Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.Cl[C:23]1[C:28]([C:29]#[N:30])=[C:27]([CH3:31])[N:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C.CCOC(C)=O>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:23]3[C:28]([C:29]#[N:30])=[C:27]([CH3:31])[N:26]=[CH:25][CH:24]=3)[CH3:13])[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=2[CH:21]=1
Reactant: Cc1nccc(Cl)c1C#N
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1nccc(N[C@@H](C)c2nc3ccc(F)cc3n2-c2ccccc2)c1C#N
Reaction time: 86 h
Yield: 24.6 %

Procedure:
(S)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (0.083 g, 0.25 mmol), 4-chloro-2-methylnicotinonitrile (0.035 g, 0.23 mmol) and diisopropylethylamine (0.160 mL, 0.92 mmol) in isopropanol (1 mL) was heated to 80° C. in a sealed tube under argon for 2 h then at 75° C. for 86 h. The reaction mixture was cooled, diluted with EtOAc (20 mL) and washed with water (10 mL). The organic extracts were dried (Na2SO4), evaporated to dryness and purified by column chromatography (Si—PCC, gradient 0-8% (9:1 MeOH/0.880 NH3) in DCM). Product containing fractions were evaporated and freeze dried to give 340 as a pale brown solid, (21 mg, 24%). LCMS (Method C): RT 3.11 min [M+H]+ 372.08. 1H NMR δ (ppm DMSO-d6): 7.98 (1H, d, J=6.15 Hz), 7.77 (1H, dd, J=8.82, 4.86 Hz), 7.52-7.50 (5H, m), 7.12-7.11 (2H, m), 6.85 (1H, dd, J=8.91, 2.51 Hz), 6.40 (1H, d, J=6.24 Hz), 5.11 (1H, dq, J=7.04 Hz), 2.41 (3H, s), 1.56 (3H, d, J=6.64 Hz)
Reaction SMILES: C[C:2]([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)([CH3:6])[C:3]([O-])=O.[Li+].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:21])C=CC=CC=1.C([N:33]([CH2:36]C)CC)C>C(O)(C)(C)C>[N:11]1[CH:12]=[C:7]([C:2]([N:33]=[C:36]=[O:21])([CH3:3])[CH3:6])[CH:8]=[N:9][CH:10]=1
Reactant: CC(C)(C(=O)[O-])c1cncnc1
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Li+]
Solvent: CC(C)(C)O
Product: CC(C)(N=C=O)c1cncnc1

Procedure:
A mixture of lithium 2-methyl-2-(5-pyrimidinyl)propionate (4.11 g), diphenylphosphoryl azide (13.2 g), triethylamine (4.86 g) and anhydrous tert-butyl alcohol (100 mL) was heated to reflux for 6 h, then allowed to cool and concentrated in vacuo. The residue was partitioned between chloroform (250 mL) and water (100 mL), and the chloroform was extracted, dried (MgSO4) and evaporated under reduced pressure. Chromatography on silica gel, eluting with chloroform; 5% methanol gave a partially purified sample of 2-(5-pyrimidinyl)-2-propylisocyanate as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([O:9][CH2:10][CH:11]=O)[CH2:6][CH:7]=[CH2:8])[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].Cl.[NH2:19][OH:20]>C(O)C.O>[CH:1]1([CH2:4][CH:5]([O:9][CH2:10]/[CH:11]=[N:19]/[OH:20])[CH2:6][CH:7]=[CH2:8])[CH2:3][CH2:2]1
Reactant: C=CCC(CC1CC1)OCC=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCC(CC1CC1)OC/C=N/O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
[(1-Cyclopropylpent-4-en-2-yl)oxy]acetaldehyde (C67) (17 g from the previous step, ≦83 mmol) was dissolved in a 2:1 mixture of ethanol and water (450 mL). Sodium acetate (41 g, 500 mmol) was added; after the reaction mixture had been stirred for 15 minutes, hydroxylamine hydrochloride (98%, 21 g, 300 mmol) was added. The reaction mixture was heated to 60° C. for 24 hours. The reaction mixture was concentrated under reduced pressure to remove ethanol and extracted with dichloromethane (3×140 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 22° C. Silica gel chromatography (Gradient: 0% to 20% ethyl acetate in petroleum ether) provided the product as a colorless oil. By 1H NMR analysis, this material consisted of a roughly 1:1 mixture of E and Z oxime isomers. Yield: 10 g, 55 mmol, 49.6% over two steps.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[C:12]1([C:18]2[C:19]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[C:20]3[CH:26]=[N:25][NH:24][C:21]3=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:33]([O:37][C:38]([N:40]1[C:44]([CH3:46])([CH3:45])[CH2:43][CH2:42][C@H:41]1[C@H:47]([C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=1)[C:48](O)=[O:49])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:57][C:54]1[CH:53]=[CH:52][C:51]([C@@H:47]([C@H:41]2[N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[C:44]([CH3:46])([CH3:45])[CH2:43][CH2:42]2)[C:48](=[O:49])[N:30]2[CH2:29][CH2:28][N:27]([C:19]3[C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:23][N:22]=[C:21]4[NH:24][N:25]=[CH:26][C:20]=34)[CH2:32][CH2:31]2)=[CH:56][CH:55]=1
Reactant: c1ccc(-c2cnc3[nH]ncc3c2N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Cl)cc2)CCC1(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)N2CCN(c3c(-c4ccccc4)cnc4[nH]ncc34)CC2)c2ccc(Cl)cc2)CCC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
DIEA (0.0475 mL, 0.273 mmol) was added to a solution of 5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.030 g, 0.0681 mmol, See Example 1), (S)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (0.0251 g, 0.0681 mmol, see Example D) and TBTU (0.0263 g, 0.0818 mmol) in DCM (1 mL) and stirred at room temperature for 16 hours. The mixture was directly loaded onto a silica column and purified by chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 5-((S)-1-(4-chlorophenyl)-2-oxo-2-(4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)ethyl)-2,2-dimethylpyrrolidine-1-carboxylate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour and then concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-2-((S)-5,5-dimethylpyrrolidin-2-yl)-1-(4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)ethanone (0.019, 46%). MS APCI (+) m/z 529.3 detected.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:16][N:17]([CH3:31])[C:18]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C(O)(=O)C>ClCCCl>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:4]2[CH2:3][CH2:2][N:1]([CH:21]3[CH2:20][CH2:19][C:18]([N:17]([CH3:31])[CH3:16])([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][CH2:22]3)[CH2:6][CH:5]=2)=[CH:8]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(N2CC=C(c3c[nH]c4ccccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (182 mg, 1 mmole) and 4-dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmole) were dissolved in dry 1,2-dichloroethane (10 ml). Glacial acetic acid (1 mmole) and sodium triacetoxy boron hydride (300 mg, 1.4 mmole) were added to this mixture. The reaction mixture was then stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (4×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The product was a mixture of two diastereoisomeric compounds, which could not be separated by chromatography. The diastereoisomer mixture was obtained as a colourless solid in a yield of 320 mg (80%).
Reaction SMILES: C([O:5][C:6](=[O:17])[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[CH2:8][NH2:9])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:26]>>[ClH:26].[NH2:9][CH2:8][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:6]([OH:17])=[O:5]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)C(CN)c1ccccc1F
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCC(C(=O)O)c1ccccc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-amino-2-(2-fluoro-phenyl)-propionic acid tert-butyl ester (1.4 g) and TFA (10 mL) in DCM (10 mL) was stirred at rt for 1.5 h, which was then concentrated, co-evaporated with aqueous HCl solution (50 mL, 2 M) and acetonitrile respectively. Ether was added to the resulting mixture; solids were collected via filtration and air dried to give HCl salt of 3-amino-2-(2-fluoro-phenyl)-propionic acid (1.25 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([CH2:21][OH:22])[CH:20]=1)[O:6][CH2:7][CH2:8][N:9]([CH3:17])[C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14].[CH3:23][Si](C=[N+]=[N-])(C)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH3:23][O:14][C:13](=[O:15])[CH2:12][CH2:11][C:10]([N:9]([CH2:8][CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=1)[CH3:17])=[O:16]
Reactant: CN(CCOc1cc(CO)cc(CO)c1)C(=O)CCC(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCC(=O)N(C)CCOc1cc(CO)cc(CO)c1
Reaction time: 0.67 h

Procedure:
To a cooled (0° C.) solution of N-[2-(3,5-Bis-hydroxymethyl-phenoxy)-ethyl]-N-methyl-succinamic acid (225 mg) in methanol (1 mL), was added (trimethylsilyl)diazomethane 2M in hexanes (840 μL) until persistence of the yellow colour. After 40 min, ethyl acetate (5 mL) and acetic acid (50 μL) were added, then, one minute later, a saturated aqueous solution of sodium hydrogen carbonate until pH=7. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to a residue. The residue was purified by silica gel chromatography (Merck SuperVarioFlash 25 g column, Si60 15-40 μm), using gradient elution with a mixture of DCM (A)/MeOH (B), (gradient: 98% A: 2% B down to 90% A: 10% B) to give N-[2-(3,5-Bis-hydroxymethyl-phenoxy)-ethyl]-N-methyl-succinamic acid methyl ester (103 mg). LC/MS (Method A3): ES: m/z 348 (M+Na)+; m/z 326 (M+H)+ m/z 308 (M−H2O+H)+; RT=0.43 min
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:38])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:32][C:33]3[NH:34][CH:35]=[CH:36][N:37]=3)[CH2:25][C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>N1C=CC=CC=1>[CH3:39][N:40]([CH3:44])[C:41]([N:37]1[CH:36]=[CH:35][N:34]=[C:33]1[CH2:32][N:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([C:16](=[O:38])[NH:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[CH:14][CH:13]=2)=[CH:22][CH:21]=1)[CH2:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1)=[O:42]
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2)cc1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3nccn3C)Cc3nccn3C(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42 %

Procedure:
The compound (95.0 mg) obtained in Example 49-1 was dissolved in pyridine (5.0 ml) and added with N,N-dimethylcarbamoyl chloride (20.0 mg). After the solution had been stirred at room temperature for 15 hours, pyridine was distilled off and the residue was then added with a saturated aqueous sodium bicarbonate solution and extracted with chloroform. The extract was concentrated and purified through column chromatography (chloroform/methanol), thereby obtaining the subject compound (45.4 mg) as a white solid.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:22]=[CH:21][C:20]([NH:23][CH3:24])=[CH:19][C:11]=1[C:12]([CH2:14][CH2:15][C:16](O)=[O:17])=O)([CH3:4])([CH3:3])[CH3:2].O.[NH2:27][NH2:28]>>[C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:22]=[CH:21][C:20]([NH:23][CH3:24])=[CH:19][C:11]=1[C:12]1[CH2:14][CH2:15][C:16](=[O:17])[NH:27][N:28]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CNc1ccc(OCC(O)CNC(C)(C)C)c(C(=O)CCC(=O)O)c1
Solvent: O
Product: CNc1ccc(OCC(O)CNC(C)(C)C)c(C2=NNC(=O)CC2)c1

Procedure:
By subjecting 3-[2-(3-t-butylamino-2-hydroxypropoxy)-5-(methylamino)benzoyl]propionic acid to cyclisation with hydrazine hydrate by a method similar to that described in Example 19(ix), the title compound may be prepared.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=[O:12])[CH:4]=[C:3]1C(O)=O.N1C2C(=CC=CC=2)C=CC=1>[Cu]=O.Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=[O:12])[CH:4]=[CH:3]1
Reactant: Cn1c(C(=O)O)cc2cccc(C(=O)O)c21
Agent: O=[Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: Cn1ccc2cccc(C(=O)O)c21
Temperature: 180 °C
Yield: 49.5 %

Procedure:
A mixture of 4.60 g (21.0 mmol) of 1-methyl-indole-2,7-dicarboxylic acid, 0.5 g of copper (II) oxide and 50 ml of quinoline was stirred for an hour with heating at 180° C. After cooling, the reaction mixture was poured onto 200 ml of 2N hydrochloric acid. The mixture was extracted three times with ethyl acetate and the combined extracts were washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was isolated and purified by silica gel column chromatography to give 1.82 g (49.0%) of 1-methyl-7-indolecarboxylic acid.
Reaction SMILES: C[O:2][C:3](=[O:44])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[CH:19]=[C:18]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:17]=2)=[CH:8][C:7]=1[CH3:43].[Li+].[OH-].O.Cl>C1COCC1.CO>[CH3:43][C:7]1[CH:8]=[C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[CH:19]=[C:18]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:17]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:44])=[O:2]
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccc(C(F)(F)F)cc3)c2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccc(C(F)(F)F)cc3)c2)ccc1OCC(=O)O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of (2-methyl-4-{3-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(4-trifluoromethylphenylethynyl)-phenyl]-prop-2-ynyloxy}-phenoxy)-acetic acid methyl ester (0.26 g, 0.51 mmol) in THF (5.3 ml) and methanol (1 ml) was added a ice-cold solution of LiOH (1 M, 5.3 ml). The reaction mixture was stirred at 0° C. for 45 min., after which water (10 ml) and aqueous HCl (1M, 7.4 ml) were added. The mixture was extracted with ethyl acetate (2×80 ml), and the combined organic phases were dried and evaporated to give the title compound in 272 mg (94%) yield.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:25]1([NH:31][C:32](=[O:49])[CH2:33][C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)[O:41]3)=[CH:36][CH:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](C[N:57]3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1[O:79][C:80]([C:82]1[CH:87]=[C:86]([O:88]C)C(OC)=C(OC)C=1)=[O:81]>C(#N)C>[C:80]([OH:79])(=[O:81])/[CH:82]=[CH:87]\[C:86]([OH:88])=[O:41].[C:80]([OH:79])(=[O:81])/[CH:82]=[CH:87]\[C:86]([OH:88])=[O:41].[C:80]([OH:79])(=[O:81])/[CH:82]=[CH:87]\[C:86]([OH:88])=[O:41].[C:25]1([NH:31][C:32](=[O:49])[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:10]3[C:3]4[C:2]([NH2:57])=[N:7][CH:6]=[N:5][C:4]=4[N:8]([C@H:12]4[CH2:17][CH2:16][C@H:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[CH:9]=3)=[CH:36][CH:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC1(C)OB(c2ccc(CC(=O)Nc3ccccc3)cc2)OC1(C)C
Reactant: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Reactant: CN1CCN([C@H]2CC[C@H](n3cc(I)c4c(Cl)ncnc43)CC2)CC1
Solvent: CC#N
Product: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(CC(=O)Nc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Product: O=C(O)/C=C\C(=O)O

Procedure:
trans-N-phenyl-2-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)acetamide trismaleate was prepared from trans-4-chloro-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 2.18 mmol) and N1-phenyl -2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide in a similar method to that described for the cis-isomer: 1H NMR (DMSO-d6, 400 MHz) 10.18(s, 1H), 8.18(s, 1H), 7.61(d, 2H), 7.51(m, 5H), 7.31(t, 2H), 7.04(t, 1H), 6.3(bs, 2H), 6.11(s, 6H), 4.58(m, 1H), 3.69(s, 2H), 2.6-3.6(bm, 9H), 2.68(s, 3H), 1.91-2.04(m, 6H), 1.51-1.59(m, 2H);); RP-HPLC (Hypersil HS C18, 5 m, 100 A, 250×4.6 mm; 25%-100% acetonitrile over 10 min, 1 mL/min) tr 6.07 min.; MS:MH+ 524.3.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].Cl[CH2:12]Cl.[CH:14]([NH2:16])=O>>[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:14]=[N:16][CH:12]=[N:10]1
Reactant: NNc1ccccc1Br
Reactant: ClCCl
Reactant: NC=O
Agent: Cl
Product: Brc1ccccc1-n1cncn1
Temperature: 140 °C

Procedure:
A suspension of 2-bromophenylhydrazine hydrochloride (5.0 g, 22 mmol) in formamide (10 ml) was heated at 140° C. for 16 h. The reaction mixture was cooled to ambient temperature, diluted into dichloromethane (50 ml) and washed with water (3×20 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. Purification by chromatography on silica gel eluting with dichloromethane gave 1-(2-bromophenyl)-1H-[1,2,4]triazole (4.80 g) as a tan solid: δH (400 MHz, CDCl3) 8.49 (1H, s), 8.14 (1H, s), 7.76 (1H, dd, J 1 and 8), 7.44-7.53 (2H, m), 7.34-7.39 (1H, m).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:35]=[CH:34][C:15]2[C:16]([CH2:19]CC3CCN(CC4C=CC=CC=4)CC3)=[N:17][O:18][C:14]=2[CH:13]=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:6]1[C:1]([S:7]([NH2:11])(=[O:9])=[O:8])=[CH:2][CH:3]=[CH:4][CH:5]=1.[CH3:19][C:16]1[C:15]2[CH:34]=[CH:35][CH:12]=[CH:13][C:14]=2[O:18][N:17]=1
Reactant: Nc1ccc2c(CCC3CCN(Cc4ccccc4)CC3)noc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1noc2ccccc12
Product: NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 72.1 %

Procedure:
Benzenesulfonyl chloride (0.528 mL, 4.14 mmol) was added to a cold (0° C.) solution of 6-amino-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole(0.613 g, 4.14 mmol) and pyridine (0.670 mL, 8.28 mmol) in CH2Cl2 (30 mL). After 1.3 hours, saturated sodium bicarbonate (NaHCO3) was added and the resulting mixture was stirred overnight at room temperature. The organic layer was separated and washed with water and brine and dried (MgSO4), filtered, and concentrated. Purification by silica gel flash chromatograph (5% EtOAc/CH2Cl2) gave the title compound (0.867 g, 83%) as a white solid.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:23]=[C:22](F)[C:19]([C:20]#[N:21])=[C:18]([F:25])[CH:17]=2)[CH:9]=1)[CH3:2].[Na].[CH3:27][SH:28].O>CN(C=O)C>[CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:23]=[C:22]([S:28][CH3:27])[C:19]([C:20]#[N:21])=[C:18]([F:25])[CH:17]=2)[CH:9]=1)[CH3:2]
Reactant: CS
Reactant: CC[C@@H]1CCCN1c1cc(-c2cc(F)c(C#N)c(F)c2)nc(NC)n1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@@H]1CCCN1c1cc(-c2cc(F)c(C#N)c(SC)c2)nc(NC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a solution of 4-[6-[(2R)-2-ethyl-1-pyrrolidinyl]-2-(methylamino)-4-pyrimidinyl]-2,6-difluorobenzonitrile (140 mg, 0.408 mmol) in DMF (4 mL), was added methyl mercaptan sodium salt (ca. 15% in water) (252 mg, 0.543 mmol). The orange colored solution was stirred at room temperature overnight in a capped 10 mL vial. LCMS was very clean. The mixture was poured into water (15 mL). The formed solid was filtered, washed by water and dried to afford the title compound (136 mg) as a light yellow solid. LC-MS (ES) m/z=372 [M+H]+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:46])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:46])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(Cc2ccccc2Cl)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(Cc2ccccc2Cl)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (2.1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(2-chlorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.6 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.45 g, 67%).
Reaction SMILES: CNC(=O)C1C=CC=C(C2C=CC([O:16][C@@H]3[C@@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O3)=C(C)C=2)C=1.C([O:33][C@@H:34]1[C@@H:39]([O:40]C(=O)C)[C@@H:38]([CH2:44][O:45]C(=O)C)[O:37][C@H:36]([O:49][C:50]2[CH:55]=[CH:54][C:53](Br)=[CH:52][C:51]=2[Cl:57])[C@H:35]1CC([O-])=O)(=O)C.[CH3:62][O:63][C:64]([C:66]1[CH:67]=[C:68](B(O)O)[CH:69]=[CH:70][CH:71]=1)=[O:65]>>[Cl:57][C:51]1[CH:52]=[C:53]([C:68]2[CH:67]=[C:66]([CH:71]=[CH:70][CH:69]=2)[C:64]([O:63][CH3:62])=[O:65])[CH:54]=[CH:55][C:50]=1[O:49][C@@H:36]1[C@@H:35]([OH:16])[C@@H:34]([OH:33])[C@H:39]([OH:40])[C@@H:38]([CH2:44][OH:45])[O:37]1
Reactant: CNC(=O)c1cccc(-c2ccc(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)c(C)c2)c1
Reactant: CC(=O)OC[C@H]1O[C@H](Oc2ccc(Br)cc2Cl)[C@@H](CC(=O)[O-])[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: COC(=O)c1cccc(B(O)O)c1
Product: COC(=O)c1cccc(-c2ccc(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)c(Cl)c2)c1
Yield: 43 %

Procedure:
4b was prepared using the same procedure as for 5b with [(2R,3S,4S,5R,6R)-4,5-diacetoxy-6-(acetoxymethyl)-2-(4-bromo-2-chloro-phenoxy)tetrahydropyran-3-yl]acetate and 3-methoxycarbonylphenyl boronic acid as the reactants. It was further purified by HPLC (C18, 15*150 mm column; eluent: acetonitrile/water (0.1% TFA)). Yield: 43%. 1H NMR (300 MHz, METHANOL-d4) δ ppm 3.59-3.71 (m, 1H) 3.71-3.85 (m, 3H) 3.94 (s, 3H) 4.01 (dd, J=9.34, 3.30 Hz, 1H) 4.12 (dd, J=3.30, 1.92 Hz, 1H) 5.61 (d, J=1.65 Hz, 1H) 7.40-7.49 (m, 1H) 7.49-7.62 (m, 2H) 7.68 (d, J=2.20 Hz, 1H) 7.82 (ddd, J=7.76, 1.85, 1.10 Hz, 1H) 7.98 (dt, J=7.83, 1.30 Hz, 1H) 8.14-8.25 (m, 1H). MS (ESI): found [M+H]+, 425.1.