Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:27]=[CH:26][C:7]2[N:8]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH2:9][CH2:10][CH2:11][CH:12]([NH:13][C:14]3[S:18][N:17]=[C:16]([CH3:19])[CH:15]=3)[C:6]=2[CH:5]=1.[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:33]Br>O1CCCC1.C(OCC)(=O)C>[F:28][C:29]([F:42])([F:43])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=1)[CH2:33][N:13]([C:14]1[S:18][N:17]=[C:16]([CH3:19])[CH:15]=1)[CH:12]1[CH2:11][CH2:10][CH2:9][N:8]([C:20]([O:22][CH:23]([CH3:24])[CH3:25])=[O:21])[C:7]2[CH:26]=[CH:27][C:4]([Br:3])=[CH:5][C:6]1=2
Reactant: Cc1cc(NC2CCCN(C(=O)OC(C)C)c3ccc(Br)cc32)sn1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C2CCCN(C(=O)OC(C)C)c3ccc(Br)cc32)sn1

Procedure:
Add sodium hydride to a stirring solution of isopropyl 7-bromo-5-(3-methylisothiazol-5-ylamino)-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate in anhydrous tetrahydrofuran at room temperature under nitrogen. After the appropriate stirring time, treat the mixture with 3,5-bis(trifluoromethyl)benzyl bromide and continue stirring for an appropriate time. Dilute the mixture with ethyl acetate, wash with water and brine and dry over sodium sulfate. Remove the solvents under reduced pressure and purify the residue by flash column chromatography on silica gel to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:12]=1[NH2:13]>CO.O>[CH3:10][C:11]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:12]=1[NH:13][C:2]1[N:7]=[C:6]([NH:13][C:12]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:11]=2[CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CO
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1ncc(F)c(Nc2cc([N+](=O)[O-])ccc2C)n1
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (33 mg, 0.2 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 2-Methyl-5-nitroaniline (122 mg, 0.8 mmol) was added and the mixture was refluxed for 2 days (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 9:1) to give N2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6+CD3OD): δ 8.31 (d, 1H, J=2.3 Hz), 8.20 (d, 1H, J=2.3 Hz), 8.06 (d, 1H, J=3.5 Hz), 7.91 (dd, 1H, J=2.3, 8.2 Hz), 7.65 (dd, 1H, J=2.9, 8.8 Hz), 7.41 (m, 1H), 7.28 (d, 1H, J=8.2 Hz), 2.28 (s, 3H), 2.24 (s, 3H); LCMS purity: 87.4%; MS (m/e): 399.20 (M+, 100).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[CH:14][S:15][C:8]=12.S([C:26]#[N:27])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:26]#[N:27])[S:15][C:8]=12
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: Clc1ccnc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cc2nccc(Cl)c2s1
Temperature: 25 °C
Yield: 31.9 %

Procedure:
n-Butyllithium (2.2 mmol, 0.88 mL) was added dropwise to a solution of 7-chloro-thieno[3,2-b]pyridine (0.250 g, 1.48 mmol) in THF (10 mL) at −78° C. while the internal temperature was kept below −70° C. After 1 h TsCN (0.804 mg, 4.44 mmol) was added. After 3 h the reaction was quenched with distilled water (10 mL), warmed to rt, and the layers were separated. The aqueous layer was further extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried (Na2SO4), then concentrated under reduced pressure. Purification by flash chromatography using a Biotage 40 S column eluting with hexane/ethyl acetate (7/3) afforded the title compound as a white solid (92 mg, 32%). MS: 195/197 (MH+); HPLC Rf: 4.89 min; HPLC purity: 85%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]([CH3:15])[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:18]=[CH:17][CH:16]=[C:4]([CH2:5][N:6]([CH3:15])[C:7](=[O:14])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:3]=2)=[CH:23][CH:22]=1)=[O:20]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CN(Cc1cccc(Br)c1)C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Temperature: 90 °C

Procedure:
8.8 g (29 mmol) of N-(3-bromo benzyl)-N-methylbenzamide, 8.7 g (58 mmol) of 4-formylbenzene-boronic acid and 125 ml of toluene are introduced into a three-necked flask under argon. 36 ml (72 mmol) of aqueous potassium carbonate solution (2M) are added dropwise, the reaction medium is degassed with argon and 1 g of tetrakis(triphenylphosphine)palladium(0) chloride is added with heating at 90° C. for 24 hours. The reaction medium is poured into water and extracted with dichloromethane, and the organic phase is separated out after settling of the phases has taken place, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a column of silica eluded with a mixture of heptane and ethyl acetate (50/50). After evaporation of the solvents, 7.2 g (75%) of the expected product are collected.
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[CH:4][C:5]([F:18])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)[CH:7]=1.CCO[C:23]([S-:25])=[S:24].[K+].Cl>CN(C)C=O>[F:18][C:5]1[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)=[CH:7][C:2]2[N:1]=[C:23]([SH:25])[S:24][C:3]=2[CH:4]=1
Reactant: Cc1nn(-c2cc(N)c(Br)cc2F)c(=O)n1C(F)F
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2cc3nc(S)sc3cc2F)c(=O)n1C(F)F
Temperature: 140 °C
Yield: 73 %

Procedure:
30 mL N,N-dimethylformamide was charged with 0.01 mol 1-(5-amino-4-bromo-2-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. The mixture was stirred until it became clear. Then, 0.02 mol potassium ethyl xanthogenate was added to the mixture in two portions. The mixture was refluxed at 140° C. for 5 h, cooled, and poured into 100 mL ice water slurry. Then, the mixture was acidified with 6 mol/L hydrochloric acid, and a large amount of solids crushed out. The title compound was obtained in a 73% yield as a white solid after filtration.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[C:6]([NH:8][N:9]1[C:13](I)=[C:12]([CH3:15])[N:11]=[C:10]1[CH2:16][CH2:17][CH3:18])=[O:7])[CH3:2].[Cu][C:24]#[N:25].N1C=CC=CC=1>ClCCl>[C:24]([C:13]1[N:9]([NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[O:3][CH2:1][CH3:2])[C:10]([CH2:16][CH2:17][CH3:18])=[N:11][C:12]=1[CH3:15])#[N:25]
Reactant: N#C[Cu]
Reactant: CCCc1nc(C)c(I)n1NC(=O)c1ccccc1OCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1nc(C)c(C#N)n1NC(=O)c1ccccc1OCC
Temperature: 100 °C

Procedure:
2-Ethoxy-N-(5-iodo-4-methyl-2-propylimidazol-1-yl)benzamide from Example 1a (0.5 g, 1.2 mmol) and copper(I) cyanide (0.7 g, 7.5 mmol) are introduced into 10 ml of pyridine and heated at 100° C. for three hours. The reaction mixture is cooled to room temperature, 50 ml of dichloromethane are added, and the solid is removed by filtration. The filtrate is washed three times with 50 ml of water each time, and the organic phase is re-extracted with 50 ml of dichloromethane. The combined organic phase is dried with sodium sulphate and concentrated. To remove the remaining pyridine, the residue is taken up in 50 ml of dichloromethane and washed six times with 100 ml of water each time. The organic phase is dried with sodium sulphate and concentrated in a rotary evaporator. The residue is finally mixed with 100 ml of toluene and concentrated.
Reaction SMILES: CO/[CH:3]=[C:4](\[C:11]([O:13][CH3:14])=[O:12])/[CH:5]=[CH:6]/[C:7]([O:9]C)=O.[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.O>CN(C=O)C>[CH:15]1([N:21]2[C:7](=[O:9])[CH:6]=[CH:5][C:4]([C:11]([O:13][CH3:14])=[O:12])=[CH:3]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCC1
Reactant: CO/C=C(/C=C/C(=O)OC)C(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(=O)n(C2CCCCC2)c1
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a solution of dimethyl (2E,4Z)-4-(methoxymethylene)-2-pentenedioate (1.23 g) in DMF (30 mL) was added cyclohexanamine (670 mg) at 0° C., and the mixture was stirred at the same temperature for 30 min under a nitrogen atmosphere. The reaction mixture was heated to reflux for 5 hr. The mixture was cooled with an ice-water bath and poured into water (100 mL). The resulted mixture was extracted with EtOAc (100 mL×2), and the organic phases were combined, washed with brine two times, dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc-hexane (1:2-1:1) to give methyl 1-cyclohexyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (520 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>O.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>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Clc1ccc2ccccc2n1
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: COCCOC
Product: Clc1cccc(-c2ccc3ccccc3n2)c1
Yield: 77.5 %

Procedure:
2-chloroquinoline (9.25 g, 56.5 mmol), (3-chlorophenyl)boronic acid (9.28 g, 59.4 mmol), Pd(PPh3)4 (1.634 g, 1.413 mmol) were charged into the reaction flask with 300 mL of 1,2-dimethoxyethane. Sodium carbonate (14.98 g, 141 mmol) was dissolved in 50 mL of water and was charged into the reaction flask. The reaction flask was then evacuated and back-filled with nitrogen then was heated to reflux for 20 hours. The organic layer was separated and dried over magnesium sulfate. The organics were filtered and stripped under vacuum. The crude residue was passed through a silica gel column using 5-25% ethyl acetate/hexanes yielding 2-(3-chlorophenyl)quinoline (10.5 g, 77% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1F.[CH3:11][C@H:12]([OH:16])[CH2:13][CH:14]=[CH2:15].[H-].[Na+]>C1COCC1.CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:16][C@H:12]([CH2:13][CH:14]=[CH2:15])[CH3:11]
Reactant: C=CC[C@H](C)O
Reactant: N#Cc1ccc(Br)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC[C@H](C)Oc1cc(C#N)ccc1Br
Reaction time: 5 h
Yield: 70.6 %

Procedure:
To a solution of 4-bromo-3-fluorobenzonitrile (1.0 g, 5.00 mmol, 1 equiv) and (S)-pent-4-en-2-ol (0.52 g, 6.00 mmol, 1.2 equiv) in THF (25 mL) was added NaH (0.24 g of a 60% suspension in mineral oil, 6.00 mmol, 1.2 equiv). Slow gas evolution with considerable foaming observed. After 5 h, dilute with ether then wash with water and brine. The ether layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-10% EtOAc in hexane) to provide the product as a colorless oil (0.94 g, 71%). 1H NMR (400 MHz, CDCl3) δ 7.69-7.62 (m, 1H), 7.15-7.08 (m, 2H), 5.89 (ddt, J=17.1, 10.1, 7.2 Hz, 1H), 5.23-5.12 (m, 2H), 4.54-4.42 (m, 1H), 2.61-2.51 (m, 1H), 2.51-2.40 (m, 1H), 1.39 (d, J=6.0 Hz, 3H).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][N:14]2[N:17]=[CH:18][CH:19]=[C:13]2[N:12]=1.[Br:20]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Br:20][C:19]1[CH:18]=[N:17][N:14]2[CH:15]=[CH:16][C:11]([NH:10][CH2:9][CH2:8][O:7][CH3:6])=[N:12][C:13]=12
Reactant: BrBr
Reactant: COCCNc1ccn2nccc2n1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCCNc1ccn2ncc(Br)c2n1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
Sodium acetate [127-09-3] (457.6 mg, 5.6 mmol) was added to a solution of N-(2-methoxyethyl)pyrazolo[1,5-a]pyrimidin-5-amine (706.4 mg, 3.7 mmol) in glacial acetic acid (40 mL) and allowed to stir at ambient temperature until all of the solid had dissolved. Bromine [7726-95-6] (0.2 mL, 3.7 mmol) was added into the ambient temperature, buffered acetic acid reaction solution over 2 minutes, then the reaction solution was slowly poured into stirring water (1 L). The pH was increased by the addition of solid sodium bicarbonate until the pH of the supernatant was determined to be approximately 8 by pH paper. Precipitated product was isolated by filtration, the filter cake washed with water, and allowed to dry to afford 819.6 mg of white powder. LRMS (ESI) m/z 271.0/273.0 [(M+H)]+, calc'd for C9H11BrN4O: 271.12.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([C:23](=O)[NH2:24])=[CH:19][C:18]=4[CH3:26])[C:15]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=4[CH3:26])[C:15]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(-n3ccnc3)cc2)n1-c1ccc(C(N)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CCc1ccc(-c2ccc(-n3ccnc3)cc2)n1-c1ccc(C#N)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.2 %

Procedure:
To a solution of ethyl 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (30A) (2.0 g, 4.52 mmol) in DMF (9 mL) was added POCl3 (693 mg, 4.52 mmol) at 0° C., and then stirred at room temperature for 1.5 h. After cooling to room temperature, the reaction mixture was added to ice-water (20 mL). Sat. Na2CO3 was added to adjust pH=8 followed by extraction with ethyl acetate (50 mL×4). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (PE:EA=1:1) to afford ethyl 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (30B) (1.02 g, 53%), LC-MS: [M+H]+ 425.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[N:8][C:9](Cl)=[CH:10][CH:11]=2)[N:6]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:5]1=[O:23])[CH:2]=[CH2:3].[NH3:24]>>[CH2:1]([N:4]1[C:12]2[C:7](=[N:8][C:9]([NH2:24])=[CH:10][CH:11]=2)[N:6]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:5]1=[O:23])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=O)n(-c2ccc3c(c2)OCO3)c2nc(Cl)ccc21
Reactant: N
Product: C=CCn1c(=O)n(-c2ccc3c(c2)OCO3)c2nc(N)ccc21

Procedure:
Heat a mixture of 2.5 g. of the imidazopyridin product of Step D and 25 ml. of liquid ammonia in a bomb at 150° C. for 3 hours. Remove the excess ammonia and crystallize the residue from dimethyl formide-water.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@@H:3]([CH3:24])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:22][CH2:21][C:13]3([CH2:20][CH2:19][C:16]4([O:18][CH2:17]4)[CH2:15][CH2:14]3)[C:12]2=[O:23])=[CH:7][CH:6]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[O:23]=[C:12]1[C:13]2([CH2:14][CH2:15][CH:16]([CH:17]=[O:18])[CH2:19][CH2:20]2)[CH2:21][CH2:22][N:11]1[C:8]1[CH:7]=[CH:6][C:5]([O:4][C@H:3]([CH3:24])[C:2]([F:25])([F:1])[F:26])=[CH:10][CH:9]=1
Reactant: C[C@@H](Oc1ccc(N2CCC3(CCC4(CC3)CO4)C2=O)cc1)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: C[C@@H](Oc1ccc(N2CCC3(CCC(C=O)CC3)C2=O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
To a solution of 8-[4-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-1-oxa-8-aza-dispiro[2.2.4.2]dodecan-7-one (50 mg, 135 umol, obtained in example 252, Step 2) in chloroform was added tosic acid (26 mg, 135 umol) and the reaction mixture was stirred overnight at room temperature and then diluted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (grad 0% to 80% EtOAc in heptane) to yield the title compound as a white solid (7 mg, 14%). MS (m/e): 370.1 (MH+).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([O:25][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Reactant: OC1CCCCC1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)OC1CCCCC1

Procedure:
The title compound, white solid, m.p. 117-119° C. and MS: m/e=337.4 (M+H+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and cyclohexanol.
Reaction SMILES: [CH2:1]([N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].Cl[CH2:19][CH2:20][CH2:21][CH2:22][S:23]([O-:26])(=[O:25])=[O:24].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>C1COCC1>[CH2:14]([N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH3:17].[CH2:27]([N:29]([CH2:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH2:22][S:23]([O-:26])(=[O:25])=[O:24])[CH3:28]
Reactant: CCNCC
Reactant: O=S(=O)([O-])CCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCN(CC)CCCCS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tetrabutylammonium-4-chlorobutylsulfonate in THF sodium carbonate is added. To the resulting suspension, a solution of diethylamine in THF is added. The suspension is stirred at room temperature for 1 h. The precipitate is filtered off and the remaining solution is concentrated with a rotary evaporator to yield tetrabutylammonium-4-diethylaminobutylsulfonate.
Reaction SMILES: [CH3:1][C@@:2]12[C:11]3[CH:12]=[CH:13][C:14]([S:16][C:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]=4)=[CH:15][C:10]=3[CH2:9][CH2:8][C@H:7]1[NH:6][C:5](=[O:27])[CH2:4][CH2:3]2.[CH3:28]I>>[CH3:28][N:6]1[C@H:7]2[C@@:2]([CH3:1])([C:11]3[CH:12]=[CH:13][C:14]([S:16][C:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]=4)=[CH:15][C:10]=3[CH2:9][CH2:8]2)[CH2:3][CH2:4][C:5]1=[O:27]
Reactant: CI
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(Sc3ccc4ccccc4c3)ccc12
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5ccccc5c4)cc3CC[C@@H]12

Procedure:
A 282 mg portion of (4aR)-(10bR)-10b-methyl-8-(2-naphthylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3one was methylated with methyl iodide following the process of Example 95 to obtain 137 mg of the desired product. mp 138°-139.5° FDMS: m/e=387. α[D]589 =+69.6, α[D]365 =+261 (chloroform).
Reaction SMILES: C([O:4][C@H:5]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:27])[CH:16]([O:23][C:24](=[O:26])[CH3:25])[CH2:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:6]1)(=O)C.C(O)C.C(=O)(O)[O-].[Na+]>O>[C:24]([O:23][CH:16]([C@H:15]([C@@H:14]1[C@:28]2([CH3:36])[C@H:11]([C@H:10]3[C@H:31]([CH2:30][CH2:29]2)[C@:32]2([CH3:35])[C:7]([CH2:6][C@@H:5]([OH:4])[CH2:34][CH2:33]2)=[CH:8][CH2:9]3)[CH2:12][CH2:13]1)[CH3:27])[CH2:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(CCC(C)(C)C)[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)OC(CCC(C)(C)C)[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a solution of 1 part of 25-methylcholest-5-ene-3β,22-diol 3,22-diacetate in 40 parts of ethanol is added 5 parts of aqueous 5% sodium bicarbonate. The resultant mixture is heated and stirred at the boiling point under reflux for 21/2 hours, then diluted with an equal volume of water. The solid precipitate which eventuates is isolated by filtration, dried in air, and recrystallized from ethanol to give 25-methylcholest-5-ene-3β,22-diol 22-acetate melting at 210°-211.5°. The product has the formula ##STR16##
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:20][OH:21]>CCO>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:7]=[CH:6][C:3]=1[CH:4]=[N:20][OH:21]
Reactant: NO
Reactant: CCCCCCCCOc1ccc(C=O)c(O)c1
Agent: Cl
Solvent: CCO
Product: CCCCCCCCOc1ccc(C=NO)c(O)c1
Reaction time: 2 h

Procedure:
To a solution of 2-hydroxy-4-octyloxy-benzaldehyde (3.64 g; 14.5 mmol) in abs. EtOH (30 mL) was added hydroxylamine hydrochloride [50% H2O (w/w)] and the slurry was stirred for 2 hours. The reaction mixture was evaporated to dryness and the resulting solid triturated in H2O (20 mL) and EtOAc/diethylether (20 mL+10 mL) to give 1.8 g (47%) as a white solid. MS (direct; EI): 265 (M).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].[CH3:12][C:13]([CH3:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17]>CCO.O>[C:13]([C:14]1[CH:15]=[C:16]([NH2:17])[N:10]([C:4]2[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=2[CH3:2])[N:11]=1)([CH3:20])([CH3:19])[CH3:12]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Cc1ccc(NN)c(C)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)c(C)c1
Yield: 36 %

Procedure:
To a heated solution of 2,4-dimethylphenylhydrazine hydrochloride (1.38 g, 8 mmol) in EtOH/water/1M NaOH (20 mL/12 mL/8 mL) at 50° C., 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8 mmol) was added and the reaction heated until finished by LC-MS. The solution was partitioned between EtOAc and water, and extracted twice. The extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated. Purification using silica gel chromatography eluting with an EtOAC/hexane gradient (5-20%) gave 3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-amine (700 mg, 36% yield). 1H NMR (300 MHz, DMSO d6) δ 1.09 (s, 9H), 1.98 (s, 3H), 2.32 (s, 3H), 4.76 (s, 2H), 5.26 (s, 1H), 7.11 (m, 3H). LC-MS (ESI) m/z 244 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][C:6]=2[C:16]=1[O:17][CH3:18].Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[N:25][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][C:6]=3[C:16]=2[O:17][CH3:18])=[N:21][CH:22]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCC(NCCO)CC2
Product: COc1c(Nc2ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n2)ccc2c1CCC(NCCO)CC2
Yield: 21 %

Procedure:
In an analogous manner to Experimental 691, part c, 2-(2-Amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino)-ethanol and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide were combined to yield N-((1R,2R)-2-{5-Chloro-2-[7-(2-hydroxy-ethylamino)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide (40.88 mg, 21% yield) as a beige foam. Purification separated the sample into its enantiomers. 1H-NMR (CDCl3) δ 7.94 (s, 1H), 7.93 (d, J=8.52, 1H), 7.29 (s, 1H), 6.88 (d, J=8.1 Hz, 1H), 5.42 (d, J=7.4 Hz, 1H), 3.91 (m, 1H), 3.72 (s, 3H), 3.63 (m, 2H), 3.23 (m, 2H), 2.85 (m, 2H), 2.79 (s, 3H), 2.68 (m, 1H), 2.48 (m, 1H), 2.21 (m, 4H), 1.83 (m, 2H), 1.50-1.26 (m, 5H). LC/MS=553 (M+H).