Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:16][C:17]4[C:22]([N:23]=3)=[CH:21][C:20]([C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=4)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:15]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:16][C:17]4[C:22]([N:23]=3)=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][CH:18]=4)[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4cccc(Cl)c4)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4cccc(Cl)c4)CC3)nc2c1

Procedure:
To a solution of methyl 3-(4-(3-chlorophenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (143.5 mg, 0.29 mmol, 1.00 equiv, 91%) in methanol (15 mL) was added a solution of sodium hydroxide (62.8 mg, 1.57 mmol, 5.00 equiv) in water (2 mL) dropwise with stirring. The resulting solution was stirred overnight at 50° C. in an oil bath, then concentrated under vacuum. The resulting solids were washed with methanol yielding 44 mg (34%) of 3-(4-(3-chlorophenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[CH2:21]([O:24][C:25]1[N:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1)[C:22]#[CH:23]>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31]([C:28]3[CH:27]=[N:26][C:25]([O:24][CH2:21][C:22]#[CH:23])=[CH:30][N:29]=3)=[O:32])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: C#CCOc1cnc(C(=O)O)cn1
Product: C#CCOc1cnc(C(=O)Nc2ccc(F)c([C@]3(C)C[C@@H](C(F)(F)F)OC(N)=N3)c2)cn1

Procedure:
The title compound was synthesized by procedures and steps analogous to those described in Method F (Example 32) above, but using (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (intermediate 4i) and 5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylic acid (J. Med. Chem. 2013, 56, 3980). The desired product was purified by reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 80% over 20 min. The product containing fractions were combined and neutralized with 1N NaOH solution. The free-based product was extracted with DCM. The organic phase was dried over Na2SO4 and the solvent was removed under reduced pressure to afford the title compound. MS m/z=452.1 [M+H]+. Calculated for C20H17ClF4N5O3: 451.1
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][C:6]=2[CH:23]=1.B([O-])([O-])O[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][CH3:38])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(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.C1(C)C=CC=CC=1>[C:15]([O:14][C:12]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][CH3:38])=[CH:28][CH:27]=3)=[CH:23][C:6]=2[CH:7]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[CH2:9][CH2:10]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C(=O)OC(C)(C)C)CC1
Reactant: CCOCCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
A mixture of methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.0 g), 4-(3-ethoxypropoxy)phenyl borate (0.62 g), 1M potassium carbonate solution (8 ml), ethanol (8 ml) and toluene (50 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.12 g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-(t-butoxycarbonyl)-7-[4-(3-ethoxypropoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.2 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][C:11]2([S:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:4][CH:3]=1>[Pd].CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]2([S:18]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)C2(CC#Cc3ccc(Cl)cc3)SC(=O)NC2=O)cc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COc1ccc(S(=O)(=O)C2(CCCc3ccc(Cl)cc3)SC(=O)NC2=O)cc1

Procedure:
A sample of 5-[3-(4-Chlorophenyl)prop-2-ynyl]-5-(4-methoxy-benzenesulfonyl)thiazolidine-2,4-dione (U.S. Pat. No. 5,605,918; February 1997; Wrobel, et al.) was hydrogenated in the presence of palladium on charcoal (10%) in methanol plus 2% water to give the title compound as a colorless glass, NMR (CDCl3) δ1.57 (m, 1H); 1.97(m, 1H); 2.20 (triplet of doublet), 1H); 2.45 (m, 1H); 2.61 (q, 2H); 3.92 (s, 3H); 7.0 (dd, 4H); 7.26 (d, 2H) 7.98 (d, 2H).
Reaction SMILES: [C:1]1([C:7](=[O:22])[C:8]([S:20][CH3:21])=[CH:9][CH:10]=[C:11]([N:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:28][N:29](C)[C:30](C(OCC)=O)=CC=[N+](C)C.CC[O-].[Na+]>C(O)C>[CH3:19][N:17]([CH3:18])[C:11](=[CH:10][CH:9]=[C:8]([S:20][CH3:21])[C:7]([C:1]1[CH:2]=[CH:3][C:4]([N:29]([CH3:30])[CH3:28])=[CH:5][CH:6]=1)=[O:22])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Reactant: CCOC(=O)C(=CC=C(SC)C(=O)c1ccccc1)N(C)C
Agent: CC[O-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=CC=C(SC)C(=O)c1ccc(N(C)C)cc1)N(C)C

Procedure:
The procedure is as in Example 4 for the preparation of ethyl 6-phenyl-6-oxo-5-methylthio-2-dimethylamino-2,4-hexadienoate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (8.6 g), a 2M ethanolic solution of sodium ethylate (15 cc) and α-methylthio-4-dimethylaminoacetophenone (5.8 g) in ethanol (60 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluent, ethyl 2-dimethylamino-6-(4-dimethylaminophenyl)-5-methylthio-6-oxo-2,4-hexadienoate (5.5 g) is obtained in the form of an orange-coloured oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[C:7]=1[OH:17])([CH2:4][CH3:5])([CH3:3])[CH3:2].[C:18]([OH:22])(=[O:21])[CH:19]=O.Cl>C(O)(=O)C>[C:12]([C:8]1[C:7](=[O:17])[C:6]([C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])=[CH:11][C:10](=[CH:19][C:18]([OH:22])=[O:21])[CH:9]=1)([CH2:15][CH3:16])([CH3:14])[CH3:13]
Reactant: O=CC(=O)O
Reactant: CCC(C)(C)c1cccc(C(C)(C)CC)c1O
Agent: Cl
Solvent: CC(=O)O
Product: CCC(C)(C)C1=CC(=CC(=O)O)C=C(C(C)(C)CC)C1=O
Temperature: 0 °C
Yield: 35 %

Procedure:
15.0 g (0.064 Mol) of 2,6-di-tert-amylphenol and 11.4 g (0.077 mol) of 50% aqueous glyoxylic acid are dissolved in 100 ml of acetic acid. The solution is then saturated at 15°-25° C. with hydrogen chloride gas and stirred at room temperature for additional four hours. The mixture is then poured in 400 ml of ice-water and extracted with 200 ml of ethyl acetate. The ethyl acetate layer is washed several times with water, dryed over anhydrous sodium sulfate, and evaporated in vacuo. The oily residue is then chromatographed on silica gel with ethyl acetate:hexane (1:20→1:3). The pure fractions are recrystallized from hexane to give 6.5 g of the title compound as orange needles, melting at 109°-110° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:34]([N:35]2[CH2:46][CH2:45][N:44]3[C:37](=[CH:38][C:39]4[CH2:40][C:41]([CH3:48])([CH3:47])[CH2:42][C:43]=43)[C:36]2=[O:49])=[CH:33][C:32]([F:50])=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1)(=[O:26])[CH3:25]>>[C:24]([O:27][CH2:28][C:29]1[C:30]([C:2]2[N:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:31][C:32]([F:50])=[CH:33][C:34]=1[N:35]1[CH2:46][CH2:45][N:44]2[C:37](=[CH:38][C:39]3[CH2:40][C:41]([CH3:48])([CH3:47])[CH2:42][C:43]=32)[C:36]1=[O:49])(=[O:26])[CH3:25]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CN1CCC(c2ccc(Nc3nc(Br)cn(C)c3=O)cc2)CC1
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc(C4CCN(C)CC4)cc3)n2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Yield: 81 %

Procedure:
Following Example 150b, 282c and (2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 230a were reacted to give 294a in 81% yield. LCMS: (M+H)+ 667
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][C:30]2=[O:34])=[O:24])[C:5]1=[O:35].[N:36]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][C:30]4=[O:34])=[O:24])[C:5](=[O:35])[N:4]3[CH2:3][CH2:2][NH:1][C:42]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:43])=[N:9][CH:10]=2)=[CH:16][CH:17]=1
Reactant: NCCn1c(=O)c(C(=O)NCCCN2CCCC2=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(NCCCN1CCCC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide and 4-morpholinecarbonyl chloride employing methods similar to those described in Example 450 and was obtained as an orange solid: ES+ MS: 595 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][C:4]=1[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=1.Cl.[Cl:24]CCl>O1CCOCC1>[C:19]([C:16]1[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[C:4]([CH:15]=1)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Cl:24])=[CH:9][CH:8]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: ClCCl
Reactant: COc1ccc(C(C)(C)C)cc1C=Cc1ccc(CO)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C(C)(C)C)cc1C=Cc1ccc(CCl)cc1
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of 2'-methoxy-5'-tert-butylstilbene-4-methanol (5.83 g, 19.7 mmol) in 1,4-dioxane (25 ml) was poured into concd. hydrochloric acid (120 ml). A colourless precipitate appeared immediately. The mixture was stirred for 1 h. Then dichloromethane (250 ml) was added. The organic layer was washed with water (500 ml), brine (250 ml), dried over anhydrous magnesium sulfate, filtered and concentrated vacuo. The residue was purified by column chromatography over silica (dichloromethane) and by recrystallisation from hot hexane to yield (19) (4.26 g, 69%) in form of colourless crystals, m.p. 103°-104° C.; (Found: C, 76.42; H, 7.42. C20H24ClO requires C, 76.30; H, 7.36%); δH (CDCl3) 1.40 (9 H, s, tert-butyl), 3.90 (3 H, s, OCH3), 4.62 (2 H, s, CH2Cl), 6.88 (1 H, d, J=8.7 Hz, Phil), 7.17 (1 H, d, J=16.5 Hz, vinylic H), 7.32 (1 H, dd, J=8.6, 2.5 Hz, PhH), 7.40 and 7.57 (4 H, AA'BB', PhH), 7.54 (1 H, d, J=16.0 Hz, vinylic H), 7.65 (1 H, d, J=2.4 Hz, PhH); m/z 316, 314 (35, M+), 301, 299 (29, 91%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:19][CH2:20][CH2:21][S:22]([OH:25])(=[O:24])=[O:23]>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:19][CH2:20][CH2:21][S:22]([OH:25])(=[O:24])=[O:23])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: NCCS(=O)(=O)O
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=S(=O)(O)CCNc1cc(Cl)nc(Cl)n1
Yield: 254.4 %

Procedure:
A stirred mixture of 2,4,6-trichloropyrimidine (6.9 g) in 75 ml of tetrahydrofuran is treated with diisopropylethylamine (15 ml) and solid taurine (4.7 g). The resulting suspension is heated at reflux for 48 hours. The reaction mixture is cooled to 20°-25° followed by solvent evaporation which gives 26 g of an oil which is chromatographed on 170 g of silica gel and eluting with chloroform/5.0M ammonia in methanol (7/3). An initial fraction of 250 mL is collected followed by 20 ml fractions. Fractions 23-57 contained the desired product. Solvent evaporation gives a semi-solid which is taken up in chloroform/methanol (10/1) and stirred at 20°-25° for 30 minutes. Filtration provided 3.71 g of a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[C:25]([O:33][CH3:34])=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[C:25]([O:33][CH3:34])=[C:26]([NH:30][C:31]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: COc1c(Cl)cccc1N=C=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc(Cl)c4OC)cc3)c2cc1OC
Yield: 80 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (58 mg) was dissolved in toluene (5 ml) with heat, 3-chloro-2-methoxyphenyl isocyanate (0.1 ml) was added, and the admixture was refluxed with heat for 22 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 75 mg of the title compound (yield: 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](Cl)=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[NH4+:21].[OH-]>O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([NH2:21])=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=C(Cl)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Reaction time: 1 h
Yield: 92 %

Procedure:
The product from Example 168b (1.8 g, 6.13 mmol) was added to cold NH4OH (15 mL) and stirred for 1 h. The reaction was poured into water and extracted with ethyl acetate. The organic layer washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum to gave the title compound (1.66 g, 92%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.C(N(CC)CC)C.[S:16](Cl)([CH3:19])(=[O:18])=[O:17]>ClCCl>[CH3:19][S:16]([O:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCCOC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tetrahydro-2H-pyran-3-ylmethanol (4.92 g) in dry dichloromethane (140 ml) at 0° C. and under nitrogen, was added anhydrous triethylamine (13.6 ml) in one go, followed by mesyl chloride (4.3 ml) dropwise over 5 minutes. The reaction was allowed to warm to room temperature and stirred at this temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate (50 ml). The organic layer was separated, passed through a hydrophobic frit to dry and concentrated in vacuo to yield a red oil (8.8 g).
Reaction SMILES: C[O-].[Na+].CO.[SH:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[CH:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[CH2:13]>C(O)C>[N:17]1[CH:18]=[CH:19][C:14]([CH2:12][CH2:13][S:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:15][CH:16]=1
Reactant: C=Cc1ccncc1
Reactant: COC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: COC(=O)CSCCc1ccncc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
Under a nitrogen atmosphere, sodium methoxide (1.62 g., 0.03 mole) is dissolved in 36 ml. of stirring methanol and the solution cooled in an ice bath. Methyl 2-mercaptoacetate (3.18 g., 0.03 mole) in 6 ml. of methanol is added over approximately 5 minutes. Finally, 4-vinylpyridine (3.22 g., 0.03 mole) in approximately 20 ml. of absolute ethanol is added over 15 minutes. The reaction mixture is allowed to warm to room temperature and stirred for 23 hours. The reaction mixture is concentrated to dryness in vacuo. The residue is added slowly to a stirred mixture of water and chloroform. The chloroform phase is separated and the aqueous phase further extracted with chloroform. The combined chloroform phases are extracted with saturated sodium chloride, dried over anhydrous sodium sulfate, and stripped to yield title product.
Reaction SMILES: [C:1](#[N:4])[CH2:2]O.[C:5]([O:9][C:10](=[O:15])[NH:11][CH2:12][CH2:13][NH2:14])([CH3:8])([CH3:7])[CH3:6]>C(O)C>[C:5]([O:9][C:10](=[O:15])[NH:11][CH2:12][CH2:13][NH:14][CH2:2][C:1]#[N:4])([CH3:8])([CH3:6])[CH3:7]
Reactant: N#CCO
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNCC#N

Procedure:
Glycolonitrile (70%, 5.10 g, 62.5 mmol), tert-butyl-N-(2-aminoethyl)carbamate (10.0 g, 62.5 mmol), and ethanol (200 mL) were combined under Ar and heated at reflux for 4 h. Removal of the solvent in vacuo gave 111 as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CCN(CC)CC.[Cl:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>C(Cl)Cl>[Cl:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([N:2]([CH3:3])[CH3:1])=[O:17]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: CNC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1cccc(CCl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
A solution of dimethylamine (2.91 mL, 5.82 mmol, 2.0M THF), NEt3 (0.885 mL, 6.35 mmol) and CH2Cl2 30 mL was cooled to 0° C. 3-(Chloromethyl)benzoyl chloride (1.0 g, 5.29 mmol) was added as a CH2Cl2 solution (3 mL) and the solution was stirred at 0° C. for 2 hours and then at ambient temperature for 2 hours. The reaction was washed with 1N HCl followed by brine, and the organic layer was dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography (EtOAc) to provide 0.745 g (71%) of the product as colorless oil.
Reaction SMILES: [S:1]1[N:5]=[CH:4][C:3]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:2]1.[N:12](OCCC(C)C)=[O:13]>>[OH:13][N:12]=[C:6]([C:3]1[CH:4]=[N:5][S:1][N:2]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CC(C)CCON=O
Reactant: CCOC(=O)Cc1cnsn1
Product: CCOC(=O)C(=NO)c1cnsn1

Procedure:
Ethyl 2-(1,2,5-thiadiazol-3-yl)acetate (9.5 g.) and isopentyl nitrite (10 ml.) were reacted according to a similar manner to that of Example 3(a) (1) to give ethyl 2-hydroxyimino-2-(1,2,5-thiadiazol-3-yl)acetate (a mixture of syn and anti isomers) (10.5 g.), mp 60° to 66° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][S:9](=[O:12])(=[O:11])[CH:8]([CH3:13])[C:6]=2[N:7]=1.C(N(CC)CC)C.[CH3:22][C@H:23]1[CH2:28][O:27][CH2:26][CH2:25][NH:24]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][C@@H:23]2[CH3:22])[C:5]2[CH2:10][S:9](=[O:12])(=[O:11])[CH:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: C[C@H]1COCCN1
Reactant: CC1c2nc(Cl)nc(Cl)c2CS1(=O)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1c2nc(Cl)nc(N3CCOC[C@@H]3C)c2CS1(=O)=O
Yield: 39.7 %

Procedure:
To a solution of 2,4-dichloro-7-methyl-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (160 mg, 0.63 mmol), and triethylamine (64 mg, 0.63 mmol) in DMF (3 mL) at 0° C. was added 3-(S)-methylmorpholine (57 mg, 0.57 mmol). The resultant mixture was stirred at rt for 2 h. The solvent was removed under vacuum and the residue obtained partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to give the product which was purified by preparative TLC (petroleum ether/ethyl acetate=2/1) to produce 2-chloro-7-methyl-4-[(3S)-3-methylmorpholin-4-yl]-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (72 mg, 36% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:12]([CH3:14])[CH3:13].[CH2:22]([N:24]([CH2:38][CH3:39])[C:25](=[O:37])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)[CH3:23]>CCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:33]([C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:25]([N:24]([CH2:38][CH3:39])[CH2:22][CH3:23])=[O:37])=[CH:32][CH:31]=1)(=[O:35])=[O:34])[C:6](=[O:11])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:12]([CH3:14])[CH3:13]
Reactant: CN(C)C1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3Cl)(N(C)C)c3cc(Cl)ccc32)cc1

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 0.500 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(dimethylamino)indol-2-one and 0.453 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride. Chromatography on silica using a gradient of a hexane/AcOEt mixture (80/20; v/v to 60/40; v/v) as the eluent gives the expected product after crystallization from a DCM/iso ether mixture. m=0.520 g. M.p.=146°-150° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[N:25]1([C:30]([C:32]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=2)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([C:30]([N:25]5[CH2:26][CH2:27][CH2:28][CH2:29]5)=[O:31])[CH:37]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: O=C(c1cccc(B(O)O)c1)N1CCCC1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(C(=O)N5CCCC5)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 9.7 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL of tube under Ar2 was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(pyrrolidine-1-carbonyl)phenylboronic acid (10 mg, 0.045 mmol). The mixture was heated at 120° C. in a microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 2′-amino-1′-methyl-2-phenyl-6-(3-(pyrrolidine-1-carbonyl)phenyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (2.10 mg, 8%). 1H-NMR (MeOD): 1.82 (m, 2H), 1.91 (m, 2H), 2.04 (m, 1H), 2.21 (m, 1H), 3.02 (s, 3H), 3.39 (t, 2H), 3.52 (t, 2H), 5.82 (d, 1H), 6.95 (d, 1H), 7.15 (m, 1H), 7.27 (m, 1H), 7.34 (m, 3H), 7.46 (m, 4H), 7.54 (m, 2H).