Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Br[CH2:10][C:11]1[NH:16][C:15]2=[N:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:19]=[C:14]2[CH:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:12]=1[C:34]#[N:35].O>CN(C=O)C>[C:23]([O:22][C:20]([N:18]1[CH:19]=[C:14]2[C:15]([NH:16][C:11]([CH2:10][N:3]3[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)=[C:12]([C:34]#[N:35])[CH:13]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])=[N:17]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)n1cc2c(n1)NC(CBr)=C(C#N)C2c1ccccc1Cl
Reactant: C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cc2c(n1)NC(CN1CCOCC1)=C(C#N)C2c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine (22.9 g), di-t-butyl dicarbonate (19.4 g) and dimethylaminopyridine (0.5 g) in tetrahydrofuran (200 ml) was stirred at room temperature for 30 minutes. The reaction mixture was ice-cooled and the precipitated crystals were collected by filtration to give 2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine (21.8 g) as white crystals. 2-(t-Butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine (5.0 g), N-bromosuccinimide (2.5 g) and azobisisobutyronitrile (66 mg) were suspended in benzene (50 ml) and the suspension was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (2:1)) and crystallized from ethyl acetate to give 6-bromomethyl-2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine as white crystals. To a suspension of sodium hydride (32 mg) in DMF (10 ml) was added morpholine (70 μl) and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 6-bromomethyl-2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (0.36 g) and the mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added water, and the precipitated crystals were collected by filtration and washed with hexane to give 2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(morpholin-4-yl)methyl-2H-pyrazolo[3,4-b]pyridine (450 mg) as white crystals. A solution of 2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(morpholin-4-yl)methyl-2H-pyrazolo[3,4-b]pyridine (440 mg) in trifluoroacetic acid (5 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and 4M hydrochloric acid-dioxane solution was added. The precipitated crystals were collected by filtration and washed with ethyl acetate to give the title compound (250 mg) as pale-yellow crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18]O)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.C(Cl)(Cl)(Cl)[Cl:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][Cl:21])[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCCCN1CCN(c2cccc3sccc23)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: ClCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 25 °C

Procedure:
3.56 g (12.9 mmol) of 3-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)propan-1-ol was suspended in 30 ml of methylene chloride, and carbon tetrachloride (30 ml) and triphenyl phosphine (4.06 g, 15.5 mmol) were added thereto followed by stirring under reflux for 3 hours. The reaction mixture was cooled to room temperature, then methanol and methylene chloride were added thereto so as to make the mixture uniform. Silica gel (30 g) was added to the uniform solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel: 300 g, n-hexane:ethyl acetate=2:1), then concentrated under reduced pressure to obtain 1-benzo[b]thiophen-4-yl-4-(3-chloropropyl)piperazine (2.36 g) as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[C:22]([O:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(C=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Oc1cc(C=CC(=O)c2ccccc2)cc([N+](=O)[O-])c1O

Procedure:
1.0 g of the product obtained in Example 8 was dissolved in 5 ml of tetrahydrofuran, 4.7 ml of pivaloyl chloride was added and the mixture was refluxed for 16 h. The solvent was evaporated in vacuo and the residue was purified in a silicagel column by using toluene-acetic acid-dioxane (18:1:1) mixture as an eluent. The product was crystallized from ether, m.p. 148°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1.Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1
Reactant: ClCCN1CCOCC1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCNC3
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CCN1CCOCC1)C3
Temperature: 25 °C

Procedure:
A mixture of 7.85 g (0.03 m) of 1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano [3,4-c]pyridin-5-one, 6.15 g (0.033 m) of N-(2-chloroethyl) morpholine HCl and 7.08 g (0.07 m) of triethylamine in 250 cc of ethanol was refluxed for 6 hr. and filtered hot. Treatment of the hot reaction solution with excess HCl 6 hr. and cooling to room temperature afforded crude product. Crystallization from 75% EtOH afforded analytical material mp. 238°-40°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([CH3:23])=[C:16]([CH:22]=1)[NH:17][CH2:18][CH:19]([CH3:21])[CH3:20]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[CH:14][C:15]([CH3:23])=[C:16]([NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:22]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)cc1NCC(C)C
Reactant: OB(O)c1ccc(F)cc1
Product: Cc1ccc(-c2ccc(F)cc2)cc1NCC(C)C
Yield: 83 %

Procedure:
Using the same method as in Example 19-(ii), 4-fluoro-benzene boronic acid was reacted with 5-bromo-2-methyl-N-(2-methylpropyl)aniline to give 4′-fluoro-4-methyl-N-(2-methylpropyl)biphenyl-3-amine (yield: 83%).
Reaction SMILES: C([N:4]1[C:8]2=[N:9][C:10](Br)=[CH:11][CH:12]=[C:7]2[C:6]([C:14]#[N:15])=[CH:5]1)(=O)C.C(N(CC)CC)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH2:57]([O:59][C:60]1[CH:65]=[CH:64][C:63](B(O)O)=[CH:62][N:61]=1)[CH3:58]>O1CCOCC1>[CH2:57]([O:59][C:60]1[N:61]=[CH:62][C:63]([C:10]2[N:9]=[C:8]3[NH:4][CH:5]=[C:6]([C:14]#[N:15])[C:7]3=[CH:12][CH:11]=2)=[CH:64][CH:65]=1)[CH3:58]
Reactant: CC(=O)n1cc(C#N)c2ccc(Br)nc21
Reactant: CCOc1ccc(B(O)O)cn1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOc1ccc(-c2ccc3c(C#N)c[nH]c3n2)cn1
Temperature: 100 °C
Yield: 66.7 %

Procedure:
In a 100 mL round-bottomed flask, 1-acetyl-6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (250 mg, 947 μmol, Eq: 1.00), triethylamine (575 mg, 792 μl, 5.68 mmol, Eq: 6) and X-PHOS (181 mg, 379 μmol, Eq: 0.40) were combined with dioxane (25 ml) to give a colorless solution. [1,1′-bis(diphenylphosphino)ferrocene]dichloropaladium(II) (173 mg, 237 μmol, Eq: 0.25) and 2-ethoxy-5-pyridineboronic acid (205 mg, 1.23 mmol, Eq: 1.3) were added and the resultant mixture was degassed for 5 minutes under Nitrogen. The reaction mixture was heated to 100° C. and stirred for O/N h. The reaction mixture was poured into 50 mL H2O and extracted with EtOAc (3×50 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 20% to 30% EtOAc in hexanes) to give 6-(6-ethoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (167 mg, 67%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH2:22][CH2:21][NH:29][C:2]2[CH:7]=[C:6]([C:8]3[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=4)[N:11]=[C:10]([CH3:20])[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cccc(-n2nc(C)cc2-c2ccnc(Cl)c2)c1
Reactant: NCCc1ccccc1
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(NCCc3ccccc3)c2)c1
Temperature: 200 °C
Yield: 74 %

Procedure:
A mixture of 2-chloro-4-[1-(3-methylphenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 45; 0.5 g, 0.0018 mol) and phenethylamine (15 mL) was heated at 200° C. for 24 hours. The excess amine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 1:1) to give 0.48 g (74% yield) of product as a yellow oil, which solidified upon standing: mp: 86-87° C. Anal. Calc'd. for C24H24N4: C, 78.23; H, 6.56; N, 15.20. Found: C, 78.07; H, 6.82; N, 14.71.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([CH2:12][NH2:13])[N:10]=2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]2([CH3:33])[O:32][CH2:31][CH2:30][O:29]2)=[CH:24][CH:23]=1)[CH3:2].[CH:34](OCC)=[O:35]>>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([CH2:12][NH:13][CH:34]=[O:35])[N:10]=2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=1[C:22]1[CH:23]=[CH:24][C:25]([C:28]2([CH3:33])[O:32][CH2:31][CH2:30][O:29]2)=[CH:26][CH:27]=1)[CH3:2]
Reactant: CCc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc(CN)nc12
Reactant: CCOC=O
Product: CCc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc(CNC=O)nc12
Temperature: 25 °C
Yield: 100.1 %

Procedure:
(7-Ethyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine (0.250 g, 0.533 mmol, prepared using D from Preparation #5 with (E)-styrylboronic acid, E, F, G and I) in ethyl formate (3.30 mL, 40.5 mmol) was heated to about 65° C. for about 2 h. The mixture was cooled to rt then the solvent was re removed under reduced pressure to give N-((7-ethyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)formamide (0.265 g, 100%): LC/MS (Table 2, Method b) Rt=2.71 min; MS m/z 497 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:22]=[C:23](OS(C(F)(F)F)(=O)=O)[C:24]4[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:25]=4[N:26]=3)=[CH:16][CH:15]=2)=[CH:12][N:11]=[CH:10]1>O1CCOCC1.CN(C=O)C>[CH2:1]([NH:8][C:23]1[C:24]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:25]=2[N:26]=[C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([C:13]3[O:9][CH:10]=[N:11][CH:12]=3)=[CH:19][CH:18]=2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(nc(Nc3ccc(-c4cnco4)cc3)nc2OS(=O)(=O)C(F)(F)F)C1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(nc(Nc3ccc(-c4cnco4)cc3)nc2NCc2ccccc2)C1
Temperature: 25 °C
Yield: 86 %

Procedure:
Benzylamine (0.030 g, 0.28 mmol) was added to tert-butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.15 g, 0.28 mmol, Example 5b) in dioxane (10 mL) and DMF (0.5 mL). The reaction was stirred at rt over night. The solvent was removed under reduced pressure and the crude product redissolved in EtOAc, washed with saturated NaHCO3 and H2O. The organic layer was dried (MgSO4), filtered and concentrated to give tert-butyl 4-(benzylamino)-2-(4-(oxazol-5-yl)phenylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.120 g, 87%). No further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N:17]([CH3:19])[CH3:18])[CH:14]=[C:13](Cl)[N:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:16]=[C:15]([N:17]([CH3:19])[CH3:18])[CH:14]=[C:13]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[N:12]=1
Reactant: CN(C)c1cc(Cl)nc(Cl)c1
Reactant: OCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)c1cc(Cl)nc(OCc2ccsc2)c1

Procedure:
To a solution of 3-thiophenemethanol (0.526 g, 0.0042×1.1 mol) in 10 ml of dry tetrahydrofuran, sodium hydride (0.335 g, (ca.60% in mineral oil), 0.0042×2.0 mol) was added. After the bubbling ceased, a solution of 2,6-dichloro-4-dimethylaminopyridine (0.8 g, 0.0042 mol) in 20 ml of dry tetrahydrofuran was added dropwise at room temperature.
Reaction SMILES: [O:1]=[C:2]1[NH:10]/[C:9](=[N:11]\[N:12]=[CH:13]\[CH2:14][CH2:15][C:16]([OH:18])=[O:17])/[N:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2>C(O)(=O)C>[O:1]=[C:2]1[N:10]2[C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:12][N:11]=[C:9]2[N:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2
Reactant: CCCCCn1/c(=N/N=C/CCC(=O)O)[nH]c(=O)c2[nH]cnc21
Solvent: CC(=O)O
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CCC(=O)O)nnc12
Yield: 79.5 %

Procedure:
The mixture of (4E)-4-[(2E)-(6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene)hydrazono]butanoic acid (1.367 g, 5.1 mmol) in acetic acid (70 ml) was refluxed for 1 hour. Evaporation of solvent afforded the desired product (1.29 g, 99%) as yellowish solid. LCMS calculated for C14H19N6O3 (M+H): 319.2. found: 319.2.
Reaction SMILES: [CH3:1][CH:2]1[O:6][CH2:5][S:4][C:3]1=[N:7][OH:8].[CH3:9][N:10]([S:14][C:15]([CH3:22])([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH3:16])[C:11](Cl)=[O:12].C(N(CC)CC)C>O1CCOCC1>[CH3:9][N:10]([S:14][C:15]([CH3:16])([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH3:22])[C:11]([O:8][N:7]=[C:3]1[CH:2]([CH3:1])[O:6][CH2:5][S:4]1)=[O:12]
Reactant: CC1OCSC1=NO
Reactant: CC(C)C(=O)C(C)(C)SN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)C(=O)C(C)(C)SN(C)C(=O)ON=C1SCOC1C

Procedure:
Prepared as in Example I by reacting 2.64 g (0.02 m) of 5-methyl-4-oximino-1,3-oxathiolane, 4.47 g (0.02 m) of N-methyl-N-(2,4-dimethyl-3-oxo-2-pentanesulfenyl)carbamoyl chloride and 2.02 g (0.02 m) of triethylamine in 25 ml of dioxane. Crystallized from isopropyl etherto yield 1.2 g of a white solid, m.p. 90°-92° C.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:4]=2[CH2:3]1.[N:21]1([CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][O:31][C:30]2=[O:34])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(Cl)(Cl)Cl>[F:18][C:17]([F:20])([F:19])[C:15]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:2]([N:24]3[CH2:25][CH2:26][N:21]([CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][O:31][C:30]4=[O:34])[CH2:22][CH2:23]3)[CH2:3][C:4]=2[CH:16]=1
Reactant: FC(F)(F)c1ccc2c(c1)CC(Cl)c1ccccc1S2
Reactant: O=C1OCCN1CCN1CCNCC1
Solvent: ClC(Cl)Cl
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(C(F)(F)F)ccc3Sc3ccccc32)CC1

Procedure:
17 g of 10-chloro-10,11-dihydro-2-trifluoromethyl-dibenzo[b,f]thiepin in 90 ml of chloroform and 26.2 g of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone are heated under reflux for 14 hours. The mixture is evaporated and the residue treated with ice-water, ether and 2-N aqueous sodium hydroxide. After equilibration, the organic phase is washed with water and acidified with ethanolic hydrochloric acid. The precipitate which separates is filtered off and dissolved in about 400 ml of water. The aqueous solution is extracted with ether. The aqueous solution is treated with ice, made alkaline with aqueous sodium hydroxide solution and extracted with about 350 ml of benzene. The benzene phase is dried over sodium sulphate, filtered and evaporated. There is obtained 3-[2-[4-(10,11-dihydro-2-trifluoromethyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2 -oxazolidinone as an oil. By treatment with maleic acid there is obtained the corresponding maleate which is crystallised from ethanol/ether; melting point 168°-169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:24]([O-])=O)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1>C1COCC1.CO.[Ni]>[NH2:24][C:12]1[C:13]([CH:21]2[CH2:23][CH2:22]2)=[CH:14][C:15]2[C:10]([CH:11]=1)=[N:9][N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:16]=2[C:17]([NH:19][CH3:20])=[O:18]
Reactant: CNC(=O)c1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Cl)cc1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1c2cc(C3CC3)c(N)cc2nn1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-nitro-2H-indazole-3-carboxamide (127 mg, 0.34 mmol) in THF (2.5 mL) and MeOH (7.5 mL) was added Raney nickel (20 mg) and the reaction was stirred vigorously under an atmosphere of hydrogen at 60° C. for 2 h. The reaction mixture was diluted with MeOH (40 mL), filtered and then concentrated to dryness to give 6-amino-2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamide as a tan solid (97 mg, 83%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[N:4]=[N:3]1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[CH:14]=1>>[Br:15][C:13]1[CH:14]=[C:9]([NH:7][C:5]2[N:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1
Reactant: Cn1cc(N)nn1
Reactant: Cn1cc(Br)cc(Br)c1=O
Product: Cn1cc(Nc2cc(Br)cn(C)c2=O)nn1

Procedure:
Following the procedure in Example 148c, and starting with 149b (500 mg, 5.10 mmol, 1.0 eq.) and 3,5-dibromo-1-methylpyridin-2(1H)-one (2.04 g, 7.65 mmol, 1.5 eq.), 149c was obtained as a yellow solid (760 mg, 52%). MS-ESI: [M+H]+ 283.9.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1([CH2:15][CH2:16][OH:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:17][CH2:16][CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: OCCc1ccccc1
Product: Brc1cccc(OCCc2ccccc2)n1

Procedure:
Prepared according to the procedure described in Example 139, Step 1, using 2,6-dibromo-pyridine and 2-phenyl-ethanol.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[N:3]1[CH:7]=[CH:6][NH:5][NH:4]1.Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([S:19][CH2:20][CH2:21][CH3:22])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:20]([S:19][C:13]1[CH:12]=[C:11]([N:5]2[CH:6]=[CH:7][N:3]([C:2]([F:9])([F:8])[F:1])[NH:4]2)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16])[CH2:21][CH3:22]
Reactant: CCCSc1cc(Cl)ccc1C#N
Reactant: FC(F)(F)N1C=CNN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCSc1cc(N2C=CN(C(F)(F)F)N2)ccc1C#N
Temperature: 25 °C
Yield: 38.2 %

Procedure:
1.06 g (7.7 mmol) of 3-trifluoromethyl-1H-triazol, 1.38 g (6.5 mmol) of 4-chloro-2-n-propylthiobenzonitrile and 1.07 g (7.7 mmol) of potassium carbonate were stirred in 10 ml of N,N-dimethylformamide at 150° C. for 2 hours. The resulting reaction mixture was cooled to the room temperature and poured into 100 ml of water, and the organic matters were extracted with 50 ml of ethyl acetate twice. The ethyl acetate layers were combined, then washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 0.78 g of 2-propylthio-4-(3-trifluoromethyl-1H-triazolyl)benzonitrile (yield 38.2%) as a milk-white powder (m.p. 143-144° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:22][N:23]=[C:24]=[O:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:15][C:24]([NH:23][CH3:22])=[O:25])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CN=C=O
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(N)=O)cc1Cl
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)[C@H](CC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 100 °C
Yield: 41.7 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (160 mg, 0.49 mmol) in toluene (5 mL) was treated with methyl isocyanate (0.12 mL, 1.94 mmol). The reaction mixture was then heated at 100° C. for 16 h. At this time, the reaction was concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded 1-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea (79 mg, 42%) as a white foam: [α]23589=−8.9° (c=0.09, chloroform); FAB-HRMS m/e calcd for C17H23ClN2O4S (M+H)+387.1145, found 387.1142.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:6]=[C:5]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24]C(=O)C)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:4]=1>[OH-].[Na+]>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([NH:14][C:5]2[CH:4]=[C:3]([NH:2][CH3:1])[N:8]=[C:7]([N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[N:6]=2)(=[O:16])=[O:17])=[CH:19][CH:20]=1
Reactant: CNc1cc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)nc(N2CCCC2)n1
Agent: [Na+]
Agent: [OH-]
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(N2CCCC2)n1
Yield: 30.6 %

Procedure:
0.30 g (0.00077 mol) of N-[4-(6-methylamino-2-pyrrolidin-1-yl-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamide was boiled at reflux in 30 ml of 1N aqueous sodium hydroxide for 3 hours. The mixture was cooled and extracted with ethyl acetate. Crystals then separated from the aqueous phase and, after suction filtration, were chromatographed over silica gel with ethyl acetate/ethanol 9:1 as the eluent. There was obtained 0.082 g (30%) of 4-amino-N-(6-methylamino-2-pyrrolidin-1-yl-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p. 299-301° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH3:22][CH:23]([C:27]([NH:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[O:28])[C:24](O)=[O:25]>>[CH:11]1([CH2:10][N:7]2[C:8](=[O:9])[C@@H:2]([NH:1][C:24](=[O:25])[CH:23]([CH3:22])[C:27]([NH:29][CH2:30][CH2:31][C:32]([F:37])([F:38])[C:33]([F:36])([F:34])[F:35])=[O:28])[C:3]3[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=3[C:5]3[CH:17]=[CH:16][CH:15]=[CH:14][C:6]2=3)[CH2:13][CH2:12]1
Reactant: N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCCC(F)(F)C(F)(F)F
Product: CC(C(=O)NCCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
(S)-7-amino-5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one was coupled with 2-methyl-N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acid in analogy to the description in example 73 to yield N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-methyl-N′-(3,3,4,4,4-pentafluoro-butyl)-malonamide (epimers) as white solid.