Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]=[O:9])[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)([OH:19])N.Cl([O-])=O.[Na+].[OH-].[Na+]>O1CCCC1.O>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:19])=[O:9])[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1c(C=O)c(=O)n(-c2ccccc2)n1C
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of the commercially available 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbaldehyde (CAS No. 950-81-2) (51.6 g) in tetrahydrofuran (THF) (1 L) at 0° C. was added a solution of sulfamic acid (48.5 g) in water (640 mL). A solution of sodium chlorite (43.7 g) in water (500 mL) was added slowly maintaining the temperature below 8° C. The reaction mixture was allowed to warm to room temperature. After 5 hours, the pH of the reaction was adjusted to 8 with a 6 N aqueous solution of sodium hydroxide (NaOH). The mixture was extracted with ethyl acetate (EtOAc). The aqueous layer was acidified to pH 4 with a 6N solution of hydrochloric acid (HCl) and extracted with dichloromethane (DCM). The combined DCM extracts were washed sequentially with 5% aqueous sodium sulfite and saturated brine, dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure. The crude solid was triturated with methanol (MeOH) to give the title compound (17 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:10][CH2:11][CH2:12][CH2:13]Br.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][CH2:13][CH2:12][CH2:11][Br:10]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: BrCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccc(OCCCBr)cc1Cl
Reaction time: 2 h

Procedure:
A mixture of 3.26 g (20 mmol) of 3,4-dichlorophenol, 20.2 g (100 mmol) of 1,3-dibromopropane, 6.80 g (20 mmol) of tetra-n-butyl ammonium hydrogen sulfate, 40 ml of 1N sodium hydroxide, and 40 ml of methylene chloride was stirred rapidly at reflux. After 2 hours, the mixture was allowed to cool and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was chromatographed over silica gel using methylene chloride/hexane as eluent. The title compound (1.58 g) was found to be homogeneous by thin layer chromatography (10% by volume of methylene chloride/hexane on silica gel plates).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][NH:13][C:14]([C@:16]1([OH:45])[C@H:21]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=[C:36]([CH3:44])[CH:35]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:20][CH2:19][NH:18][CH2:17]1)=[O:15])(C)(C)C.FC(F)(F)C(O)=O>>[OH:12][NH:13][C:14]([C@:16]1([OH:45])[C@H:21]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=[C:36]([CH3:44])[CH:35]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:20][CH2:19][NH:18][CH2:17]1)=[O:15]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCNC[C@]3(O)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCNC[C@]3(O)C(=O)NO)cc2)c2ccccc2n1
Yield: 22 %

Procedure:
(3R,4R)-N-tert-Butoxy-3-hydroxy-4-(4-((2-methylquinolin-4-yl) methoxy)phenylsulfonamido)piperidine-3-carboxamide trifluoroacetic acid salt (Example 46, Step 8) was treated with neat trifluoroacetic acid (3 mL) at 45° C. for 5 days. After removal of trifluoroacetic acid, the residue was purified using preparative HPLC, eluting with a gradient of 10-30% acetonitrile with triethylamine (10 min) to yield 17.2 mg (22%) of (3R,4R)-N,3-dihydroxy-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]piperidine-3-carboxamide as white powder. HRMS: calcd for C23H26N4O6S+H+, 487.16458; found (ESI-FTMS, [M+H]1+), 487.1646
Reaction SMILES: Br[CH:2]([CH3:9])[C:3](=O)[C:4]([O:6][CH3:7])=[O:5].[CH:10]1([N:13]([CH:35]2[CH2:37][CH2:36]2)[C:14]([C:16]2[N:32]([CH2:33][CH3:34])[C:19]3=[N:20][C:21]([NH:28][C:29]([NH2:31])=[S:30])=[C:22]4[N:26]=[CH:25][N:24]([CH3:27])[C:23]4=[C:18]3[CH:17]=2)=[O:15])[CH2:12][CH2:11]1>CCO>[CH:35]1([N:13]([CH:10]2[CH2:11][CH2:12]2)[C:14]([C:16]2[N:32]([CH2:33][CH3:34])[C:19]3=[N:20][C:21]([NH:28][C:29]4[S:30][C:2]([CH3:9])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[N:31]=4)=[C:22]4[N:26]=[CH:25][N:24]([CH3:27])[C:23]4=[C:18]3[CH:17]=2)=[O:15])[CH2:36][CH2:37]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Reactant: COC(=O)C(=O)C(C)Br
Solvent: CCO
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C(=O)OC)c(C)s3)nc21
Temperature: 65 °C
Yield: 70.4 %

Procedure:
Methyl 3-bromo-2-oxobutanoate (320 mg, 1.642 mmol) was added to a suspension of N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B, 435 mg, 1.094 mmol) in EtOH (10 ml) and the reaction mixture was heated at 65° C. for 2 h. The solvent was removed in vacuo and the residue purified by silica gel chromatography (2-10% MeOH/dichloromethane) to give methyl 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-5-methylthiazole-4-carboxylate (380 mg, 70% yield) as yellow solid.
Reaction SMILES: O=S1(=O)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([CH:46]([CH3:48])[CH3:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=3)[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.ClCCN1CC[O:56]CC1>>[CH:46]([C@H:43]1[C@@H:12]2[C@@H:13]3[C@@:26]([CH3:29])([CH2:27][CH2:28][C@@:11]2([NH:10][CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][O:56][CH2:7][CH2:6]2)[CH2:45][CH2:44]1)[C@@:25]1([CH3:30])[C@@H:16]([C@:17]2([CH3:42])[C@@H:22]([CH2:23][CH2:24]1)[C:21]([CH3:31])([CH3:32])[C@@H:20]([C:33]1[CH:34]=[CH:35][C:36]([C:37]([OH:39])=[O:38])=[CH:40][CH:41]=1)[CH2:19][CH2:18]2)[CH2:15][CH2:14]3)([CH3:47])[CH3:48]
Reactant: ClCCN1CCOCC1
Reactant: CC(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: CC(C)[C@@H]1CC[C@]2(NCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 4-(2-chloroethyl)morpholine as the alkylating reagent in Step 3. The product was isolated as a colorless oil (4 mg, 39%). LCMS: m/e 647.58 (M+H)+, 2.35 min (method 11). 1H NMR (500 MHz, Acetic) δ 8.02 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 3.94 (d, J=3.7 Hz, 4H), 3.73-3.44 (m, 4H), 3.27 (br. s., 4H), 2.50 (d, J=10.4 Hz, 1H), 2.32-1.01 (m, 26H), 1.21 (s, 3H), 1.12 (s, 3H), 1.08 (s, 3H), 0.93 (d, J=6.7 Hz, 3H), 0.86 (d, J=6.7 Hz, 3H), 0.83 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[C:8]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH:30]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:31]([O:33][CH3:34])=[O:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:30]([C:31]([O:33][CH3:34])=[O:32])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:15][CH:16]=2)[C:8]([S:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(O)cc1
Reactant: COC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A mixture of 322 mg (0.81 mmol) of 3-butyl-4-(4-hydroxybenzyl)-5-(4-nitrobenzylthio) -(4H-1,2,4-triazole (Example 1, Step E), 278 mg (1.21 mmol) of methyl α-bromophenylacetate, 168 mg (1.22 mmol) of anhydrous K2CO3, and 3 ml of dry DMF was stirred under N2 at 60° C. for 24 hours. The mixture was concentrated in vacuo (oil pump, 50° C.), and the residue was partitioned between EtOAc and H2O. The organic solution was dried (MgSO4), filtered, and concentrated. The residual oil was chromatographed on a column of silica gel (elution with a gradient of 0.5-10% MeOH in CH2Cl2). TLC (97:3 CHCl3 -iPrOH and 98:2 CH2Cl2 -MeOH) and NMR were used to identify the appropriate product fractions, which were combined and concentrated to give the product as a gum.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[Na+]>COCCOC.[Cl-].[Na+].O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: Sc1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Brc1ccc(Sc2ccccc2)nc1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a solution of 2,5-dibromopyridine (12.0 g) and thiophenol (5.46 mL) in DME (50 mL) was added sodium tert-butoxide (5.35 g) at room temperature and the mixture was stirred at 100° C. for 15 h. The reaction mixture was poured into brine, extracted with EtOAc, washed with brine, dried over sodium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane-EtOAc 30:1) to give 5-bromo-2-(phenylsulfanyl)pyridine (13.69 g) as an oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:10]2[C:11](=[O:16])[CH:12]=[C:13]([CH3:15])[O:14][C:9]=2[C:8]([O:17][CH3:18])=[C:7]([OH:19])[C:6]=1[C:20]([O:22][CH3:23])=[O:21].I[CH3:25].CO>CN(C)C=O.C(OCC)C.O>[CH3:15][C:13]1[O:14][C:9]2[C:8]([O:17][CH3:18])=[C:7]([O:19][CH3:25])[C:6]([C:20]([O:22][CH3:23])=[O:21])=[C:5]([O:4][CH3:3])[C:10]=2[C:11](=[O:16])[CH:12]=1
Reactant: CI
Reactant: COC(=O)c1c(O)c(OC)c2oc(C)cc(=O)c2c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1c(OC)c(OC)c2oc(C)cc(=O)c2c1OC
Reaction time: 2 h
Yield: 76.5 %

Procedure:
With protection from moisture, 0.42 g (10.6 mmol) of sodium hydride (60% dispersion) is slowly added at 60° C., with stirring, to 3.10 g (10.6 mmol) of methyl 5,8-dimethoxy-7-hydroxy-2-methyl-4-oxo-4H-1-benzopyran-6-carboxylate dissolved in 50 ml of anhydrous dimethylformamide. After a contact period of 11/2 hours, 1.30 ml (21.2 mmol) of iodomethane are added to the reaction mixture and stirring is continued for 2 hours. After decomposition of the excess sodium hydride by the addition of methanol, the reaction mixture, diluted with diethyl ether, is filtered. Evaporation of the filtrate results in an orange oil which is taken up in water and extracted 3 times with 50 ml of diethyl ether each time. The combined organic phases are washed with a saturated solution of NaCl and dried over Na2SO4 and then the solvents are removed. Chromatography of the powdery residue on a silica gel column (70-230 mesh; eluant: CH2Cl2 /CH 3 OH: 99/1) yields 2.5 g of orange crystals.
Reaction SMILES: [Na+].[Na+].[CH2:3]([O:5][P:6]([CH:11]([P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21])/[C:12](=[CH:16]/[C:17]([O-:19])=[O:18])/[C:13]([O-:15])=O)([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:9]([O:8][P:6]([CH:11]([P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21])[C:12]1[C:13]([O:19][C:17](=[O:18])[CH:16]=1)=[O:15])([O:5][CH2:3][CH3:4])=[O:7])[CH3:10]
Reactant: CCOP(=O)(OCC)C(/C(=C/C(=O)[O-])C(=O)[O-])P(=O)(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOP(=O)(OCC)C(C1=CC(=O)OC1=O)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 0.13 h
Yield: 125.4 %

Procedure:
A solution of 2.5 g of 2-[bis(diethoxyphosphoryl)methyl]maleic acid disodium salt in 50 ml of acetone is added with 2.13 g of para-toluenesulphonic acid. After 8 minutes under stirring, the formed sodium para-toluenesulphonate is separated by filtration and solvent is evaporated under reduced pressure. The residue is redissolved in 7.5 ml of anhydrous tetrahydrofuran and cooled to 0° C., then it is added dropwise with 3.8 ml of trifluoroacetic anhydride. The reaction mixture is refluxed for 30 minutes, then it is cooled to room temperature and concentrated to dryness. The residue is treated with ethyl ether, filtered and concentrated to dryness. This work up is repeated twice with toluene. 2.7 g of the product are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C@H:5]1[CH2:10][C@@H:9]2[CH2:11][CH2:12][N:6]1[C@@H:7]([CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]2=O)=[O:4].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:31]=1[CH2:32][NH2:33].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1.C1COCC1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C(O)(=O)C.O>[CH3:27][N:2]([CH3:1])[C:3]([C@H:5]1[CH2:10][C@@H:9]2[CH2:11][CH2:12][N:6]1[C@@H:7]([CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C@H:8]2[NH:33][CH2:32][C:31]1[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:30]=1[O:29][CH3:28])=[O:4]
Reactant: COc1ccc(OC)c(CN)c1
Reactant: CN(C)C(=O)[C@H]1C[C@@H]2CCN1[C@@H](C(c1ccccc1)c1ccccc1)C2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(OC)c(CN[C@H]2[C@H]3CCN([C@@H](C(=O)N(C)C)C3)[C@H]2C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.1 %

Procedure:
A mixture of compound 34 (2.22 g, 6.13 mmole), 2,5-dimethoxybenzylamine (1.23 g, 7.36 mmole) and CSA (camphersulfonic acid) (20 mg) in toluene (50 ml) was heated at reflux for 24 hours with Dean Stark water separator. The solvent was removed under reduced pressure. The crude imine was used to the next step without purification. A solution of the crude imine in dry THF (20 ml) was added to a solution of NaBH(OAc)3 (3.9 g, 18.4 mmole) and acetic acid (3 ml) in dry THF (20 ml) at 5° C. and stirred at room temperature for 15 hours. The pH value was adjusted to pH=10 by 1N NaOH, and extracted with EtOAc (20 ml×3). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated down. The crude oil was purified by silica gel chromatography (EtOAc:Hexane=1:1 as eluent) to give colorless oil. The oil was purified by recrystallization from MeOH to give compound 35 as colorless crystal (2.21 g, 4.3 mmole, 70%).
Reaction SMILES: CO[CH:3]([O:6][CH3:7])[O:4][CH3:5].[CH3:8][C@@:9]12[C@H:19]3[CH2:20][CH2:21][C@:22]4([CH3:30])[C@:26]([OH:29])([C:27]#[CH:28])[CH2:25][CH2:24][C@H:23]4[C@@H:18]3[CH2:17][CH2:16][C:15]1=[CH:14]C(=O)[CH2:11][CH2:10]2.O.C([O-])(=O)C.[Na+]>C(O)CO.CO>[CH2:7]1[CH2:5][O:4][C:3]2([CH2:11][CH2:10][C@@:9]3([CH3:8])[C:15](=[CH:16][CH2:17][C@@H:18]4[C@@H:19]3[CH2:20][CH2:21][C@@:22]3([CH3:30])[C@H:23]4[CH2:24][CH2:25][C@@:26]3([OH:29])[C:27]#[CH:28])[CH2:14]2)[O:6]1
Reactant: COC(OC)OC
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: O
Solvent: CO
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@H]3CC[C@@]21C)OCCO5

Procedure:
Trimethylorthoformate (20 ml.) and p-TSA monohydrate (1.9 g.) is added to a slurry of ethisterone (I, 31.34 g.) in ethylene glycol (100 ml.) and methanol (200 ml.). The mixture is heated to 50° until the reaction is complete (about 5 hours) as measured by TLC. The mixture is cooled to 5° and water (200 ml.) containing sodium acetate (6.6 g.) is added. The resulting suspension is filtered to recover the solids which are dried at 50° under reduced pressure (20 mm) for 6 hours to give the title compound, m.p. 245°-250°; NMR (CDCl3) 0.87, 1.03, 2.57, 3.97 and 5.23δ.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:4][CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:3][CH:4]=1
Reactant: Ic1ccc(OC2CCCCO2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a degassed solution of compound 1 (9.12 g, 30 mmol) in diisopropylamine (180 ml) under nitrogen, Pd(PPh3)2Cl2 (140 mg, 0.2 mmol) and CuI (78 mg, 0.4 mmol) were added. Then trimethylsilyl acetylene (3.3 g, 33 mmol) was added dropwise to this clear solution. The reaction mixture was stirred for 2 hours at room temperature. The salt formed during the reaction procedure was filtered off and washed well with ethyl acetate. The filtrate was evaporated to dryness and hydrolyzed with concentrated hydrochloric acid (5 ml), water (25 ml) and crushed ice (10 g), then extracted with ethyl acetate. The combined organic paste was washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatography (petroleum ether-ethyl acetate=9:1) to give a yellow oil of 2. Yield 7.9 g (96%);
Reaction SMILES: CCN=C=NCCCN(C)C.[I:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:34])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:24][CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19].[OH:35][C:36]1[CH:40]=[C:39]([CH2:41][CH2:42][C:43](O)=[O:44])[O:38][N:37]=1.COC(C1CCC(C(N2CCN(C3C=CC(C(=O)NC4C=CC=C(C(C)(C)C)C=4)=CN=3)CC2)=O)CC1)=O>>[OH:35][C:36]1[CH:40]=[C:39]([CH2:41][CH2:42][C:43]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([NH:20][C:15]4[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([I:12])[CH:14]=4)=[O:34])=[CH:23][N:24]=3)[CH2:33][CH2:32]2)=[O:44])[O:38][N:37]=1
Reactant: O=C(O)CCc1cc(O)no1
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1I
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)C1CCC(C(=O)N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)CC1
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)CCc4cc(O)no4)CC3)nc2)cc1I

Procedure:
6-{4-[3-(3-Hydroxy-isoxazol-5-yl)-propionyl]-piperazin-1-yl}-N-(3-iodo-4-methyl-phenyl)-nicotinamide was synthesized from the EDCI coupling of N-(3-iodo-4-methyl-phenyl)-6-piperazin-1-yl-nicotinamide and 3-(3-hydroxy-isoxazol-5-yl)-propionic acid in a manner similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclohexanecarboxylic acid methyl ester, above. LCMS calcd for C23H24IN5O4 (m/e) 561, obsd 562 (M+H),
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[C:16]4[N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:11][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)=[CH:4][CH:3]=1.[ClH:49]>>[ClH:49].[ClH:49].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[C:16]4[N:23]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CN1CCN(c2ccnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)CC1
Agent: Cl
Product: CN1CCN(c2ccnc3ccc(-c4c[nH]nc4-c4ccc(F)cc4)cc23)CC1

Procedure:
371 mg 6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazolyl]-4-(4-methylpiperazin-1-yl)quinoline obtained in Example 172 and 4.5 mL of 5 N hydrochloric acid were reacted in the same manner as in Example 163, to give 201 mg of the title compound as pale yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[CH:15]=[CH:14][CH:13]=2)=[N:3]1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[NH2:20][CH2:19][CH2:18][C:16]1[N:17]=[C:12]([C:4]2[S:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2](=[O:1])[N:3]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Product: NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
tert-Butyl 2-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]ethylcarbamate (0.35 g, 0.91 mmol) was dissolved in trifluoroacetic acid (4 ml), and the mixture was stirred at room temperature for 2 hrs. The solvent was evaporated, and the residue was recrystallized from methanol-diisopropyl ether to give the titled compound (0.33 g, 91%) as white crystals.
Reaction SMILES: CC1C2COC(=O)C=2C=CC=1[C@@H]1CO1.[OH:15][CH:16]([C:33]1[C:34]([CH3:43])=[C:35]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:42])[O:37][CH2:36]2)[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C@H:19]1[CH2:31][OH:32]>>[OH:15][C@H:16]([C:33]1[C:34]([CH3:43])=[C:35]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:42])[O:37][CH2:36]2)[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][C@H:19]1[CH2:31][OH:32]
Reactant: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc2c1COC2=O
Agent: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Product: Cc1c([C@@H](O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc2c1COC2=O

Procedure:
(S)-tert-Butyl 4-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate was prepared starting from 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one in an analogous fashion to that described above for the synthesis of (S)-tert-butyl 4-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate.
Reaction SMILES: [OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7](Cl)[N:6]=1.[CH2:36]([NH2:48])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].C(OCC)(=O)C>CO>[OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7]([NH:48][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[N:6]=1
Reactant: CC1(C)CC(C(O)CNc2nc(Cl)nc(NCC(O)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Reactant: CCCCCCCCCCCCN
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCNc1nc(NCC(O)C2CC(C)(C)NC(C)(C)C2)nc(NCC(O)C2CC(C)(C)NC(C)(C)C2)n1

Procedure:
Following the procedure of Example 1, 2,4-bis{2-hydroxy-N-(2,2,6,6-tetramethyl-4-piperidyl)ethylamino}-6-chloro-1,3,5-triazine (5.2 g) was reacted with dodecylamine (2.8 g) to afford an oily product. It was treated with alumina column chromatography (eluent=ethyl acetate:methanol=10:1) and the resulting crystals were recrystallized from n-hexane to afford the desired product as white crystals melting at 107°-109° C.