Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[C:9]2[C:10]([C:24]#[N:25])=[CH:11][C:12]([O:14][CH2:15][C:16]3[C:17]([CH3:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[CH:13][C:8]=2[S:7][CH:6]=1.C1COCC1.[OH-].[Na+].Cl>CO>[C:24]([C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:26])=[O:2])=[CH:6][S:7][C:8]=2[CH:13]=[C:12]([O:14][CH2:15][C:16]2[C:17]([CH3:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[CH:11]=1)#[N:25]
Reactant: COC(=O)Cc1csc2cc(OCc3ccc(C)nc3C)cc(C#N)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(COc2cc(C#N)c3c(CC(=O)O)csc3c2)c(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.7 %

Procedure:
To a mixture of methyl(4-cyano-6-((2,6-dimethylpyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetate (96 mg), THF (3 mL) and MeOH (3 mL) was added 1N NaOH (1.179 mL) at room temperature. The mixture was stirred at room temperature for 12 h. The mixture was neutralized with 1N HCl at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The crystals were crystallized from EtOAc to give the title compound (80 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](Cl)=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:2].[I:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]=[C:27](N3CCOCC3)[C:26]2=[O:37])=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>CCOC(C)=O.O>[CH2:1]([O:3][C:4]([C:5]1[C:28]2[CH2:29][CH2:30][N:25]([C:22]3[CH:23]=[CH:24][C:19]([I:18])=[CH:20][CH:21]=3)[C:26](=[O:37])[C:27]=2[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:6]=1)=[O:17])[CH3:2]
Reactant: O=C1C(N2CCOCC2)=CCCN1c1ccc(I)cc1
Reactant: CCOC(=O)C(Cl)=NNc1ccc(OC)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(I)cc1)C2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A solution of chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester (34, 100 g, 0.39 mol) in EtOAc (800 mL) was treated with 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (10, 150 g, 0.39 mol, 1.0 equiv) at 0–5° C. under N2, and the resulting reaction mixture was treated with triethylamine (TEA, 78.8 g, 109 mL, 0.78 mol, 2.0 equiv) at 0–5° C. under N2. The reaction mixture was then warmed up to room temperature for 30 min before being warmed up to reflux for an additional 6 h. When HPLC and TLC showed that the reaction was complete, the reaction mixture was cooled down to 5–10° C. before being treated dropwise with 4.0 N aqueous HCl solution (488 mL, 1.95 mol, 5.0 equiv) at 0–5° C. The resulting mixture was stirred at 5–20° C. for 4 h. The resulting slurry was then treated with water (400 mL) before being stirred at 5–20° C. for an additional 30 min. The solids were collected by filtration, washed with water (2×200 mL) and 50% of isopropyl acetate/hexane (2×200 mL), dried in vacuo at 40–45° C. for 12 h. The crude desired 1-(4-methoxy-phenyl)-6-(4-iodo-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (55, 175.5 g, 201.8 g theoretical, 87% for two steps) was obtained as pale-yellow solids, which was found to be essentially pure to do the following reaction without further purification. For 55, CIMS m/z 518 (M++H, C22H20IN3O4).
Reaction SMILES: [OH:1][C@@H:2]([CH3:11])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:14]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][O:15][C:13]([O:1][C@@H:2]([CH3:11])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[O:14])=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@H](O)CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[C@@H](CC(=O)OC(C)(C)C)OC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 62.7 %

Procedure:
To a solution of 3.84 g of tert-butyl (S)-3-hydroxybutyrate and 5.86 g of 4-dimethylaminopyridine in 20 ml of methylene chloride was added at 0° C. within 20 minutes a solution of 6.47 g of p-nitrobenzyl chloroformate in 20 ml of methylene chloride. The mixture was stirred for 3 hours at 0° C., then diluted with 50 ml of methylene chloride and washed successively with 1N hydrochloric acid, saturated sodium bicarbonate solution, and with brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated in vacuo. The residual oil was chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as eluent to yield 5.10 g of tert-butyl (S)-3-(4-nitrobenzyloxycarbonyloxy)-butyrate as a colourless oil.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[N+:16]([O-:18])=O)([C:3](OCC)=[O:4])=[O:2]>[Pd].CN(C=O)C>[F:15][C:12]1[CH:11]=[C:10]2[C:9]([NH:8][C:1](=[O:2])[C:3](=[O:4])[N:16]2[OH:18])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(=O)Nc1ccc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccc(F)cc2n(O)c1=O
Yield: 85.8 %

Procedure:
To a mixture of 5.6 g of 2-ethoxalylamino-5-fluoronitrobenzene and 170 ml of DMF was added 0.3 g of 10% Pd-C, and hydrogenation reaction was carried out at ordinary temperature and pressure. The reaction mixture was then filtered and concentrated under reduced pressure. The resulting residue was recrystallized from ethanol to provide 3.68 g (85%) of 7-fluoro-1-hydroxyquinoxaline-2,3-(1H,4H)-dione
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([CH:15]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:16])[CH:6]=[CH:5][C:4]1=2.[CH3:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][C:45]=1[C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH:41]=O>>[CH2:49]([O:48][C:46](=[O:47])[C:45]1[CH:44]=[CH:43][C:40](/[CH:41]=[C:15](/[C:7]2[CH:6]=[CH:5][C:4]3[C:3]([CH3:36])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=3[CH:8]=2)\[CH3:16])=[CH:39][C:38]=1[CH3:37])[CH3:50]
Reactant: CC(c1ccc2c(c1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(C=O)cc1C
Agent: [Br-]
Product: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1C

Procedure:
In a manner analogous to that described in Example 1, from [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]-triphenylphosphonium bromide and 3-methyl-4-ethoxycarbonyl-benzaldehyde there can be obtained p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-2-methyl-benzoic acid ethyl ester as a colourless oil which is uniform according to thin-layer chromatography, (Rf=0.6; hexane/15% ether).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16]CN[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.F[C:18](F)(F)[C:19](O)=O>C(Cl)(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:12][CH2:13][CH2:11][N:10]([CH:6]([C:19]4[CH:18]=[CH:8][CH:9]=[CH:4][CH:3]=4)[CH3:5])[CH2:16]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: c1cc2[nH]ncc2cc1NC1CCNCC1
Solvent: ClC(Cl)Cl
Product: CC(c1ccccc1)N1CCCC(Nc2ccc3[nH]ncc3c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound prepared in Example 181 (700 mg) was dissolved in chloroform (3 ml), and 95% trifluoroacetic acid (3 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 2 hr and was then concentrated. Potassium carbonate (690 mg) and dimethylformamide (3 ml) were added to the concentrate, and the mixture was stirred. A solution (2 ml) of (1-bromoethyl)benzene (408 mg) in acetonitrile was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (3 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give 185 mg of the title compound as two diastereomers (ratio=ca. 50:50).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=2)[CH:6]=1.[CH3:29][S:30]([O-:32])=[O:31].[Na+].N1CCC[C@H]1C(O)=O.CS(C)=O>O.[Cu]I>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:11]=2)[CH:6]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc3ccc(Br)cc23)cc1
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc3ccc(S(C)(=O)=O)cc23)cc1
Temperature: 115 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A mixture of [6-bromo-4-(4-ethanesulfonyl-phenoxy)-naphthalen-2-yl]-acetic acid methyl ester (32 mg, 0.07 mmol, methyl ester of example 15-1), sodium methanesulfinate (10 mg, 0.09 mmol), L-proline (4 mg, 0.028 mmol), copper(I) iodide (3 mg, 0.014 mmol) and dimethyl sulfoxide (0.3 mL) was stirred at 115° C. overnight under an argon atmosphere. The resulting mixture was diluted with water (5 mL), and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (30% ethyl acetate in petroleum ether) to give [4-(4-ethanesulfonyl-phenoxy)-6-methanesulfonyl-naphthalen-2-yl]-acetic acid methyl ester (11 mg) as a yellow solid.
Reaction SMILES: O[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[CH:10]=[N:9][C:8]([C:11]#[N:12])=[N:7][C:6]=2[N:13]=1.O=P(Cl)(Cl)[Cl:22]>CC#N>[Cl:22][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[CH:10]=[N:9][C:8]([C:11]#[N:12])=[N:7][C:6]=2[N:13]=1
Reactant: N#Cc1ncc2cc(-c3ccccc3)c(O)nc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1ncc2cc(-c3ccccc3)c(Cl)nc2n1

Procedure:
The solution of 7-hydroxy-6-phenylpyrido[2,3-d]pyrimidine-2-carbonitrile (2-3; 0.300 g, 1.21 mmol) in CH3CN and POCl3 (2 mL) was heated to 100° C. for 4 h. The mixture was concentrated and the residue was basified with saturated NaHCO3 at 0° C. Extracted with CH2Cl2 and the combined organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (10-20% EtOAc in hexane) to give the title compound (2-4). LRMS m/z (M+H) Calcd: 267.7, found: 267.2.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:20])[N:4]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:5](CC2C=CC=CC=2)=[CH:6][CH:7]=1.[K+].[Br-].[CH3:23]OC(=O)CN1C(CCC2C=CC=CC=2)=CC=C(N)C1=O>>[NH2:1][C:2]1[C:3](=[O:20])[N:4]([CH:15]([CH3:23])[C:16]([O:18][CH3:19])=[O:17])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cn1c(CCc2ccccc2)ccc(N)c1=O
Reactant: COC(=O)Cn1c(Cc2ccccc2)ccc(N)c1=O
Agent: [Br-]
Agent: [K+]
Product: COC(=O)C(C)n1cccc(N)c1=O

Procedure:
A mixture of 2(S) methyl-2[3-benzyloxycarbonylamino-1,2-dihydro-2-oxo-1-pyridyl)propionate (49a) (2.75 g, 8.33 mmol), methanol (100 ml), and 10% palladium on carbon (300 mg) was stirred under an atmosphere of hydrogen for 30 min. The mixture was filtered and concentrated to afford 1.63 g (100%) of a colorless solid: 1H NMR (d6-DMSO) δ 8.35 (1H, brs), 7.46 (1H, d), 7.22 (1H, d), 6.29 (1H, t), 5.22 (1H, q), 3.63 (3H, s), 1.55 (3H, d). The following compounds were prepared in a similar manner: Methyl [3-amino-6-benzyl-1,2-dihydro-2-oxo-1-pyridyl]acetate (50b). 100% yield as a grey solid: mp. 134-6° C.; IR (KBr) 3418, 3312, 1723, 1658, 1596, 1548, 1435, 1290, 1245, 1011; 1H NMR (d6-DMSO) δ 7.25 (5H, m), 6.45 (1H, d, J=7.4), 5.92 (1H, d, J=7.4), 5.00 (2H, s), 4.63 (2H, s), 3.88 (2H, s), 3.51 (3H, s). Methyl[3-amino-1,2-dihydro-2-oxo-6-phenethyl-1-pyridyl]acetate (50c). 99% yield as a viscous oil: IR (KBr) 3456, 341, 2953, 1745, 1649, 1600, 1548, 1219;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:20]([NH2:22])=O)[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>O1CCCC1>[Cl:19][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH2:20][NH2:22]
Reactant: NC(=O)c1cc(Cl)c(Sc2cccc3ccccc23)c(Cl)c1
Solvent: C1CCOC1
Product: NCc1cc(Cl)c(Sc2cccc3ccccc23)c(Cl)c1

Procedure:
A solution of 25 g of 3,5-dichloro-4-[(l-naphthyl)thio]benzene carboxamide in 150 ml of dry tetrahydrofuran (THF) is treated with 230 ml of 1.0 M BH3 -THF complex. The resulting solution is heated at reflux for 16 hours. The reaction mixture is cooled with ice and quenched with excess 2 N HCl. The mixture is then made basic with NaOH and extracted with methylene chloride. The combined extracts are washed with water and dried with anhydrous magnesium sulfate. Concentration under reduced pressure affords the crude product which is purified by column chromatography on silica gel.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([CH3:36])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH2:29][C@H:30]4[CH2:34][O:33]C(=O)[NH:31]4)[CH3:21])[C:14]3=[O:37])[CH:7]=2)[CH2:3][CH2:2]1.[OH-].[K+]>O.CO>[NH2:31][C@H:30]([CH2:34][OH:33])[CH2:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]([NH:19][C:15]1[C:14](=[O:37])[N:13]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=2[CH3:12])[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:38])[CH:18]=[CH:17][N:16]=1)([CH3:21])[CH3:36]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OC[C@H]2COC(=O)N2)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OC[C@H](N)CO)c1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 18.4 %

Procedure:
A solution of N-cyclopropyl-4-methyl-3-[3-{[1-methyl-1-(2-{[(4S)-2-oxo-1,3-oxazolidin-4-yl]methoxy}phenyl)ethyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide (Example 305a) (0.6 g) in water (10 mL) and MeOH (10 mL) was treated with potassium hydroxide (0.130 g) under nitrogen. The resulting mixture was stirred at 50° C. for 16 h. The reaction mixture was diluted with water (200 mL), and extracted with ethyl acetate (250 mL). The organic phase was dried (MgSO4), filtered and evaporated. Purification by preparative HPLC (Phenomenex Gemini column, eluting with a gradient of acetonitrile in 0.2% (v/v) aqueous ammonia) gave the title compound as a solid (0.105 g).
Reaction SMILES: C(OC[N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])=[CH:16][N:15]=2)[N:11]=[N:10]1)(=O)C(C)(C)C.[OH-].[Na+].Cl.O>CO>[CH2:25]([O:24][CH:20]([O:21][CH2:22][CH3:23])[C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:11]=[N:10][NH:9][CH:13]=2)=[N:15][CH:16]=1)[CH3:26]
Reactant: CCOC(OCC)c1ccc(-c2cn(COC(=O)C(C)(C)C)nn2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(OCC)c1ccc(-c2c[nH]nn2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
In methanol (12 mL) was dissolved (4-(5-(diethoxymethyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (1.96 g, 5.41 mmol) obtained in Step 3. To the solution was added a 1 mol/L aqueous sodium hydroxide solution (11.9 mL, 11.9 mmol) and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture were added 1 mol/L hydrochloric acid (11.9 mL) and water. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure to give 5-(diethoxymethyl)-2-(1H-1,2,3-triazol-4-yl) pyridine (1.34 g, 100% yield).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=1[CH3:33].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:33][C:25]1[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=[CH:29][C:24]=1[C:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])ccc1C1=CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A suspension of N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.29 g, 0.93 mmol), 1-bromo-2-methyl-4-nitrobenzene (0.20 g, 0.93 mmol), PdCl2(PPh3)2 (0.03 g, 0.05 mmol) and 3 M aqueous Na2CO3 (0.93 mL, 2.8 mmol) in 1,4-dioxane (10 mL) was degassed with nitrogen for 10 minutes then heated at reflux for 16 hours. The resulting mixture was concentrated under reduced pressure and purified using silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-30% EtOAc in petroleum benzine 40-60° C.) to give the title compound A38 (0.25 g, 83%); 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=2.4 Hz, 1H), 8.03-7.98 (m, 1H), 7.22 (d, J=8.4 Hz, 1H), 5.63 (s, 1H), 4.09-4.04 (m, 2H), 3.64 (t, J=5.6 Hz, 2H), 2.38 (s, 3H), 2.35 (s, 2H), 1.51 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:25]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[O:25]([C:32]1[CH:33]=[CH:34][C:35]([NH:36][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:13][C@@H:11]4[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][C@@H:10]4[CH2:15]3)[CH:17]=[N:18][CH:19]=2)=[O:22])=[CH:37][CH:38]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)Nc4ccc(Oc5ccccc5)cc4)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 4-phenoxyaniline were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 501 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[CH3:26]B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH3:26][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1
Reactant: CB(O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Br
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: [K+]
Solvent: C1COCCO1
Product: Cc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C

Procedure:
A mixture of tert-butyl N-[(1S,2S)-2-{[3-bromo-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]carbamate (800 mg, 1.88 mmol), methylboronic acid (CAS number 13061-96-6; 338 mg, 5.64 mmol), tetrakis(triphenylphosphine)palladium (217 mg, 0.19 mmol) and, 2 M potassium carbonate (aq, 3.8 ml, 7.53 mmol) in 1,4-dioxane (6.3 ml) was sealed, evacuated and purged with nitrogen and then subjected to microwave irradiation at 120° C. for 2 hours. The reaction mixture was then diluted with ethyl acetate (40 ml) and water (10 ml). The organics were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was then purified by column chromatography (silica, 0-50% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]([NH2:13])=O)=[CH:9][C:8]=1[N+:19]([O-:21])=[O:20].O>C(#N)C>[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]#[N:13])=[CH:9][C:8]=1[N+:19]([O-:21])=[O:20]
Reactant: Cc1c([N+](=O)[O-])cc(C(N)=O)cc1[N+](=O)[O-]
Solvent: CC#N
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c([N+](=O)[O-])cc(C#N)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 18 h
Yield: 96.3 %

Procedure:
Phosphorus oxychloride (91.3 kg) is added over about 30 minutes into a mixture of 4-methyl-3,5-dinitrobenzamide (6) (66.6 kg) in acetonitrile (250.2 kg). The mixture is heated at reflux (about 80° C.) for about 2.5 hours. The solution is then cooled to ambient temperature and added to water (335 L) over about 1.5 hour, while maintaining a temperature of less than about 30° C. The mixture is cooled to about 5° C. and held at this temperature for about 18 hours. The product that precipitates is isolated via centrifugation, washed with water (469 L), and dried in a convection tray dryer at about 45° C. for about 22 hours to provide 4-methyl-3,5-dinitrobenzonitrile (4) (59 kg, 96% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)[CH3:2].[Cl:21][CH2:22][C:23](Cl)=[O:24].O>CN(C)C(=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1[N:7]=[C:8]([NH:11][C:23](=[O:24])[CH2:22][Cl:21])[S:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)c1csc(N)n1
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(NC(=O)OC(C)(C)C)c1csc(NC(=O)CCl)n1
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of 1.26 g of α-t-butyloxycarbonylamino-α-(2-aminothiazol-4-yl)acetic acid ethyl ester in 5 ml of N,N-dimethylacetamide is added 708 mg of chloroacetyl chloride under stirring. After the stirring for further 1 hour at room temperature, the reaction solution is poured into water and extracted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate aq. solution and then water and dried over anhydrous magnesium sulfate. The distillation of the solvent gives 1.435 g of α-t-butyloxycarbonylamino-α-[2-(chloroacetamido)thiazol-4-yl]acetic acid ethyl ester as crystals (yield, 90.8%). Melting point: 192°-193° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:8]2[NH:13][N:12]=[C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].Cl.[F:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:8]2[NH:13][N:12]=[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:38]3[CH2:39][CH2:40][CH:35]([F:34])[CH2:36][CH2:37]3)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(C#CCCCCCl)c2n1
Reactant: FC1CCNCC1
Agent: Cl
Product: CCCCc1nc(NCc2ccc(OC)c(OC)c2)c2[nH]nc(CCCCCCN3CCC(F)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 24 from 5-butyl-3-(6-chlorohex-1-yn-1-yl)-N-(3,4-dimethoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine and 4-fluoropiperidine hydrochloride