Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1>CN(C)C=O>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:3]2[C:4](=[O:15])[C:5]3[C@@H:6]4[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]4)[C:10]=3[N:2]2[CH3:1])=[C:19]([C:25]([F:26])([F:27])[F:28])[CH:18]=1
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccc(F)cc1C(F)(F)F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 55.1 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 210 mg, 1.02 mmol) and 4-fluoro-2-trifluoromethyl-benzyl bromide (470 μL, 3.04 mmol) in N,N-dimethylformamide (10 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40M system, eluting with 0-0.5% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(4-fluoro-2-trifluoromethyl-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (215 mg, 55%) as an off-white solid. APCI-MS (M+H) 383.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:35])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([OH:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].Cl(O)(=O)(=O)=O>C(Cl)Cl.C(OC(C)(C)C)(=O)C>[CH2:1]([O:4][C:5]1([CH3:35])[CH2:6][CH2:7][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:34][C:5]([CH3:35])([CH3:10])[CH3:6])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](O)C(=O)OCC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Solvent: ClCCl
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Reaction time: 3 h
Yield: 106.6 %

Procedure:
To a stirred solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (8.5 g, 15.64 mmol) in DCM (250 mL) and t-butyl acetate (175 mL) was added perchloric acid (4.03 mL, 46.9 mmol) at rt. After 3 h, the reaction mixture was diluted with DCM (100 mL), carefully quenched with sat. NaHCO3 (50 mL), organic layer separated and washed with brine (100 mL), dried (Na2SO4), filtered and concentrated to give yellow liquid. This was purified by flash column chromatograpgy on silica gel column using (10-50% EtOAc/Hex as eluant) to afford the desired (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (5 g, 8.34 mmol, 53.3% yield) as light yellow solid. 3 g of starting material was also recovered. 1H NMR (500 MHz, CDCl3) δ 8.23-8.11 (m, 1H), 7.94 (d, J=7.7 Hz, 1H), 7.56-7.51 (m, 1H), 7.33 (t, J=7.9 Hz, 1H), 6.81 (s, 1H), 6.10 (br. s., 1H), 6.00 (br. s., 1H), 5.49 (d, J=16.6 Hz, 1H), 5.28 (d, J=10.2 Hz, 1H), 4.30-4.14 (m, 2H), 4.10-4.00 (m, 2H), 2.65 (s, 3H), 2.09-1.85 (m, 3H), 1.74 (br. s., 1H), 1.38 (s, 3H), 1.28-1.16 (m, 12H). 4 missing piperidine hydrogens. LCMS (M+H)=601.5.
Reaction SMILES: Cl.C(O[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])C.C([O-])(=O)C.[NH4+:18]>C(O)(=O)C>[N+:11]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[NH2:18])([O-:13])=[O:12]
Reactant: CCOc1ccncc1[N+](=O)[O-]
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ccncc1[N+](=O)[O-]
Yield: 79.4 %

Procedure:
A 22 liter 4-neck flask fitted with a reflux condenser, thermometer and mechanical stirrer was charged with 1300 g (6.35 mol) of 4-ethoxy-3-nitropyridine hydrochloride, 2438 g (31.62 mol) of ammonium acetate and 13 1. of glacial acetic acid. The reaction mixture was refluxed for 3 hours and cooled. The volatiles were evaporated under reduced pressure and the residue was dissolved in 1N hydrochloric acid. The insoluble material was removed by filtration and the pH of the filtrate was adjusted to approximately 8.5 with concentrated ammonium hydroxide. The precipitated solid was collected by filtration, washed with water and dried in a forced air oven to provide 701 g of 3-nitro-4-aminopyridine. Yield 79.3%. mp=187°-195° C. The identity of the product was also confirmed by chromatography in a 10:1 ethyl acetate:triethylamine solvent system by comparison to a reference standard.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](=[N:15]O)[NH2:14])=[CH:11][CH:10]=1>CO>[C:1]([C:2]1[N:14]=[C:13]([C:12]2[CH:17]=[CH:18][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)[NH:15][CH:3]=1)([O:5][CH3:6])=[O:4]
Reactant: C#CC(=O)OC
Reactant: COc1ccc(C(N)=NO)cc1
Solvent: CO
Product: COC(=O)c1c[nH]c(-c2ccc(OC)cc2)n1
Reaction time: 8 h
Yield: 30.1 %

Procedure:
A solution of methyl propiolate (25.4 g, 0.3 mol), p-methoxybenzamidoxime (50 g, 0.3 mol) and CH3OH (700 ml) was heated at reflux with stirring. After 8 hours, the reaction mixture was concentrated to dryness, and the residue treated with diphenyl ether (300 ml) and heated at reflux. After 2.5 hours, the reaction mixture was poured in C6H14 (2 L) and allowed to stand. The C6H14 was decanted off and the residue chromatographed on silica gel. The product was eluted with 2% CH3OH--CHCl3 to yield 21 g (30%) of 63; m.p. 188°-90° C. (trituration with Et2O). Analysis calculated for C12H12N2O3.
Reaction SMILES: OO.[C:3]([O:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[N:15]([OH:20])[C:14]([CH3:22])([CH3:21])[CH2:13]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23]S(C)=O.[OH-].[Na+]>O>[C:3]([O:11][CH:12]1[CH2:13][C:14]([CH3:22])([CH3:21])[N:15]([O:20][CH3:23])[C:16]([CH3:18])([CH3:19])[CH2:17]1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CS(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 81 %

Procedure:
A solution of 5.9 g (52 mmol) of 30% aqueous hydrogen peroxide is added dropwise, under nitrogen, over 90 minutes to a mixture of 10.0 g (36.2 mmol) of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 11.2 g (40.3 mmol) of ferrous sulfate heptahydrate, and 135 ml of dimethyl sulfoxide which is initially at 24° C. The reaction temperature increases to 37° C. as the peroxide is added. After the addition is complete, the reaction mixture is stirred for 1.75 hours at ambient temperature. The mixture is cooled in an ice-water bath and diluted with water (80 ml). A solution of 5 g of sodium hydroxide in 45 ml of water is added to make the reaction mixture basic. The mixture is extracted with methylene chloride (250 ml, then 2×150 ml), and the combined organic layers are concentrated at reduced pressure to obtain a light orange liquid. Purification of the crude product by flash chromatography on silica gel (20:1 heptane/ethyl acetate) affords 8.5 g (81% yield) of the title compound, a white solid, mp 67°-69° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:26]2[CH:30]=[C:29]([C:31]3[C:32]4[CH:39]=[CH:38][N:37](COCC[Si](C)(C)C)[C:33]=4[N:34]=[CH:35][N:36]=3)[CH:28]=[N:27]2)[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][C:19](B(O)O)=[C:18]([F:25])[CH:17]=3)=[O:15])[CH2:10][CH2:9]2)[CH2:5]1)#[N:2].Br[C:49]1[CH:50]=[C:51]2[C:56](=[CH:57][CH:58]=1)[N:55]=[CH:54][CH:53]=[CH:52]2.C(N(CC)CC)C>CN(C=O)C.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.C(O)(C(F)(F)F)=O.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>[F:25][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[C:49]1[CH:50]=[C:51]2[C:56](=[CH:57][CH:58]=1)[N:55]=[CH:54][CH:53]=[CH:52]2)[C:14]([N:11]1[CH2:10][CH2:9][CH:8]([N:6]2[CH2:5][C:4]([CH2:3][C:1]#[N:2])([N:26]3[CH:30]=[C:29]([C:31]4[C:32]5[CH:39]=[CH:38][NH:37][C:33]=5[N:34]=[CH:35][N:36]=4)[CH:28]=[N:27]3)[CH2:7]2)[CH2:13][CH2:12]1)=[O:15]
Reactant: Brc1ccc2ncccc2c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCN(C(=O)c6ccc(B(O)O)c(F)c6)CC5)C4)c3)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3ccc(-c4ccc5ncccc5c4)c(F)c3)CC2)C1
Temperature: 140 °C
Reaction time: 0.42 h

Procedure:
To a solution of {4-[(4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-fluorophenyl}boronic acid (50 mg, 0.08 mmol) in DMF (2 mL) were added 6-bromoquinoline (15 mg, 0.076 mmol), triethylamine (0.021 mL, 0.15 mmol) and 3 drops of 2 N K2CO3 aqueous solution. The mixture was degased and bis(triphenylphosphine)palladium(II) chloride (5.4 mg, 0.0076 mmol) was added. The reaction mixture was stirred at 140° C. in a microwave oven for 25 minutes, then cooled to room temperature and filtered. The filtrate was purified by HPLC to afford a white powder. The white powder was dissolved in a 5 mL of DCM/TFA (1:2). After being stirred at room temperature for 1 hour, the solution was concentrated. The residue was dissolved in 5 mL of 10% ethylenediamine in THF. After being stirred at room temperature for 2 hours, the solution was concentrated. The residue was purified by HPLC (method B) to afford the title compound {1-[1-(3-fluoro-4-quinolin-6-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. LC-MS: 612.2 (M+H)+.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][CH2:19][OH:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21]I.[H-].[Na+]>CN(C=O)C>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][CH2:19][O:20][CH3:21])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: OCCC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCC1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 42.1 %

Procedure:
1-Benzhydryl-3-(2-hydroxyethyl)azetidine (1.58 g, 5.91 mmol) was suspended in DMF (30 mL), and under a nitrogen stream, methyl iodide (0.37 mL, 5.91 mmol) and 60% sodium hydride (355 mg, 8.87 mmol) were added at 0° C. with stirring. The reaction mixture was stirred for two hours at the same temperature and then poured onto ice water, and the mixture was extracted with ethyl acetate. The combined extract was washed with ice water and saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 40M, ethyl acetate:n-hexane=5:95), to obtain the title compound (700 mg, 42%) as an oily matter.
Reaction SMILES: [CH3:1][S@:2](=[O:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[N:7][CH:6]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][N:27]=1>>[Cl:25][C:26]1[N:27]=[CH:28][C:29]([C:12]#[C:11][C:9]2[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=2)[C:4]([N:3]=[S@@:2]([CH3:1])(=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:30][CH:31]=1
Reactant: C[Si](C)(C)C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Reactant: Clc1ccc(I)cn1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc(Cl)nc2)c1)c1ccccc1
Yield: 90.2 %

Procedure:
In a manner similar to that described in Example 443, (S)—N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (250 mg, 0.70 mmol) and 2-chloro-5-iodopyridine (173 mg, 0.70 mmol) were reacted to give the title compound as white solid (250 mg).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:35])[N:22]=[N:23][C:24]=3[CH:25]([CH3:27])[CH3:26])=[CH:14][C:13]=2[Cl:36])[CH:5]=1.[OH-].[Na+]>CO>[Cl:36][C:13]1[CH:14]=[C:15]([O:18][CH2:19][C:20]2[N:21]([C:28]3[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:35])[N:22]=[N:23][C:24]=2[CH:25]([CH3:26])[CH3:27])[CH:16]=[CH:17][C:12]=1[CH:11]=[CH:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:37])=[O:2]
Reactant: COC(=O)c1cccc(C=Cc2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1COc1ccc(C=Cc2cccc(C(=O)O)c2)c(Cl)c1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
To a solution of 3-(2-{2-chloro-4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-vinyl)-benzoic acid methyl ester (0.459 g, 0.825 mmol) in methyl alcohol (20 mL) is added 1 N sodium hydroxide solution (2.5 mL). The reaction is heated to mild reflux for 1 h and is cooled to room temperature. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in water and the aqueous solution is acidified with 5 N hydrochloric acid solution to form a white precipitate. The solid is filtered and dried overnight under reduced pressure to give the title compound (0.395 g). ES/MS m/e 542.0 (M+1), 542.0 (M-H); HPLC purity: 95.56
Reaction SMILES: O=[C:2]([CH2:8][S:9][C:10]#[N:11])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH3:12][NH:13][CH3:14]>C1COCC1>[CH3:12][N:13]([CH3:14])[C:10]1[S:9][CH:8]=[C:2]([CH2:3][C:4]([O:6][CH3:7])=[O:5])[N:11]=1
Reactant: COC(=O)CC(=O)CSC#N
Reactant: CNC
Solvent: C1CCOC1
Product: COC(=O)Cc1csc(N(C)C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of methyl 3-oxo-4-thiocyanatobutanoate (350 mg, 2.02 mmol) in THF (4 ml) was added a vessel containing dimethylamine in THF (2M; 1.01 ml, 2.02 mmol), the reaction mixture was stirred at rt for 3 h. LCMS showed that the desired product was detected, the mixture was concentrated to give the residue, the residue was purified by a standard method to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](O)(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1.[NH4+].[OH-]>O>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:9]2[NH:8][C:7]3[C:2]([N:1]=2)=[N:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=1
Reactant: Nc1cccnc1N
Reactant: O=C(O)c1cccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: c1cncc(-c2nc3ncccc3[nH]2)c1
Yield: 66.3 %

Procedure:
A solution of 2,3-diaminopyridine (1.1 g, 10 mmol) and nicotinic acid (1.23 g, 10 mmol) in polyphosphoric acid (15 mL) was heated at 160° C. for 4 hours and poured into 150 mLs of water. The pH was adjusted to pH 8 with NH4OH with cooling. The precipitate was filtered and air dried. Recrystallization from EtOH to give 1.3 g of product (66%), m.p.=133°-135° C. Anal. Calcd. for: C, 67.34; H, 4.11, N, 28.36. Found: C, 67.21; H, 4.04; N, 28.11.
Reaction SMILES: Cl.C(OCC)(=O)C.[CH2:8]([O:15][C@H:16]1[C@@H:21]([NH:22][C:23]([C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)=[O:24])[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Br[C:47]1[S:48][C:49]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:50][N:51]=1.Cl>>[CH2:8]([O:15][C@H:16]1[C@@H:21]([NH:22][C:23]([C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)=[O:24])[CH2:20][CH2:19][N:18]([C:47]2[S:48][C:49]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:50][N:51]=2)[CH2:17]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)c2ncc[nH]2)[C@H](OCc2ccccc2)C1
Reactant: CCOC(=O)c1cnc(Br)s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3ncc[nH]3)[C@H](OCc3ccccc3)C2)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.1 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (10 mL, 40 mmol) was added to tert-butyl cis(±)-3-(benzyloxy)-4-[(1H-imidazol-2-ylcarbonyl)amino]piperidine-1-carboxylate obtained in Example (90e) (0.3 g, 0.75 mmol), and the mixture was stirred at room temperature for 20 minutes. Following concentration under reduced pressure, the residue was dissolved in DMF (8 mL). Diisopropylethylamine (0.45 g, 3.5 mmol) and ethyl 2-bromo-1,3-thiazole-5-carboxylate (0.21 g, 0.9 mmol) were added, and the mixture was stirred at 70° C. for 1.5 hours. Dilute hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=5/1, ethyl acetate) to obtain 0.26 g of the title compound as a light brown solid (76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([S:17][CH3:18])[C:14]([F:19])=[CH:13][N:12]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1>ClCCl.C1C=C(Cl)C=C(C(OO)=O)C=1>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([S:17]([CH3:18])=[O:38])[C:14]([F:19])=[CH:13][N:12]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-fluoro-3-[5-fluoro-4-(methylthio)pyrimidin-2-yl]-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 44b, (48.2 g, 111.5 mmol) was dissolved in dichloromethane (2.3 L) and treated portionwise with m-CPBA (27.5 g, 122.6 mmol) while keeping the temperature below 20° C. After addition was complete, the reaction was stirred at room temperature for 2 hours, then treated with another portion of m-CPBA (1.9 g) and stirred for another hour. The reaction mixture was washed with 12% aqueous K2CO3 (2×1.0 L) and the organic layer was dried on Na2SO4 and concentrated in vacuo to provide 50 g of 5-fluoro-3-[5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl]-1-tosyl-1H-pyrrolo[2,3-b]pyridine as a yellow solid.
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]([N:11]([CH3:18])[C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH:21]C(C)CC(C)C)[CH3:20].BrCC#N.C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][CH2:6][C@H:7]([N:11]([CH3:18])[C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[C:8]([O:10][CH2:20][C:19]#[N:21])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCC(=O)N(C)[C@@H](COC(C)(C)C)C(=O)O
Reactant: CCNC(C)CC(C)C
Agent: N#CCBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCCC(=O)N(C)[C@@H](COC(C)(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.1 %

Procedure:
(S)-3-(tert-butoxy)-2-(N-methylpent-4-enamido)propanoic acid (Compound SP746) (1.01 g, 3.92 mmol) and N-ethylisopropylpropan-2-amine (EtN(iPr)2, 1.37 mL, 7.85 mmol) were dissolved in N,N-dimethylformamide (3.92 ml) under a nitrogen atmosphere, 2-bromoacetonitrile (0.82 ml, 11.8 mmol) was added and the mixture was stirred at room temperature for 45 minutes. 50 ml of ethyl acetate was added to the reaction solution, and the organic layer was separated by 50 ml of a saturated aqueous ammonium chloride solution and 50 ml of brine. The organic layer was collected and concentrated under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol solution) to afford (S)-cyanomethyl 3-(tert-butoxy)-2-(N-methylpent-4-enamido)propanoate (Compound SP747) (1.00 g, 86%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([C:14]#[N:15])=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[N:28]([Sn](C)(C)C)=[N+:29]=[N-:30].O.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([C:14]2[NH:30][N:29]=[N:28][N:15]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1C#N
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1-c1nnn[nH]1
Temperature: 70 °C
Reaction time: 168 h

Procedure:
A mixture of 0.682 g (1.73 mM) of 2-cyano-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation XV, and 1.24 g (6.05 mM) of azidotrimethyltin in 10 ml of toluene is prepared and this mixture is stirred at 70° C. for 7 days. After cooling, the reaction medium is poured onto a mixture of water and ethyl acetate and brought to pH 1 by addition of an N hydrochloric acid solution. The aqueous phase is extracted, brought to pH 5 by addition of a dilute sodium hydroxide solution and extracted with ethyl acetate. This organic phase is separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The crude product obtained is purified by chromatography on silica gel, elution being carried out with a dichloromethane/methanol mixture (95/5;v/v). The expected compound is thus obtained in the form of a white foam (yield=30%).
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH2:6][O:7][C:8](=[O:24])[C@@H:9]([CH:21]([CH3:23])[CH3:22])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:3]([OH:5])=[O:4].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:44][CH2:45]I>O1CCOCC1>[Cl:44][CH2:45][O:4][C:3](=[O:5])[C:2]([CH3:1])([CH3:25])[CH2:6][O:7][C:8](=[O:24])[C@@H:9]([CH:21]([CH3:22])[CH3:23])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12]
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)C(=O)O
Reactant: ClCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)C(=O)OCCl
Reaction time: 18 h

Procedure:
(2,2-dimethyl-3-(N-CBz-D-valyloxy)-propionic acid (4.5 g, 12.8 mmole) was dissolved in dioxane (20 ml). To the solution was added tetrabutylammonium hydroxide aqueous solution (40%, 8.3 ml, 12.8 mmole). The solution was dried in vacuo, and it was coevaporated with toluene several times. The residue was dissolved in methylene chloride and then chloroiodomethane (18 ml, 260 mmole) was added to the solution. After 18 hr, the reaction solution was evaporated and the product was isolated with silica gel column chromatography. 3.5 g.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16]C(C)(C)C)=[O:15])=[C:12]([C:23]([F:26])([F:25])[F:24])[CH:11]=1)#[N:9]>ClCCl>[C:8]([C:10]1[CH:22]=[CH:21][C:13]([C:14]([OH:16])=[O:15])=[C:12]([C:23]([F:24])([F:25])[F:26])[CH:11]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)c1ccc(C#N)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
Trifluoroacetic acid (0.55 ml) was added to a solution of tert-butyl 4-cyano-2-(trifluoromethyl)benzoate (194 mg) in dichloromethane (2 ml) under ice cooling, followed by stirring at the temperature for one hour. It was warmed to room temperature and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, a 1M aqueous sodium hydroxide solution (2 ml) was added thereto, followed by washing with diethyl ether. 1M hydrochloric acid (2 ml) was added to the aqueous layer, followed by extraction with ethyl acetate-methanol mixed solution (4:1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 4-cyano-2-(trifluoromethyl)benzoic acid (136 mg) as a colorless solid.