Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C(O)C.[CH2:6]([N:13]1[C:17]2[CH:18]=[C:19]([C:22]([O:24]CC)=[O:23])[CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:27][CH2:28][CH3:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>O>[CH2:6]([N:13]1[C:17]2[CH:18]=[C:19]([C:22]([OH:24])=[O:23])[CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:27][CH2:28][CH3:29])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCc1nc2ccc(C(=O)OCC)cc2n1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1nc2ccc(C(=O)O)cc2n1Cc1ccccc1
Yield: 96 %

Procedure:
A 10% sodium hydroxide aqueous solution (3.61 g), 5 ml of ethanol and 3 ml of water were added to 0.97 g of 1-benzyl-6-ethoxycarbonyl-2-n-propylbenzimidazole, and the mixture was heat-refluxed for 1 hour. The reaction solution was adjusted to a pH of 6 with 10% hydrochloric acid, and was concentrated under reduced pressure. Ethanol was added to the residue, and the inorganic salt was separated through filtration. The filtrate was concentrated under reduced pressure to give 0.85 g of 1-benzyl-6-carboxy-2-n-propylbenzimidazole (126).
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6](=O)[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]([OH:14])=[C:4]([C:1](=[O:3])[CH3:2])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)c1[nH]c(=O)c2ccccc2c1O
Product: CC(=O)c1nc(Cl)c2ccccc2c1O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-acetyl-4-hydroxyisoquinolin-1(2H)-one (10.0 g, 49.2 mmol) and phosphoryl chloride (45.87 mL) was heated at 70° C. for 24 hours. After cooling to room temperature, the mixture was poured onto crushed ice and stirred for 30 minutes. The precipitated solid was collected by filtration in vacuum and air dried (9.82 g, 90%). LCMS calculated for C11H9ClNO2 (M+H)+: m/z=222.0; Found: 222.1.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[CH:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:21]1[N:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]2)=[CH:23][CH:22]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:21]4[N:26]=[CH:25][C:24]([CH2:27][N:28]5[CH2:29][CH2:30][CH:31]([OH:34])[CH2:32][CH2:33]5)=[CH:23][CH:22]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[CH:19][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OC1CCN(Cc2ccc(Cl)nc2)CC1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: OC1CCN(Cc2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Yield: 14.3 %

Procedure:
In a 10 mL microwave reaction vessel were placed compound 4 (40 mg, 158 μmol), 1-(6-chloro-pyridin-3-ylmethyl)piperidin-4-ol (36 mg, 158 μmol), tris(dibenzylideneacetone)dipalladium (0) (7.2 mg, 7.9 μmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (11 mg, 20 μmol), and cesium carbonate (25 μl, 316 μmol) followed by 1,4-dioxane (3 mL). The vessel was purged with N2 for 5 min, then capped and subjected to microwave condition (1.5 h at 120° C.). After the volatiles were removed, the residue was purified by combi-flash column chromatography followed by reverse phase preparative HPLC (acetonitrile/H2O containing 0.1% TFA each, 40 min from 10 to 40%). Lyophilization provided compound 342 (10 mg) as an off-white solid (TFA salt). 1H NMR (500 MHz, DMSO-d6) δ ppm 10.00 (1 H, s), 9.32 (1 H, s), 9.03 (1 H, s), 8.46 (1 H, d, J=5.1 Hz), 8.32 (1 H, d, J=8.3 Hz), 8.19 (1 H, d, J=1.7 Hz), 8.04-8.10 (1 H, m), 7.72 (1 H, dd, J=8.6, 2.0 Hz), 5.39 (1 H, quin, J=8.8 Hz), 4.54 (1 H, d, J=3.9 Hz), 3.43 (3 H, s), 2.64-2.72 (2H, m), 2.37-2.45 (2 H, m), 2.00-2.17 (6 H, m), 1.65-1.84 (4 H, m), 1.39 (2 H, t, J=9.9 Hz). LCMS-ESI (POS), M/Z, M+1: Found 444.2.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:14][C:15]([S@@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1/[CH:4]=[N:20]/[S@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 20.4 %

Procedure:
A mixture of 2-fluoro-5-(trifluoromethyl)benzaldehyde (1.00 g, 5.21 mmol), (S)-2-methylpropane-2-sulfinamide (631 mg, 5.21 mmol), and copper sulfate (1.66 g, 10.4 mmol) in dichloromethane is stirred at room temperature for 12 hours. Additional copper sulfate (1.66 g, 10.4 mmol) is added, and the mixture is stirred at room temperature for 5 hours. Then, the mixture is filtered through a pad of Celite, and the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (10:1) to give 314 mg (20% yield) of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]2[N:9]=[C:10]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[S:11][C:5]2=[N:4][C:3]=1Cl.[F-:20].[K+].S1(CCCC1)(=O)=O.C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[C:7](=[O:8])[N:6]2[N:9]=[C:10]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[S:11][C:5]2=[N:4][C:3]=1[F:20]
Reactant: [F-]
Reactant: CCCCCCSc1nn2c(=O)c(Cl)c(Cl)nc2s1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CCCCCCSc1nn2c(=O)c(Cl)c(F)nc2s1
Reaction time: 0.75 h
Yield: 71 %

Procedure:
A solution of 4.4 g of the thus obtained 6,7-dichloro-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one, 2.2 g of spray dry potassium fluoride and 20 ml of sulfolane was heated to 185°~200° C. and stirred for 45 minutes. After cooling, toluene and water were added to the reaction solution and extraction was carried out. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was separated by silica gel column chromatography using an ethyl acetate/toluene mixture as an elutant. Thus 3.0 g of 6-chloro-7-fluoro-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21](=[O:26])[NH:22][CH2:23][C:24]#[CH:25])=[CH:11][CH:12]=2)[N:7](C2CCCCO2)[N:6]=1)=[O:4].C(Cl)Cl.OC(C(F)(F)F)=O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21](=[O:26])[NH:22][CH2:23][C:24]#[CH:25])=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:4]
Reactant: C#CCNC(=O)c1ccccc1Nc1ccc2c(C(=O)NC)nn(C3CCCCO3)c2c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C#CCNC(=O)c1ccccc1Nc1ccc2c(C(=O)NC)n[nH]c2c1
Yield: 49.7 %

Procedure:
Dissolved 6-(2-Prop-2-ynylcarbamoyl-phenylamino)-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carboxylic acid methylamide (30 mg) in 1.5 mL of a 90:10:1 mixture of CH2Cl2:Trifluoroacetate TFA:triethyl silane and heat to reflux for 2 hours. Diluted the solution with toluene (40 mL) and concentrate by rotary evaporation to an oil. Dissolved the oil in DMF (1 mL), and filter using a 0.2-micron syringe filter. Used prep-HPLC to isolate the desired compound (12 mg, 50%). 1H NMR (CDCl3-d) δ 9.96 (1H, s), 9.49 (1H, s), 8.28 (1H, d, J=8.85 Hz), 7.47 (1H, m), 7.34 (1H, m), 7.22 (1H, m), 7.15 (1H, dd, J1=8.76 Hz, J2=1.79 Hz), 6.99 (1H, m), 6.86 (1H, t, J=6.97 Hz), 6.31 (1H, m), 4.23 (2H, dd, J1=5.18 Hz, J2=2.54 Hz), 3.49 (3H, s), 2.29 (s,1H).
Reaction SMILES: [H-].[Na+].[C:3]([C:11]1[CH:15]=[C:14]([CH3:16])[N:13]([CH:17]([CH3:20])[CH2:18][OH:19])[C:12]=1[CH3:21])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:22]I>C(COC)OC>[CH3:22][O:19][CH2:18][CH:17]([N:13]1[C:14]([CH3:16])=[CH:15][C:11]([C:3](=[O:10])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[C:12]1[CH3:21])[CH3:20]
Reactant: CI
Reactant: Cc1cc(C(=O)c2ccccc2)c(C)n1C(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COCC(C)n1c(C)cc(C(=O)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
Sodium hydride (50% content, 115 mg, 2.3 mmoles) was washed with 20 ml of petroleum ether twice, and 15 ml of dimethoxyethane was added. To the mixture was added 300 mg (1.17 mmoles) of 2-(3-benzoyl-2,5-dimethylpyrrol-1-yl)-2-methylethanol, and the mixture was stirred at room temperature for 2 hours. Then, 5 ml of methyl iodide was added, and the mixture was further stirred at room temperature for 5 hours. After the reaction, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to afford 270 mg of a crude product. The product was chromatographed on a column of silica gel using cyclohexane/ethyl acetate (4/1) as an eluent to afford compound (206) (220 mg, 0.81 mmole, 69.4%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].C1(C)C=CC=CC=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=1)([O-:19])=[O:18]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[C:2]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[NH:8][N:9]=2)=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: NNc1ccccc1I
Reactant: C#Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cc2n[nH]c3ccccc23)cc1
Yield: 19.3 %

Procedure:
Into a dry reaction vessel, 10.3 g (44 mmol) (2-iodophenyl)hydrazine, 100 mL toluene, 50 mL triethylamine, 8.41 g (57.2 mmol) p-nitro phenylacetylene, 500 mg (Ph3P)2PdCl2, 250 mg cuprous iodide were respectively added, and reacted at 110° C. under protection of nitrogen for 4.5 h. It was cooled, rotate evaporated to dryness to remove the solvent, chromatographed on a column to obtain a red liquid 2.15 g (8.50 mmol), at a yield of 19.3%.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10](Cl)[C:5]2=[N:4][C:3]=1[CH3:12].Cl.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>C(O)C(C)C>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:20][CH:21]=3)[C:5]2=[N:4][C:3]=1[CH3:12]
Reactant: Cc1nc2c(Cl)nccn2c1Br
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CC(C)CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(NCc3ccc(S(N)(=O)=O)cc3)nccn2c1Br
Temperature: 108 °C
Reaction time: 16 h
Yield: 29.9 %

Procedure:
To a solution of 3-bromo-8-chloro-2-methyl-imidazo[1,2-a]pyrazine (0.77 g, 3.12 mmol) in iBuOH (10 ml) is added 4-aminomethyl-benzenesulfonamide hydrochloride (1.04 g, 4.69 mmol) and DIPEA (1.63 ml, 9.36 mmol). The reaction is heated to 108° C. and stirred for 16 h. After this time the solution is allowed to cool, resulting in a thick white precipitate. The precipitate is filtered and washed with diethyl ether to give 4-[(3-Bromo-2-methyl-imidazo[1,2-a]pyrazin-8-ylamino)-methyl]-benzenesulphonamide as a white solid (0.37 g, 30%)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Cl:8][C:9]1[C:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:13][C:12]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]=[CH:31][CH:30]=[C:29]3Cl)=[CH:11][N:10]=1>CN(C=O)C>[Cl:8][C:9]1[C:14]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)(=[O:17])=[O:18])=[CH:13][C:12]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]=[CH:31][CH:30]=[C:29]3[O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:11][N:10]=1
Reactant: COCCO
Reactant: O=S(=O)(Nc1cc(-c2ccc3nccc(Cl)c3c2)cnc1Cl)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccnc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4)c3)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 25.6 %

Procedure:
(Some starting materials may be obtained from Aldrich, St. Louis, Mo.) To a solution of 2-methoxyethanol (0.2 mL, 2 mmol) in DMF (10 mL) at 0° C. was added sodium hydride, 60% dispersion in mineral oil (0.09 mL, 2 mmol). After the addition, the ice bath was removed. The reaction mixture was warmed up to rt and continued to stir at rt. After 20 min, N-(2-chloro-5-(4-chloroquinolin-6-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (0.1 g, 0.2 mmol) was added. It was continued to stir for 20 h. LC/MS showed total conversion. Reaction was quenched with water. The resulting mixture was partitioned between EtOAc/water. The organic layer was washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified using SiO2 (12 g) chromatography with hexanes:acetone=80%:20% as the solvent system to afford the desired product as light yellow solid (25 mg). A peak at 28 min was collected. The solvent was removed in vacuo to afford the desired product as light yellow solid (80.0 mg). MS (ESI pos. ion) m/z: calc'd for C23H19ClFN3O4S: 487.1; found: 488.4 (M+1). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.53 (s, 3 H) 3.90-4.00 (m, 2 H) 4.35-4.49 (m, 2 H) 6.84 (d, J=5.26 Hz, 1 H) 7.19 (t, J=8.55 Hz, 2 H) 7.88 (ddd, J=8.62, 4.17, 3.87 Hz, 3 H) 8.17 (d, J=8.77 Hz, 1 H) 8.33 (d, J=2.34 Hz, 1 H) 8.43 (d, J=1.90 Hz, 1 H) 8.50 (d, J=2.34 Hz, 1 H) 8.81 (d, J=5.26 Hz, 1 H).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][O:11]C(=O)C)[CH:5]=1>CO>[CH3:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][OH:11])[CH:5]=1
Reactant: CC(=O)OCc1cc(C)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccnc(CO)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
5 N Aqueous sodium hydroxide solution (2 mL) and methanol (4 mL) were added to acetic acid 4-methyl-pyridin-2-ylmethyl ester (774 mg, 4.69 mmol) described in Manufacturing Example 11-1-2, and this mixture was stirred for 10 minutes at 60° C. The reaction solution was partitioned into water and ethyl acetate. The separated aqueous layer was further extracted with ethyl acetate twice. The ethyl acetate layers were combined and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure to obtain the title compound (410 mg, 71.0%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.S(O[CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[F:46])(=O)(=O)C>C(O)C>[F:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[CH2:39][CH2:38][CH2:37][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1
Reactant: CS(=O)(=O)OCCCc1ccccc1F
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCC1CCN(CCCc2ccccc2F)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
Under nitrogen gas, 0.38 ml (4.90 mM) of methanesulfonyl chloride was added to a solution of 499 mg (3.24 mM) of 2-fluorophenylpropanol and 0.90 ml (6.47 mM) of triethylamine in methylene chloride (6 ml) at 0° C. and the mixture was stirred at the prevailing temperature for 20 minutes. The reaction was stopped by adding saturated aqueous solution of sodium hydrogen carbonate. The reaction mixture was then extracted with diethyl ether. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide 0.722 g (3.24 mM) of 2-fluorophenylpropyl mesylate. To a solution of 0.58 g (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.2 mM) of triethylamine in ethanol was added 0.60 g (2.69 mM) of 2-fluorophenylpropyl mesylate at room temperature, and the mixture was refluxed under nitrogen for 16 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic -layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/ethyl acetate 20-50%) to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([OH:10])=O.[NH2:11][CH2:12][CH2:13][NH:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([NH:11][CH2:12][CH2:13][NH:14][C:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:10]
Reactant: Cn1ncc(C(=O)O)c1N
Reactant: NCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc(C(=O)NCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
To a solution of 5-amino-1-methyl-1H-pyrazole-4-carboxylic acid (7.1 g), N-(2-aminoethyl)tritylamine (15.1 g) and triethylamine (10.1 g) in chloroform (200 ml) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (9.6 g), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate and dried in vacuo to give 5-amino-1-methyl-N-[2-(tritylamino)ethyl]-1H-pyrazole-4-carboxamide (11.4 g) as a solid.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[ClH:8].[CH3:9]O>>[ClH:8].[CH3:9][O:4][C:3](=[O:5])[C:2]([NH2:1])([CH3:7])[CH3:6]
Reactant: CC(C)(N)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C(C)(C)N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-aminoisobutyric acid in 125 ml of methanol is added 125 ml of methanol saturated with HCl. The initial mixture becomes a solution and the reaction is sealed and allowed to stir at room temperature overnight. The next day the reaction is evaporated, first neat and then from toluene to give a solid.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH2:16])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]3[O:31][C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=3)[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:30]6[O:31][C:32]([C:35]([F:38])([F:36])[F:37])=[N:33][N:34]=6)[CH:28]=5)[N:23]=[CH:22][N:21]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Reactant: Nc1ccc2c(cnn2Cc2ccc(F)cc2)c1
Product: Fc1ccc(Cn2ncc3cc(Nc4ncnc5ccc(-c6nnc(C(F)(F)F)o6)cc45)ccc32)cc1

Procedure:
The title compound was prepared according to Procedure A from 1-(4-fluoro-benzyl)-1H-indazol-5-ylamine and 4-chloro-6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.91(1H,bs), 9.55(1H,s), 8.91(1H,s), 8.69(1H,dd), 8.23(1H,s), 8.14(2H,m), 7.88(1H,d), 7.69(1H,dd), 7.36(2H,m), 7.18 (2H,dd), 5.71(2H,s); m/z (M+1+) 506.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:19])[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:3]=1.C1C(=O)N(Br)C(=O)C1.C1CCN2C(=NCCC2)CC1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:19])[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:3]=1
Reactant: O=C1CCc2c(cc(Br)nc2-c2ccccc2Cl)N1c1ccccc1Cl
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=c1ccc2c(-c3ccccc3Cl)nc(Br)cc2n1-c1ccccc1Cl

Procedure:
7-Bromo-1,5-bis(2-chlorophenyl)-3,4-dihydro[1,6]naphthyridin-2(1H)-one (30 mg, 0.067 mmol) in carbon tetrachloride (5 ml) was treated with NBS (15 mg) and AlBN (1.1 mg) and heated under reflux for 1.5 h. DBU (10 μl) was added, the mixture cooled, and dichloromethane (5 ml) added, followed by 8% sodium bicarbonate (10 ml). The mixture was passed through a hydrophobic frit and evaporated in vacuo to give the product as an off-white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH3:13])[CH:6]=1.[Li]C(C)(C)C.[CH:19](=[O:22])[CH2:20][CH3:21]>CCCCC>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH3:13])[CH:8]=[CH:9][C:10]=1[CH:19]([OH:22])[CH2:20][CH3:21]
Reactant: CCCc1cccc(OCOC)c1
Reactant: CCC=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Product: CCCc1ccc(C(O)CC)c(OCOC)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
To a solution of 1-(methoxymethoxy)-3-propylbenzene (14.0 g, 77.7 mmol) in pentane (80 mL) at 0° C. was added tert-BuLi (55 mL, 93.2 mmol, 1.7 M in pentane) slowly. The resulting suspension was stirred at 0° C. for 1.5 h and then the precipitate was allowed to settle without stirring at 0° C. for 1.5 h. The supernatant was removed via a syringe and THF (180 mL) was added. To the thick slurry at 0° C. was added propionaldehyde (11.2 mL, 155.4 mmol, ran through basic alumina) slowly. The resulting solution was stirred at 0° C. for 1 h and then at room temperature for 12 h. About half of the solvent was removed in vacuo, the reaction solution was quenched with water, and most of the remaining THF was removed in vacuo. Extraction in EtOAc (2×200 mL) with 1:1 saturated NH4Cl/brine (100 mL) and flash chromatography with silica gel (gradient to 32% EtOAc/hexanes) provided the title compound as a colorless liquid (12.9 g, 70% yield): 1H NMR (300 MHz, CDCl3) δ 0.94 (t, 3H, J=7.2 Hz), 0.96 (t, 3H, J=7.2 Hz), 1.61 (m, 2H), 1.82 (m, 2H), 2.37 (broad s, 1H), 2.55 (t, 2H, J=7.7 Hz), 3.50 (s, 3H), 4.82 (t, 1H, J=6.6 Hz), 5.22 (s, 2H), 6.84 (d, 1H, J=7.7 Hz), 6.91 (s, 1H), 7.23 (d, 1H, J=7.7 Hz); MS m/e 221 (M+H−H2O)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][S:8]2)[CH:2]=1.[OH:13]O>ClCCl.C(O)C.CC(O)=CC(C)=O.CC(O)=CC(C)=O.[Cu]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][S@:8]2=[O:13])[CH:2]=1
Reactant: c1cncc([C@@H]2CCCCS2)c1
Reactant: OO
Agent: [Cu]
Agent: CC(=O)C=C(C)O
Solvent: CCO
Solvent: ClCCl
Product: O=[S@@]1CCCC[C@H]1c1cccnc1
Reaction time: 7 h

Procedure:
A solution of (S)-2-(3-pyridyl)tetrahydro-2H-thiopyran (1.5 g) in dichloromethane (15 ml) is treated with ethanol (15 ml), followed by copper acetylacetonate (0.22 g). The green-blue solution is treated with a solution of hydrogen peroxide (2 ml; 27.5%) in ethanol (2 ml). After 2 hours the solution is treated with a further quantity of solution of hydrogen peroxide (1 ml; 27.5%) in ethanol (1 ml), followed by a similar further quantity each hour for seven hours. Thus, a total of 10 ml of 27.5% hydrogen peroxide is used. After a further period of four hours, the mixture is treated with dichloromethane (10 ml) and extracted with water (4×25 ml). The combined aqueous extract is treated with sodium ethylenediaminetetraacetate (0.5 g), followed by sufficient solid sodium chloride to form a saturated solution. This is then extracted with dichloromethane (4×50 ml), and the combined organic extract is dried over magnesium sulphate and evaporated, to give (1R,2S)-2-(3-pyridyl)tetrahydro-2H-thiopyran 1-oxide (1.1 g), in the form of a yellow solid.