Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[C:41]([C:49]([F:52])([F:51])[F:50])[CH:40]=2)/[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1>C(Cl)Cl>[CH:28]1(/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:46])=[O:47])=[C:41]([C:49]([F:51])([F:52])[F:50])[CH:40]=2)/[C:36]([NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)O)cc1C(F)(F)F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
A solution of triphenylphosphine (1.39 g, 5.3 mmol) in methylene chloride (50 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (0.94 g, 5.3 mmol). The reaction mixture was stirred at 0° C. For 30 min and then treated with a solution of (E)-3-cyclohexyl-2-(4-(methanesulfonyl)-3-(trifluoromethyl)-phenyl)-acrylic acid (1.00 g, 2.66 mmol) in methylene chloride (10 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (800 mg, 7.98 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (100 mL) and a 1N aqueous hydrochloric acid solution (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 5/1 to 3/2 hexanes/ethyl acetate) afforded the (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-acrylamide (367 mg, 30%) as an amorphous solid: EI-HRMS m/e calcd for C20H21F3N2O3S2 (M+) 458.0946, found 458.0947.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]C(=O)N(C)C)=[C:6]([CH2:16][CH2:17][CH3:18])[C:5]=1[OH:19])(=[O:3])[CH3:2].[OH-].[K+].C(O)C.Cl>O>[OH:19][C:5]1[C:6]([CH2:16][CH2:17][CH3:18])=[C:7]([SH:10])[CH:8]=[CH:9][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CCCc1c(SC(=O)N(C)C)ccc(C(C)=O)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1c(S)ccc(C(C)=O)c1O
Yield: 94.1 %

Procedure:
Reflux a stirred mixture of dimethyl-thiocarbamic acid S-(4-acetyl-3-hydroxy-2-propyl-phenyl) ester (1.08 g, 3.84 mmol), potassium hydroxide (1.1 g, 19.2 mmol), ethanol (25 mL), and water (10 mL) for 2 hours. Cool the reaction in an ice/water bath and adjust the pH to 2 with aqueous 5N hydrochloric acid. Extract the mixture with ethyl acetate (3×50 mL). Combine the extracts and wash with water (50 mL) and brine (50 mL) and dry over magnesium sulfate, filter, and concentrate to afford the title compound (0.76 g, 94%) as a brown oil which solidifies on standing. LCMS (m/z) 211 M−1.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: Nn1nc(-c2ccc(F)cc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2ccc(F)cc2)c2ccccc2c1=O

Procedure:
The product of Example 129A and 2-(4-chlorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.71-11.73 (bs, 1H), 8.39-8.45 (m, 1H), 7.90-8.03 (m, 2H), 7.69-7.74 (m, 1H), 7.62-7.68 (m, 2H), 7.37-7.44 (m, 6H), 3.71 (s, 2H); MS (APCI+) M/Z 408 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:42])[C:3](=[O:41])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[O:26])[CH:20]=4)[CH:17]=3)[N:12](COCC[Si](C)(C)C)[N:11]=2)[CH:5]=1.C(=O)(O)[O-].[Na+]>Cl(O)(=O)(=O)=O.C(O)(=O)C>[CH3:1][N:2]([CH3:42])[C:3](=[O:41])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([N:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)=[O:26])[CH:20]=4)[CH:17]=3)[NH:12][N:11]=2)[CH:5]=1
Reactant: CN(C)C(=O)c1cccc(-c2nn(COCC[Si](C)(C)C)c3ncc(-c4cccc(C(=O)N5CCOCC5)c4)cc23)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: CN(C)C(=O)c1cccc(-c2n[nH]c3ncc(-c4cccc(C(=O)N5CCOCC5)c4)cc23)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18 %

Procedure:
A solution of N,N-dimethyl-3-(5-(3-(morpholine-4-carbonyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide in 5% of perchloric acid in acetic acid (1 mL) was stirred for 1 h at room temperature. Saturated sodium bicarbonate solution was then added to the solution slowly until pH ˜8 and the mixture was stirred for 24 hours at room temperature. Ethyl acetate was then used for extraction and the organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Mass triggered reverse phase HPLC purification afforded N,N-dimethyl-3-(5-(3-(morpholine-4-carbonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide (7.4 mg, 18% yield over two steps) as light yellow solids. 1H NMR (500 MHz, CDCl3) δ 2.99 (s, 3H), 3.10 (s, 3H), 3.46 (br, 2H), 3.61 (br, 2H), 3.76 (br, 4H), 7.40 (d, J=7.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.52 (m, 2H), 7.64 (d, J=7.5 Hz, 1H), 7.68 (s, 1H), 7.98 (m, 2H), 8.62 (s, 1H), 8.85 (br, 1H). MS: m/z 456.1 (M+H+).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([C:11](Cl)=[O:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH2:24][C@@H:25]([NH:27][CH2:28][CH3:29])[CH3:26])=[CH:23][C:18]=2[CH2:17][CH2:16]1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH2:24][C@@H:25]([N:27]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)=[O:12])[CH2:28][CH3:29])[CH3:26])=[CH:23][C:18]=2[CH2:17][CH2:16]1
Reactant: CS(=O)(=O)N1CCC(C(=O)Cl)CC1
Reactant: CCN[C@@H](C)Cc1ccc2c(c1)CCO2
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(C(=O)C1CCN(S(C)(=O)=O)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-methanesulfonylpiperidine-4-carbonyl chloride in dichloromethane (10 ml) was added to a suspension of (S)-N-[2-(2,3,-dihydrobenzofuran-5-yl)-1-methylethyl]-ethylamine hydrochloride (1.21 grams, 5 mmole) in dichloromethane (10 ml). The mixture was cooled to 0° C., and triethylamine (1.7 ml, 12.2 mmol) was added dropwise. When the addition was complete, the mixture was warmed to room temperature and stirred for about 1 hour. Saturated ammonium chloride was added (20 ml) and the separated organic layer was extracted once with dichloromethane (20 ml). The combined organic layers were washed with 1N hydrochloric acid (25 ml), saturated sodium bicarbonate (25 ml), dried over magnesium sulfate, and concentrated to give (S)-N-[2-(2,3,-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(1-methanesulfonylpiperidin-4-ylcarbonyl)amine as an off white foam (2.21 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: BrCCCOCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(CCCOCc2ccccc2)c2cc([N+](=O)[O-])c(N)cc21
Yield: 100.4 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.49 g) is alkylated using (3-bromo-propoxymethyl)-benzene (1,36 g; 5.95 mmol) and K2CO3 (2.07 g; 15.0 mmol) at RT for 16 h. After aqueous work-up the crude material is de-acetylated in hydrochloric acid (6 N, 60 ml) at reflux. After aqueous work-up 5-amino-1-(3-benzyloxy-propyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (2.1 g) is obtained and used without further purification.
Reaction SMILES: [CH3:1][NH:2][N:3]=[C:4]([CH3:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7].O1CCCC1.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26](=[O:30])[C:27](Cl)=[O:28])=[CH:18]1>O>[CH3:1][N:2]([C:27](=[O:28])[C:26]([C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]([CH3:16])[CH:18]=1)=[O:30])[N:3]=[C:4]([CH3:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: Cn1cc(C(=O)C(=O)Cl)c2ccccc21
Reactant: CNN=C(C)CS(C)(=O)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(CS(C)(=O)=O)=NN(C)C(=O)C(=O)c1cn(C)c2ccccc12
Reaction time: 2 h
Yield: 72 %

Procedure:
To a 50 ml volume three-necked flask, 1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine (5-2-1) (2.22 g) and tetrahydrofuran (anhydrous) (10 ml) were added under a nitrogen atmosphere. To the mixture, 2-(1-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (26-a) (3.0 g) was added dropwise under ice-cooling, and stirred for 2 hours. The reaction mixture was added to iced water, and the precipitated solids were collected by filtration, washed with water and hexane, and dried under reduced pressure to give 3.4 g of 1-methyl-1-[2(1-methyl-1H-indol-3-yl)-2-oxoacetyl]-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-203-(13)28).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([O:15][CH3:16])=[CH:12]2)=[CH:7][CH:6]=1)#[C:2][CH2:3][CH3:4].CCCCCC>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([O:15][CH3:16])=[CH:12]2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC#Cc1ccc2ccc(OC)cc2c1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCc1ccc2ccc(OC)cc2c1
Yield: 97 %

Procedure:
Using 7-methoxy-2-naphthyltrifluoromethanesulfonate (30.63 g, 0.10 mol) and butyne gas (a product manufactured by TOKYO CHEMICAL INDUSTRY CO., LTD., 100 g, large excess), 7-butyn-1-yl-2-methoxynaphthalene was synthesized by the same operation as that in the method for synthesizing 7-decyl-2-methoxynaphthalene according to Example 3, and subjected to column chromatography (silica gel, developed with a mixture of toluene and hexane) to obtain a light yellow oil product of 7-butyn-1-yl-2-methoxynaphthalene (18.1 g, yield of 56%). The obtained 7-butyn-1-yl-2-methoxynaphthalene (total amount) was subjected to catalytic reduction in toluene (275 ml) under a hydrogen atmosphere by adding 10% Pd/C (1.83 g). The obtained product was subjected to column chromatography (silica gel, developed with a mixture of toluene and hexane) to obtain 7-butyl-2-methoxynaphthalene (compound (3)-04, 17.80 g, yield of 97%).
Reaction SMILES: [F:1][C:2]([C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)([F:5])[CH2:3]I.[N-:12]=[N+:13]=[N-:14].[Na+].CS(C)=O>O>[N:12]([CH2:3][C:2]([C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)([F:5])[F:1])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(CI)c1ncccn1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC(F)(F)c1ncccn1
Temperature: 95 °C
Reaction time: 72 h
Yield: 102.6 %

Procedure:
A mixture of 2-(1,1-difluoro-2-iodo-ethyl)-pyrimidine (841 mg, 3.11 mmol), as prepared in the previous step, NaN3 (338 mg, 5.19 mmol), and DMSO (2.35 mL) was stirred at 95° C. for 3 days. The reaction was then shaken with water (10 mL) and extracted with ether (3×8 mL). The organic layers were combined, dried (Na2SO4), and concentrated to give the intermediate 2-(2-azido-1,1-difluoro-ethyl)-pyrimidine as a clear yellow oil (591 mg) that was immediately used in the next step without further purification or characterization.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10]CC)=[O:9])=[C:5]([CH3:7])[N:6]=1.[OH-].[Na+]>O1CCCC1.O>[NH2:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: CCOC(=O)c1sc(N)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(N)sc1C(=O)O
Yield: 92.6 %

Procedure:
A mixture of ethyl 2-amino-4-methylthiazole-5-carboxylate (6.58 g, 35.5 mmol) and NaOH (5.40 g, 135 mmol) in tetrahydrofuran (60 mL) and water (30 mL) was heated to reflux overnight. Tetrahydrofuran was removed in vacuo, and the residue was neutralized with 5% hydrochloric acid solution to pH 5˜6. The precipitate obtained was collected by filtration and dried to afford the crude 2-amino-4-methylthiazole-5-carboxylic acid (5.20 g, 94%): 1H NMR (300 MHz, DMSO-d6) δ 7.63 (s, 2H), 2.30 (s, 3H); MS (ES+) m/z 159.1 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:27])[C@@H:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8][C:9]1[CH:19]=[CH:18][C:12]2[O:13][C:14]([F:17])([F:16])[O:15][C:11]=2[CH:10]=1)(=[O:3])[CH3:2].[Li].CC([O-])(C)C.CC([O-])(C)C.CC([O-])(C)C.[Al+3]>C(O)C>[C:1]([O:4][CH2:5][C@@H:6]([OH:27])[C@@H:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8][C:9]1[CH:19]=[CH:18][C:12]2[O:13][C:14]([F:16])([F:17])[O:15][C:11]=2[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@H](Cc1ccc2c(c1)OC(F)(F)O2)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Al+3]
Agent: [Li]
Solvent: CCO
Product: CC(=O)OC[C@@H](O)[C@H](Cc1ccc2c(c1)OC(F)(F)O2)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A solution of (S)-3-(tert-butoxycarbonyl)-4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-oxobutyl acetate (1100 mg, 2741 μmol) in 45 mL of ethanol cooled to 0° C. was added to lithium aluminum tri-tert-butoxyhydride (1 M in THF, 5481 μA 5481 μmol) in 15 mL of ethanol at −78° C. dropwise via cannula over 5 minutes. After stirring at −78° C. for 2 hours the reaction was quenched with 10 mL of 1 N HCl and the mixture was diluted with ethyl acetate (500 mL). The reaction was poured into 200 mL of water, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organics were washed with water, brine, and dried over sodium sulfate, filtered and concentrated to provide (2S,3S)-3-(tert-butoxycarbonyl)-4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-hydroxybutyl acetate (1060 mg, 96% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[N+:13]([O-])([O-:15])=[O:14].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[NH2:12]
Reactant: CC(C)(C)c1ccc(N)c(Br)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)(C)c1cc(Br)c(N)cc1[N+](=O)[O-]
Temperature: -7.5 °C
Yield: 77.4 %

Procedure:
2-Bromo-4-tert-butyl-phenylamine (160 g, 0.71 mol) was added dropwise to H2SO4 (410 mL) at room temperature to yield a clear solution. This clear solution was then cooled down to −5 to −10° C. A solution of KNO3 (83 g, 0.82 mol) in H2SO4 (410 mL) was added dropwise while the temperature was maintained between −5 to −10° C. Upon completion, the reaction mixture was poured into ice/water and extracted with EtOAc. The combined organic layers were washed with 5% Na2CO3 and brine, dried over Na2SO4 and concentrated. The residue was purified by a column chromatography (ethyl acetate/petroleum ether 1:10) to give 2-bromo-4-tert-butyl-5-nitro-phenylamine as a yellow solid (150 g, 78%).
Reaction SMILES: O.[OH-].[Li+].C([O:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:26][C:25]([CH2:49][C:50]#[N:51])([N:27]4[CH:31]=[C:30]([C:32]5[C:33]6[CH:40]=[CH:39][N:38](COCC[Si](C)(C)C)[C:34]=6[N:35]=[CH:36][N:37]=5)[CH:29]=[N:28]4)[CH2:24]3)[CH2:19][CH2:18]2)=[O:16])[N:12]=[C:11]([C:52]([F:55])([F:54])[F:53])[N:10]=1)(=O)C>O.O1CCCC1>[OH:7][CH2:8][C:9]1[N:10]=[C:11]([C:52]([F:55])([F:54])[F:53])[N:12]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:26][C:25]([CH2:49][C:50]#[N:51])([N:27]4[CH:31]=[C:30]([C:32]5[C:33]6[CH:40]=[CH:39][NH:38][C:34]=6[N:35]=[CH:36][N:37]=5)[CH:29]=[N:28]4)[CH2:24]3)[CH2:19][CH2:18]2)=[O:16])[CH:14]=1
Reactant: CC(=O)OCc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6c5ccn6COCC[Si](C)(C)C)cn4)C3)CC2)nc(C(F)(F)F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3cc(CO)nc(C(F)(F)F)n3)CC2)C1
Reaction time: 0.08 h

Procedure:
Lithium hydroxide monohydrate (3.6 mg, 0.085 mmol) in water (0.10 mL) was added to a solution of [6-[(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-(trifluoromethyl)pyrimidin-4-yl]methyl acetate (21 mg, 0.028 mmol, from Example 376, Step D) in tetrahydrofuran (0.40 mL). The mixture was stirred for 5 minutes and was then treated with 1N HCl to neutralize. Solvent was then removed in vacuo. The residue was stirred in a solution of 1:1 TFA/DCM for one hour, then solvents were removed in vacuo again. The residue was redissolved in MeOH (1 mL) and ethylenediamine (0.2 mL) was added. When deprotection was complete, the product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: 0.004 g (25%); LC-MS: 567.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.14 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.90 (s, 1H), 7.61 (d, 1H), 7.06 (d, 1H), 5.94 (br s, 1H), 4.71 (s, 2H), 4.12-4.02 (m, 1H), 3.75 (dd, 2H), 3.63-3.46 (m, 5H), 3.31-3.22 (m, 1H), 3.17-3.07 (m, 1h), 2.61-2.53 (m, 1H), 1.84-1.75 (m, 1H), 1.71-1.61 (m, 1H), 1.37-1.18 (m, 2H). 19F NMR (400 MHz, DMSO-d6): δ −69.46 (s, 3F).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)([O-:16])=[O:15].O>O1CCCC1>[N+:14]([C:17]1[CH:18]=[C:19]([CH:20]=[CH:3][C:1]#[N:2])[CH:22]=[CH:23][CH:24]=1)([O-:16])=[O:15]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC=Cc1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
At 0° C., 75.5 g of diethyl cyanomethylphosphonate dissolved in tetrahydrofuran are poured into a suspension of sodium hydride in tetrahydrofuran. After 30 minutes' contact at ambient temperature, 56 g of 3-nitrobenzaldehyde dissolved in tetrahydrofuran are poured in. After 1 hour, hydrolysis is carried out with 300 ml of water and then the solvent is concentrated. Following extraction with dichloromethane, washing the organic phase with water, drying over magnesium sulphate and concentration, the precipitate is taken up in diethyl ether and filtered off.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>CC#N>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(NS(C)(=O)=O)C1
Reaction time: 2.5 h

Procedure:
To a solution of (+/−)-3-amino-1N—BOC-pyrrolidine (0.5 g) in MeCN (10 mL) was added triethylamine (0.41 mL) then methanesulfonyl chloride (0.22 mL). The mixture was stirred for 2.5 h. An aqueous work-up followed by purification on silica gave 3-methanesulfonylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (0.49 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]CC)=O)=[CH:9][N:10]=2)[CH:7]=1.O.[NH2:17][NH2:18]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([NH:17][NH2:18])=[O:13])=[CH:9][N:10]=2)[CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1cnc2ccc(Br)cn12
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cnc2ccc(Br)cn12

Procedure:
A mixture of 1.94 g ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate, 6 mL hydrazine monohydrate and 20 mL ethanol was heated for 1 hour under reflux. The precipitated crystals were collected by filtration, washed with ethanol and dried under reduced pressure by a vacuum pump to give 1.71 g of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5]C1C=CC=CC=1)C.[C:12]1([C:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:27])[CH2:19][CH2:20]N2CCCCC2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][N:2]1[CH2:4][CH2:5][CH2:20][C@H:19]1[C:18]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[OH:27]
Reactant: CN(C)CCc1ccccc1
Reactant: OC(CCN1CCCCC1)(c1ccccc1)c1ccccc1
Product: CN1CCC[C@H]1C(O)(c1ccccc1)c1ccccc1

Procedure:
LC-MS (ESI) m/z (%): 268 (0) [M0+H]+, 269 (4), 270 (13), 271 (22), 272 (22), 273 (16), 274 (14), 275 (7), 276 (1).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:19]([O:26][C:27](ON1C(=O)CCC1=O)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27]([NH:2][C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCOC(=O)C[C@@H](N)c1cccc([N+](=O)[O-])c1
Agent: Cl
Product: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1cccc([N+](=O)[O-])c1
Yield: 83 %

Procedure:
Using a procedure analogous to that used to prepare 34B, 39A (2.75 g, 10 mmol) was reacted with N-(Benzyloxycarbonyloxy)succinimide to afford 39B (3.1 g, 83%) as a white solid. MS (ESI) m/z 395.13 (M+Na)+.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[C:16]([C:22]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[O:23])=[N:17][C:18](Cl)=[CH:19][CH:20]=1.O>CN(C)C=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][C:15]1[C:16]([C:22]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[O:23])=[N:17][C:18]([S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:19][CH:20]=1
Reactant: Cc1csc(NC(=O)c2nc(Cl)ccc2Cl)n1
Reactant: Sc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(NC(=O)c2nc(Sc3ccccn3)ccc2Sc2ccccn2)n1
Temperature: 100 °C
Reaction time: 15 h
Yield: 23 %

Procedure:
2-Mercaptopyridine (24 mg; 0.205 mmol) and 68 g (0.492 mmol) of potassium carbonate were added to a solution (2 ml) of 3,6-dichloro-N-(4-methyl-thiazole-2-yl)-2-pyridine carboxamide produced by the same method as in Production Example 1 in N,N-dimethylformamide followed by stirring at 100° C. for 15 hours. Water was added to the reaction solution followed by extracting with ethyl acetate and washing with a saturated aqueous saline solution. After drying and concentrating, the resulting residue was purified by a thin-layer silica gel chromatography (chloroform:methanol=20:1) to give 15 mg (yield: 23%) of the title compound as a yellow solid.