Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:9](O)[CH3:10].S(=O)(=O)(O)O.O>C1C=CC=CC=1>[O:1]=[C:2]([CH3:8])[CH2:3][CH2:4][C:5]([O:7][CH2:9][CH3:10])=[O:6]
Reactant: CC(=O)CCC(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)CCC(C)=O

Procedure:
100 g (0.86 mol) of 4-oxopentanoic acid, 150 g of ethanol and 1 ml of sulfuric acid in 200 ml of benzene were refluxed until water separation in the Dean-Stark trap ceased. The cooled reaction mixture was washed with water, sodium carbonate solution and again with water and then dried under reflux with the Dean-Stark trap. When removal of the water phase was complete, the solvent was removed by distillation and the residue was distilled under reduced pressure. Boiling point 85-87° C./16 mm Hg, yield 105.5 g (85%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:5][C@H:4]([N:6]2[C:10]3=[N:11][CH:12]=[CH:13][N:14]=[C:9]3[C:8]([CH3:16])([CH3:15])[C:7]2=[O:17])[CH2:3]1.Cl[C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[NH:1][C@H:2]1[CH2:5][C@H:4]([N:6]2[C:10]3=[N:11][CH:12]=[CH:13][N:14]=[C:9]3[C:8]([CH3:15])([CH3:16])[C:7]2=[O:17])[CH2:3]1
Reactant: Clc1nc2ccccc2o1
Reactant: CC1(C)C(=O)N([C@H]2C[C@H](N)C2)c2nccnc21
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)N([C@H]2C[C@H](Nc3nc4ccccc4o3)C2)c2nccnc21
Temperature: 90 °C
Reaction time: 17 h

Procedure:
To a round bottomed flask was added 5-(trans-3-aminocyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (Intermediate 30, 0.1663 g, 0.716 mmol, [00391]), 2-chlorobenzo[d]oxazole (0.132 g, 0.859 mmol, Sigma-Aldrich Chemical Company, Inc.), and diisopropylethylamine (0.249 ml, 1.432 mmol, Sigma-Aldrich Chemical Company, Inc.) in DMSO (2.386 ml) to stir at 90° C. for 17 hours. The crude product was purified by reverse-phase preparative HPLC using 0.1% TFA in CH3CN/H2O, gradient 10% to 90% over min. Product was taken up in DCM and loaded onto a Silicycle Si-carbonate cartridge to remove any salts to give 5-(trans-3-(benzo[d]oxazol-2-ylamino)cyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (32.2 mg, 0.092 mmol, 12.87% yield). LCMS showed product peak at 1.625 min (m+1=350.0). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (s, 6 H) 2.42-2.48 (m, 1 H) 3.18-3.29 (m, 2 H) 4.47-4.60 (m, 1 H) 5.17 (quin, J=8.31 Hz, 1 H) 6.95-7.04 (m, 1 H) 7.12 (td, J=7.63, 0.98 Hz, 1 H) 7.28 (d, J=7.24 Hz, 1 H) 7.37 (d, J=7.63 Hz, 1 H) 8.18 (d, J=3.33 Hz, 1 H) 8.23 (d, J=3.13 Hz, 1 H) 8.42 (d, J=6.65 Hz, 1 H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.O>CC(C)=O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:13][S:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:3]3)(=[O:11])=[O:12])=[O:25])=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc2c(c1)CCC2
Yield: 87.4 %

Procedure:
To a mixture of 93.2 g of indane-5-sulfonamide in 300 ml of acetone were added 490 ml of 1N sodium hydroxide. A solution of 79.36 g of 4-chlorophenylisocyanate in 250 ml of acetone was added to the reaction mixture with stirring. After stirring at room temperature for about 18 hours, the reaction mixture was filtered and 490 ml of 1N hydrochloric acid were added to the filtrate, thereby providing a fine white precipitate. One liter of water was added, and the solid was recovered by filtration to provide 144.86 g of the desired title product. m.p. 169-172° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=3)[C:11]([CH3:20])([CH3:19])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[C:26](=[O:28])=[O:27]>C1COCC1>[CH3:19][C:11]1([CH3:20])[CH2:10][CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:17]2[CH:16]=[C:15]([C:26]([OH:28])=[O:27])[CH:14]=[CH:13][C:12]1=2
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(Br)cc32)cc1
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=O)O)cc32)cc1
Temperature: 25 °C

Procedure:
A solution of 3,4-dihydro-1-(4-methylphenyl)-4,4-dimethyl-7-bromonaphthalene (Compound D) (250.0 mg, 0.764 mmol) in 2.0 ml of THF was cooled to -78° C. and 1.0 ml of t-butyllithium (1.68 mmol, 1.7 M solution in pentane) was added slowly. After stirring for 1 hour at -78° C. gaseous CO2 (generated by evaporation of Dry-Ice, and passed though a drying tube) was bubbled through the reaction for 1 hour. The solution was then allowed to warm to room temperature and the reaction was quenched by the addition of 10% HCl. Extraction with EtOAc was followed by washing the combined organic layers with H2O and saturated aqueous NaCl, and drying over MgSO4. Removal of the solvents under reduced pressure and washing of the solid with hexanes afforded the title compound as a colorless solid. 1H NMR (CDCl3): δ 7.94 (1H, dd, J=1.8, 8.1 Hz), 7.76 (1H, d, J=1.8 Hz), 7.45 (1H, d, J=8.1 Hz), 7.24 (4H, m), 6.01 (1H, t, J=4.7 Hz), 2.40 (3H, s), 2.36 (2H, d, J=4.7 Hz), 1.35 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7]1.C[N+]1([O-])CCOCC1.C([N+](CCC)(CCC)CCC)CC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7]1
Reactant: COC(=O)C(CC1CCC(O)C1)c1ccc(Cl)c(Cl)c1
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COC(=O)C(CC1CCC(=O)C1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-3-(3-hydroxy-cyclopentyl)-propionic acid methyl ester (prepared as in Example 36, 356.4 mg, 1.12 mmol), N-methylmorpholine N-oxide (197 mg, 1.68 mmol), and powdered molecular sieves (1.12 g) in methylene chloride (2.25 mL) at 25° C. was treated with tetrapropylammonium perrhuthenate (20 mg, 0.05 mmol). The resulting mixture was stirred at 25° C. for 30 min. At this time, the reaction was filtered through a pad of celite (ethyl acetate as eluent). The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 75/25 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(3-oxo-cyclopentyl)-propionic acid methyl ester (261.3 mg, 73.8%) as a clear oil: EI-HRMS m/e calcd for C15H16Cl2O3 (M+Na)+ 337.0370, found 337.0371.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:36])=[C:10]([CH:35]=1)[C:11]([C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16]([CH3:34])=[CH:15][N:14]=1)=[O:12]>C1COCC1.CC(O)=O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:19][C:18]2[C:13]([C:11](=[O:12])[C:10]3[CH:35]=[C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])[CH:7]=[CH:8][C:9]=3[Cl:36])=[N:14][CH:15]=[C:16]([CH3:34])[CH:17]=2)(=[O:22])=[O:21])=[CH:24][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: CN=C=O
Reactant: Cc1cnc(C(=O)c2cc(N)ccc2Cl)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(Cl)c(C(=O)c2ncc(C)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.1 %

Procedure:
Methylisocyanate (17 μL, 0.235 mmol) was added to N-[2-(5-amino-2-chloro-benzoyl)-5-methyl-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzene sulfonamide (59 mg, 0.117 mmol) in THF (2 mL) and AcOH (0.5 mL) and stirred at room temperature for 4 h. The reaction mixture was directly purified by preparative HPLC (20-80% acetonitrile in water) to afford 4-chloro-N-{2-[2-chloro-5-(3-methyl-ureido)-benzoyl]-5-methyl-pyridin-3-yl}-3-trifluoromethyl-benzene sulfonamide (25 mg) in 38% yield. 1H NMR (400 MHz, CDCl3+CD3OD) δ 8.14 (m, 2H), 7.95 (m, 2H), 7.63 (d, 1 H), 7.58 (dd, 1 H), 7.41 (dd, 1 H), 7.19 (d, 1 H), 2.76 (s, 3H), 2.42 (s, 3H); ESMS m/z (relative intensity): 561 (M+H)+ (100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][CH3:13])=[CH:7]2.Cl.C([O:19][C:20](=[O:23])[CH2:21][NH2:22])(C)(C)C>>[ClH:1].[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:22][CH2:21][C:20]([OH:23])=[O:19])=[CH:3][CH:4]=[N:5]2)=[N:10][CH:9]=1
Reactant: COc1cnc2c(Cl)ccnc2c1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Product: COc1cnc2c(NCC(=O)O)ccnc2c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 80.1 %

Procedure:
In a 100 mL round bottom flask were dissolved 8-chloro-3-methoxy-1,5-naphthyridine (5.00 g, 25.7 mmol) and glycine tert-butyl ester hydrochloride (17.2 g, 103 mmol) in 50 mL of 2-BuOH then stirred and heated at 100° C. After 5 h the solvent based on LC-MS was removed by reduced pressure and then the solid was dissolved in 200 mL of HCl 1N and stirred at 60° C. overnight. After 10 h the reaction mixture based on LC-MS was cooled down to rt then 0° C. and the desired acid precipitate. Filtered the solid (3.97 g) then evaporated the aqueous solution and triturated in 75 mL of H2O at 0° C. then filter again and washed with 25 mL of H2O at 0° C. (1.58 g) to afforded total 2-(7-methoxy-1,5-naphthyridin-4-ylamino)acetic acid hydrochloride (5.55 g, 80.1% yield) as a tan solid. MS m/z=234.1 [M+1]+. Calc'd for C11H11N3O3: 233.1.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Br[CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:34][C:33]([CH3:36])([CH3:35])[C:32](=[O:37])[CH2:31][N:6]1[C:7](=[O:28])[C:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=[C:2]([CH3:1])[N:29]=[C:5]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(=O)C(C)(C)C)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (3 g), 1-bromo-3,3-dimethylbutan-2-one (1.1 mL), potassium carbonate (2.1 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate 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 (0.53 g, 15%).
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:42]([OH:44])=[O:43])[CH2:20][CH2:21][C:22](=[O:41])[NH:23][CH:24]([P:33]([CH2:38][CH:39]=[CH2:40])([CH2:35][CH:36]=[CH2:37])=[O:34])[P:25]([CH2:30][CH:31]=[CH2:32])([CH2:27][CH:28]=[CH2:29])=[O:26])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[CH2:30]([P:25]([CH:24]([P:33]([CH2:35][CH:36]=[CH2:37])([CH2:38][CH:39]=[CH2:40])=[O:34])[NH:23][C:22](=[O:41])[CH2:21][CH2:20][C@@H:19]([C:42]([OH:44])=[O:43])[NH2:18])([CH2:27][CH:28]=[CH2:29])=[O:26])[CH:31]=[CH2:32]
Reactant: C=CCP(=O)(CC=C)C(NC(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)P(=O)(CC=C)CC=C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: C=CCP(=O)(CC=C)C(NC(=O)CC[C@H](N)C(=O)O)P(=O)(CC=C)CC=C
Reaction time: 4 h

Procedure:
Fmoc-protected compound 97 (898 mg, 1.18 mmol) was treated with a 5% v/v solution of piperidine in DMF (5.9 mL). After stirring for 4 h, the reaction mixture was concentrated to dryness and purified by silica gel chromatography on a Biotage™ flash chromatography system using a gradient of 0-5% methanol in CH2Cl2. Compound 98 was obtained as a colorless oil (274 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.72-1.81 (m, 1H), 2.04-2.31 (m, 3H), 2.36-2.43 (m, 1H), 2.46-2.54 (m, 1H), 3.41 (dd, J=9.5, 4.3 Hz, 1H), 4.59-4.67 (m, 8H), 5.15 (dt, J=22.1, 9.1 Hz, 1H), 5.23-5.26 (m, 4H), 5.35-5.39 (m, 4H), 5.88-5.98 (m, 4H), 7.50 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]3[CH:19]=[CH:20][N:21]=[C:9]23)=[C:4]([F:22])[CH:3]=1.[N+:23]([O-])([OH:25])=[O:24]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:7]([N+:23]([O-:25])=[O:24])=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[N:10]3[CH:19]=[CH:20][N:21]=[C:9]23)=[C:4]([F:22])[CH:3]=1
Reactant: O=c1cc(C(F)(F)F)n2ccnc2n1-c1ccc(Br)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1cc(C(F)(F)F)n2ccnc2n1-c1cc([N+](=O)[O-])c(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8-(4-Bromo-2-fluorophenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (12 g) was dissolved into concentrated sulfuric acid (50 ml) to which then nitric acid (60%, d=1.38; 5.0 g) was added under ice-cooled condition, and stirred for 2 hours at room temperature. The reaction solution was poured into ice water and the thus obtained solid was filtered off. The solid was washed with water and dried to give the compound of interest (12.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]2[C:8](=[O:28])[N:9]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:10]3[C:15]([C:6]=2[CH:5]=1)=[CH:14][N:13]=[C:12]1[CH:16]=[C:17]2[O:22][CH2:21][O:20][C:18]2=[CH:19][C:11]=31)([O-])=O.O.NN>C(O)C.[Ni]>[NH2:1][C:4]1[CH:30]=[CH:29][C:7]2[C:8](=[O:28])[N:9]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:10]3[C:15]([C:6]=2[CH:5]=1)=[CH:14][N:13]=[C:12]1[CH:16]=[C:17]2[O:22][CH2:21][O:20][C:18]2=[CH:19][C:11]=31
Reactant: CN(C)CCn1c(=O)c2ccc([N+](=O)[O-])cc2c2cnc3cc4c(cc3c21)OCO4
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C)CCn1c(=O)c2ccc(N)cc2c2cnc3cc4c(cc3c21)OCO4
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
To a solution of compound 5a (40 mg, 0.1 mmol) in ethanol (10 mL), Ra—Ni (˜50 mg) and then hydrazine hydrate (0.2 mL) were added and the reaction stirred at room temperature for 3 h. The catalyst was filtered through Celite and filtrate was concentrated in vacuo to provide 23 mg of a solid (61.1% yield); mp 300–301° C.; 1H NMR (CDCl3) δ 2.36 (s, 6H), 3.01 (t, 2H, J=6.6), 4.33 (s, 2H), 4.63 (t, 2H, J=7), 6.18 (s, 2H), 6.91(dd, 1H, J=2.2, 8.8), 7.46 (s, 1H), 7.45 (d, 1H, J=2.2), 7.83 (s, 1H), 8.30 (d, 1H, J=8.8), 9.35 (s, 1H); HRMS m/z calcd for C21H20N4O3H: 377.1614. found 377.1606.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][S:8][C:4]=2[CH:3]=1.N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18].O>ClCCl>[Si:20]([O:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][S:8][C:4]=2[CH:3]=1)([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: Oc1ccc2ccsc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2ccsc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
6-Hydroxybenzothiophene (22, 8.55 g, 56.9 mmol) and imidazole (4.65 g, 68.3 mmol) were dissolved in dichloromethane (120 mL) and TBDMS-Cl (9.73 g, 62.6 mmol) dissolved in dichloromethane (50 mL) was slowly added at 0° C. The reaction mixture was agitated at 0° C. for 1 hour. After adding water and transferring the resulting solution to a separatory funnel, the dichloromethane layer was separated. The remaining organic compound was extracted three times with dichloromethane. After removing water using sodium sulfate, the solvent was removed under reduced pressure. Column chromatography yielded 6-(t-butyldimethylsilyloxy)benzothiophene (23, 13.6 g, 90%) as a liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][O:18][C@H:19]4[CH2:23][CH2:22][O:21][CH2:20]4)[CH:15]=3)[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C([SiH](C(C)C)C(C)C)(C)C.FC(F)(F)C(O)=O.C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][O:18][C@H:19]4[CH2:23][CH2:22][O:21][CH2:20]4)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(CO[C@H]4CCOC4)cc23)c1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Fc1cccc(-c2n[nH]c3ccc(CO[C@H]4CCOC4)cc23)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
To a solution of 82 mg of 3-(3-fluorophenyl)-5-{[(3S)tetrahydro-3-furanyloxy]methyl}-1-trityl-1H-indazole in 1.6 ml methylene chloride were added 0.05 ml of triisopropylsilane and 0.4 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture was added ethyl acetate. The mixture was sequentially washed with saturated aqueous sodium hydrogencarbonate solution (×2) and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. Then, the resulting crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=1:4), to give 36 mg of the title compound as a viscous colorless oil.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[N:12]1([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([C:25]2[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=2)=[O:24])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:17][C@@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:7]3[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=3)=[CH:29][CH:30]=2)=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(c1ccc(Br)cc1)N1CCCC1CN1CCCC1
Reactant: CC(=O)c1ccc(B(O)O)s1
Product: CC(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)s1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure Q starting from 5-Acetyl-2-thiophene boronic acid and 4-(2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl bromide to give 42 mg (37%). MS (ES+) 383.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:23])=[C:14]([C:19](=[N:21]O)[NH2:20])[C:15]([F:18])=[CH:16][CH:17]=3)=[N:7][C:6]=2[CH:24]=1.C([O-])=O.[NH4+]>C(O)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:23])=[C:14]([C:19](=[NH:20])[NH2:21])[C:15]([F:18])=[CH:16][CH:17]=3)=[N:7][C:6]=2[CH:24]=1
Reactant: NC(=NO)c1c(F)ccc(OCc2nc3cc(Cl)ccc3s2)c1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: N=C(N)c1c(F)ccc(OCc2nc3cc(Cl)ccc3s2)c1F
Yield: 21 %

Procedure:
A mixture of 3-[(5-chloro-1,3-benzothiazol-2-yl)methoxy]-2,6-difluoro-N′-hydroxybenzenecarboximidamide (156, mg, 0.42 mmol, 1 equiv.), 10% Pd/C (63 mg) and ammonium formate (133 mg, 2.1 mmol, 5 equiv.) in glacial acetic acid (2 ml) was stirred under reflux for 3 h. The mixture was filtered through a pad of celite, alkalised to pH 10 with 0.5N NaOH and extracted with EtOAc (3×15 ml). The combined organic extracts were dried (MgSO4) and evaporated to dryness under reduced pressure. The crude residue was dissolved in DMSO and precipitated by addition of H2O. The solid was filtered, washed with H2O and pentane, to give 49 mg (33% yield). Purity 62% by HPLC (Gemini C18, 50×4.6 mm): m/z 354 [M+H]+, Rt=3.09 min. HPLC-MS analysis suggested that there was also 6% un-reacted starting material and 21% of the title compound without the Cl atom.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH:12]2[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH:12]2[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:3]=1
Reactant: CCOC(=O)C1CCC(Cc2cc(O)n3nccc3n2)CC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)C1CCC(Cc2cc(Cl)n3nccc3n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 100 mL round-bottom flask was charged ethyl 4-((7-hydroxypyrazolo[1,5-a]pyrimidin-5-yl)methyl)cyclohexanecarboxylate (Int-4f, 2.48 g, 8.19 mmol), N,N-dimethylaniline (4 mL) and POCl3 (40 mL). The resulting solution was allowed to stir at room temperature for 18 hours. After 18 hours, the solvent was removed in vacuo. The residue was cooled to 0° C. in ice bath. The cooled residue was slowly quenched with saturated NaHCO3 (aq), and then extracted with DCM (x3). The combined organic extracts were dried over Na2SO4 and the residue purified via silica gel chromatography to yield the title compound as clear oil. Yield=2.29 g.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[NH2:14][NH2:15]>N1C=CC=CC=1>[NH:14]([C:2]1[N:3]=[CH:4][C:5]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1)[NH2:15]
Reactant: NN
Reactant: Clc1ncc2c(n1)CCCCCC2
Solvent: c1ccncc1
Product: NNc1ncc2c(n1)CCCCCC2

Procedure:
2-Chloro-5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidine (1.5 g) was treated with anhydrous pyridine (15 mL) and anhydrous hydrazine (7 mL) at 120° C. for 3.75 h. The solvent was removed under vacuum. The residue was partitioned between chloroform and 1M aqueous potassium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 2-hydrazinyl-5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidine as a beige solid, 1.28 g; 1H NMR (CDCl3, 300 MHz) 8.00 (s, 1H), 6.63 (br s, 1H), 3.93 (br s, 2H), 2.76 (m, 2H), 2.60 (m, 2H), 1.74 (m, 2H), 1.63 (m, 2H), 1.40 (m, 4H) ppm; 13C NMR (CDCl3, 75 MHz) 170.57, 163.81, 157.22, 124.14, 34.31, 32.65, 30.24, 28.66, 26.32, 26.08; MS (ES) 193 (M+H).
Reaction SMILES: [N:1]([C@:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[C:5]([O:7]C)=O)=[C:2]=[S:3].[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>O>[CH3:9][C@@:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:1][C:2](=[S:3])[N:23]([NH:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]1=[O:7]
Reactant: NNc1ccccc1
Reactant: COC(=O)[C@@](C)(N=C=S)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: C[C@@]1(c2ccccc2)NC(=S)N(Nc2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
0.7 g (0.00316 mol) of methyl (+)-(2S)-2-isothiocyanato-2-phenylpropionate, diluted in 15 ml of dry tetrohydrofuran, is introduced into a 100 ml three-necked flask under a dry nitrogen atmosphere. 0.32 ml (0.00316 mol) of phenylhydrazine, diluted in 5 ml of tetrohydrofuran, is run in at 20° C. in a single step. The temperature rises by 2° C. The medium is kept magnetically stirring for 30 minutes. A dark-beige precipitate appears. The medium is neutralized with 0.4 ml of acetic acid and then treated with 20 ml of water. After separating, the aqueous phase is extracted with 3 times 20 ml of ethyl ether. The organic phases are combined, washed with 2 times 30 ml of water, dried over magnesium sulfate and then concentrated under reduced pressure. The solid residue obtained is chromatographed on a silica column, using an eluent mixture composed of heptane and ethyl acetate in the proportions of 50/50.