Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[C:9]([C:11](=[O:24])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:8]=[N:7][C:6]=1[N:25]1[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]1)C.[Li+].[OH-].O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCO>[OH:30][C@@H:27]1[CH2:28][CH2:29][N:25]([C:6]2[N:7]=[CH:8][C:9]([C:11](=[O:24])[NH:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]([F:22])([F:21])[F:23])=[CH:17][CH:18]=3)=[CH:10][C:5]=2[C:4]([OH:31])=[O:3])[CH2:26]1
Reactant: CCOC(=O)c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(C(=O)O)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-2-(3-hydroxypyrrolidin-1-yl)-5-((4-(trifluoromethoxy)phenyl)carbamoyl)nicotinic acid ethyl ester (Stage 72.4, 3.20 g, 7.28 mmol) and LiOH in EtOH (18 mL)/water (6 mL) was stirred at 50° C. for 8 h. The solution was cooled to RT, acidified with citric acid monohydrate and resulting crystalline title compound was filtered and dried. m.p. 242-245° C., HPLC (Condition 4) tR=4.45 min, UPLC-MS (Condition 8) tR=0.80 min, m/z=412 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.92 (br. s, 2H), 3.10 (d, J=12.12 Hz, 1H), 3.39 (br. s, 1H), 3.50-3.75 (m, 2H), 4.31 (br. s, 1H), 4.80-5.01 (m, 1H), 7.30 (d, J=8.60 Hz, 2H), 7.74-7.88 (m, 2H), 8.39 (d, J=2.35 Hz, 1H), 8.76 (d, J=2.35 Hz, 1H), 10.23 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[F:9].[CH3:10][C:11]([CH3:14])([O-])C.[K+].BrC1CC1.COC(C)(C)C>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:14]2[CH2:11][CH2:10]2)=[CH:4][C:3]=1[F:9]
Reactant: CC(C)(C)[O-]
Reactant: Fc1cc(S)ccc1Br
Agent: BrC1CC1
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: Fc1cc(SC2CC2)ccc1Br
Temperature: 90 °C
Reaction time: 30 h
Yield: 27.3 %

Procedure:
A stirred mixture of 4-bromo-3-fluorobenzenethiol (Preparation 26, 400 mg, 1.93 mmol), potassium tert-butoxide (238 mg, 2.12 mmol) and bromocyclopropane (701 mg, 5.80 mmol) in DMSO (10 mL) was heated at 90° C. for 16 hours. Additional potassium tert-butoxide (43 mg, 0.386 mmol) and bromocyclopropane (467 mg, 3.86 mmol) were added and heating continued at 90° C. for 30 hours. The mixture was cooled to room temperature and poured into 2-methoxy-2-methylpropane (30 mL). The mixture was washed with water (2×30 mL), dried over Na2SO4, concentrated in vacuo and purified by silica gel column chromatography eluting with heptanes to give the title compound as a colourless oil 27% yield, 130 mg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH2:25]/[CH:26]=[CH:27]/[C:28](Cl)=[O:29])[CH3:24]>CN1C(=O)CCC1>[CH3:22][N:23]([CH3:24])[CH2:25]/[CH:26]=[CH:27]/[C:28]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:12]=[CH:11][N:10]=2)[N:7]=1)=[O:29]
Reactant: Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Reactant: CN(C)C/C=C/C(=O)Cl
Solvent: CN1CCCC1=O
Product: CN(C)C/C=C/C(=O)Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of acetonitrile (20 mL) and DMF (0.05 mL) under N2 was added N,N-dimethylamino crotonic acid hydrochloride (0.47 g, 2.8 mmol). After 10 min this solution was cooled to 0-5° C. Oxalyl chloride (0.44 g, 3.5 mmol) was added and the reaction mixture was maintained at 0-5° C. for 30 min. It was allowed to warm to rt and stirring was continued for 2 h. It was then heated to 40° C. for 5 min and again brought to rt and stirred for 10 min to get a light greenish colored solution of dimethylaminocrotonyl chloride that was used as such for next step. To a stirred solution of N4-(6-aminopyridin-2-yl)-N6-phenylpyrimidine-4,6-diamine (0.2 g, 0.7 mmol) in NMP (10 mL) was added dropwise under N2 atmosphere at 0° C. the solution of dimethylaminocrotonyl chloride. The reaction mixture was maintained at this temperature for 30 min and was warmed to rt and stirred for 2 h. The mixture was quenched with sodium bicarbonate solution (1 mL) and was extracted with EtOAc (2×35 mL). The combined ethyl acetate extract was washed with water (20 mL) and brine (20 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 60-120, product was eluted at 4-6% methanol in chloroform) to give (E)-4-(dimethylamino)-N-(6-(6-(phenylamino)pyrimidin-4-ylamino)pyridine-2-yl)but-2-enamide (I-73) as a yellowish solid. 1H NMR (DMSO-d6) δ ppm: 2.24 (s, 6H), 3.13 (d, J=5.76 Hz, 2H), 6.56 (d, J=15.52 Hz, 1H), 6.80 (d, J=15.36 Hz, 1H), 6.95 (t, J=7.36 Hz, 1H), 7.11 (t, J=1.16 Hz, 1H), 7.29 (t, J=7.56 Hz, 2H), 7.58 (s, 1H), 7.65-7.7 (m, 4H), 8.31 (d, J=2.44 Hz, 1H), 9.23 (s, 1H), 9.68 (s, 1H), 10.16 (s, 1H); LCMS: m/e 390.3 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][N:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:9]=2)[C:5](Br)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:24]1([N:30]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:31]2[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[Na+]>ClCCl.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.O.C1(C)C=CC=CC=1.O1CCOCC1>[C:24]1([N:30]([C:40]2[CH:45]=[CH:44][C:43]([C:2]3[C:10]4[C:6](=[N:7][N:8]([C:11]5[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=5)[N:9]=4)[C:5]([C:43]4[CH:42]=[CH:41][C:40]([N:30]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:45][CH:44]=4)=[CH:4][CH:3]=3)=[CH:42][CH:41]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Brc1ccc(Br)c2nn(-c3ccncc3)nc12
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)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: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)c4nn(-c5ccncc5)nc34)cc2)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of Intermediate A (purity 90%, 1.95 g, 5 mmol), sodium carbonate (2.69 g, 25 mmol), 4-(diphenylamino)phenylboronic acid (3.47 g, 12 mmol), tetrakis(triphenylphosphine)palladium (0) (0.58 g, 0.5 mmol), water (20 mL), dioxane (80 mL), and toluene (10 mL) was heated under argon at 110° C. for 48 hours. The reaction mixture was poured into water (200 mL), diluted with dichloromethane (200 mL), treated with 2N NaOH (50 mL), stirred for 1 hour, and the dichloromethane layer was separated. The aqueous phase was washed with dichloromethane (200 mL). Both dichloromethane solutions were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography and recrystallization from ethyl acetate/ethanol (1:1) to give 4,7-bis(4-(N,N-diphenylamino)phenyl)-2-(pyridin-4-yl)-2H-benzo[d][1,2,3]triazole (Example 1), orange crystals, 1.71 g (50%). 1H NMR (400 MHz, CDCl3): δ 8.80 (m, 2H, pyridine), 8.34 (m, 2H, pyridine), 8.06 (d, J=8.7 Hz, 4H, p-phenylene), 7.67 (s, 2H, benzotriazole), 7.31 (m, 8H, Ph), 7.21 (m, 12H, p-phenylene and Ph), 7.08 (tt, J=7.3 and 2.2 Hz, 4H, Ph). UV-vis spectrum (dichloromethane): λmax=451 nm. Fluorimetry (dichloromethane): λmax=593 nm.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH:10]([OH:16])[CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](=[O:24])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[NH2:18]>>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH:10]([OH:16])[CH2:11]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[O:16]=[C:10]1[CH:9]2[CH2:15][CH2:14][CH:12]([CH2:13][N:18]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[CH2:11]1
Reactant: CC(C)(C)OC(N)=O
Agent: OC1CC2CCC1N(Cc1ccccc1)C2
Product: CC(C)(C)OC(=O)N1CC2CCC1C(=O)C2

Procedure:
2-benzyl-2-azabicyclo[2.2.2]octan-6-ol is prepared using a method analogous to that described in U.S. Ser. No. 05/147,873. 2-benzyl-2-azabicyclo[2.2.2]octan-6-ol is debenzylated and subsequently protected as the tert-butyl carbamate using procedures analogous to those described in Example 1. Oxidation of the resulting intermediate alcohol using the Swern protocol affords the title product.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[N:4]([C:9](=[O:13])[CH2:10][O:11][CH3:12])[CH2:5][C:6]([CH3:8])=O.Cl.[CH3:20][O:21][NH2:22].C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[N:4]([CH2:5][C:6](=[N:22][O:21][CH3:20])[CH3:8])[C:9](=[O:13])[CH2:10][O:11][CH3:12]
Reactant: CON
Reactant: COCC(=O)N(CC(C)=O)c1c(C)cccc1C
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COCC(=O)N(CC(C)=NOC)c1c(C)cccc1C
Yield: 94.3 %

Procedure:
20 g (0.08 mol) of 2,6-dimethyl-N-methoxyacetyl-N-acetonylaniline, 7.5 g (0.09 mol) of O-methyl-hydroxylamine hydrochloride and 9.1 g (0.09 mol) of triethylamine in 100 ml of ethanol were heated under reflux for 5 hours. After distilling off the solvent in vacuo, the residue was partitioned between water/methylene chloride. The organic phase was separated off, dried over sodium sulphate and concentrated. After adding petroleum ether, the residue crystallized. 21 g (94% of theory) of 2,6-dimethyl-N-(2-methoxyimino-prop-1-yl)-N-methoxyacetylaniline of melting point 56°-57° C. were obtained.
Reaction SMILES: [CH3:1][Mg]Cl.CON(C)[C:7](=[O:18])[CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[C:10]=1[F:17]>C1COCC1>[F:17][C:10]1[C:11]([F:16])=[CH:12][C:13]([F:15])=[CH:14][C:9]=1[CH2:8][C:7](=[O:18])[CH3:1]
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)Cc1cc(F)cc(F)c1F
Solvent: C1CCOC1
Product: CC(=O)Cc1cc(F)cc(F)c1F
Temperature: 47.5 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of CeCl3 (11.44 g, 0.045 mol) in THF (350 mL) was degassed for 1 h and heated to 45-50° C. for 5 h. When the solution was cooled to −10-5° C., MeMgCl (19.44 g, 0.26 mol) in THF was added and the mixture was stirred for 1 h at −10-5° C. After amide 43 (30.3 g, 0.13 mol) was charged into the reaction mixture at −10-5° C., the mixture was stirred for 5 h at 10-20° C. After the reaction was complete, the mixture was quenched by 1M HCl, and then partitioned with water and EtOAc. The organic phase was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (2-10% EtOAc/PE) to give 44 (20.8 g, 85% yield). 1H NMR (CDCl3, 400 MHz): δ 6.91-6.78 (m, 1H), 6.69 (dd, 1H), 3.77 (d, 2H), 2.25 (s, 3H); MS (ESI) m/e [M+H]+: 189.05.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19](C)[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH:8]=[CH:7][C:6]=2[CH:23]=1.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:38])[Cl:37])=[O:33].ClC([O-])=O>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:17][CH2:18][N:19]([C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:38])[Cl:37])=[O:33])[CH2:20][CH2:21]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH:8]=[CH:7][C:6]=2[CH:23]=1
Reactant: CN1CCC(=C2c3ccc(Cl)cc3C=Cc3cccnc32)CC1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(OCC(Cl)(Cl)Cl)N1CCC(=C2c3ccc(Cl)cc3C=Cc3cccnc32)CC1
Temperature: 90 °C
Yield: 56.4 %

Procedure:
To a mixture of 755 mg (2.34 mmole) of 8-chloro-11-(1-methyl-4-piperidylidene)-11H-benzo[5,6]cyclohepta[1,2-b]pyridine and 1.5 mL of triethylamine in 25 mL of dry toluene at room temperature and under a nitrogen atmosphere was added 650 μL (4.72 mmole) of 2,2,2-trichloroethyl chloroformate. The mixture was then heated to 90° C. Additional amounts of the chloroformate (500 μL and 300 μL) and triethylamine (1.0 mL each time) were added to the mixture after 2 hr. and 3 hr. 40 min., respectively. After a total reaction time of 5 hr. the mixture was poured into water and extracted three times with CH2Cl2. The combined organic portions were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography [11/2% MeOH in CH2Cl2 ] to afford 639 mg (56%) of the title compound as a glass.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:13][CH3:14])[CH2:10]2)=[CH:5][CH:4]=1.[C:15](#[N:18])[CH:16]=[CH2:17]>CO>[CH3:14][N:13]([CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10]1)[CH2:17][CH2:16][C:15]#[N:18]
Reactant: CNC1CCc2ccc(OC)cc2C1
Reactant: C=CC#N
Solvent: CO
Product: COc1ccc2c(c1)CC(N(C)CCC#N)CC2

Procedure:
First, 7-methoxy-2-methylamino-1,2,3,4-tetrahydronaphthalene (5.76 g, 0.0253 mol) is dissolved in methanol (100 ml) with stirring. Acrylonitrile (2.07 ml, 0.0316 mol) is added and the mixture is heated for 3 hours to 50°-55° C. Then the solvent is distilled off. Yield: 6.2 g. Rf value: 0.75 (alumina, eluant: methylene chloride).
Reaction SMILES: CS[C:3]1[N:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][CH:11]=[C:7]2[CH:6]=[C:5]([S:18][CH3:19])[N:4]=1.C[O-:21].[Na+]>>[CH3:19][S:18][C:5]1[CH:6]=[C:7]2[CH:11]=[N:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]2[C:3](=[O:21])[N:4]=1
Reactant: CSc1cc2cnc(-c3ccccc3)n2c(SC)n1
Reactant: C[O-]
Agent: [Na+]
Product: CSc1cc2n(c(=O)n1)C(c1ccccc1)N=C2

Procedure:
Using the method of Part H, Example 1, 5,7-bis(methylthio)-3-phenylimidazo[1,5-c]pyrimidine was reacted with aqueous sodium methoxide to provide 7-methylthio-3-phenylimidazo[1,5-c]pyrimidin-5-one, m.p. 198°-199° C. Analysis: Calculated for C13H11N3OS: %C, 60.7; %H, 4.3; %N, 16.3; Found: %C, 60.7; %H, 4.1; %N, 16.7.
Reaction SMILES: [NH2:1][C:2]1[C:5](=O)[C:4](=[O:7])[C:3]=1[O:8]C.[CH3:10][N:11]([CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH:15]=1)[CH3:12]>N1C=CC=CC=1>[CH3:10][N:11]([CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:5]2[C:4](=[O:7])[C:3](=[O:8])[C:2]=2[NH2:1])[CH:15]=1)[CH3:12]
Reactant: COc1c(N)c(=O)c1=O
Reactant: CN(C)Cc1ccnc(OCCCN)c1
Solvent: c1ccncc1
Product: CN(C)Cc1ccnc(OCCCNc2c(N)c(=O)c2=O)c1

Procedure:
1-Amino-2-methoxy-cyclobut-1-ene-3,4-dione is mixed with 3-[4-(dimethylaminomethyl)pyrid-2-yloxy]prop-1-yl-amine in anhydrous pyridine and is heated at reflux temperature to give the title product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:26])[CH:12]=[CH:13][N:14]2[CH:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22].[Br:27]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:27][C:12]1[C:11](=[O:26])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[N:14]([CH:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCC(CCC)n1ccc(=O)c2c(-c3ccc(C)cc3C)cccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CCC)n1cc(Br)c(=O)c2c(-c3ccc(C)cc3C)cccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
5-(2,4-Dimethylphenyl)-1-(1-propylbutyl)quinolin-4(1H)-one, (0.21 g, 0.61 mmol), was dissolved in N,N-dimethylformamide (10 mL). The solution was cooled to 0° C. and N-bromosuccinimide (0.11 g, 0.62 mmol) was added. After 10 minutes, the solution was diluted with water, extracted with ethyl acetate, dried (Na2SO4), and concentrated. Flash chromatography (20% ethyl acetate/hexanes) gave 0.136 g (53% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[C:13](Cl)(=O)[CH3:14].O.Cl>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:13][CH3:14])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC(=O)Cl
Reactant: CC1(C)CCSc2ccccc21
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCc1ccc2c(c1)SCCC2(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 14.3 g (80.21 mmol) of 4,4-dimethylthiochroman (Compound 61) and 6.76 g (86.12 mmol) of acetyl chloride in 65 ml benzene was cooled in an ice bath and treated dropwise with 26.712 g (102.54 mmol) of stannic chloride. The mixture was stirred at room temperature for 12 hours, then treated with 65 ml water and 33 ml conc. hydrogen chloride and heated at reflux for 0.5 hours. After being cooled to room temperature, the organic layer was separated and the aqueous layer extracted with 5×50 ml benzene. The recovered organic fractions were combined and washed with 5% sodium carbonate, water, saturated NaCl and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) followed by kugelrohr distillation (150 degrees C, 0.7 mm) to give the title compound as a pale yellow oil. PMR (CDCl3): & 1.35 (6H, s), 1.92-1.98 (2H, m) 2.54 (3H, s), 3.02-3.08 (2H, m), 7.13 (1H, d, J~8.6 Hz), 7.58 (1H, dd, J~8.6 Hz, 2 Hz), 7.99 (1H, d, J~2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:19](O)[CH2:20][OH:21].O.CC1C=CC(S(O)(=O)=O)=CC=1>CC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[O:21][CH2:20][CH2:19][O:9]2)=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1
Yield: 97.8 %

Procedure:
A mixture of (4-chlorophenyl)(4-nitrophenyl)methanone (0.0382 mol), 1,2-ethanediol (0.0764 mol) and 4-methylbenzenesulfonic acid monohydrate 96% (0.19 mol) in methylbenzene (150 ml) was stirred and refluxed in a Dean Stark apparatus for 24 hours. The mixture was washed with K2CO3 (10%) and then with water. The organic layer was dried, filtered off and evaporated. The product was used without further purification, yielding 11.42 g (98%) of 2-(4-chlorophenyl)-2-(4-nitrophenyl)-1,3-dioxolane (interm. 1).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].[CH:14]1([CH2:19][NH:20][CH2:21][CH3:22])[CH2:18][CH2:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH:14]1([CH2:19][N:20]([C:2]2[N:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=2[C:4]#[N:5])[CH2:21][CH3:22])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1nc(Cl)c(C#N)cc1[N+](=O)[O-]
Reactant: CCNCC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCN(CC1CCCC1)c1nc(C)c([N+](=O)[O-])cc1C#N
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-6-methyl-5-nitronicotinonitrile (997 mg, 5.05 mmol), N-(cyclopentylmethy)-N-ethylamine (770 mg, 6.05 mmol), and K2CO3 (1.7 g, 12.3 mmol) in toluene (20 mL) is heated to 110° C. After stirring for 3 hours, the reaction mixture is filtered to remove the resulting precipitate. The filtrate is diluted with EtOAc and washed with H2O and brine. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica-gel column chromatography to give 2-[N-(cyclopentylmethyl)-N-ethylamino]-6-methyl-5-nitronicotinonitrile as orange oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([NH:18][CH3:19])=[C:8]([N+:15]([O-])=O)[CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]=2[O:3]1.Cl>[Fe].CO>[NH2:15][C:8]1[CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]2[O:3][C:2]([CH3:20])([CH3:1])[CH2:6][C:5]=2[C:7]=1[NH:18][CH3:19]
Reactant: CNc1c([N+](=O)[O-])cc(C(=O)OC)c2c1CC(C)(C)O2
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: CNc1c(N)cc(C(=O)OC)c2c1CC(C)(C)O2
Yield: 94.8 %

Procedure:
The title compound was prepared following the procedure described for Step-9 of Intermediate-1 using methyl 2,2-dimethyl-4-(methylamino)-5-nitro-2,3-dihydrobenzofuran-7-carboxylate (1.3 g), iron powder (cat. amt.), conc HCl (catalytic amount) and methanol (100.0 mL) to afford 1.1 g of desired product.
Reaction SMILES: [C:1]([C:6]1[C:7](O)=[N:8][C:9]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)=[N:10][CH:11]=1)([O:3][CH2:4][CH3:5])=[O:2].P(Cl)(Cl)([Cl:21])=O>C(O)C>[C:1]([C:6]1[C:7]([Cl:21])=[N:8][C:9]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)=[N:10][CH:11]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1cnc(N2CCSCC2)nc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(N2CCSCC2)nc1Cl

Procedure:
5-Carbethoxy-4-chloro-2-thiomorpholino-pyrimidine was prepared in analogous manner from 5-carbethoxy-4-hydroxy-2-thiomorpholino-pyrimidine and phosphorus oxychloride/phosphoruc pentachloride. M.p. 81°-83°C (ethanol). Preparation of end products of the formula I:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].CCN(C(C)C)C(C)C.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[OH:5][CH:3]([CH3:4])[CH2:2][NH:1][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(O)CN
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)CNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
Prepare a solution of 1-amino-2-propanol (5.0 g, 66.6 mmol) in methylene chloride (250 mL) at 0° C. under nitrogen. Add Hünig's Base (11.6 mL, 66.6 mmol) followed by benzoyl chloride (7.7 mL, 66.6 mmol). Warm the reaction mixture to room temperature and stir overnight. Wash the solution sequentially with brine (100 mL) and 1M HCl (75 mL), dry (Na2SO4), filter, and concentrate to afford 10.0 g of N-(2-hydroxypropyl)benzamide. MS: m/e=180 (MH+)
Reaction SMILES: O[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[CH:14][CH:15]=2)[C:10]([CH3:21])([CH3:20])[C:9]1=[O:22].CS(O)(=O)=O.[OH-].[Na+]>>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][C:16]2[CH2:17][C:8]3[C:7]4[CH:2]=[CH:3][N:4]=[CH:5][C:6]=4[O:22][C:9]=3[C:10]([CH3:20])([CH3:21])[C:11]=2[CH:12]=1
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)C(c1ccncc1O)C2
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(c1)C(C)(C)c1oc3cnccc3c1C2
Temperature: 110 °C
Yield: 43.4 %

Procedure:
Mixture of 3-(3-hydroxy-pyridin-4-yl)-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound GT15-9, 270 mg) and methanesulfonic acid (1 ml) was stirred and heated at 110° C. for 0.5 hrs. After cooling, the reaction mixture was neutralized with 2 N aqueous solution of sodium hydroxide. The resulting mixture was extracted with the mixture of DCM and MeOH (DCM:MeOH=9:1). The organic layer was concentrated under reduced pressure, and the resulting residues were purified by silica gel column (DCM/MeOH) to obtain the title compound (110 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([CH:18]([F:20])[F:19])[N:15]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:27][S:28]([C:31]1[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29].Cl>>[CH3:27][S:28]([C:31]1[CH:32]=[C:33]([NH:37][C:24]([C:23]2[CH:22]=[N:21][N:15]3[C:16]([CH:18]([F:20])[F:19])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:10])([F:11])[F:9])=[C:2]([Cl:1])[CH:3]=4)=[N:13][C:14]=23)=[O:26])[CH:34]=[CH:35][CH:36]=1)(=[O:29])=[O:30]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)c(Cl)c3)nc12
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3-chloro-4-trifluoromethyl-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.15) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Light brown solid. MS (ISP) 543.0 [(M+H)+]; mp 228° C.