Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]([C:18]([OH:20])=[O:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:21][O:19][C:18]([CH:10]1[N:11]([S:14]([CH3:17])(=[O:15])=[O:16])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)C(C(=O)O)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
To a solution of 4-methanesulfonyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester (8.4 g, crude) in DMF (50 mL) was added K2CO3 (7.5 g) and iodomethane (8.5 mL) The mixture was stirred overnight at R.T. An aqueous work-up followed by purification on silica gave 4-methanesulfonyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (3.267 g). A solution of 4-methanesulfonyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (3.2 g) in dry THF (20 mL) was added via cannular to a mixture of lithium aluminium hydride (0.75 g) in THF (30 mL) at 0° C. and under N2 atmosphere. The resultant mixture was then warmed to R.T. and stirred for 2.5 h. The reaction was carefully quenched with aqueous ammonium chloride (5 mL) then filtered over Celite. An aqueous work-up followed by purification on silica gave 3-hydroxymethyl-4-methanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester (1.13 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[CH:9]([CH2:10]I)[CH2:8][C:7]1=[O:12].[CH3:19][N:20](C)C=O.[C-]#N.[Na+]>O>[C:19]([CH2:10][CH:9]1[N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7](=[O:12])[CH2:8]1)#[N:20]
Reactant: COc1ccc(CN2C(=O)CC2CI)c(OC)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: COc1ccc(CN2C(=O)CC2CC#N)c(OC)c1
Yield: 70 %

Procedure:
A solution of 1.2 g (3.3 millimoles) of 1-(2,4-dimethoxy-benzyl)-4-iodomethyl-2-azetidinone and 5 ml of dimethyl formamide is stirred with 0.35 g (7 millimoles) of sodium cyanide at room temperature for 48 hours. The solution is poured onto 30 ml of water and extracted five times with 20 ml of ether each. The etheral solution is dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo. Thus 0.6 g of 4-cyanomethyl-1-(2,4-dimethoxy-benzyl)-2-azetidinone are obtained. Yield: 70%.
Reaction SMILES: FC1C(I)=C(C(N2[C@@H:14]3[CH2:15]C[C@H]2[C@H:12]([NH:17][C:18]2N=CC(C(F)(F)F)=CN=2)[CH2:13]3)=O)C=CC=1.I[C:30]1[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:31]=1[C:37]([N:39]1[C@@H:43]2[CH2:44][CH2:45][C@H:40]1[C@H:41]([NH:46][C:47]1[N:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][N:48]=1)[CH2:42]2)=[O:38].C([Sn](CCCC)(CCCC)C1OC=CN=1)CCC.C([Sn](CCCC)(CCCC)C1C=CC=CN=1)CCC>>[CH3:36][C:35]1[C:30]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:18][N:17]=2)=[C:31]([C:37]([N:39]2[C@@H:43]3[CH2:44][CH2:45][C@H:40]2[C@H:41]([NH:46][C:47]2[N:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][N:48]=2)[CH2:42]3)=[O:38])[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(c1cccc(F)c1I)N1[C@@H]2CC[C@H]1[C@H](Nc1ncc(C(F)(F)F)cn1)C2
Reactant: Cc1cccc(C(=O)N2[C@@H]3CC[C@H]2[C@H](Nc2ncc(C(F)(F)F)cn2)C3)c1I
Agent: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: CCCC[Sn](CCCC)(CCCC)c1ncco1
Product: Cc1cccc(C(=O)N2[C@@H]3CC[C@H]2[C@H](Nc2ncc(C(F)(F)F)cn2)C3)c1-c1ccccn1

Procedure:
Prepared analogous to Example 284 substituting title compound of Example 277 with title compound of Example 276 and 2-(tributylstannyl)oxazole with 2-(tributylstannyl)pyridine. MS (ESI) mass calcd. for: C24H22F3N5O, 453.2 m/z found 454.2 [M+H]+. 1H NMR (400 MHz, Chloroform-d) 8.72-8.66 (m, 1H), 8.45 (s, 0.5H), 8.39 (s, 1.5H), 7.86-7.75 (m, 1H), 7.52-7.44 (m, 1H), 7.38-7.20 (m, 4.2H), 7.18-7.12 (m, 0.8H), 4.72-4.65 (m, 0.8H), 4.49-4.45 (m, 0.2H), 4.32 (s, 0.8H), 4.03-3.95 (m, 1H), 3.88-3.83 (m, 0.2H), 2.26 (s, 2.2H), 2.23 (s, 0.8H), 2.16 (dd, J=12.8, 7.9 Hz, 0.8H), 1.98-1.08 (m, 5.2H).
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[CH2:16]([OH:21])[C:17]([CH3:20])([CH3:19])[CH3:18].[H-].[Na+]>O>[CH2:16]([O:21][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CC(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 330.9 %

Procedure:
To dimethylformamide solution (78 ml) containing 4-chloronitrobenzene (15.7 g) and neopentyl alcohol (10.6 g) was added by portions sodium hydride (60% content, 4.8 g) under ice-cooling. The mixture was stirred under ice-cooling for 1 h. The mixture was warmed to room temperature and stirred further for 1 h. The reaction mixture was poured into water and extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The obtained oily substance was distilled under reduced pressure to give 4-neopentyloxynitrobenzene (69 g), boiling point: 120–125° C./0.1 mmHg.
Reaction SMILES: C([O:8][C:9]1[CH:14]=CN=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][C@@H:36]4[CH3:41])[C:25]4[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][C:26]=4[N:27]=3)=[CH:18][CH:17]=2)[N:10]=1)C1C=CC=CC=1.CO.O1CC[CH2:46][CH2:45]1>[OH-].[OH-].[Pd+2]>[CH:32]([N:29]1[CH2:30][CH2:31][C:25]2[C:24]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][C@@H:36]3[CH3:41])=[N:23][C:22]([C:19]3[CH:18]=[CH:17][C:16]([NH:15][C:11]4[NH:10][C:9](=[O:8])[CH:14]=[CH:46][CH:45]=4)=[CH:21][CH:20]=3)=[N:27][C:26]=2[CH2:28]1)([CH3:34])[CH3:33]
Reactant: C1CCOC1
Reactant: CC(C)N1CCc2c(nc(-c3ccc(Nc4nccc(OCc5ccccc5)n4)cc3)nc2N2CCOC[C@@H]2C)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)N1CCc2c(nc(-c3ccc(Nc4cccc(=O)[nH]4)cc3)nc2N2CCOC[C@@H]2C)C1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Step 2—Synthesis of compound xa: (S)-4-(benzyloxy)-N-(4-(7-isopropyl-4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)pyrimidin-2-amine (0.186 g, 0.337 mmol) was purged under nitrogen then added 20% Palladium hydroxide on carbon (2:8, Palladium hydroxide:carbon black, 0.14 g) followed by dry Methanol (4.85 mL, 1.20E2 mmol) Acetic acid (0.46 mL, 8.1 mmol) and dry Tetrahydrofuran (4.85 mL, 59.8 mmol) purged with hydrogen, heated at 40° C. and stirred overnight under an atmosphere of hydrogen. The reaction mixture was purged with nitrogen, added celite, filtered through celite, concentrated, chromatographed through silica gel (12 g, 0-10% MeOH in dichloromethane), and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 9.24 (s, 1H), 8.24 (d, J=8.7, 2H), 8.16 (s, 1H), 7.80 (s, 1H), 7.73 (d, J=8.5, 2H), 5.86 (d, J=5.7, 1H), 4.14 (d, J=6.4, 1H), 3.87 (d, J=11.3, 1H), 3.75-3.56 (m, 7H), 3.47-3.39 (m, 2H), 2.88 (dt, J=13.0, 6.5, 1H), 2.74-2.63 (m, 3H), 2.61-2.55 (m, 2H), 2.51 (m, 1H), 1.24 (d, J=6.6, 3H), 1.08 (d, J=6.5, 6H). LC/MS-m/z+462.2 (M+H)+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([P:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])[NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:9]1([P:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])[N:16]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=P(N=Cc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 39.6 %

Procedure:
P,P-diphenyl-N-phenylmethylene phosphinic amide was prepared following the method of Jennings (ibid) by adding titanium tetrachloride (635 ml; 5.78 mmol) in dry dichloromethane (10 ml) to a stirred solution of benzaldehyde (1.17 ml; 11.59 mmol), P,P-diphenylphosphinic amide (2.52 g; 11.59 mmol) and anhydrous triethylamine (4.84 ml; 34.78 mmol) in dry dichloromethane (50 ml) at 0° C. Upon completion of the addition, the stirring was maintained at 0° C. for a further 4 hours. Subsequent work-up gave P,P-diphenyl-N-phenylmethylene phosphinic amide (1.4 g; 40%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[CH3:11][O:12][N:13]=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]Br)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][O:12][N:13]=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: CON=C(C(=O)OC)c1ccccc1CBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(C(=O)OC)c1ccccc1COc1ccc(C(C)=O)cc1
Yield: 73.9 %

Procedure:
3.0 g (0.022 mol) of 4-hydroxyacetophenone and 6.0 g (0.021 mol) of methyl 2-bromomethylphenylglyoxylate O-methyloxime are dissolved in 30 ml of dimethylformamide, and 5.5 g (0.040 mol) of potassium carbonate are added. The mixture is stirred at room temperature for 24 hours, hydrolyzed with water and extracted with methyl tert-butyl ether. The organic phase is washed with water, dried and concentrated. 5.3 g (78%) of methyl 2-(4-acetylphenoxymethyl)phenylglyoxylate O-methyloxime are obtained as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH2:31][OH:32])([CH2:29][OH:30])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:13]([C:25]([F:28])([F:27])[F:26])[CH:12]=1)(C)(C)C.O1CCOCC1.[ClH:40]>C(Cl)Cl>[ClH:40].[NH2:7][C:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:13]([C:25]([F:28])([F:26])[F:27])[CH:12]=1)([CH2:29][OH:30])[CH2:31][OH:32]
Reactant: CCCCCCCSc1ccc(CCC(CO)(CO)NC(=O)OC(C)(C)C)cc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCCCCSc1ccc(CCC(N)(CO)CO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound 24-1 (390 mg) was dissolved in methylene chloride (5 ml), dioxane containing hydrogen chloride (4 mol/l, 5 ml) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. The white powder was purified by preparative HPLC, ether containing hydrogen chloride (1 mol/l, 15 ml) was added to the obtained residue to give a hydrochloride. The precipitate was collected by filtration and dried to give the object product (200 mg) as a white powder.
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.[NH:10]1[C:18]2[CH:17]=[CH:16][N:15]=[C:14]([NH:19][C:20](=[O:24])[O:21][CH2:22][CH3:23])[C:13]=2[CH:12]=[CH:11]1>C1COCC1>[I:1][C:12]1[C:13]2[C:14]([NH:19][C:20](=[O:24])[O:21][CH2:22][CH3:23])=[N:15][CH:16]=[CH:17][C:18]=2[NH:10][CH:11]=1
Reactant: NC(=O)CCC(=O)NI
Reactant: CCOC(=O)Nc1nccc2[nH]ccc12
Solvent: C1CCOC1
Product: CCOC(=O)Nc1nccc2[nH]cc(I)c12
Reaction time: 0.25 h
Yield: 72 %

Procedure:
N-Iodosuccinamide (0.030 g, 0.13 mmol, 1.0 eq) was added to a solution of ethyl 1H-pyrrolo[3,2-c]pyridin4-ylcarbamate (0.027 g, 0.13 mmol, 1.0 eq) in THF (1 mL) at room temperature and the reaction mixture was stirred for 15 minutes. The reaction mixture was quenched with 10% NaHSO3 solution and extracted with 10/1 CHCl3/MeOH. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, eluting 0-5% CHCl3/MeOH) to afford the product (0.031 g, 72%) as a solid. 1H NMR (CD3OD) δ 7.87 (d, 1H, J=5.9 Hz), 7.38 (s, 1H), 7.25 ((d, 1H, J=5.9 Hz), 4.14 (q, 2H, J=7.1 Hz), 1.12 (t, 3H, J=7.1 Hz); MS(ESI+) m/z 332 (M+H)+. Calculated: 331.9896, found: 331.9884.
Reaction SMILES: [CH:1]1[O:2][CH:3]=[C:4]2[C:9]([CH2:10][C:11]([N:13]([CH:15]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=3)[CH2:16][CH:17]3[CH2:21][CH2:20][CH:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:18]3)[CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][C:5]=12.C(=O)([O-])[O-].[K+].[K+].[C:43]([O:47][C:48](=[O:51])[CH2:49]Br)([CH3:46])([CH3:45])[CH3:44].O>CN(C)C=O>[C:43]([O:47][C:48](=[O:51])[CH2:49][O:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([CH:15]([N:13]([C:11](=[O:12])[CH2:10][C:9]2[C:4]3[CH:5]=[CH:1][O:2][C:3]=3[CH:6]=[CH:7][CH:8]=2)[CH3:14])[CH2:16][CH:17]2[CH2:21][CH2:20][CH:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:18]2)[CH:31]=1)([CH3:46])([CH3:45])[CH3:44]
Reactant: CN(C(=O)Cc1cccc2cocc12)C(CC1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)Cc1cccc2occc12)C(CC1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(OCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of Example 35 1.63 g, 3.2 mmol) in dimethylformamide (22 mL) was added potassium carbonate (1.37 g, 9.9 mmol) and, under argon, t-butylbromoacetate (0.47 mL, 3.2 mmol). After stirring at room temperature for 23 hours, the reaction was poured into water (160 mL), extracted with dichloromethane (160 mL), dried (MgSO4), and the solvent removed in vacuo. Purification by column chromatography (dichloromethane:methanol 39:1 followed by ethyl acetate:heptane 4:1) gave the product as a clear oil, 1.4 mmol, 45%.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[NH:11][C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][CH2:21][CH2:22][O:23][CH3:24])[N:13]=2.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH:37]1[CH2:41][CH2:40][O:39][CH2:38]1)(=O)=O>CN(C=O)C>[CH3:8][O:9][C:10]1[N:11]([CH2:36][CH:37]2[CH2:41][CH2:40][O:39][CH2:38]2)[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][CH2:21][CH2:22][O:23][CH3:24])[N:13]=2
Reactant: COCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CS(=O)(=O)OCC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1nc(N)c2nc(OC)n(CC3CCOC3)c2n1
Temperature: 60 °C
Yield: 44.9 %

Procedure:
8-(Methoxy)-2-{[2-(methoxy)ethyl]oxy}-9H-purin-6-amine trifluoroacetate salt (0.30 g) was dissolved in dry DMF (5 mL). To this was added anhydrous potassium carbonate (0.47 g) and then heated to 60° C. for 1.5 hours. The reaction mixture was cooled to room temperature and tetrahydro-3-furanylmethyl methanesulfonate (0.168 g) was added. The reaction mixture was then heated to 90° C. for 3.5 hours. The reaction mixture was then quenched into water (100 mL) and extracted into ethyl acetate (50 mL, 3 times). The organic was separated and dried by passing through a hydrophobic frit and then evaporated under reduced pressure to give a glassy solid. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (10-45%). This gave the title compound as a white solid (0.1233 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2([C:21]([O:23]CC)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]2([C:21]([OH:23])=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(CCN2CCN(Cc3ccccc3)CC2)CCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1(CCN2CCN(Cc3ccccc3)CC2)CCCC1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
The mixture of ethyl 1-[2-(4-benzyl-1-piperazinyl)ethyl]cyclopentanecarboxylate (300 mg, 0.871 mmol) and KOH (85%, 0.36 g, 3.49 mmol) in methanol (5.0 ml) and water (1.2 ml) was stirred at 95° C. overnight. To the mixture was added 2 N HCl until the pH became 5. After the solvent was removed in vacuo, the residue was extracted with dichloromethane (30 ml). The extract was washed with brine, dried over NASO4, filtered and concentrated in vacuo to provide a yellow oil (276 mg/100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:38][N:39]1[CH2:44][CH2:43][C:42]2[N:45]=[C:46]([C:48]([NH:50][C@@H:51]3[CH2:55][CH2:54][CH2:53][C@H:52]3[NH2:56])=[O:49])[S:47][C:41]=2[CH2:40]1>CN(C)C=O.C(N(CC)CC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:56][C@@H:52]1[CH2:53][CH2:54][CH2:55][C@H:51]1[NH:50][C:48]([C:46]1[S:47][C:41]3[CH2:40][N:39]([CH3:38])[CH2:44][CH2:43][C:42]=3[N:45]=1)=[O:49])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CN1CCc2nc(C(=O)N[C@@H]3CCC[C@H]3N)sc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCc2nc(C(=O)N[C@@H]3CCC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 107.8 %

Procedure:
5-Chloroindole-2-carboxylic acid (80 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98 mg), 1-hydroxybenzotriazole monohydrate (23 mg) and triethylamine (141 μl) were added to a solution with (±)-trans-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine hydrochloride (120 mg) dissolved in N,N-dimethylformamide (5 ml), and the mixture was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and dichloromethane and a saturated aqueous solution of sodium hydrogencarbonate were added to the residue to conduct liquid separation. The resultant organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography on silica gel (dichloromethane:methanol=93:7). After dichloromethane (5 ml) and a 1N ethanol solution (282 μl) of hydrochloric acid were added to the thus-obtained pale yellow solid. Ethyl acetate was added, solvent was distilled off under reduced pressure and precipitate formed was collected by filtration to obtain the title compound (109 mg) as a pale yellow solid.
Reaction SMILES: [C:1]([C:9]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:12]2[CH2:13][CH:14]3[C:19](=[O:20])[N:18]([CH:21]([CH3:23])[CH3:22])[C:17](=[O:24])[N:15]3[CH2:16][C:11]=2[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:33].[Na+].Cl>CO>[C:1]([C:9]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:12]2[CH2:13][CH:14]([C:19]([OH:20])=[O:33])[N:15]([C:17]([NH:18][CH:21]([CH3:22])[CH3:23])=[O:24])[CH2:16][C:11]=2[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC(C)N1C(=O)C2Cc3c(nc(C(=O)c4ccccc4)n3Cc3ccccc3)CN2C1=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)NC(=O)N1Cc2nc(C(=O)c3ccccc3)n(Cc3ccccc3)c2CC1C(=O)O

Procedure:
A suspension of 0.5 g of the product from Example 269, methanol (50 mL) and 1N sodium hydroxide (10 mL) is heated on a steam bath for 15 min. The resulting solution is cooled in an ice bath and treated with 1N hydrochloric acid (10 mL) to precipitate the product. Filtration and trituration of the damp cake with methanol (2 mL) gives pure product; mp 192°-194° C. (dec).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([O:12][S:1](=[O:4])(=[O:3])[NH2:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NS(=O)(=O)Cl
Reactant: Oc1ccccc1
Product: NS(=O)(=O)Oc1ccccc1
Yield: 30 %

Procedure:
The compound was prepared by procedures of Example 33 from sulfamoyl chloride and phenol in 30% yield as white solid, mp 81°-85° C.
Reaction SMILES: [F:1][CH:2]1[C:11]2[C:6](=[C:7]([C:12](OC)=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.C(=O)=O.CC(C)=O.CC(C[AlH]CC(C)C)C>C1COCC1>[F:1][CH:2]1[C:11]2[C:6](=[C:7]([CH2:12][OH:13])[CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1
Reactant: COC(=O)c1cccc2c1CN(C(=O)OC(C)(C)C)CC2F
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2c(CO)cccc2C(F)C1
Temperature: 25 °C

Procedure:
To a flask containing 2-tert-butyl 8-methyl 4-fluoro-3,4-dihydroisoquinoline-2,8(1H)-dicarboxylate (24-6) (214 mg, 0.692 mmol), was added anhydrous THF (3.5 ml) then cooled to −78 C (dry ice/acetone bath) while stirring under an atmosphere of N2. Then added DIBAL-H (2.4 ml, 2.400 mmol) dropwise. The reaction mixture was then stirred at −78 C for ˜20 minutes, then warmed to room temperature. Followed by LC/MS. After 10 minutes at room temperature quenched by dropwise addition of saturated solution of Rochelle's Salt (Na+/K+ Tartrate) in water, then suspended in EtOAc, washed with saturated NaHCO3, then H2O, then brine; organics dried over Na2SO4, filtered & concentrated. Purification by silica gel chromatography (0-40%; isocratic @ 30% EtOAc/Hex; 24 g ISCO); desired fractions concentrated to yield tert-butyl 4-fluoro-8-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-7). HRMS [M+H]; calculated; 282.1500, observed; 282.1491.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24])=[O:19].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:9][CH2:10][N:11]([C:23]([C:22]3[CH:21]=[C:20]([CH:28]=[CH:27][CH:26]=3)[C:18]([O:17][CH3:16])=[O:19])=[O:24])[CH2:12][CH2:13]2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(OC2CCNCC2)cc1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a stirred solution of 4-(4-chlorophenoxy)piperidine hydrochloride (200 mg, 0.81 mmol), 3-(methoxycarbonyl)benzoic acid (145 mg, 0.81 mmol), and N,N-diisopropylethylamine (0.56 mL, 3.22 mmol) in N,N-dimethylformamide (4 mL) was add HBTU (458 mg, 1.21 mmol) at room temperature. After stirring at 60° C. for 2 hours, the mixture was poured into water (20 mL). This was extracted with ethyl acetate (20 mL) and washed with water (20 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (NH-gel, eluting with ethyl acetate) to give 301 mg (>99% yield) of the title compound as yellow syrup.
Reaction SMILES: N1C=CC=CC=1.F.[CH3:8][O:9][C:10](=[O:54])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[C@@H:21](/[CH:22]=[CH:23]/[C@@H:24]([O:32][Si](C(C)(C)C)(C)C)[CH2:25][C@H:26]([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30])[C@H:20]([O:40][Si](C(C)(C)C)(C)C)[CH2:19][C:18]=1[O:48][C:49](=[O:53])[CH:50]([CH3:52])[CH3:51]>>[CH3:8][O:9][C:10](=[O:54])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[C@@H:21](/[CH:22]=[CH:23]/[C@@H:24]([OH:32])[CH2:25][C@H:26]([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30])[C@H:20]([OH:40])[CH2:19][C:18]=1[O:48][C:49](=[O:53])[CH:50]([CH3:52])[CH3:51]
Reactant: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(OC(=O)C(C)C)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Product: CCCC[C@@H](C)C[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(OC(=O)C(C)C)C[C@H]1O
Yield: 60.6 %

Procedure:
Using as the material and reagent a hydrogen fluoride-pyridine solution (0.6 ml) and methyl(11R,12S,13E,15S,17R)-9-isobutyryloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (466 mg), the same procedure as in Example 2 was performed to obtain methyl(11R,12S,13E,15S,17R)-9-isobutyryloxy-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate (192 mg, 64%).