Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:22]([CH:5]2[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]2=[O:9])=[O:23])(=[O:19])=[O:20])=[CH:16][CH:17]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: c1ccccc1
Product: CC1(C)CC(=O)C(C(=O)NS(=O)(=O)c2ccc(Cl)cc2)C(=O)C1

Procedure:
Reaction of equimolar amounts of 5,5-dimethylcyclohexane-1,3-dione with p-chlorobenzenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 2-(N-p-CHLOROBENZENESULFONYLCARBAMOYL)-5,5-DIMETHYLCYCLOHEXANE-1,3-DIONE, m.p. 103°-105.5° C. (corr.).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:20]O>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH2:12][C:13]([O:15][CH3:20])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cccc2ccc(O)cc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cccc2ccc(O)cc12

Procedure:
Dissolve the compound obtained in Step A in 100 ml of methanol. Cool the mixture in an ice-bath. Add thionyl chloride dropwise and maintain the reaction mixture at that temperature for 20 minutes after the addition. Leave for 1 hour at room temperature with stirring. Remove the methanol by evaporation under reduced pressure, and recrystallise the resulting solid from a mixture of toluene/cyclohexane (4/1).
Reaction SMILES: [CH:1]12[CH2:7][CH2:6][CH:5]1[CH2:4][N:3]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=1)[CH2:2]2>[Pd]>[CH:5]12[CH2:6][CH2:7][CH:1]1[CH2:2][N:3]([C:8]1[N:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)[CH2:4]2
Reactant: O=[N+]([O-])c1ccc(N2CC3CCC3C2)nc1
Agent: [Pd]
Product: Nc1ccc(N2CC3CCC3C2)nc1
Yield: 92.2 %

Procedure:
According to a procedure similar to that described in Stage 14.2, starting from 0.12 g (0.55 mmol) of 2-(3-azabicyclo[3.2.0]hept-3-yl)-5-nitropyridine, prepared in the preceding stage, and 0.17 g of palladium on charcoal at 10%, we obtain 0.096 g of the expected compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].Cl.[CH3:14][N:15]([CH2:17][CH2:18]Cl)[CH3:16]>>[CH3:14][N:15]([CH:17]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)[CH3:18])[CH3:16]
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: Cl
Product: CC(N(C)C)n1ccc2cc([N+](=O)[O-])ccc21
Yield: 76.9 %

Procedure:
Prepared according to the method of Example 15a) from 5-nitroindole (0.217 g) and dimethylaminoethyl chloride hydrochloride (0.21 g) to leave sub-title compound as an orange/brown solid (0.24 g).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH3:15])=[C:11]([NH2:14])[CH:12]=2)[C:7]([CH3:17])([CH3:16])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CC([O-])(C)C.[Na+].I[C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:30]([O:29][C:27](=[O:28])[C:26]1[CH:32]=[CH:33][C:34]([NH:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([CH3:17])([CH3:16])[CH2:6][CH2:5][N:4]3[CH:1]([CH3:3])[CH3:2])=[CH:9][C:10]=2[CH3:15])=[CH:35][CH:25]=1)[CH3:31]
Reactant: CCOC(=O)c1ccccc1I
Reactant: Cc1cc2c(cc1N)N(C(C)C)CCC2(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CCN3C(C)C)cc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 78.5 %

Procedure:
1-Isopropyl-4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-7-ylamine (Compound 45, 500 mg, 2.152 mmol) was placed into the round bottom flask charged with argon. Pd2 (dab)3 (4.926 mg, 0.25 mol %), and BINAP (10.05 mg, 0.75 mol %) were added, followed by NaOtBu (405.27 mg, 3.012 mmol), ethyl iodobenzoate (831.7 mg, 3.012 mmol) and toluene (8 mL). The resulting mixture was stirred at 80° C. for 3 days, cooled to room temperature, and filtered through Celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (10% ethyl acetate in hexane, Rf=0.26) to give the title compound (642.76 mg, 79%) as a pale yellow solid:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:10][S:11][CH2:12]Cl.C(N(CC)CC)C>>[C:1]([O:9][CH2:10][S:11][CH3:12])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CSCCl
Reactant: CCCCCCC(=O)O
Solvent: CCN(CC)CC
Product: CCCCCCC(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting heptanoic acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 80°-81° C./2 mm Hg, n20 1.4591.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:17][C:18]1[C:27]2[CH:26]=[N:25][C:24](S(C)=O)=[N:23][C:22]=2[N:21]([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=2)[C:20](=[O:42])[CH:19]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:4]=1[NH:5][C:24]1[N:25]=[CH:26][C:27]2[C:18]([CH3:17])=[CH:19][C:20](=[O:42])[N:21]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=3)[C:22]=2[N:23]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1N
Reactant: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(S(C)=O)nc32)c1
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C)CC5)cc4OC)nc32)c1
Temperature: 100 °C
Yield: 31 %

Procedure:
To a suspension of 2-methoxy-4-(4-methylpiperazin-1-yl)aniline (Green Chempharm; 3.45 g, 15.57 mmol) and N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b) (4.59 g, 12.46 mmol) in anhydrous tert-butanol (40 mL) and dioxane (5 mL) at RT was added DIEA (4.33 mL, 24.92 mmol). The mixture was heated at 100° C. for 40 h. The reaction mixture was concentrated under reduced pressure (rotary evaporator) to remove the volatiles and the resulting crude residue was suspended in Et2O and filtered. The greenish-brown amorphous solid was washed with Et2O (3×50 mL) and this removed most of the remaining aniline starting material. The crude material was dry-packed on silica gel and purified on a silica gel column (1-20% MeOH in DCM) affording N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5) (2.03 g, 3.86 mmol, 31% yield) as a yellow amorphous solid. m/z (ESI, +ve ion) 526.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (1H, s), 8.80 (1H, s), 8.09 (1H, s), 7.88 (1H, d, J=8.2 Hz), 7.56 (1H, J=1.9 Hz), 7.50 (1H, t, 1=8.1 Hz), 7.27 (1H, d, J=8.8 Hz), 6.97 (1H, dt, J=6.9, 1.0 Hz), 6.52 (1H, d, J=2.5 Hz), 6.37-6.48 (1H, m), 6.29-6.35 (1H, m), 6.19-6.29 (1H, m), 6.01 (1H, br. s.), 5.71-5.80 (1H, m), 3.78 (3H, s), 3.02 (4H, br. s.), 2.46 (3H, s), 2.43 (4H, t, J=4.9 Hz), 2.22 (3H, s).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[N:24][CH:25]=1.[CH:27](OCC)=[O:28]>C1COCC1>[Br:19][C:20]1[CH:25]=[N:24][C:23]([F:26])=[C:22]([CH:21]=1)[CH:27]=[O:28]
Reactant: Fc1ccc(Br)cn1
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: O=Cc1cc(Br)cnc1F
Temperature: -65 °C
Reaction time: 1.5 h

Procedure:
To a solution of diisopropylamine (17 mL, 0.17 mol) in dry THF (200 mL) was added 2.5 M n-BuLi in hexane (68 mL, 0.17 mol) dropwise at 0° C. under N2 atmosphere. After the addition, the resulting mixture was cooled to −65° C. A solution of 5-bromo-2-fluoropyridine (25 g, 0.14 mol) in dry THF (100 mL) was then added dropwise. The resulting mixture was stirred at −65° C. for 90 minutes. Then ethyl formate (15.6 g, 0.21 mol) was added dropwise to the mixture. After stirred for 10 minutes, the reaction mixture was quenched with a solution of 10% citric acid in THF (100 mL) at −65° C. The resulting mixture was warmed up to room temperature, poured into water (100 mL) and extracted with EtOAc (200 mL). The organic layer was separated and washed with saturated aqueous NaCl (100 mL×2), dried over Na2SO4 and concentrated in vacuo to yield compound D-1-2 (25 g, 85%) as a yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Al](Cl)(Cl)Cl.O.O.O.O.O.O.[Na+].[Br-].Cl>CN(C)C=O.O>[OH:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1cc(OC)c(C(=O)O)cc1OC
Agent: Cl
Agent: Cl[Al](Cl)Cl
Agent: [Br-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(O)c(C(=O)O)cc1OC
Temperature: 100 °C
Reaction time: 5 h
Yield: 73.2 %

Procedure:
In 11 mL of dimethylformamide (DMF) were suspended 2.12 g of compound (1a), 4.82 g of AlCl3.6H2O, and 2.06 g of NaBr in a stream of argon, which was then heat stirred at 100° C. for 5 hours. The reaction mixture was allowed to stand to cool, to which 10.4 g of 35% hydrochloric acid was then added dropwise before adding 11 mL of water, followed by heat stirring at 70° C. for one hour. The precipitated crystal was collected by filtration and washed with water. The resultant crystal was dried under reduced pressure at 60° C. to provide 1.45 g of compound (2a) at a yield of 73%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C(Cl)Cl.[C:10]([OH:29])(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>O>[CH2:30]([N:32]([CH2:33][CH3:34])[C:10](=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:31]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CCNCC
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CC)CC
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
In a nitrogen atmosphere, oxalyl chloride (0.46 mL, 5.4 mmol) was dropped into an absolute methylene chloride solution (8.5 mL) of oleic acid (503 mg, 1.8 mmol) under ice cooling. The solution was then stirred at room temperature for four hours. Thereafter it was concentrated under reduced pressure. Diethylamine (1.0 mL, 9.7 mmol) was added to the resultant residue, which was then stirred at room temperature for 0.5 hour. Water was then added, and extraction was performed with ethyl acetate. The organic layer thus obtained was washed with saturated saline, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The crude extract thus obtained was purified using column chromatography (n-hexane:ethyl acetate=1:2). Thus (Z)-N,N-diethyl-9-octadecenamide (495 mg, 82%) was obtained as a colorless oily matter.
Reaction SMILES: [I: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=O.[NH:13]([C:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[I: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=[N:14][NH:13][C:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=1)=[O:16]
Reactant: COC(=O)c1ccc(C(=O)NN)nc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)nc1
Temperature: 100 °C
Yield: 73 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added methyl 6-(hydrazinocarbonyl)nicotinate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 33 mg of the title compound (73%) as a yellow solid in 89.7% purity by HPLC (Rt: 4.44, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][C:25](Cl)=[O:26])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][OH:34]>>[CH2:2]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][C:25]([O:34][CH2:33][CH2:32][N:31]([CH3:35])[CH3:30])=[O:26])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CN(C)CCO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)Cl)cc1
Agent: Cl
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OCCN(C)C)cc1

Procedure:
As in the method of Example 21, 4-(hexadecylamino) hydrocinnamoyl chloride hydrochloride is treated with 2-dimethylaminoethanol to provide 2-dimethylaminoethyl 4-(hexadecylamino)hydrocinnamate.
Reaction SMILES: [F:1][C:2]1[C:16]([F:17])=[C:15]([CH:18]=[O:19])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1.C([O-])([O-])=[O:21].[K+].[K+].CS(C)=O>O>[F:1][C:2]1[C:16]([F:17])=[C:15]([CH:18]=[O:19])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([NH2:10])=[O:21])=[CH:7][N:6]=1
Reactant: N#Cc1ccc(Oc2ccc(C=O)c(F)c2F)nc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)c(F)c2F)nc1
Reaction time: 1 h
Yield: 148.1 %

Procedure:
Add 30% aq. B202 (7.95 ml) to a suspension of 6-(2,3-difluoro-4-formyl-phenoxy)-nicotinonitrile (2.07 g, 7.95 mmol), K2CO3 (550 mg, 3.98 mmol) and DMSO (20 ml) stirring in an ice/water bath. After one hour, pour the reaction mixture into water and extract with EtOAc. Wash the extract with water and brine before drying (MgSO4) and concentrating to give 6-(2,3-difluoro-4-formyl-phenoxy)-nicotinamide (1.64 g) as a white solid. 1HNMR (DMSO-d6): 10.14 (s, 1H), 8.58 (s, 1H), 8.33 (d, 1H), 8.07 (s, 1H), 7.74 (t, 1H), 7.55 (s, 1H), 7.33 (d, 1H), 7.27 (t, 1H).
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:15][NH:16][C:17]([C:19]2[N:20]=[C:21]([C:37]#[N:38])[C:22]3[C:27]([C:28]=2[OH:29])=[CH:26][CH:25]=[C:24]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=3)=[O:18])[CH2:13][CH2:12][S:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:37]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[C:24]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:23]=2)[C:28]([OH:29])=[C:19]([C:17]([NH:16][CH2:15][C:8]2([C:6]([OH:7])=[O:5])[CH2:9][CH2:10][S:11](=[O:14])[CH2:12][CH2:13]2)=[O:18])[N:20]=1)#[N:38]
Reactant: CC(C)(C)OC(=O)C1(CNC(=O)c2nc(C#N)c3cc(Oc4ccccc4)ccc3c2O)CCS(=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nc(C(=O)NCC2(C(=O)O)CCS(=O)CC2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A mixture of 4-{[(1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-methyl}-1-oxo-hexahydro-1λ4-thiopyran-4-carboxylic acid tert-butyl ester (23 mg), TFA (5 mL) and DCM (5 mL) was stirred at rt overnight; then concentrated, the residue was treated with water and added 2 M HCl solution, solids were collected via filtration, washed with water and air dried to give the desired product (20 mg). LC MS ESI+: 480 (M+1)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH3:4])[C@:16]1([CH:17]=[O:18])[C:11](=[CH:12][CH2:13][CH2:14][C@@H:15]1[CH3:22])[CH2:10][CH2:9]3.[CH3:23][Si:24]([CH3:27])([CH3:26])Cl.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:22][C@@H:15]1[C@@:16]2([CH:17]=[O:18])[C:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:19]2[CH2:20][CH2:21][C@@:3]2([CH3:4])[C@H:5]3[CH2:6][CH2:7][C@@H:2]2[O:1][Si:24]([CH3:27])([CH3:26])[CH3:23])=[CH:12][CH2:13][CH2:14]1
Reactant: C[Si](C)(C)Cl
Reactant: C[C@H]1CCC=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21C=O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: C[C@H]1CCC=C2CC[C@H]3[C@@H]4CC[C@H](O[Si](C)(C)C)[C@@]4(C)CC[C@@H]3[C@]21C=O

Procedure:
A mixture of 17β-hydroxy-1α-methyl-4-androsten-19-one, trimethylchlorosilane and pyridine is refluxed in benzene for a period of about 18 hours. The suspension is filtered and the benzene removed under vacuum. The resulting oil is eluted from a silica gel chromatograph with benzene and crystallized from hexane to yield 1α-methyl-17β-trimethylsiloxy-4-androsten-19-one.
Reaction SMILES: Br[C:2]([CH3:16])([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].[Na].[CH3:18][SH:19].O>CO>[CH3:18][S:19][C:2]([CH3:16])([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: CS
Reactant: CC(C)(Br)C(=O)c1ccc(C(F)(F)F)cc1
Agent: [Na]
Solvent: O
Solvent: CO
Product: CSC(C)(C)C(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
To 1 g of 2-bromo-4'-(trifluoromethyl)isobutyrophenone dissolved in methanol was added under ice-cooling 1.74 g of 15% solution of methyl mercaptan sodium salt, and the mixture was stirred for 30 minutes. The reaction mixture was poured into ice-cooled water and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography using n-hexane/dichloromethane to obtain 0.61 g of an oily product of 2-methylthio-4'-(trifluoromethyl)isobutyrophenone (yield: 68.7%).
Reaction SMILES: [CH2:1]([NH:9][C:10]1[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:12][C:13]2[C:18]([N:19]=1)=[CH:17][C:16]([C:20]([O:22]C)=[O:21])=[CH:15][CH:14]=2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[CH2:1]([NH:9][C:10]1[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:12][C:13]2[C:18]([N:19]=1)=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(NCCc3ccccc3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(NCCc3ccccc3)nc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask (1 atm), was placed a solution of methyl 3-(phenethylamino)-2-phenylquinoxaline-6-carboxylate (120 mg, 0.31 mmol, 1.00 equiv) in methanol (15 mL), a solution of sodium hydroxide (50.08 g, 1.25 mol, 4.00 equiv) in water (2 mL). The resulting solution was stirred for 2 h at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was diluted in 20 mL of water. The pH value of the solution was adjusted to 4-5 with aq hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. This resulted in 60 mg (52%) of 3-(phenethylamino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [ClH:1].Cl.[C:3]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([OH:5])=[O:4].[CH:28]1(O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[ClH:1].[ClH:1].[CH:28]1([O:4][C:3]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[O:5])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)COc1ccc(N2CCN(CCC3CCNCC3)CC2)cc1
Reactant: OC1CCCCCC1
Agent: Cl
Product: O=C(COc1ccc(N2CCN(CCC3CCNCC3)CC2)cc1)OC1CCCCCC1

Procedure:
Prepared from 1-(4-carboxymethyloxyphenyl)-4-[2-(piperidin-4-yl)ethyl]piperazine dihydrochloride and cycloheptanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[BH4-].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCc2cc(Br)ccc21
Yield: 99.1 %

Procedure:
5-bromo-2,3-dihydro-1H-inden-1-one (2.0 g) was dissolved in methanol (20 mL), and to the resultant solution, sodium borohydride (0.54 g) was added at room temperature, followed by stirring the resultant reaction mixture at room temperature for 14 hours. To the reaction mixture, 1M hydrochloric acid (50 mL) was added, followed by extracting the resultant reaction mixture with ethyl acetate (50 mL) three times, and the organic phase was washed sequentially with water (50 mL) and a saturated saline (50 mL) and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure to obtain the subject compound (2.0 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][CH:14]=C)[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC[O:18]CC.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[C:7]([C:6]1[C:5]([OH:12])=[C:4]([CH2:13][CH:14]=[O:18])[CH:3]=[C:2]([Cl:1])[CH:11]=1)([O:9][CH3:10])=[O:8]
Reactant: CCOCC
Reactant: C=CCc1cc(Cl)cc(C(=O)OC)c1O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: COC(=O)c1cc(Cl)cc(CC=O)c1O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Osmium tetroxide (1.0 g, 3.9 mmol) was added to a mixture of methyl 5-chloro-2-hydroxy-3-(2-propenyl)benzoate (4c) (22.7 g, 0.1 mol), ether (400 ml), and water (400 ml). After stirring at room temperature for 5 minutes, sodium periodate (47.06 g, 0.22 mol) was added in portions. The mixture was stirred at room temperature for another 21 hours, and then poured into 800 ml of water. The layers were separated and the aqueous layer extracted with ethyl ether (2×400 ml). The organic layers were combined, dried over anhydrous Na2SO4 and then filtered through a column of Florisil (85 g) to remove inorganic impurity. Evaporation of the ether yielded 5c quantitatively as a brown solid, m.p. 49°-59° C., which appeared hygroscopic. The crude product was used for the next reaction without purification. NMR (CDCl3) δ0.90 (s, 1H, OH), 9.67 (t, 1H, J=1.5 Hz, CHO), 7.70 (d, 1H, J=3 Hz, aromatic proton), 7.23 (d, 1H, aromatic proton), 3.97 (s, 3H, CH3) and 3.70(d, 2H, CH2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH:16]([OH:34])[C:17]2[CH:33]=[CH:32][C:20]3[CH2:21][CH2:22][N:23](C(=O)C(F)(F)F)[CH2:24][CH2:25][C:19]=3[CH:18]=2)[C:11](=[O:35])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH:16]([OH:34])[C:17]2[CH:33]=[CH:32][C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:19]=3[CH:18]=2)[C:11](=[O:35])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N1CCc2ccc(C(O)Cn3ccc(OCc4ccccc4)cc3=O)cc2CC1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=c1cc(OCc2ccccc2)ccn1CC(O)c1ccc2c(c1)CCNCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 100 mg (0.21 mmol) 4-benzyloxy-1-{2-hydroxy-2-[3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-ethyl}-1H-pyridin-2-one (example 22.2) in 5.0 mL MeOH is added 0.41 mL (0.41 mmol) aqueous 1 M sodium hydroxide solution. The reaction mixture is stirred 2 h at RT. The solvent is evaporated, the residue is dissolved in DMF and purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).