Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][N:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:12]1([C:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][N:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:10]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)CCCCCCCCn1cc(-c2ccccc2)c(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCCCCn1cc(-c2ccccc2)c(-c2ccccc2)c1
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
A mixture of methyl 3,4-diphenyl-1H-pyrrole-1-nonanoate (2.50g, 6.4mmol), 5N sodium hydroxide solution (3.86mL, 19mmol) and methanol (50mL) was heated on a steam bath. After 30 minutes, the solvent was evaporated, the residue diluted with 1N HC1 solution and extracted with CH2Cl2. The combined extracts were dried over sodium sulfate, concentrated in vacuo and the residual oil chromatographed on a column of silica gel. Elution with a mixture of diethyl ether and hexanes (3:2) gave 3,4-diphenyl-1H-pyrrole-1-nonanoic acid (2.20g, 91%) as an oil.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][NH:15]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BrH:24].[NH+]1C=CC=CC=1.S([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:14]([Br:24])[NH:15]2)=[CH:11][CH:10]=1)(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Br
Reactant: CC(C)(C)NS(=O)(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Agent: O=S([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)NS(=O)(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Yield: 78.3 %

Procedure:
To a solution of N-tert-butyl-3-cyclohexyl-1H-indole-6-sulfonamide (2.29 g, 6.86 mmol) in chloroform (30 ml) was added pyridinium hydrobromide perbromide (2.40 g, 7.50 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 30 min. 1M aqueous sodium hydrogen sulfite solution was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. A mixed solvent of hexane:ethyl acetate (5:1) was added to the residue. The precipitated solid was collected by filtration and dried in vacuo to give N-tert-butyl-2-bromo-3-cyclohexyl-1H-indole-6-sulfonamide (2.19 g, yield 78.3%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[Li+].[Li+].Cl[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31].O>CN(C=O)C>[OH:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][N:13]1[CH2:12][CH2:11][CH:10]([C:7]2[C:6]3[CH:16]=[CH:17][C:3]([F:2])=[CH:4][C:5]=3[O:9][N:8]=2)[CH2:15][CH2:14]1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: OCCCCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 100 °C
Yield: 24.8 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (1g, 3.9 mmol), lithium carbonate (865 mg, 1.7 mmol) and 6-chloro-1-hexanol (534 mg, 3.9 mmol) in 5 ml dry DMF was heated at 100° C. for 48 h. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with water, brine, dried with sodium sulphate and concentrated in vacuo. The crude product was purified by chromatography on silica gel 60 eluting with ethyl acetate:methanol (9:1, v/v). Concentration of the appropriate fractions afforded 310 mg (25.6%) of 3-[1-(1-hydroxyhex-6-yl)-4-piperidinyl]-6-fluoro-1, 2-benzisoxazole as an oil.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.COC1C(OC)=C(OC)C=C(/[CH:46]=[CH:47]/[C:48]([N:50]2[C:55](=[O:56])[CH:54]=[CH:53][CH2:52]C2)=[O:49])C=1.CN(CCO)CCO>C1(C)C=CC=CC=1.C1COCC1>[C:48]([NH:50][C:55](=[O:56])/[CH:54]=[CH:53]/[CH3:52])(=[O:49])[C:47]([CH3:46])=[CH2:1]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(/C=C/C(=O)N2CCC=CC2=O)cc(OC)c1OC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CN(CCO)CCO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)NC(=O)/C=C/C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
Experimental Procedure: Triphenylphosphine (77.0 mg, 0.29 mmol) and DIAD (60.0 mg, 0.29 mmol) were dissolved to a 1:1 mixture of THF and toluene (2 mL); then mono-demethylated piperlongumine (40.0 mg, 0.13 mmol) was added. After 10 min, N-methyldiethanolamine (120 mg, 0.06 mmol) was added to the mixture; the reaction was stirred at room temperature for 3 h. At the end, the solvent was evaporated under vacuum. The crude product was purified by preparative TLC(CH2Cl2/MeOH=9/1) to afford the desired product in 78% yield.
Reaction SMILES: C([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([O:17][CH:18]([CH3:20])[CH3:19])[CH:10]=1)C1C=CC=CC=1.CC1CC=CCC=1>[Pd]>[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([O:17][CH:18]([CH3:20])[CH3:19])[CH:10]=1
Reactant: CC(C)Oc1cc(OCc2ccccc2)ccc1C=O
Agent: [Pd]
Agent: CC1=CCC=CC1
Product: CC(C)Oc1cc(O)ccc1C=O
Temperature: 25 °C

Procedure:
A suspension of 10% palladium on carbon (0.793 g, 0.745 mmol) in a solution of 4-(benzyloxy)-2-isopropoxybenzaldehyde (4.03 g, 14.91 mmol) and 1-methyl-1,4-cyclohexadiene (16.75 mL, 149 mmol) in DOH (298 mL) was heated at reflux for 2 h. The reaction mixture was cooled to room temperature, filtered through a plug of Celite and washed through with EtOAc. The filtrate was concentrated in vacuo to afford 4-hydroxy-2-isopropoxybenzaldehyde, as a colorless solid. LCMS calc.=181.1; found=181.0 (M+H)+. 1H NMR (500 MHz, CHCl3): δ 10.12 (s, 1H); 7.74 (d, J=8.6 Hz, 1 H); 6.52 (dd, J=8.7, 2.1 Hz, 1 H); 6.47 (d, J=2.1 Hz, 1 H); 4.62-4.54 (m, 1 H); 1.36 (d, J=6.1 Hz, 6 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[O:12][C:13]([CH:16]=[CH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][CH:15]=1.[H][H]>[Ni].CO>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[O:12][C:13]([CH2:16][CH2:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][CH:15]=1
Reactant: CCCCCC(=O)C=Cc1ccc(CCCCCCCC(=O)OC)o1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CCCCCC(=O)CCc1ccc(CCCCCCCC(=O)OC)o1
Yield: 63.5 %

Procedure:
III (11.37 g, 0.0326 mole), methanol (150 ml), and Raney nickel (2.5 g) were stirred at room temperature under 1 atmosphere of hydrogen, until one molequivalent of hydrogen had reacted. After filtration, the solvent was removed by distillation from a water bath (60°C) under reduced pressure, at last under 15 mm Hg. The residual, light yellow oil (11.4 g) was purified by preparative tlc (thin layer chromatography) on silica gel (mixture of petroleum ether (b.<50°C) and ether (2:1) as eluent). 7.25 g of the title compound were obtained as a yellowish oil. Further purification by distillation under nitrogen gave 7.05 g (62%) of the title compound as an almost colourless oil, b0.07 172°-180°C, nD25 1.4723.
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[CH2:4][CH:3]1[NH:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20]>CO.[Pd]>[Cl:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[NH:18][P:19](=[O:20])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]
Reactant: CCOP(=O)(NC1CN(C(=O)OCc2ccccc2)CCC1Cl)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(NC1CNCCC1Cl)OCC
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of benzyl 4-chloro-3-(diethoxyphosphorylamino)piperidine-1-carboxylate (1.0 equiv.) in degassed MeOH was added Pd/C (10% by weight) and the reaction was stirred under a hydrogen atmosphere for 1 h. The solution was filtered, then concentrated to yield diethyl 4-chloropiperidin-3-ylphosphoramidate in 92% yield. LCMS (m/z): 271.0 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15]([CH2:23][CH2:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][C:27]=2[F:38])([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]1.[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][C:15]([CH2:23][CH2:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][C:27]=2[F:38])([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]1
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCSc2cc(F)ccc2F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CCN(CCSc4cc(F)ccc4F)CC3)c2c1
Temperature: 70 °C
Reaction time: 17 h
Yield: 121.6 %

Procedure:
A mixture of 0.26 g of ethyl 1-[2-(2,5-difluorophenylthio)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate in 3 cm3 of dioxane, 3 cm3 of methanol and 1.4 cm3 of aqueous 5N sodium hydroxide solution was stirred at a temperature in the region of 70° C. for 17 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 45° C. The residue was taken up in 5 cm3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and was then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200μ; mass 10 g), eluting with a mixture of dichloromethane/methanol/aqueous ammonia (90/9/0.9 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (77.5/19.5/3). The fractions containing the product were combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and dried in a desiccator (10 kPa). 0.3 g of 1-[2-(2,5-difluorophenylthio)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylic acid was obtained in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[C:16]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[C:22]([F:24])[CH:23]=1)#[N:17]>>[CH3:13][C:7]1([CH3:14])[C:6]2[CH:15]=[C:2]([C:20]3[CH:19]=[C:18]([CH:23]=[C:22]([F:24])[CH:21]=3)[C:16]#[N:17])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Product: CC1(C)OCC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-cyano-5-fluorophenyl boronic acid generally according to the coupling procedure described in example 1. A white solid: mp 238-239° C.; 1H NMR (DMSO-d6): δ 10.1 (s, 1H), 8.14 (t, J=1.5 Hz, 1H), 7.98 (m, 1H), 7.80 (m, 1H), 7.69 (d, J=1.9 Hz, 1H), 7.64 (dd, J=8.3, 2.0 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 4.27 (s, 2H), 1.63 (s, 6H). MS m/z 309 ([M−H]−); Anal. calcd for C18H15FN2O2: C, 69.67; H, 4.87; N, 9.03. Found: C, 69.51; H, 4.63; N, 9.07.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]([C:13]2[N:18]=[C:17]3[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][C:25]=4[Cl:33])[C:20]([CH3:22])=[N:21][C:16]3=[CH:15][CH:14]=2)=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:34](O)[CH3:35].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl>CN(C)C=O.O.C(OCC)(=O)C>[C:1]1([S:7]([NH:10][C:11]([C:13]2[N:18]=[C:17]3[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]([O:32][CH2:34][CH3:35])=[O:31])=[CH:26][C:25]=4[Cl:33])[C:20]([CH3:22])=[N:21][C:16]3=[CH:15][CH:14]=2)=[O:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)nc2n1Cc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Cn2c(C)nc3ccc(C(=O)NS(=O)(=O)c4ccccc4)nc32)c(Cl)c1
Yield: 67.5 %

Procedure:
To a solution of 5-(benzenesulfonylcarbamoyl)-3-(4-carboxy-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (25 mg, 0.052 mmol) in N,N-dimethylformamide (0.3 ml) were added ethanol (4 mg, 0.088 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12 mg, 0.062 mmol) and 1-hydroxybenzotriazole (10 mg, 0.075 mmol) at room temperature. Three hours later, ethyl acetate and water were added to the reaction mixture and the mixture was adjusted to pH 4 with 1N hydrochloric acid. The organic layer was washed with water four times, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel thin layer chromatography (eluent: chloroform/methanol=10/1) and crystallized from ethyl acetate to give 5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-(ethoxycarbonyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (18 mg) as colorless crystals.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.[CH:14](=[N:21][CH:22]([CH2:27][CH2:28][CH2:29][CH2:30][N:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:23]([O:25][CH3:26])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl:39][CH2:40]Br>O1CCCC1.CCCCCC.CN(C)P(N(C)C)(N(C)C)=O>[Cl:39][CH2:40][C:22]([N:21]=[CH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([CH2:27][CH2:28][CH2:29][CH2:30][N:31]=[CH:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(CCCCN=Cc1ccccc1)N=Cc1ccccc1
Reactant: ClCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(CCl)(CCCCN=Cc1ccccc1)N=Cc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of lithium diisopropylamide (10 mmol) prepared in situ from a solution of 1N diisoproppylamine in tetrahydrofuran (THF) and a solution of butyl lithium (2N) in hexane and hexamethylphosphoramide (HMPA) (2.5 ml) in THF cooled to -78° C., magnetically stirred, and kept under nitrogen, is added slowly a solution of methyl 2,6-bis(benzylideneamino)hexanoate (3.365 g, 10 mmol) in dry THF (20 ml). The reaction mixture is stirred at -78° C. for 1/2 hour, and then a solution of chlorobromomethane (1.3 g, about 10 mmol) in dry THF (10 ml) is added rapidly. The temperature is allowed to rise slowly to room temperature, and the stirring is continued overnight. The reaction mixture is quenched with water and extracted with ether. The ether extract is washed with water and concentrated at reduced pressure to give methyl 2-chloromethyl-2,6-bis(benzylideneamino)hexanoate as an oily residue.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH:19]=[O:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[C:18]([CH2:19][OH:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc2ncccc2c1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc2ncccc2c1OCc1ccccc1

Procedure:
Treatment of 5-(benzyloxy)quinoline-6-carbaldehyde with sodium borohydride in methanol following the procedure described for Example 4, step 1 provides [5-(benzyloxy)quinolin-6-yl]methanol.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[O:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1>C1COCC1>[OH:21][C:18]1([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]#[N:9])[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1
Reactant: N#CCc1ccccc1
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CC(c1ccccc1)C1(O)CCOCC1
Reaction time: 0.5 h

Procedure:
To benzyl cyanide (1.970 ml, 19.39 mmol) was added THF (100 ml) and the solution cooled to −78° C. n-butyllithium (2.5 M in hexanes, 7.84 ml, 19.59 mmol) was added dropwise over 20 min via syringe pump and the solution stirred 30 min. Tetrahydro-4H-pyran-4-one (1.791 ml, 19.39 mmol) was added over 20 min via syringe pump and the solution stirred for 3 hours. The reaction was quenched by addition of ice-cold satd. NH4Cl and then partitioned between cold satd. NH4Cl and CH2Cl2. The aqueous portion was extracted 2×CH2Cl2, dried (Na2SO4), and concentrated in vacuo. Took up material in CH2Cl2 and allowed to crystallize over the weekend. The crystals were washed with diethyl ether and used without further purification. 3.14 g, 81%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:18][CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1>C(O)(=O)C.C1COCC1>[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH:30][C:2]3[N:3]=[C:4]([NH:18][CH3:19])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccc(Cl)cc1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
2-Chloro-7-(4-chlorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (101 mg, 0.343 mmol) was added to a solution of 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (77 mg, 0.343 mmol) in acetic acid (2 mL) and THF (2 mL). The reaction mixture was heated at 80° C. overnight. Partial conversion to the desired product was observed. The reaction was further heated at 120° C. for 6 h. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine, TFA salt (35.5 mg, 0.059 mmol, 17.19% yield). LC-MS (M+H)+=481.3. 1H NMR (500 MHz, CDCl3) δ ppm 11.08 (1H, s), 8.33 (1H, s), 7.48 (2H, d, J=2.1 Hz), 7.30 (2H, d, J=8.2 Hz), 7.20 (1H, d, J=1.5 Hz), 7.13 (2H, d, J=8.5 Hz), 5.83-5.93 (1H, m), 4.38-4.48 (1H, m), 3.97 (1H, s), 3.86 (3H, s), 3.22 (3H, d, J=4.9 Hz), 2.85-2.95 (1H, m), 2.77 (2H, dd, J=8.7, 5.3 Hz), 2.20-2.32 (1H, m).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:19][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:3].[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH3:3][CH:2]([C:4]1[S:19][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17]4[NH:22][N:21]=[N:20][N:18]=4)=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:1]
Reactant: CC(C)c1cc2c(=O)n3cc(C#N)ccc3nc2s1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1cc2c(=O)n3cc(-c4nnn[nH]4)ccc3nc2s1
Temperature: 124 °C
Yield: 55.8 %

Procedure:
A mixture of 5.1 g (0.01894 mol) of 2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile (Example 16), 6.5 g (0.1 mol ) of sodium azide and 5.35 g (0.1 mol) of ammonium chloride in 150 ml of dimethylformamide is stirred and heated at 124° C. for twenty-two hours under nitrogen. The reaction mixture is cooled, filtered and the filtrate evaporated. The residue is treated with 1 1 water and acidified with concentrated hydrochloric acid. The resulting precipitate is collected, suspended in hot water, the suspension cooled and filtered to give 3.3 g of 2-(1-methylethyl)-7-(1H-tetrazol-5-yl)-4H-pyrido-[1,2-a]thieno[2,3-d]pyrimidin-4-one; mp 288° C. (dec) after recrystallization from pyridine-ethanol.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[CH2:12]([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26](C#N)=[CH:25][C:24]=1[O:31][CH3:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([C:1]2[NH:2][C:3](=[O:11])[C:4]3[C:5]([CH:10]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:25][C:24]=1[O:31][CH3:32])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CNC(=O)c1ccccc1C
Reactant: COc1cc(C#N)ccc1OCCOCc1ccccc1
Product: COc1cc(-c2cc3ccccc3c(=O)[nH]2)ccc1OCCOCc1ccccc1
Yield: 23.6 %

Procedure:
According to the method of Example 10-1, N-methyl-2-methylbenzamide (5.97 g) and 4-(2-benzyloxyethoxy)-3-methoxybenzonitrile (9.57 g) were reacted, to give 3-[4-(2-benzyloxyethoxy)-3-methoxyphenyl]isoquinolin-1-one (3.20 g).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.[CH2:36]=[C:37]([CH2:40]O)[CH2:38][OH:39].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:36]=[C:37]1[CH2:38][O:39][C:32]2([CH2:31][CH2:30][CH:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:34][CH2:33]2)[O:35][CH2:40]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: C=C(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=C1COC2(CCC(n3c(=O)c(Cc4ccc(-c5ccccc5C#N)cc4)c(CCC)n4ncnc34)CC2)OC1
Yield: 62.6 %

Procedure:
A mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.50 g), 2-methylidenepropane-1,3-diol (0.18 g), 4-methylbenzenesulfonic acid (0.020 g) and toluene (20 mL) was heated with a Dean-Stark apparatus under reflux for 21 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.36 g, 64%).
Reaction SMILES: [CH:1]([S:4]([CH2:7][C:8]#[N:9])(=[O:6])=[O:5])([CH3:3])[CH3:2].CSC.B.Cl>C1COCC1>[CH:1]([S:4]([CH2:7][CH2:8][NH2:9])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)CC#N
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)CCN
Reaction time: 0.67 h

Procedure:
Prepared according to Procedure K. 2-iso-Propylsulfonylacetonitrile (0.50 g, 3.39 mmol) was dissolved in THF and warmed to reflux under N2. Borane dimethylsulfide (2M, 1.7 mL, 3.39 mmol) was added dropwise and the reaction was stirred for an additional 40 minutes at reflux. After cooling the reaction to rt, HCl (2 M in MeOH) was added to the reaction slowly due to gas evolution. The volatiles were removed and fresh methanol was added to the resulting residue. Again, the volatiles were removed and the resulting residue was taken up in CH2Cl2 (25 mL) and washed with saturated potassium carbonate (aqueous). The organic layer was dried over sodium sulfate and the volatiles were removed to afford the title compound. GC-MS m/z 152 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:45])[C@@H:41]([OH:42])[CH2:40][CH2:39][C@@:38]2([CH3:43])[C:12]1=[CH:13][CH2:14][C@@H:15]1[C@@H:37]2[CH2:36][CH2:35][C@@:34]2([CH3:44])[C@H:16]1[CH2:17][CH2:18][C@@H:19]2[C@@H:20]([CH2:22][O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH3:21]>>[C:1]([O:42][C@H:41]1[CH2:40][CH2:39][C@@:38]2([CH3:43])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:37]2[CH2:36][CH2:35][C@@:34]2([CH3:44])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@@H:20]([CH2:22][O:23][Si:24]([CH:25]([CH3:26])[CH3:27])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH3:21])[C:11]1([CH3:10])[CH3:45])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](OC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)(C(C)C)C(C)C
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)[Si](OC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
34.4 ml of benzoylchloride were added to a solution of 70 g crude (20S)-4,4-dimethyl-20-[((triisopropylsilyl)oxy)methyl]-pregna-5-en-3β-ol (Example 1c) (not purified by chromatography) in 670 mg pyridine at 0-3° C. The reaction mixture was stirred for 2 h at room temperature and poured into ice-water. The precipitate was filtered off, washed with water and recrystallized from acetone to give 42 g of (20S)-4,4-dimethyl-20-[((triisopropylsilyl)oxy)methyl]-pregna-5-en-3β-ol benzoate.