Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[NH:10][N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:3]=12.[CH3:20][Si:21]([CH3:29])([CH3:28])[CH2:22][CH2:23][O:24][CH:25](Cl)Cl.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:29])([CH3:28])[CH3:20])[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:3]=12
Reactant: CSc1nc(Cl)c2c(-c3ccccc3Cl)n[nH]c2n1
Reactant: C[Si](C)(C)CCOC(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2c(-c3ccccc3Cl)nn(COCC[Si](C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a solution of 4-chloro-3-(2-chloro-phenyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (2.30 g, 7.39 mmol) and 2-(trimethylsilyl)-ethoxymethylene chloride (1.96 mL, 11.086 mmol) in dry DMF (40 mL) at 0° C. under nitrogen was added sodium hydride (0.354 g of 60% solids in mineral oil, 14.78 mmol). The reaction mixture was stirred for two hours and allowed to warm to room temperature during this time. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was separate, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica (01% to 20% EtOAc in hexanes) to give 2.30 g of 4-chloro-3-(2-chloro-phenyl)-6-methylsulfanyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:9][CH3:10])[C:6]([OH:8])=O)(=[O:3])[CH3:2].N1C=CC=CC=1.ClC(=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1>[C:1]([NH:4][CH:5]([CH2:9][CH3:10])[C:6](=[O:8])[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCC(NC(C)=O)C(=O)O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)C(CC)NC(C)=O
Temperature: 25 °C

Procedure:
9.2 g (63.4 mmol) 2-(Acetylamino)butanoic acid are suspended in 120 ml tetra-hydrofurane and heated to reflux together with 15.0 g (190 mmol) pyridine and a bit of N,N-dimethylaminopyridine. While heating at reflux, 17.3 g (127 mmol) ethyl chloro(oxo)acetate are added dropwise. The reaction mixture is heated at reflux until no more evolution of gas can be observed. After cooling down to room temperature, the reaction mixture is added to ice water and the organic phase extracted with ethyl acetate. The dried organic phase is evaporated to dryness in vacuo, dissolved in ethanol and the solution directly used for the next reaction.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH3:14][O:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>C(#N)C>[CH3:14][O:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20](=[O:21])[NH:6][C:5]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COC(=O)CCCC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CC#N
Product: COC(=O)CCCC(=O)Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 23 h

Procedure:
To a solution of 2,4-dinitroaniline (6.00 g, 32.76 mmol) in acetonitrile (60 mL) was added methyl-5-chloro-5-oxo-valerate (5.44 mL, 39.31 mmol, 1.2 equiv) at 20° C. in one portion. The reaction mixture was then heated to 75° C. Reaction progress was monitored periodically by HPLC (HPLC Method A). The reaction was complete after stirring for 23 hours at 75° C. to give 4-(2,4-dinitro-phenylcarbamoyl)-butyric acid methyl ester. This reaction mixture was cooled to 20° C. and a portion of the solvent was then removed in vacuo to yield a total reaction volume of approximately 25 mL. To the concentrated mixture was then added potassium carbonate (13.58 g, 98.26 mmol, 3.0 equiv) and methyl iodide (10.20 mL, 163.48 mmol, 5.0 equiv.) at 20° C. Reaction progress was monitored periodically by HPLC Method A. The reaction was complete after 17 hours at 20° C. to give 4-[(2,4-dinitro-phenyl)-methyl-carbamoyl]-butyric acid methyl ester. The reaction mixture was filtered to remove excess K2CO3 and the filtrate was poured into cold water (200 mL) to yield off-white solids. The solid product was collected by vacuum filtration and dried at 60° C. under vacuum/N2 sweep overnight to give 8.914 g, (84% yield) as a light tan solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.C([Li])CCC.CN(C)[CH:34]=[O:35].[Cl-].[NH4+]>O1CCCC1>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([CH:34]=[O:35])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C(=O)c1cc2c(s1)-c1cc(C=O)ccc1OC2)c1ccc(F)cc1F
Temperature: 24 °C
Reaction time: 0.25 h

Procedure:
To a solution of 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp (19.6 mg, 0.0449 mmol, 1 equiv) in tetrahydrofuran (1 mL) at −78° C. was added n-butyllithium (54 μL, 0.14 mmol, 3.0 equiv, 2.5 M in hexanes) dropwise. After 15 min, N,N-dimethylformamide (35 μL, 0.45 mmol, 10 equiv) was added. After 40 min, the reaction mixture was warmed to 24° C. for 50 min. Saturated aqueous ammonium chloride solution (5 mL) was added to the reaction mixture, and the resulting solution was extracted with ethylacetate (3×3 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated to afford the corresponding aldehyde, N-(2,4-difluorophenyl)-8-formyl-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide. LCMS (ESI) m/z: 386.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][CH:48]([CH3:53])[CH2:49][C:50](Cl)=[O:51].O>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:50](=[O:51])[CH2:49][CH:48]([CH3:53])[CH3:47])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: CC(C)CC(=O)Cl
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)CC(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 2.1 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.400 g, 0.66 mmol) in pyridine (4 mL) was added 3-methylbutanoyl chloride (0.100 mL, 0.80 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave the title compound (0.005 g, 5% yield) which was isolated by filtration: 1H NMR (DMSO-d6) δ 14.20 (br s, 1H), 13.43 (s, 1H), 10.08 (s, 1H), 8.69 (s, 1H), 8.25 (s, 1H), 8.10 (d, 1H), 7.75 (d, 1H), 7.69 (t, 3H), 7.49 (t, 1H), 2.24 (d, 2H), 2.18 (m, 1H), 0.96 (d, 6H); ES-MS (m/z) 361 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:33])[C:5]([CH2:34]O)=[N:4]1)[CH3:2].CS(Cl)(=O)=O.[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>ClCCl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:11]=2)[C:6](=[O:33])[C:5]([CH2:34][N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(CO)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Reactant: C1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCn1nc(CN2CCCCC2)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Reaction time: 2 h
Yield: 57 %

Procedure:
To a suspension of 1-ethyl-3-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy)cinnolin-4(1H)-one (Example 8d) (2.13 g, 4.47 mmol) in Dichloromethane (DCM) (40 mL) in an ice bath under N2 was added TEA (1.495 mL, 10.73 mmol) followed by methanesulfonyl chloride (0.627 mL, 8.05 mmol) (white suspension turned into a light yellow clear solution). The mixture was stirred in an ice bath for 2 h, and then the above reaction mixture was added dropwise into a stirred solution of piperidine (1.195 mL, 12.07 mmol) in dichloromethane (DCM) (40.0 mL) at room temperature overnight. The reaction mixture was concentrated and purified through column chromatography eluting with dichloromethane and methanol/dichloromethane/ammonium hydroxide (from 0% to 100%) over 15 mins twice to afford 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-3-(piperidin-1-ylmethyl)cinnolin-4(1H)-one (1.54 g, 2.55 mmol, 57.0% yield). LCMS (M+H)+: 544.0
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[CH:20][N:19]=2)=[O:23])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nc1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NC2CC2)nc1
Yield: 75 %

Procedure:
As described for example 23f, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (75 mg, 0.23 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (63 mg, 75%), which was obtained as a white solid. MS: m/e=369.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][CH2:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:21]([N:24]([CH3:26])[CH3:25])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][CH2:12][C:13]2([OH:18])[CH2:14][CH2:15][CH2:16][CH2:17]2)=[CH:8][C:9]=1[N:10]=[CH:21][N:24]([CH3:26])[CH3:25])=[O:4]
Reactant: COC(=O)c1sc(CCC2(O)CCCC2)cc1N
Reactant: COC(OC)N(C)C
Product: COC(=O)c1sc(CCC2(O)CCCC2)cc1N=CN(C)C

Procedure:
3-Amino-5-[2-(1-hydroxycyclopentyl)ethyl]thiophene-2-carboxylic acid methyl ester and dimethoxymethyldimethylamine were reacted by method B. The product with the molecular weight of 324.45 (C16H24N2O3S) was obtained in this way; MS (ESI): 325 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:26][O:27][CH3:28]>C(Cl)Cl>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][O:13][CH2:26][O:27][CH3:28])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC[C@](C)(O)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 25 °C
Reaction time: 46 h
Yield: 69.2 %

Procedure:
(R)-2-Chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (7.4 g, 31 mmol) was dissolved in methylene chloride (120 ml). N,N-diisopropylethylamine (13.1 ml, 74 mmol) and chloromethylmethyl ether (7.1 ml, 74 mmol) were added to the solution followed by stirring at room temperature for 46 hours. The reaction mixture was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford (R)-2-chloro-1-(2-hydroxy-3-methoxymethoxy-2-methylpropyl)-4-nitroimidazole (6.0 g, yield 69%) as a light yellow oil.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:22][C:23]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>ClCCCl.C(O)(=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:23]([NH:22][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)ccc1NC1CCCCC1
Temperature: 25 °C

Procedure:
Cyclohexanone and sodium triacetoxyborohydride were added to a 1,2-dichloroethane-acetic acid solution of methyl 2-amino-5-chlorobenzoate, followed by stirring at room temperature. By post-treating the reaction liquid, methyl 5-chloro-2-(cyclohexylamino)benzoate was obtained.
Reaction SMILES: C([N:5]1[C:9]([N:10]([NH:19][C:20](=[O:30])[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]([C:31]([CH3:34])([CH3:33])[CH3:32])=[N:6]1)(C)(C)C>C(O)=O.O>[C:31]([C:7]1[CH:8]=[C:9]([N:10]([NH:19][C:20](=[O:30])[CH2:21][C:22]2[CH:23]=[C:24]([F:29])[CH:25]=[C:26]([F:28])[CH:27]=2)[C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:5][N:6]=1)([CH3:32])([CH3:33])[CH3:34]
Reactant: CCOC(=O)CC(=O)N(NC(=O)Cc1cc(F)cc(F)c1)c1cc(C(C)(C)C)nn1C(C)(C)C
Solvent: O=CO
Solvent: O
Product: CCOC(=O)CC(=O)N(NC(=O)Cc1cc(F)cc(F)c1)c1cc(C(C)(C)C)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
250 mg of compound 23 (Example 119) was refluxed in 3 mL of formic acid for 20 min. The mixture was cooled to 25° C. and diluted with 12 mL of distilled water. The resulting precipitate was collected by filtration and dried in a stream of air. It was suspended in 5 mL of chloroform and filtered. The solvent was evaporated from the filtrate at reduced pressure. The residue was stirred with 5 mL of tert-butyl methyl ether for one hour, and then recovered by filtration. The product was obtained as a white powder. Analysis gave 56.84% C, 5.87% H, 13.28% N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)=[O:16].[OH-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:20]2[CH:21]=[CH:22][C:17]([C:15](=[O:16])[CH2:14][CH3:13])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: CCC(=O)c1ccc(F)cc1
Reactant: COc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc(SCc2ccc(OC)cc2)cc1
Reaction time: 0.17 h

Procedure:
To (4-methoxyphenyl)methane thiol (20 g) in N,N-dimethylformamide (200 ml) solution, sodium hydride (60% mineral oil dispersion) was added under ice cooling and the mixture was stirred for 10 minutes. 4-fluoropropiophenone was added to the reaction solution and the mixture was stirred at room temperature for 3 hours. 1N sodium hydroxide aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over with anhydrous sodium sulfate, then concentrated. Methanol was added to the residue, and the precipitated solid was collected by filtration to obtain the title compound (37.4 g).
Reaction SMILES: NC1C=CC(F)=CC=1[C:4](N(OC)C)=[O:5].C([Mg]Cl)(C)C.[CH3:20][C:21]1[C:22]([Mg]Br)=[N:23][CH:24]=[CH:25][CH:26]=1>C1COCC1>[CH3:20][C:21]1[C:22]([CH:4]=[O:5])=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1cccnc1[Mg]Br
Reactant: CON(C)C(=O)c1cc(F)ccc1N
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cccnc1C=O
Reaction time: 0.67 h

Procedure:
To a solution of 2-amino-5-fluoro-N-methoxy-N-methylbenzamide (1.0 g, 5.05 mmol) in THF (4.2 mL) was added isopropylmagnesium chloride (2.0M in THF, 5.0 mL, 10.1 mmol) at −40° C. The temperature was allowed to rise to −10° C. over 40 min then was lowered to −40° C. in an acetonitrile/dry ice bath. 3-Methyl-2-pyridinylmagnesium bromide (0.25M in THF, 20.2 mL, 5.0 mmol) was added dropwise and the solution was allowed to rise to rt over one hour. The solution was partitioned between satd ammonium chloride solution and DCM; organic extracts were concentrated then purified by silica gel column chromatography eluting with a gradient of 10-70% EtOAc in hexane to afford 2-amino-5-fluorophenyl)(3-methylpyridin-2-yl)methanone as a yellow oil: LC-MS (ESI) m/z 231.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:4][C:3]1=[O:18].S(Cl)([Cl:22])(=O)=O.N>C(Cl)Cl>[CH3:1][N:2]1[C:7]2[S:8][C:9]([Cl:22])=[CH:10][C:6]=2[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:4][C:3]1=[O:18]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cn1c(=O)nc(-c2ccccc2F)c2ccsc21
Agent: N
Solvent: ClCCl
Product: Cn1c(=O)nc(-c2ccccc2F)c2cc(Cl)sc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 0.5 g of 1-methyl-4-(o-fluorophenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 20 ml of methylene chloride is added dropwise 1.21 g of sulfuryl chloride. After stirring the reaction mixture for 72 hours at room temperature, the reaction mixture is neutralized with aqueous ammonia, then extracted with methylene chloride. The methylene chloride extracts are washed with water, dried and evaporated under reduced pressure to a residue, to give crystals which are recrystallized from ethanol to give 1-methyl-4-(o-fluorophenyl)-6-chloro-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 192.5° - 194°C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[S:8][C:7]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:6]1=2)=[O:4]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:7]=2[S:8][C:9]=1[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)=[O:4]
Reactant: COC(=O)C1c2ccc(OC)cc2SC1c1ccc(OC)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2ccc(OC)cc2)sc2cc(OC)ccc12
Yield: 93.8 %

Procedure:
To toluene (20 ml) and 2,3-dihydro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carboxylic acid methyl ester (0.7365 g, 2.33 mmol) is added dichlorodicyanoquinone (0.5405 g, 2.38 mmol, 2.38 mmol). The mixture is placed under nitrogen and heated to reflux for 16 hours, then cooled and filtered. The filter cake is rinsed with additional toluene and the filtrate and rinse are combined and concentrated to afford crude product, which is purified by silica gel chromatography (9:1 hexanes:ethyl acetate) to afford 0.7178 g (98%) of title compound: mp 85.4-86.6° C.; IR (KBr) 3010, 2860, 1700, 1608, 1478, 1251, 1068, 1020 cm-1 ; 1H NMR (CDCl3): δ8.21 (d, 1 H, J=8.7 Hz), 7.44 (d, 2 H, J=8.4 Hz), 7.24 (s, 1 H), 7.07 (d, 1 H, J=9 Hz), 6.95 (d, 2 H, J=8.4 Hz), 3.87 (s, 3 H), 3.85 (s, 3 H), 3.78 (s, 3 H); 13C NMR (CDCl3): d 164.6, 160.2, 157.7, 149.6, 139.8, 132.7, 130.9, 126.4, 125.4, 115.2, 113.7, 104.2, 55.7, 55.4, 51.6. Anal. Calcd. for C18H16O4S: C, 65.84; H, 4.91; S, 9.76. Found: C, 65.72; H, 4.90; S, 10.04.
Reaction SMILES: CC([Mg]Cl)C.[Br:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][N:8]=1.CN(C)[CH:16]=[CH:17][CH:18]=[O:19].Cl>C1COCC1>[Br:6][C:7]1[N:8]=[CH:9][C:10]([CH:16]=[CH:17][CH:18]=[O:19])=[CH:11][CH:12]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN(C)C=CC=O
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=CC=Cc1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
2-Propylmagnesium chloride (2.0 M in THF, 5.00 mL 10.00 mmol) was added to a solution of 2,5-dibromopyridine (2.37 g, 10.00 mmol) in THF (5.0 mL) at RT. The resulting brown suspension was stirred for 1 h and then cooled to 0° C. 3-Dimethylaminoacrolein (95%, 1.30 mL, 12.36 mmol) was added and the mixture was warmed to RT and stirred for 2 h. 2 N HCl was added and after 5 min the mixture was cooled to 0° C. The precipitated solids were removed by filtration and partitioned between ethyl acetate (75 mL) and 10% NaOH (25 mL). The ethyl acetate layer was washed with brine (25 mL), dried (MgSO4), and concentrated. Recrystallization from ethyl acetate provided 550 mg (26%) of the title compound as shiny brown flakes. MS 211 (M+H)+.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[CH3:21][C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]([C:34](O)=[O:35])=[CH:24][N:23]=1>>[CH3:21][C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]([C:34]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:35])=[CH:24][N:23]=1
Reactant: Cc1ncc(C(=O)O)c(-c2ccccc2)n1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Product: Cc1ncc(C(=O)N2[C@H](CNC(=O)c3cccc4c3OCCO4)C[C@@H]3C[C@@H]32)c(-c2ccccc2)n1

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-methyl-4-phenyl-pyrimidine-5-carboxylic acid. LC-MS (basic): tR=1.27 min; [M+H]+=471.2.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12](=O)[CH2:13]Cl)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH2:16][C:17]([NH2:19])=[S:18].O.O.O.C([O-])(=O)C.[Na+].C(O)C>O>[NH2:19][C:17]1[S:18][CH:13]=[C:12]([C:6](=[N:5][O:4][CH2:3][CH2:2][Cl:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:16]=1
Reactant: CCOC(=O)C(=NOCCCl)C(=O)CCl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NOCCCl)c1csc(N)n1
Yield: 45.7 %

Procedure:
Ethyl 2-(2-chloroethoxyimino)-3-oxo-4-chlorobutyrate (syn isomer, 68 g.), thiourea (20.2 g.), sodium acetate trihydrate (36.2 g.), ethanol (270 ml.) and water (170 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetate (syn isomer, 33.7 g.), mp 126° to 128° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][C:4]=1[F:14].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:15])[CH3:1])=[C:4]([F:14])[CH:5]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CN(C)c1ccc(C2CCCN2)cc1F
Product: CN(C)c1ccc(C2CCCN2S(=O)(=O)c2ccc(Cl)cc2)cc1F

Procedure:
The title compound, white solid, m.p. 99° C. and MS: m/e=383.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-dimethylamino-3-fluoro-phenyl)-pyrrolidine and 4-chloro -benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][C@@:2]1([OH:22])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[CH:11]([CH2:12][C@@H:13]2[O:21][C@@H:14]2[CH2:15]1)[CH2:10][CH2:9]3.O.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>ClCCl>[CH3:1][C@@:2]1([OH:22])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[CH:11]([CH2:12][C@H:13]([OH:21])[C@@H:14]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:15]1)[CH2:10][CH2:9]3
Reactant: C[C@]12C[C@H]3O[C@H]3CC1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@]2(C)O
Reactant: C1CNCCN1
Solvent: O
Solvent: ClCCl
Product: C[C@]12C[C@H](N3CCNCC3)[C@@H](O)CC1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@]2(C)O
Temperature: 150 °C
Yield: 60.2 %

Procedure:
To compound 28 (103 mg, 0.34 mmol) was added water (1 mL) and piperazine (3.5 g, 41 mmol). The solution was subsequently heated at 150° C. over a period of 24 h. The resulting mixture was diluted with dichloromethane (50 mL) and washed with water, dried with Na2SO4, filtered and evaporated under reduced pressure. The crude compound was purified by flash chromatography (DCM/MeOH: 9:1 containing 1.0% of TEA) to yield compound 29 (80 mg, 60%). 1H NMR (CDCl3) δ: 0.85 and 0.86 (2s, 18-CH3 and 19-CH3), 1.20 (s, 17α-CH3) 0.65-1.90 (residual CH and CH2), 2.50-3.30 (broad m, 2×CH2N, 2×CH2NH and 2α-CH), 3.85 (m, 3β-CH).