Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[I-].[CH3:4][N+:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[CH:15]=1>O.CO>[CH3:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[CH:15]=1
Reactant: C[n+]1ccccc1-c1cc2ccccc2o1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCCCC1c1cc2ccccc2o1
Temperature: 25 °C

Procedure:
6.15 g of sodium borohydride dissolved in 50 ml of water is added dropwise in the course of 30 minutes, with stirring and ice-water cooling, to a solution of 18.2 g of 1-methyl-2-(2-benzofuranyl)-pyridinium-iodide in 150 ml of methanol. Stirring is maintained for 1 hour at room temperature, and the light-yellow solution then poured into 1000 ml of water. The precipitating oil is extracted with chloroform; the chloroform extracts are dried over anhydrous sodium sulphate, and the solvent distilled off in vacuo. The oily residue is taken up in a little methylene chloride, and chromatographed through 150 g of aluminum oxide (2% water). The methylene chloride eluates yield after concentration by evaporation 13.2 g of 1-methyl-2-(2-benzofuranyl)-1,4,5,6-tetrahydropyridine in the form of light-yellow oil. This is dissoled in 130 ml of ethyl acetate and, after the addition of 1 g of palladium-charcoal catalyst (10%), hydrogenated at room temperature. After absorption of 935 ml of hydrogen in the course of 19 hours, hydrogenation ceases. The catalyst is filtered off, the filtrate concentrated in vacuo, and the residue distilled in high vacuum to obtain 1-methyl-2-(2-benzofuranyl)-piperidine as colourless oil, B.P. 93°-97° (0.02 Torr). The hydrochloride is obtained as colourless crystals, M.P. 188°-189°, by dissolving the distilled base in the fivefold amount of acetone, and neutralising the solution with a 2 N solution of hydrogen chloride in ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[F:25])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.BrC1[S:35][C:36]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:37]([CH3:39])[N:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:35][C:36]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:37]([CH3:39])[N:38]=3)[CH2:14][C@H:13]2[F:25])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)nc1Cl
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](F)C2)nc1C
Yield: 81.9 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl trans(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-fluoropiperidine-1-carboxylate obtained in Example (197b) (37.0 mg, 0.099 mmol), 4 N hydrochloric acid/1,4-dioxane (1 mL), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (29.6 mg, 0.118 mmol) and sodium carbonate (105 mg, 0.987 mmol), to obtain 36 mg of the title compound (82%) as a colorless solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[CH:7][N:6]=1)=[O:4].[OH-].[Li+].Cl>O1CCCC1.O>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[C:8]([O:18][CH2:19][CH:20]3[CH2:21][CH2:22]3)=[CH:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[N:10]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ncc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ncc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a solution of 2.655 g 4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acid methyl ester in 27 mL tetrahydrofuran was added 11 mL of a 1M solution of lithium hydroxide in water and the mixture was stirred at room temperature for 1 h. The reaction mixture was acidified by addition of 1M hydrochloric acid. The precipitate was collected by filtration washed with water and dried to constant weight under high vacuum to yield 2.473 g of the title compound as white solid, MS 305.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:18])[CH:14]=3)[C:9]2=[O:19])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24]>CN(C=O)C>[Cl:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:19])[N:8]([C:4]1[CH:3]=[C:2]([NH:1][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH:7]=[N:6][CH:5]=1)[CH2:17][CH2:16]2
Reactant: CC(C)C(=O)Cl
Reactant: Nc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 23.6 %

Procedure:
To a solution of 2-(5-amino-pyridin-3-yl)-6-chloro-3,4-dihydro-2H-isoquinolin-1-one (27.3 mg, 0.1 mmol, example 15) in dry DMF (2 mL) was added at 0° C. NaH (3.0 mg, 0.12 mmol). The reaction mixture was allowed to stir at room temperature for 5 min before isobutyryl chloride (12.7 mg, 0.12 mmol) was added into the reaction mixture. The reaction mixture was stirred for additional 1 hour and then poured into ice-water and extracted with EtOAc (2×5 mL). The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give title compound (8.1 mg, 24%) as a white solid. MS: 344.1 (M+H+).
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:14].O.C(=O)(O)[O-].[Na+]>C(O)C.[Fe]>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[O:14])=[C:4]([Cl:3])[CH:9]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: O
Product: Nc1ccc(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
Iron powder (12 g), 42 mL of ethanol, 17 mL of distilled water, and 0.09 mL of 35% hydrochloric acid were mixed together, and the mixture was heated to reflux. Subsequently, (2-chloro-4-nitrophenyl)-(4′-chlorophenyl)methanone (8.9 g) dissolved in 12.8 mL of ethanol was added dropwise to the mixed solution, and the mixture was heated under reflux for one hr. This mixed solution was then cooled to room temperature, sodium bicarbonate water was then added thereto, and the mixture was filtered. The filtrate was concentrated under the reduced pressure, and ethyl acetate and brine were added to the residue, followed by separation. The ethyl acetate layer was washed with brine and was then concentrated under the reduced pressure to give 7.56 g of (4-amino-2-chlorophenyl)-(4′-chlorophenyl)methanone (yield 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.FC1C=C([C:36]2([OH:40])[CH2:39][CH2:38][CH2:37]2)C=C(F)C=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:4]1[CH:5]=[C:6]([C:36]2([OH:40])[CH2:39][CH2:38][CH2:37]2)[CH:7]=[C:2]([F:1])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Reactant: CC1(C)OB(c2c(F)cc(C3(O)CCC3)cc2F)OC1(C)C
Product: O=C(O)c1csc(-c2c(F)cc(C3(O)CCC3)cc2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with 1-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanol (Intermediate 108) gave the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:25](O)[CH2:26][OH:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:27]1[C:2]2([CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:12][CH:13]=3)[CH2:4][CH2:3]2)[O:1][CH2:25][CH2:26]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)cc2)C(=O)O1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)cc2)C(=O)O1
Yield: 69 %

Procedure:
The compound was prepared by reacting (S)-N-{3-[4-(4-oxo-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.5 mmol), ethylene glycol (0.5 mmol), p-toluene sulfonic acid (0.3 mmol) in toluene and by purifying on silica gel column chromatography to provide title compound in 69% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([NH2:22])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[F:13][C:14]1[CH:15]=[C:16]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: COc1ccc(N)cc1F
Product: COc1ccc(Nc2nc(C)nc3ccccc23)cc1F

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (150 mg, 0.84 mmol), 3-fluoro-4-methoxy-phenylamine (118.5 mg, 0.84 mmol) by a procedure similar to example 78. 1H NMR (CDCl3): 7.89-7.75 (m, 4H), 7.53-7.48 (m, 1H)), 7.38-7.34 (m, 2H), 7.0 (t, J=8.7 Hz, 1H), 3.92 (s, 3H), 2.71 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]3[C:15](N)=[N:14][NH:13][C:9]3=[N:10]2)=[CH:5][CH:4]=1.[ClH:17]>>[Cl:17][C:15]1[C:8]2[C:9](=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[NH:13][N:14]=1
Reactant: Cl
Reactant: COc1ccc2cc3c(N)n[nH]c3nc2c1
Product: COc1ccc2cc3c(Cl)n[nH]c3nc2c1
Yield: 25 %

Procedure:
3-Chloro-7-methoxy-1H-pyrazolo[3,4-b]quinoline was prepared from 7-methoxy-1H-pyrazolo[3,4-b]quinolin-3-amine (Example 3d) by diazotization in hydrochloric acid. The product was recrystallized from ethanol and then from acetic acid and obtained in about 25% yield as a brown solid, m.p. 296°-297° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:16]([O:17]C)[C:15]=1[Cl:22].[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClCCCl>[Cl:22][C:15]1[C:16]([OH:17])=[C:19]([CH:20]=[CH:21][C:14]=1[O:13][CH3:12])[C:4]([C:3]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=1[F:1])=[O:5]
Reactant: COc1cccc(OC)c1Cl
Reactant: O=C(Cl)c1cc(F)ccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2cc(F)ccc2F)c(O)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 21 g of 2,5-difluorobenzoyl chloride and 20.4 g of 2-chlororesorcinol dimethyl ether in 250 ml of 1,2-dichloroethane at 5°-10° C. 15.7 g of AlCl3 is added in portions. The mixture is allowed to warm to room temperature and is then refluxed for 30 minutes. The mixture is poured into concentrated HCl and ice and stirred for approximately one hour. The product is extracted with ethyl acetate, dried over Na2SO4 and evaporated to give 3-chloro-2',5'-difluoro-2-hydroxy-4-methoxybenzophenone, mp 178°-180° C.
Reaction SMILES: [F:1][C:2]1([F:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]([OH:14])=O)[C:3]1=[O:15].[Br:17][C:18]1[C:19]([C:24]2[NH:28][CH:27]=[N:26][N:25]=2)=[C:20]([NH2:23])[S:21][CH:22]=1>>[Br:17][C:18]1[C:19]([C:24]2[NH:28][CH:27]=[N:26][N:25]=2)=[C:20]([NH:23][C:12](=[O:14])[CH2:11][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([F:1])([F:16])[C:3]2=[O:15])[S:21][CH:22]=1
Reactant: O=C(O)CN1C(=O)C(F)(F)c2ccccc21
Reactant: Nc1scc(Br)c1-c1nnc[nH]1
Product: O=C(CN1C(=O)C(F)(F)c2ccccc21)Nc1scc(Br)c1-c1nnc[nH]1
Yield: 14.7 %

Procedure:
The title compound was prepared from 2-(3,3-difluoro-2-oxoindolin-1-yl)acetic acid (50 mg, 0.22 mmol), 4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine (45 mg, 0.18 mmol) using protocol A. HPLC purification gave N-(4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(3,3-difluoro-2-oxoindolin-1-yl)acetamide (12 mg) as a white solid (m/z 454.0, retention of 5.696 min in [7]). 1H-NMR (300 MHz, CDCl3) δ 13.1 (s, 1H), 7.82 (s, 1H), 7.70 (dd, J=7.5, 1.5 Hz, 1H), 7.50 (td, J=7.9, 1.2 Hz, 1H), 6.99 (s, 1H), 6.92 (d, J=7.9 Hz, 1H), 4.71 (s, 2H).
Reaction SMILES: [NH2:1][C:2]([C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([F:18])[CH:11]=1)([C:4]1[N:5]([CH3:9])[CH:6]=[N:7][CH:8]=1)[CH3:3].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][C:29](O)=[O:30])[CH:24]=[CH:25][CH:26]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([C:2]([NH:1][C:29](=[O:30])[CH2:28][CH2:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=2)([C:4]2[N:5]([CH3:9])[CH:6]=[N:7][CH:8]=2)[CH3:3])=[CH:11][C:12]=1[F:18])#[N:15]
Reactant: COc1cccc(CCC(=O)O)c1
Reactant: Cn1cncc1C(C)(N)c1ccc(C#N)c(F)c1
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cccc(CCC(=O)NC(C)(c2ccc(C#N)c(F)c2)c2cncn2C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(+)-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-fluoro-benzonitrile (0.074 g, 0.25 mmol), 3-(3-methoxyphenyl)propionic acid (0.054 g, 0.3 mmol) (K. J. Hwang et al., J. Org. Chem. (1992), 57[4]1262), EDC (0.275 g, 1.2 mmol), HOAT (0.055 g, 0.40 mmol), and triethylamine (0.167 mL, 1.2 mmol) were combined in DMF (3 mL) and stirred under Ar at ambient temperature for 20 hr. The reaction mixture was partitioned between EtOAc (120 mL) and H2O (100 mL), the organic layer separated, washed with dilute NaHCO3 solution, H2O, brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13]([C:15]1[C:20]([O:21][CH2:22][CH3:23])=[C:19]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:18]=[C:17]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[N:16]=1)=[O:14])[CH3:11]>C1(C)C=CC=CC=1>[CH2:10]([O:12][C:13]([C:15]1[C:20]([O:21][CH2:22][CH3:23])=[C:19]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:18]=[C:17]([C:30]2[CH:31]=[CH:32][C:33]([NH:36][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])=[CH:34][CH:35]=2)[N:16]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1nc(-c2ccc(N)cc2)nc(N2CCOCC2)c1OCC
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)nc(N2CCOCC2)c1OCC
Yield: 83 %

Procedure:
Phenyl isocyanate (0.22 ml, 1.5 eq.) was added to a stirred solution of 2-(4-Amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic acid ethyl ester (500 mg, 1 eq.) in toluene (25 ml) and the mixture was reacted for 4 h at 80° C. The reaction mixture was cooled, the solvent was removed in vacuo, and the residue was washed with EA and filtered to give a product (550 mg, 83%).
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[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29].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]>[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]([NH:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:26]([C:21]3[N:20]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:27]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Cl
Reactant: Nc1cccc(-c2ncccn2)c1
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(-c2ncccn2)c1
Reaction time: 3 h
Yield: 52 %

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (76 mg, 0.264 mmol), 3-(pyrimidin-2-yl)aniline (64 mg, 0.375 mmol), K2CO3 (90 mg, 0.652 mmol), BINAP (30 mg, 0.048 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 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(3-(pyrimidin-2-yl)phenylamino)pyrazine-2-carbonitrile (58 mg). The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(3-(pyrimidin-2-yl)phenylamino)pyrazine-2-carbonitrile (58 mg, 0.131 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 90 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (43 mg). MS 441.2 (M+H); UV 201.1, 249.3, 301.5 nm; t 0.462 min.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N+]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)([O-])=O.C(N(C(C)C)CC)(C)C.[BH4-].[Na+]>CO.C1(C)C=CC=CC=1>[CH2:17]([NH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)[C:16]1[CH:19]=[CH:20][CH:21]=[CH:14][CH:15]=1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: c1ccc(CNc2nc3ccccc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 15.8 %

Procedure:
A 100 mL flask was charged with 1.0 g 2-aminobenzimidazole (7.51 mmol, 1.0 equiv), 1.13 g 3-nitrobenzaldehyde (7.51 mmol, 1.0 equiv), and 25 mL toluene. The flask was equipped with a Dean-Stark trap and reflux condenser and placed in a 110° C. bath. The solution was refluxed for 15.5 h, followed by the addition of 3 mL MeOH and 3 mL diisopropylethylamine. After refluxing an additional 29 h, the flask was removed, and the volatiles were removed under reduced pressure at 70° C. The remaining material was diluted with 50 mL MeOH, and cooled to 0° C. followed by the addition of 426 mg (11.27 mmol, 1.5 equiv) NaBH4. After stirring for 3 h, the solution was concentrated under reduced pressure, and the residue was applied directly to a SiO2 column (preflushed with 10% MeOH/CH2Cl2). The column was eluted with 10% MeOH/CH2Cl2 to give the product as an orange solid 320 mg (1.19 mmol). 1H NMR (DMSO-d6, 400 MHz) δ 11.0 (broad s, 1 H), 8.25 (s, 1 H), 8.11 (d, J=8.2 Hz, 1 H), 7.85 (d, J=7.5 Hz, 1 H), 7.62 (t, J=8.0 Hz, 1 H), 7.34 (m, 1 H), 7.13 (t, J=3.7 Hz, 2 H), 6.86 (s, 2 H), 4.64 (d, J=5.8 Hz, 2 H); MS: ESI(+) m/z 269.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:10])[N:4]=1.[N:11]1([CH2:17][C:18]#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CO>[CH3:1][O:2][C:3]1[C:7]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]#[C:18][CH2:17][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[N:6][S:5](=[O:10])[N:4]=1
Reactant: NCCCCC#CCN1CCCCC1
Reactant: COC1=NS(=O)N=C1OC
Solvent: CO
Product: COC1=NS(=O)N=C1NCCCCC#CCN1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (2.0 g) in methanol (100 ml) was cooled to 0° C. 7-(Piperidino)hept-5-ynylamine (2.5 g) in methanol (50 ml) was added dropwise with stirring over 30 minutes maintaining the reaction temperature at 0° C. The reaction mixture was stirred at 0° C. for a further 2 hours to give a solution of 3-methoxy-4-[7-(piperidino)hept-5-ynylamino]-1,2,5-thiadiazole-1-oxide. Ammonia gas was bubbled through this solution for 30 minutes and the mixture allowed to stand for 16 hours. The reaction mixture was evaporated under reduced pressure to give an oil which was taken up in ethyl acetate, triturated and cooled to give the title compound (3.0 g), m.p. 134°-6° C. (recrystallisation from isopropanol-ethyl acetate).
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:14](=[O:34])[N:13]1[CH:9]([CH2:10][CH:11]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:12]1)[C:8](=[O:43])[NH:7]2)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[C:39]([Si:36]([CH3:38])([CH3:37])[O:35][CH:11]1[CH2:10][CH:9]2[N:13]([C:14](=[O:34])[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH:23]3[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]2=[O:43])[CH2:24]3)[CH2:12]1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CCOC(=O)C12CC1C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)O)NC(=O)C3CC(O[Si](C)(C)C(C)(C)C)CN3C2=O)cc1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
Compound 126 (450 mg, 0.734 mmol) was dissolved in THF/MeOH/H2O (2:1:1). LiOH, 1M (7.4 ml, 7.4 mmol) was added and the reaction mixture was allowed to stir at RT over night. Acidification (5% citric acid) followed by extraction with chloroform gave the title compound (321 mg, 75%). M+H=586.
Reaction SMILES: CO[C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([N:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([CH3:20])[CH3:19])[C:12]2=[O:35])[CH:5]=1.[CH:37]1([NH2:40])[CH2:39][CH2:38]1.C([Mg]Cl)(C)C>C1COCC1.[Cl-].[NH4+]>[CH2:28]([O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]([NH:17][C:13]1[C:12](=[O:35])[N:11]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[Cl:10])[C:3]([NH:40][CH:37]2[CH2:39][CH2:38]2)=[O:36])[CH:16]=[CH:15][N:14]=1)([CH3:20])[CH3:19])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc(Cl)c(-n2ccnc(NC(C)(C)c3ccccc3OCc3ccccc3)c2=O)c1
Reactant: NC1CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2Cl)c1=O)c1ccccc1OCc1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of methyl-3-[3-({1-[2-(benzyloxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-4-chlorobenzoate (Example 330f, 2.23 g) dissolved in THF (30 mL) was treated with cyclopropylamine (2.261 mL) and 2.0M Isopropylmagnesium chloride (11.06 mL) under nitrogen. The resulting solution was stirred at 20° C. for 2 h. The reaction mixture was diluted with aqueous ammonium chloride (150 mL), and extracted with dichloromethane (250 mL). The organic was dried (MgSO4), filtered and evaporated to afford the subtitle compound (2.40 g).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([C:8]1[CH:9]=[C:10]([NH:14][C:15]([C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:20]=[CH:21]C=2O)=[O:16])[CH:11]=[CH:12][CH:13]=1)#[CH:7].Cl>O1CCCC1.N1C=CC=CC=1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][C:5]2[O:4][C:2](=[O:3])[N:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([C:6]#[CH:7])[CH:9]=3)[C:15](=[O:16])[C:17]=2[CH:18]=1
Reactant: COC(=O)Cl
Reactant: C#Cc1cccc(NC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C#Cc1cccc(-n2c(=O)oc3ccc(-c4ccc(F)cc4F)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 14 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 8 (1.39 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 20.