Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([C:40]2([C:43](=[O:52])[NH:44]C3C=CC(F)=CC=3)[CH2:42][CH2:41]2)=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH3:32])C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[S:13][C:6]=12.[C:53](O)([C:55]([F:58])(F)F)=O>ClCCl>[F:1][C:2]1[CH:36]=[C:35]([N:37]([C:2]2[CH:36]=[CH:53][C:55]([F:58])=[CH:33][CH:3]=2)[C:38]([C:40]2([C:43]([NH2:44])=[O:52])[CH2:41][CH2:42]2)=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][NH:21][CH2:29][CH2:30][O:31][CH3:32])=[CH:18][N:19]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)c3s2)nc1
Reaction time: 18 h
Yield: 69 %

Procedure:
To the compound 146 (0.59 g, 0.81 mmol) in dichloromethane (50 mL) was added TFA (3 mL). The solution was stirred for 18 h then concentrated. The residue was partitioned between dichloromethane and 1M NaOH, and filtered to remove insolubles. The organic phase was collected, washed with 1M NaOH, brine, dried (MgSO4), filtered, and concentrated to afford title compound 147 (0.35 g, 69% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.40 (s, 1H), 10.01 (s, 1H), 8.55 (d, J=1.6 Hz, 1H), 8.51 (d, J=5.3 Hz, 1H), 8.31 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.92-7.87 (m, 2H), 7.65-7.61 (m, 2H), 7.52-7.43 (m, 2H), 7.17-7.12 (m, 2H), 6.64 (d, J=5.5 Hz, 1H), 3.77 (s, 2H), 3.40 (t, J=5.7 Hz, 2H), 3.23 (s, 3H), 2.64 (t, J=5.7 Hz, 2H), 1.46 (br s, 4H). MS (m/z): 630.1 (M+H).
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:15][CH2:16][C:17]([C:32]([F:35])([F:34])[F:33])([OH:31])[CH2:18][C:19]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])([CH3:21])[CH3:20])[N:6]=1)(=O)C.[OH-].[Na+]>CCO.C1COCC1.[Na+].[Cl-]>[NH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:15][CH2:16][C:17]([C:32]([F:35])([F:33])[F:34])([OH:31])[CH2:18][C:19]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])([CH3:21])[CH3:20])[N:6]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(NC(C)=O)ccc12)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(N)ccc12)C(F)(F)F
Yield: 80.2 %

Procedure:
A solution of 535 mg (1.05 mmol) of 1-(2-acetylaminoquinolin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol in 18 ml of EtOH-THF (2:1) is refluxed with 12 ml of 3N sodium hydroxide solution for 90 minutes. The batch is diluted with saturated NaCl and extracted with ethyl acetate. The extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with ethyl acetate yields 380 mg of the product as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13](Cl)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[N:20]1[N:21]([C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])[N:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:20]1[N:21]([C:25]2[CH:26]=[C:27]([NH:28][C:13]3[C:14]([C:17]#[N:18])=[N:15][CH:16]=[C:11]([NH:10][C@@H:3]4[CH2:4][CH2:5][CH2:6][C:7]([F:9])([F:8])[C@@H:2]4[NH2:1])[N:12]=3)[CH:29]=[CH:30][CH:31]=2)[N:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(-n2nccn2)c1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1cccc(-n2nccn2)c1
Reaction time: 3 h
Yield: 37.7 %

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (76 mg, 0.264 mmol), 3-(2H-1,2,3-triazol-2-yl)aniline (60 mg, 0.375 mmol), K2CO3 (80 mg, 0.579 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 3 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 3-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)pyrazine-2-carbonitrile (41 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[N:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][CH2:12][C:13](=[O:17])[NH:14][C:15]=2[N:16]=1)(=[O:28])=[O:27]
Reactant: O=C1CCc2ccc(OCCCCO)nc2N1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCOc1ccc2c(n1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.6 %

Procedure:
A mixture of intermediate 11 (140 mg, 0.593 mmol), Et3N (240 mg, 2.37 mmol) and methylsulfonyl chloride (102 mg, 0.89 mmol) was dissolved in DCM and the solution was stirred for 6 h at rt. The solution was then washed with water, brine, and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo to give 4-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yloxy)butyl methanesulfonate (intermediate 12) (180 mg, 96%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH2:12])=[S:11].[C:13]([N:17]=[C:18]=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:18](=[O:19])[NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[S:11]
Reactant: CC(C)(C)N=C=O
Reactant: NC(=S)Nc1c(Cl)cccc1Cl
Solvent: Cc1ccccc1C
Product: CC(C)(C)NC(=O)NC(=S)Nc1c(Cl)cccc1Cl

Procedure:
To a mixture of 11 g (0.05 mole) of 1-(2,6-dichlorophenyl)thiourea and 10 ml of xylene is added 5 g of t-butylisocyanate (0.05 mole) and the mixture is refluxed for 2 hours. The reaction product is cooled, triturated with heptane and filtered. Recrystallization from 1:1 isopropanol/water results in 1-(2,6-dichlorophenyl)-3-(t-butylcarbamyl)thiourea.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:33])[C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=4)=[C:22]([CH3:32])[CH:21]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[OH-:36].[Na+].Cl>CC(C)=O>[C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]([N:10]3[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13][N:14]4[C:5]([C:3]([OH:36])=[O:4])=[CH:6][CH:7]=[C:8]4[CH2:9]3)=[O:33])=[CH:21][C:22]=2[CH3:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: [OH-]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1C1=CCCCC1
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
2,2,2-Trichloro-1-[10-(4-cyclohex-1-en-1-yl-3-methyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-ethanone of Step D (0.700 g, 1.33 mmol), was dissolved in acetone (8.9 mL) followed by addition of 2.5 N sodium hydroxide (1.60 mL, 3.99 mmol). The reaction was stirred at room temperature for 3 hours, and acidified with 2 N hydrochloric acid. The acidic mixture was extracted with diethyl ether and the organic phase extracted with 1 N sodium hydroxide. The combined basic extracts were acidified with 2 N hydrochloric acid, and extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was recrystallized from diethyl ether to afford 450 mg of the title compound as white crystals, 193° C. (dec.)
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[C:23]([F:31])[CH:22]=2)[C:11]2[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=2[CH:9]=1)=O)(C)(C)C.[NH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH3:38])[N:34]=1>>[CH3:38][N:35]1[CH:36]=[CH:37][C:33]([NH:32][C:6]([C:8]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[C:23]([F:31])[CH:22]=3)[C:11]3[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=3[CH:9]=2)=[O:5])=[N:34]1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(S(C)(=O)=O)c(F)c2)c2c(c1)OC(C)(CO)C2
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)c(F)c3)c3c(c2)OC(C)(CO)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 4-(3-fluoro-4-methanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (232a) and 3-amino-1-methyl-pyrazole. 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1 H) 7.80-7.99 (m, 1H) 7.26-7.32 (m, 1 H) 7.11 (dd, J=17.05, 1.39 Hz, 2 H) 6.73-6.92 (m, 3 H) 3.82 (s, 3 H) 3.75 (d, J=5.56 Hz, 1 H) 3.63 (d, J=7.58 Hz, 1 H) 3.23 (s, 3 H) 2.81 (d, J=16.17 Hz, 1 H) 2.04 (d, J=1.77 Hz, 1 H) 1.47 (s, 3 H); LCMS for C22H22FN3O6S m/z 476.00 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH2:19]([O:21][C:22](=[O:29])[C@:23]([F:28])([CH3:27])[C:24](O)=[O:25])[CH3:20]>>[CH2:19]([O:21][C:22](=[O:29])[C@:23]([F:28])([CH3:27])[C:24]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:25])[CH3:20]
Reactant: CN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Reactant: CCOC(=O)[C@@](C)(F)C(=O)O
Product: CCOC(=O)[C@@](C)(F)C(=O)N[C@@H]1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
In an analogous manner to that described in Example 1 a), the condensation of (S)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and (2S)-2-fluoro-2-methyl-malonic acid mono ethyl ester yielded the title compound as a colourless oil;
Reaction SMILES: C(OCC)(=O)C.[C:7]1([CH:13]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:14][CH2:15][NH:16][C:17]([C:19]2[CH:20]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[NH:21][C:22](=[O:32])[NH:23][C:24]=2[CH2:25][O:26][CH2:27][CH2:28][N:29]=[N+]=[N-])=[O:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[H][H].[Pd]>[C:40]1([CH:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][CH2:15][NH:16][C:17]([C:19]2[CH:20]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[NH:21][C:22](=[O:32])[NH:23][C:24]=2[CH2:25][O:26][CH2:27][CH2:28][NH2:29])=[O:18])[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCCOCC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)NC(=O)N1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCCOCC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)NC(=O)N1

Procedure:
10 ml of ethyl acetate was added to a mixture of 180 mg (0.330 mmol) of 6-(2-azidoethoxymethyl)-4-(3-chlorophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (3,3-diphenylpropyl)amide and a catalytic amount of 10% palladium/carbon, and they were stirred at room temperature in hydrogen atmosphere under normal pressure overnight. The catalyst was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by the basic silica gel chromatography (dichloromethane/methanol=100/1 to 20/1) to obtain the title compound.
Reaction SMILES: [S:1]1(=[O:8])(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CN(C=O)C>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([N:2]2[CH2:3][CH2:4][CH2:5][CH2:6][S:1]2(=[O:8])=[O:7])=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=S1(=O)CCCCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCCS2(=O)=O)cc1
Reaction time: 0.25 h

Procedure:
500 mg (3.7 mmol) [1,2]thiazinane-1,1-dioxide, dissolved in 10 ml DMF, are added to a suspension of 163 mg sodium hydride dispersion in mineral oil (60%, 4.07 mmol) in 5 ml DMF. The mixture is stirred for 15 minutes, then a solution of 522 mg (3.7 mmol) 1-fluoro-4-nitrobenzene in 10 ml DMF is added dropwise. After two hours the reaction mixture is poured onto ice water. The solid is filtered off, washed with water and dried.
Reaction SMILES: [CH:1]1([C:4](=[O:28])[C:5](=[CH:24][N:25](C)C)[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([NH:18][CH3:19])[C:9]=2[S:20]([CH3:23])(=[O:22])=[O:21])=[O:7])[CH2:3][CH2:2]1.[Cl-].O[NH3+].C([O-])(=O)C.[Na+]>C(O)C>[CH:1]1([C:4]2[O:28][N:25]=[CH:24][C:5]=2[C:6](=[O:7])[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([NH:18][CH3:19])[C:9]=2[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:3][CH2:2]1
Reactant: CNc1c(C(F)(F)F)ccc(C(=O)C(=CN(C)C)C(=O)C2CC2)c1S(C)(=O)=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCO
Product: CNc1c(C(F)(F)F)ccc(C(=O)c2cnoc2C2CC2)c1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.29 g (3.1 mmol) of 1-cyclopropyl-2-(dimethylaminomethylidene)-3-(3-methylamino-2-methylsulfonyl-4-trifluoromethylphenyl)propane-1,3-dione were introduced into 50 ml of ethanol. 0.30 g (4.3 mmol) of hydroxylammonium chloride was added, and the mixture was stirred for 30 min at RT. Thereafter, 0.33 g (4.0 mmol) of sodium acetate was added, and the contents were stirred for 16 h at RT. Thereupon, a further 0.15 g (2.2 mmol) of hydroxylammonium chloride was added, and, again, the mixture was stirred for 16 h at RT. Thereafter, a further 0.15 g (2.2 mmol) of hydroxylammonium chloride was added, and the mixture was stirred for a further 3 d at RT. The solvent was removed in vacuo, and the residue was taken up in ethyl acetate. The solution was washed with 1 N HCl, the organic phase was dried, and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel. This gave 1.00 g of product in 95% purity.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[NH:22]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:23][C:24](O)=[O:25].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:8]([O:7][C:5](=[O:6])[C@@H:4]([NH:12][S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14])[CH2:3][NH:2][C:24](=[O:25])[CH2:23][NH:22][C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)CNC(=O)OCc1ccccc1)NS(=O)(=O)c1ccccc1
Reaction time: 8 h

Procedure:
Amine 1-5 (0.42 g, 1.25 mmol), Cbz—Gly—OH (288 mg, 1.38 mmol), NMM (0.55 mL, 5.0 mmol) and BOP (829 mg, 1.88 mmol) were combined in 6 mL DMF. After stirring overnight the solvent was evaporated, the residue was taken up in EtOAc, the organic solution was washed with water (2×), 5% KHSO4, sat. NaHCO3 and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica, 60% EtOAc/hexane) provided 5-6 as a white glass.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:10][C:9]=1[N+:24]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2F)cc1N
Yield: 99.9 %

Procedure:
Prepared from [4-(2,4-difluoro-phenylethynyl)-2-nitro-phenyl]-carbamic acid tert.-butyl ester (Example F11) (750 mg, 2 mmol) by reduction with SnCl2.2H2O (2.26 g, 10 mmol) according to the general procedure G (method b). Obtained as a brown solid (688 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:33][CH2:34][CH:35]([OH:38])[CH2:36][CH2:37]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCC(O)CC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCC(O)CC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 19.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.6 g) and 5-amino-2-[4-(4-hydroxypiperidin-1-yl) piperidin-1-yl]benzonitrile (0.6 g), the title compound (0.2 g) was obtained, melting point: 213° C.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:47])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[C:31]3=[O:44])=[CH:27][CH:26]=1)([CH3:22])[CH2:14][CH2:13]2)=[O:7])(C)(C)C.Cl>O1CCOCC1>[C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:47])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([OH:39])=[O:38])[C:31]3=[O:44])=[CH:27][CH:26]=1)([CH3:22])[CH2:14][CH2:13]2)([OH:7])=[O:5]
Reactant: Cc1c(C)c2c(c(C)c1OCC(=O)OC(C)(C)C)CCC(C)(COc1ccc(CC3SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(C)c2c(c(C)c1OCC(=O)O)CCC(C)(COc1ccc(CC3SC(=O)N(CC(=O)O)C3=O)cc1)O2
Reaction time: 8 h

Procedure:
A mixture of 0.63 g of t-butyl α-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate (prepared as described in Example 48) and 6 ml of a 4N dioxane solution of hydrogen chloride was allowed to stand at room temperature overnight. At the end of this time, the reaction mixture was treated as the same manner described in Example 61, to give the title compound as a pale yellow powder, softening at 95°-100° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=1[S:44](Cl)(=[O:46])=[O:45].O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:44]([C:36]4[CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=[CH:40][C:35]=4[CH3:34])(=[O:45])=[O:46])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)n1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(Br)ccc3ncc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.24 mmol) in dichloromethane (6 ml) was added 2-methyl-5-nitrobenzene-1-sulfonyl chloride (53 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over sodium sulfate and crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound.
Reaction SMILES: O1CCCC1.[F:6][C:7]([F:26])([F:25])[CH:8]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]#[N:24])[CH:18]=1)[O:9][Si](CC)(CC)CC.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[F:26][C:7]([F:6])([F:25])[CH:8]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]#[N:24])[CH:18]=1)[OH:9]
Reactant: CC[Si](CC)(CC)OC(c1ccnc(C#N)c1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(C(O)C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
To 40 ml of tetrahydrofuran was added 12 g of 4-[2,2,2-trifluoro-1-(triethylsilyloxy)ethyl]pyridine-2-carbonitrile, and 15 ml of tetrabutylammonium fluoride (1M tetrahydrofuran solution) was added at 0° C. After the mixture was stirred at room temperature for 5 hours, water was added to the reaction solution, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 5.6 g of 4-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-2-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][C:5]([N:16]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4][N:3]=1.Cl>C1COCC1>[NH2:16][C:5]1[CH:6]=[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N=C(c2ccccc2)c2ccccc2)cnc1Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(N)cnc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl 2-chloro-5-(diphenylmethyleneamino)pyridin-3-ylcarbamate (0.280 g, 0.686 mmol) in THF (5 mL) was added hydrochloric acid, In (JT Baker) (0.031 mL, 1.030 mmol). The reaction was stirred at rt in closed system for 20 min. The reaction mixture was partitioned between EtOAc/sat. NaHCO3. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layer were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (24 g, 3% MeOH in DCM) to afford the desired product as a white foam-like solid (135.0 mg). MS (ESI pos. ion) m/z: 244.1. 1H NMR (300 MHz, CDCl3) δ ppm 1.54 (s, 9H) 3.73 (br. s., 2H) 6.93 (br. s., 1H) 7.52 (d, J=2.63 Hz, 1H) 7.94 (d, J=2.63 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](/[C:8](=[C:11](/N(C)C)\[CH3:12])/[C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.Cl.C[OH:20]>>[F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](/[C:8](=[C:11](/[OH:20])\[CH3:12])/[C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1
Reactant: C/C(=C(/C#N)C(=O)c1ccc(F)cc1)N(C)C
Reactant: CO
Agent: Cl
Product: C/C(O)=C(/C#N)C(=O)c1ccc(F)cc1

Procedure:
A solution of 1.35 g. (0.006 m) of 2-(p-fluorobenzoyl)-3-dimethylaminocrotononitrile in a mixture of 15 ml. methanol and 8 ml. of 1 N HCl was heated on the steam bath in an open beaker for 45 minutes. Upon cooling in an ice bath, a solid formed, was collected, and then recrystallized from cyclohexane-petroleum ether with charcoal treatment, giving 0.7 g. (64%) of light pinkish crystals, m.p. 65°-67° C.
Reaction SMILES: [CH:1]1[N:2]=[C:3]([NH2:22])[C:4]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:14][C@@H:13]4[CH2:15][O:16][P:17]([OH:20])([O:19][C@H:12]4[C@H:11]3[OH:21])=[O:18])[C:5]=2[N:6]=1.[CH2:23]([N:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26]>O.C(O)C>[CH2:32]([NH+:27]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:33][CH2:34][CH3:35].[CH:1]1[N:2]=[C:3]([NH2:22])[C:4]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:14][C@@H:13]4[CH2:15][O:16][P:17]([OH:20])([O:19][C@H:12]4[C@H:11]3[OH:21])=[O:18])[C:5]=2[N:6]=1
Reactant: CCCCN(CCCC)CCCC
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@@H]2COP(=O)(O)O[C@H]2[C@H]1O
Solvent: O
Solvent: CCO
Product: CCCC[NH+](CCCC)CCCC

Procedure:
One gram of cAMP was dissolved in a mixture of 5 ml of water, 5 ml of ethanol and 1.5 ml of tri-n-butylamine. The solution was concentrated under reduced pressure at 30° to 40° C., and dried under reduced pressure using phosphorus pentoxide to afford tri-n-butylammonium salt of cAMP. The resulting cAMP salt was dissolved in 50 ml of dehydrated dimethyl formamide, and 5 ml of tri-n-butylamine and 2 ml of ethyl iodide were added. The reaction was performed at 80° C. for 3 hours.