfonic acid amide (example B.13) (179 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (120 mg, 23%). MS (ISP) 518.1 [(M+H)+]; mp 235° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1[CH:24]=NC2N(O)N=[N:27][C:21]=2[CH:20]=1.CCN(C(C)C)C(C)C.C1(N)CCC1>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:18])[NH:27][CH:21]1[CH2:20][CH2:19][CH2:24]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2cccnc21
Reactant: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Agent: NC1CCC1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCC1)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
To a solution of 5.00 g pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester in 100 ml DMF were added 2.73 g HOAt, 3.85 g EDC, 6.9 ml DIPEA and 1.43 g cyclobutylamine. After 24 h the mixture was diluted with ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w), 0.1 M HCl and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure to give the crude which was pure enough for the subsequent transformation. Yield: 9.00 g.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[CH:24][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][N:16]=1)=[O:5].[Sn](Cl)Cl.[OH-].[Na+]>C(O)(=O)C.Cl>[NH2:28][C:26]1[CH:25]=[CH:24][C:3]([C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:13]=[CH:14]/[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][N:16]=2)=[O:5])=[C:2]([Cl:1])[CH:27]=1
Reactant: O=C(Nc1ccccc1/C=C/c1n[nH]c2ccccc12)c1ccc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)Nc2ccccc2/C=C/c2n[nH]c3ccccc23)c(Cl)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
(E)-2-chloro-N-{2-[2-(1H-indazol-3-yl)vinyl]phenyl}-4-nitrobenzamide (60 mg, 0.14 mmol) was dissolved in acetic acid (1.0 mL) and hydrochloric acid (0.5 mL). The solution was added with tin(II) chloride (114 mg, 0.6 mmol), stirred at 40° C. for 2 hours, added with 6 mol/L sodium hydroxide to neutralize and then the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethanol to obtain Compound 84 (21 mg, 38%).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:9][CH2:8][S:7][C:6](=[N:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=2[CH3:20])[NH:5]1)([CH3:3])[CH3:2].[CH2:21](Br)[CH:22]([CH3:24])[CH3:23]>>[CH2:21]([N:5]1[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8][S:7][C:6]1=[N:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[CH3:20])[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)CBr
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](C(C)C)CCS1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC[C@H](C(C)C)N1CC(C)C
Yield: 32 %

Procedure:
(R)-4-Isopropyl-2-(2-methyl-4-nitrophenylimino)-2,3,4,5-tetrahydro-1,3-thiazine Method C3a) was reacted with isobutyl bromide in a manner analogous to Method D2a to yield (4R)-3-isobutyl-4-isopropyl-2-(2-methyl-4-nitrophenylimino)tetrahydro-2H-1,3-thiazine (0.081 g, 32%). TLC (33% EtOAc/hex) Rf0.76.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:20]3[CH2:25][CH2:24][C@H:23]([CH2:26][NH:27]C(=O)OCC4C=CC=CC=4)[CH2:22][CH2:21]3)=[N:9][C:10]=2[C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[CH:6][N:7]=1>Cl.O>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:20]3[CH2:21][CH2:22][C@H:23]([CH2:26][NH2:27])[CH2:24][CH2:25]3)=[N:9][C:10]=2[C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c1c(-c1cc3ccccc3[nH]1)nc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: O
Product: NC[C@H]1CC[C@H](c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn32)CC1

Procedure:
A solution of benzyl {[trans-4-(8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}carbamate (0.163 g, 0.330 mmol) in conc. HCl (5 ml) was stirred at rt overnight. The reaction mixture was diluted with H2O (20 mL), washed with Et2O (30 mL), then basified with 1N NaOH (aq) and extracted with DCM (3×20 mL). The combined extracts were washed with water then dried over Na2SO4 and concentrated in vacuo To afford 0.085 g of desired compound. MS (ES+): m/z 361.30 [MH+].
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C.[Pd]>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([CH:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])=[CH:21][CH:20]=1
Reactant: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.4 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 22, 345 mg, 1.0 mmol) in ethyl acetate (100 mL) was treated with 10% palladium on activated carbon (34.5 mg). The reaction mixture was stirred under hydrogen gas at 60 psi at 25° C. for 6 h. The catalyst was then filtered off through a pad of celite, which was washed well with ethyl acetate. The resulting filtrate was concentrated in vacuo to give 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (288.3 mg, 91.4%) as a yellow solid: mp 102–107° C.; EI-HRMS m/e calcd for C17H21N3OS (M+) 315.1405, found 315.1401.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1>CCCCO>[Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CO[C@@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCCCO
Product: CO[C@@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Yield: 44.5 %

Procedure:
(S)—N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (120 mg, 0.38 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (228 mg, 1.14 mmol) in n-BuOH (4 mL) were heated to 160° C. for 18 hours in a sealed tube. After concentration, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-90% CH3CN/water gradient; 30 CV) to yield tert-butyl (R)-1-(5-bromo-3-((S)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (84 mg, 45% yield) as a solid.
Reaction SMILES: C[O-].[Na+].[C:4]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[N:11][CH:12]=1)(=[NH:6])[NH2:5].C[C:21](C)([C:25]([O-])=[O:26])[C:22]([O-])=[O:23].Cl>CO.O>[OH:26][C:25]1[N:6]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:18])[CH3:17])=[N:11][CH:12]=2)[NH:5][C:22](=[O:23])[CH:21]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(C(=N)N)cn1
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)C(=O)Nc1ccc(-c2nc(O)cc(=O)[nH]2)cn1
Temperature: 82 °C

Procedure:
A suspension of sodium methoxide (432 mg, 8.0 mmol), N-(5-carbamimidoylpyridin-2-yl)pivalamide (880 mg, 4.0 mmol) and dimethylmalonate (457 μL, 4.0 mmol) in 15 mL methanol is refluxed at 82° C. for 14 hours. The resulting suspension is dissolved in 15 mL water and acidified using 6M HCl. The precipitate is filtered, rinsed with water, air/vacuum dried and used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=O)[CH2:11][F:12].N1C=CC=CC=1.Cl.[CH3:21][O:22][NH2:23]>CO>[CH3:21][O:22][N:23]=[C:10]([CH2:11][F:12])[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: CON
Reactant: O=C(CF)Cc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C(CF)Cc1ccc(Cl)cc1Cl
Temperature: 23 °C
Reaction time: 16 h
Yield: 106.6 %

Procedure:
To a stirred solution of 1-(2,4-dichloro-phenyl)-3-fluoro-propan-2-one (0.34 g; 1.5 mmol) in methanol (3 ml) was added pyridine (0.4 ml; 4.9 mmol) followed by a portionwise addition of methoxyamine hydrochloride (0.41 g; 4.9 mmol). The reaction mixture was stirred for 16 hours at 23° C. The mixture was washed with water (5 ml), the aqueous layer was extracted with dichloromethane (3×5 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford 0.40 g (100% of theory) of crude 1-(2,4-dichloro-phenyl)-3-fluoro-propan-2-one O-methyl-oxime (isomers E/Z) as a yellow oil.