Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].[C:18]([C:21]1[C:26]([O:27][CH3:28])=[N:25][CH:24]=[CH:23][N:22]=1)(=O)[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C(OCC)(=O)C.C(N(CC)CC)C>[CH3:28][O:27][C:26]1[C:21]([CH:18]([N:15]2[CH2:14][CH2:13][CH:12]([C:10](=[O:11])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[F:2])[CH2:17][CH2:16]2)[CH3:19])=[N:22][CH:23]=[CH:24][N:25]=1
Reactant: O=C(Cc1ccccc1F)C1CCNCC1
Reactant: COc1nccnc1C(C)=O
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1nccnc1C(C)N1CCC(C(=O)Cc2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 9.5 %

Procedure:
After dissolving 1.012 g of triethylamine in 10 ml of ethanol, 2.575 g of 2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanone hydrochloride, 10 ml of ethanol, 2.951 ml of titanium (IV) tetraisopropoxide and 760 mg of 2-acetyl-3-methoxypyrazine were added in that order and the mixture was stirred for 5 hours and 20 minutes at room temperature. Next, 1.59 g of sodium triacetoxyborohydride was added to the reaction mixture and the mixture was stirred overnight at room temperature. A sodium carbonate solution and ethyl acetate were added to the reaction mixture and the mixture was filtered with celite. The filtrate was extracted with ethyl acetate, and the extract was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and then the residue was dissolved in ethyl acetate and filtered with silica gel. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (169 mg, 9% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([S:29]([C:32]5[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=5)(=[O:31])=[O:30])[CH2:24]4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:48](Cl)(=[O:50])[CH3:49]>C(Cl)Cl>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([S:29]([N:25]2[CH2:26][CH2:27][CH2:28][C@@H:23]([NH:22][C:18]3[N:17]=[C:16]([C:15]4[N:14]5[C:10]([S:11][CH:12]=[CH:13]5)=[N:9][C:8]=4[C:4]4[CH:3]=[C:2]([NH:1][C:48](=[O:50])[CH3:49])[CH:7]=[CH:6][CH:5]=4)[CH:21]=[CH:20][N:19]=3)[CH2:24]2)(=[O:31])=[O:30])=[CH:37][CH:36]=1
Reactant: Nc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Reaction time: 2 h
Yield: 90.1 %

Procedure:
The 4-[6-(3-aminophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-chlorophenyl)-sulfonyl]piperidin-3-yl}pyrimidin-2-amine (0.1 g, 0.177 mmol) was dissolved in DCM (5 ml) and treated sequentially with Hunig's base (46 uL, 0.265 mmol) and acetyl chloride (15 uL, 0.212 mmol). The mixture was kept at room temperature for two hours then was diluted with DCM (10 ml). The organic phase was washed with water (2×10 ml) and with an aqueous sodium chloride solution (10 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo, giving a yellow foam. The product was triturated in ether and filtered off, giving the title compound as a yellow solid (97 mg). M.p.=169-174° C. 400 MHz 1H NMR (DMSO-d6) δ: 9.89 (s, 1H), 8.72 (br. s, 1H), 8.12 (d, J=5.1 Hz, 1H), 7.82 (s, 1H), 7.80-7.75 (m, 2H), 7.70-7.64 (m, 3H), 7.41 (d, J=4.3 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.13 (d, J=7.4 Hz, 1H), 6.42 (d, J=5.5 Hz, 1H), 4.00-3.90 (m, 1H), 3.74 (d, J=8.6 Hz, 1H), 3.48 (d, J=11.7 Hz, 1H), 2.54-2.43 (m, 1H), 2.34 (t, J=10.2 Hz, 1H), 2.05 (s, 3H), 1.94-1.81 (m, 2H), 1.65-1.53 (m, 1H), 1.44-1.34 (m, 1H). LCMS: 608 [M+H]. Calc. for C28H26N7O3S2Cl.0.38 water.0.41 dioxane: C, 54.68; H, 4.65; N, 15.06. Found C, 54.68; H, 4.32; N, 15.05.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:31]=[CH:30][C:17]4[O:18][CH2:19][C:20]5[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[SH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36]>>[C:35]([CH2:34][CH2:33][S:32][CH:22]1[C:21]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:30]=[CH:31][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:37])=[O:36]
Reactant: COc1ccc2c(c1)COc1ccc(OCc3ccc4ccc(Cl)cc4n3)cc1C2O
Reactant: O=C(O)CCS
Product: COc1ccc2c(c1)COc1ccc(OCc3ccc4ccc(Cl)cc4n3)cc1C2SCCC(=O)O

Procedure:
2-(7-Chloroquinolin-2-yl)methoxy-11-hydroxy-8-methoxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([C:14](OCC)=[O:15])[C:9](OCC)=[O:10])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Na+]>ClCCl.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:19])([CH2:14][OH:15])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc(I)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(CO)(CO)c1ccc(I)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
3.1 g Diethyl 2-(4-iodophenyl)-2-methylmalonate are dissolved in 50 ml dichloromethane and cooled to −78° C. 50 ml of a 1 M solution of diisobutylaluminium hydride in dichloromethane are added dropwise and the mixture is warmed to −10° C. during 5 hours. Then 0.9 ml water and 0.9 ml of a 4 M solution of sodium hydroxide in water are added successively under cooling. The mixture is stirred vigorously for 10 minutes and is then partitioned between 600 ml ethylacetate and 500 ml of a 0.5 M hydrochloric acid. The organic phase is washed with brine and dried with magnesium sulphate. The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (petrole ether/ethylacetate 40:60 to 0:100).
Reaction SMILES: [OH-].[K+:2].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]([OH:11])=[O:10].S1C=CC=C1[CH2:17][C:18]([O-])=[O:19].[K+].[CH3:22][O:23][C:24](=[O:40])[CH2:25][NH:26][C:27](=[O:39])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35](=O)[CH2:36]Cl)[CH:29]=1>CO>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]([O-:11])=[O:10].[K+:2].[CH3:22][O:23][C:24](=[O:40])[CH2:25][NH:26][C:27](=[O:39])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35](=[S:3])[CH2:36][C:18](=[O:19])[CH3:17])[CH:29]=1
Reactant: O=C(O)Cc1cccs1
Reactant: COC(=O)CNC(=O)c1cccc(NC(=O)CCl)c1
Agent: O=C([O-])Cc1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CNC(=O)c1cccc(NC(=S)CC(C)=O)c1
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of potassium thiolacetate is prepared by adding 495 ml. of 2N-methanolic potassium hydroxide (0.99 mole) during a period of 15 min. to a solution of 74.3 ml. of thiolacetic acid (79.1 g., 1.04 mole) and 500 ml. of methanol while maintaining a temperature of 1°-5° C. The methanolic potassium thiolacetate solution thus prepared is added over 0.5 hr. to a mixture of N-[3-(chloroacetylamino)benzoyl]glycine methyl ester (267.5 g., 0.94 mole) in 2 l. of methanol while maintaining a temperature of 0°-5° C. After stirring for a period of 1 hr. without cooling, the reaction mixture is warmed at 40°-45° C. for 2 hrs., cooled, and filtered. The material collected is sequentially washed with 50% methanol, water, and 50% methanol, and then air dried to afford 262.4 g. (86% yield) of N-[3-(acetylthioacetylamino)benzoyl]glycine methyl ester, m.p. 86°-88° C. Crystallization from methanol provides analytically pure N-[3-(acetylthioacetylamino)benzoyl]glycine methyl ester, m.p. 90.0°-92.0° C.
Reaction SMILES: C([O:8][C:9]1[C:13]([CH:14]=[O:15])=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)C1C=CC=CC=1>[Pd].O1CCCC1>[OH:8][C:9]1[C:13]([CH:14]=[O:15])=[CH:12][N:11]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:10]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=Cc1cn(-c2ccccc2)nc1O
Yield: 78.9 %

Procedure:
3-Benzyloxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.30 g), 5% palladium on carbon (0.50 g) and tetrahydrofuran (10 mL) were subjected to catalytic reduction under a hydrogen atmosphere and atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated to give 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (0.16 g, yield 76%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 196-197° C.
Reaction SMILES: [N+:1]([C:4]([CH3:10])([CH:6]([OH:9])[CH2:7][CH3:8])[CH3:5])([O-:3])=[O:2].S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17]>>[N+:16]([O-:18])([O:9][CH:6]([CH2:7][CH3:8])[C:4]([CH3:10])([N+:1]([O-:3])=[O:2])[CH3:5])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: CCC(O)C(C)(C)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CCC(O[N+](=O)[O-])C(C)(C)[N+](=O)[O-]
Temperature: 0 °C

Procedure:
2-nitro-2-methyl-3-pentanol, 20 grams, was added to a mixture of 120 ml of concentrated sulfuric acid and 40 grams of 90% nitric acid over a 30-minute period at 6°-9° C. After 1/2 hour the acid solution was added to 800 ml of ice water.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9]3[CH:16]=[CH:15][C:14](N)=[CH:13][C:10]=3[C:11](=[O:12])[C:4]2=[CH:3][CH:2]=1)=[O:8].[NH2:18]C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C(N)=CC=1.NC1C2C(=O)C3C(=C(N)C=CC=3)C(=O)C=2C=CC=1.NC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C(NC(=O)C)=CC=1.NC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C(NC(=O)C2C=CC=CC=2)=CC=1.NC1C2C(=O)C3C(=C(NC(=O)C)C=CC=3)C(=O)C=2C=CC=1.NC1C2C(=O)C3C(=C(NC(=O)C4C=CC=CC=4)C=CC=3)C(=O)C=2C=CC=1.NC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C([N+]([O-])=O)=CC=1.NC1C2C(=O)C3C(=C([N+]([O-])=O)C=CC=3)C(=O)C=2C=CC=1.NC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C(Br)=CC=1.NC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C(NC)=CC=1.NC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C(NC2C=CC=CC=2)=CC=1>>[CH:1]1[CH:6]=[C:5]2[C:7]([C:9]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:18])[C:10]=3[C:11](=[O:12])[C:4]2=[CH:3][CH:2]=1)=[O:8]
Reactant: Nc1ccc2c(c1)C(=O)c1ccccc1C2=O
Reactant: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Agent: CC(=O)Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Agent: CC(=O)Nc1cccc2c1C(=O)c1cccc(N)c1C2=O
Agent: CNc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
β-aminoanthraquinone; 1,4diaminoanthraquinone; 1,5-diaminoanthraquinone; 1-amino-4-acetylaminoanthraquinone; 1-amino-4-benzoylamino anthraquinone; 1-amino-5-acetylamino-anthraquinone; 1-amino-5-benzoylamino-anthraquinone; 1-amino-4-nitro-anthraquinone; 1-amino-5-nitro-anthraquinone; 1-amino-4-bromo-anthraquinone; 1-amino-4-methylamino-anthraquinone; 1-amino-4-phenylamino-anthraquinone.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:20])[N:4]=1.CN(C=O)C.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.[K]>>[Cl:20][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:3]([CH2:2][N:30]1[C:26](=[O:36])[C:27]3[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:29]1=[O:31])=[N:4]2
Reactant: Fc1cccc(-c2nc3c(Cl)cccc3nc2CBr)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Temperature: 100 °C

Procedure:
To a heterogeneous mixture of 2-(bromomethyl)-5-chloro-3-(3-fluorophenyl)-quinoxaline (0.2401 g, 0.6829 mmol) in DMF (5.003 mL, 0.6829 mmol) was added potassium phthalimide (0.3162 g, 1.707 mmol) and the heterogeneous mixture was stirred at 100° C. After stirring at 100° C. for 1 h, the mixture was concentrated under reduced pressure and triturated with water (30 mL). The precipitate was collected by filtration. The solid was washed with water (50 mL), then MeOH (100 mL), and dried to give 2-((5-chloro-3-(3-fluorophenyl)-quinoxalin-2-yl)methyl)isoindoline-1,3-dione as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.04 (1 H, dd, J=7.6, 1.4 Hz), 7.84-7.92 (5 H, m), 7.60-7.81 (4 H, m), 7.38-7.46 (1 H, m), 5.22 (2 H, s); LC-MS (ESI) m/z 418.1 [M+H]+. The crude product was carried on crude without purification for the next step.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:12][C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2nc(-c3ccccc3)cs2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Phenyl-thiazol-2-ylamine (35.2 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1 mL of pyridine. The reaction mixture was stirred at room temperature overnight and then purified by reverse-phase preparative liquid chromatography (20.6 mg, 0.0635 mmol, 31.8%). ESI-MS m/z calc. 294.1. found 295.2 (M+1)+ Retention time 3.55 minutes.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)(=O)=O.[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:22].[O-]CC.[Na+].S([O-])(=O)(=O)C.C(O)(=O)C>CCO>[C:21]([CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 37.5 °C

Procedure:
Combine tert-butyl 4-(2-methylsulfonyloxyethyl)piperidine-1-carboxylate (5.26 kg, 17.1 mol), ethyl cyanoacetate (7 kg, 62 mol), 21% sodium ethoxide in EtOH (8.25 L, 24.75 mol) and EtOH (35 L) in a 50 L reactor under a nitrogen atmosphere. Heat the mixture at 35-40° C. for 18 h at which time NMR analysis shows 20% of the mesylate remaining Continue heating the mixture at 35-40° C. for 24 h at which time NMR analysis shows only a small amount of mesylate. Slowly cool the reaction to RT and add glacial acetic acid (1422 mL, 22.68 mol) over 30 min. Concentrate the mixture using vacuum distillation and then partition between water (25 L) and EtOAc (35 L). Separate the layers and extract the aqueous phase with EtOAc (10 L). Combine the organic portions, wash with brine (15 L), and concentrate to a red oil. Purify the oil using silica gel chromatography (75 kg silica gel, 65-250 mesh), eluting with hexane (40 L) and then 20% EtOAc/hexane to provide a fraction (7.8 kg) that is 30% ethyl cyanoacetate/70% desired product. Concentrate the material by wipe film distillation at 100° C. and 210 mtorr vacuum, collecting the non-volatile fraction to provide the title compound (4.54 kg, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1/[CH:10]=[N:11]/[N:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)[CH:25]=3)[CH:19]=2)[CH:14]=[CH:13]1.Cl>CO>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1/[CH:10]=[N:11]/[N:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]4)[CH:25]=3)[CH:19]=2)[CH:14]=[CH:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(/N=C/c5c(Cl)ccc(F)c5Cl)c4c3)cn2)CC1
Agent: Cl
Solvent: CO
Product: Fc1ccc(Cl)c(/C=N/n2ccc3ncc(-c4cnn(C5CCNCC5)c4)cc32)c1Cl
Yield: 52.6 %

Procedure:
A solution of tert-butyl 4-[4-(1-{[(E)-(2,6-dichloro-3-fluorophenyl)methylidene]amino}-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (15 mg, 0.027 mmol) in MeOH (0.5 mL) was treated with HCl (4.0M solution in dioxane, 2.0 mL) at room temperature for 2 h. Solvents were removed and the residue was treated with aqueous NaHCO3, and extracted with ethyl acetate. The organic layer was dried, evaporated to afford the desired intermediate as a yellowish solid (6.5 mg, yield 53%).
Reaction SMILES: [N:1]1([C:11]2[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:13][C:14]3[C:19]([N:20]=2)=[CH:18][C:17]([C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[N:1]1([C:11]2[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:13][C:14]3[C:19]([N:20]=2)=[CH:18][C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCCc4ccccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCCc4ccccc43)nc2c1
Yield: 68.2 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(3,4-dihydroquinolin-1(2H)-yl)-2-phenylquinoxaline-6-carboxylate (100 mg, 0.25 mmol, 1.00 equiv), sodium hydroxide (20 mg, 0.5 mmol, 2.00 equiv), and methanol/H2O (20/5 mL). The resulting solution was heated to reflux for 4 hrs and then concentrated to dryness. The residue was diluted with 15 mL water and acidified to pH=5 with 3N aq. HCl. The resulting solid was collected by filtration, washed with water, and dried to afford 65 mg (65%) of 3-(3,4-dihydroquinolin-1(2H)-yl)-2-phenylquinoxaline-6-carboxylic acid as an orange solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5=[N:34][NH:35][C:36]([NH:37][CH2:38][CH2:39][OH:40])=[C:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5=[N:34][NH:35][C:36]([NH:37][CH2:38][CH2:39][OH:40])=[C:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]c(NCCO)c3CC4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]c(NCCO)c3CC4)cc2)CCC1
Reaction time: 0.01 h
Yield: 108.3 %

Procedure:
tert-butyl(1-(4-(3-((2-hydroxyethyl)amino)-8-phenyl-4,5-dihydro-2H-pyrazolo[3,4-f]quinolin-7-yl)phenyl)cyclobutyl)carbamate (25 mg, 0.045 mmol) was dissolved in TFA (1 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and freeze-dried to give the desired product as an off-white solid (22 mg, 71% yield). 1H-NMR (500 MHz, CD3OD) δ 8.06 (1H, s), 7.50 (2H, d), 7.44 (2H, d), 7.29-7.34 (3H, m), 7.22-7.28 (2H, m), 3.78 (2H, t), 3.41 (2H, t), 3.30 (2H, t), 2.90 (2H, t), 2.71-2.82 (2H, m), 2.54-2.66 (2H, m), 2.19-2.30 (1H, m), 1.91-2.03 (1H, m). LCMS (Method A) RT=3.30 min, M+H+=452.17.
Reaction SMILES: Br[CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+].C([O:11][C:12]([C:14]1[N:15]=[C:16]([SH:19])[S:17][CH:18]=1)=[O:13])C.Cl>O>[C:3]([C:2]1[N:15]=[C:16]([S:17][CH2:18][CH2:14][C:12]([OH:13])=[O:11])[S:19][CH:6]=1)([OH:5])=[O:4]
Reactant: CC(Br)C(=O)O
Reactant: CCOC(=O)c1csc(S)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCSc1nc(C(=O)O)cs1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
6.9 g of bromopropionic acid were dissolved in 100 ml of water, and the pH was adjusted to 7 with 1N NaOH. This solution was added dropwise to a suspension of 7.5 g of 4-ethoxycarbonyl-2-mercapto-1,3-thiazole in 75 ml of H2O. The pH was adjusted to 8-10 with 2N NaOH, and the mixture was stirred at room temperature for 4 h and at 60° C. for 2 h. The pH was maintained between 8 and 10. While cooling in ice, the mixture was acidified to pH 1 with 2N HCl, and the product was filtered off.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:1][C:2]1[N:11]=[C:10]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CNc1ccccc1
Product: CN(c1ccccc1)c1nc(Cl)nc2ccccc12

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and N-methylaniline (20 μL, 0.301 mmol) by a procedure similar to Example 1b and was isolated as white powder (40 mg, 80%). 1H NMR (CDCl3): 7.76 (dd, J=8.7, and 1.5 Hz, 1H), 7.56 (ddd, J=8.1, 6.6 and 1.5 Hz, 1H), 7.46-7.35 (m, 3H), 7.24-7.20 (m, 2H), 6.98 (ddd, J=8.7, 6.6 and 1.5 Hz, 1H), 6.90 (dd, J=8.7 and 1.5 Hz, 1H), 3.65 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]([Cl:14])([CH3:13])[CH2:11][OH:12].[H-].[Na+].[Cl-].[NH4+]>O1CCCC1>[Cl:8][C:6]1[CH:7]=[C:2]([O:12][CH2:11][C:10]([Cl:14])([Cl:9])[CH3:13])[N:3]=[CH:4][N:5]=1
Reactant: CC(Cl)(Cl)CO
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(Cl)(Cl)COc1cc(Cl)ncn1
Reaction time: 2 h
Yield: 48.3 %

Procedure:
First, 0.23 g of 4,6-dichloropyrimidine and 0.2 g of 2,2-dichloro-1-propanol were dissolved in 2 ml of tetrahydrofuran, to which 0.07 g of sodium hydride (60% in oil) was added at 0° C., followed by stirring at the same temperature for 2 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel chromatography to give 0.18 g of 4-chloro-6-(2,2-dichloropropyloxy)pyrimidine.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:4]([CH:5]=[CH:6][C:7](=[O:20])[C:8]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[CH:3]=1.[Br-].[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25][Zn+]>C1COCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25][C:2]1[CH:11]=[CH:10][C:9]2[N:4]([CH:5]=[CH:6][C:7](=[O:20])[C:8]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[CH:3]=1
Reactant: Fc1ccc(C[Zn+])c(F)c1
Reactant: O=c1ccn2cc(Br)ccc2c1-c1c(F)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1ccn2cc(Cc3ccc(F)cc3F)ccc2c1-c1c(F)cccc1F
Temperature: 90 °C

Procedure:
To a solution of 7-bromo-1-(2,6-difluorophenyl)-2H-quinolizin-2-one (100 mg, 0.3 mmole) was added 2,4-difluorobenzylzincbromide (0.5 N in THF, 1.2 ml), and tetrakis (15 mg) in THF. The mixture was heated to 90° C. until reaction complete. The mixture was diluted with ethyl acetate, washed with 1N HCl, brine and dried over MgSO4. Upon concentration, the mixture was purified by gel chromatography (100% ethyl acetate) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH:10]=[N:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C.Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C#CC=NO)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(-c2ccno2)c1
Reaction time: 0.05 h
Yield: 86.9 %

Procedure:
122 mg of the resulting oxime compound was dissolved in 20 ml of ethanol, and one drop of a 1N aqueous solution of sodium hydroxide was added. The solution was left to stand for 3 minutes, and three drops of 1N HCl was added to terminate the reaction. The solvent was evaporated under reduced pressure. The residue was extracted with a mixture of water and ethyl ether. The organic layer was separated, and the solvent was evaporated to give 106 mg (yield 87%) of the captioned compound as a pale yellow oil.