Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].S(Cl)([Cl:13])=O>CCCCCC.N1C=CC=CC=1>[C:1]([Cl:13])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(O)c1ccccc1O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CCCCCC
Product: O=C(Cl)c1ccccc1O

Procedure:
Salicylic acid (5.0 g, 36.2 mmol) was suspended in dry hexane (40 ml) and thionyl chloride (4.52 g, 38 mmol) was added under nitrogen atmosphere followed by one drop of pyridine. The mixture was refluxed for two hours while stirring. The clear yellow solution was cooled and concentrated in vacuum, giving a dense oil to be used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:33]1C=CC(CCCC(O)=O)=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:33][CH:3]=1
Reactant: O=C(O)CCCc1ccc(Cl)cc1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCCc2ccc(Cl)cc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(4-chloro-phenyl)-butyric acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: NC1SC(C(OC(C)(C)C)=O)=CC=1.CS(Cl)(=O)=O.[CH3:19][S:20]([N:23]([C:28]1[S:32][C:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:30][CH:29]=1)S(C)(=O)=O)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH3:19][S:20]([NH:23][C:28]1[S:32][C:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:30][CH:29]=1)(=[O:21])=[O:22]
Reactant: CC(C)(C)OC(=O)c1ccc(N(S(C)(=O)=O)S(C)(=O)=O)s1
Agent: CC(C)(C)OC(=O)c1ccc(N)s1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc(NS(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of tert-butyl 5-aminothiophene-2-carboxylate (Int. 55) (1.481 g, 7.43 mmol) in pyridine (50 ml) cooled to 0° C., methanesulfonyl chloride (0.695 ml, 8.92 mmol) was added drop-wise. The reaction was warmed to RT and stirred for 3 days. The solvent was removed under vacuum, and the residue was portioned between EtOAc and 1N HCl; the organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The crude was purified by flash chromatography on silica gel cartridge (petroleum ether/EtOAc=8/2) to afford tert-butyl 5-(methylsulfonamido)-thiophene-2-carboxylate (Int. 56) (773 mg, 2.79 mmol, MS/ESI+299.9 [MNa]+) and tert-butyl 5-(N-(methylsulfonyl)-methylsulfonamido)thiophene-2-carboxylate (Int. 57) (420 mg, 1.182 mmol, MS/ESI+ not detectable [MH]+).
Reaction SMILES: [C:1](=[O:22])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCN(CC)CC.[F:30][C:31]([F:45])([F:44])[C:32]1[CH:33]=[C:34]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:35]=[CH:36][CH:37]=1>CN(C=O)C>[NH3:5].[F:45][C:31]([F:30])([F:44])[C:32]1[CH:33]=[C:34]([N:38]2[CH2:43][CH2:42][N:41]([C:1]([O:2][CH2:3][CH2:4][N:5]3[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]3)=[O:22])[CH2:40][CH2:39]2)[CH:35]=[CH:36][CH:37]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: CN1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(CCOC(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Product: N
Temperature: 25 °C
Reaction time: 24 h
Yield: 126.1 %

Procedure:
2-(4-Methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (Intermediate 4; 761 mg, 2.5 mmol) was dissolved in DMF (20 mL). NEt3 (0.4 mL, 2.9 mmol) and 4-(3-trifluoromethyl-phenyl)piperazine (583 mg, 2.5 mmol) were added and the reaction mixture was stirred at room temperature for 24 hours, the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in EtOAc (50 mL) and washed with 1 M aq Na2CO3 solution (5×50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 100:8:1 mixture of DCM:EtOH:NH3) to give 2-(4-methylpiperazin-1-yl)ethyl 4-(3-trifluoromethyl-phenyl)piperazine-1-carboxylate (631 mg, 64%) as a colourless oil.
Reaction SMILES: C(OCC)(=O)C.C1CCC(N=C=NC2CCCCC2)CC1.Cl.[CH2:23]([N:25]1[C:29]([OH:30])=[CH:28][CH:27]=[N:26]1)[CH3:24].CC(C)(O)C#N.[Cl:37][C:38]1[C:46]([CH:47]([O:50][CH3:51])[O:48][CH3:49])=[C:45]([S:52]([CH3:55])(=[O:54])=[O:53])[CH:44]=[CH:43][C:39]=1[C:40](O)=[O:41]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:23]([N:25]1[C:29]([OH:30])=[C:28]([C:40](=[O:41])[C:39]2[CH:43]=[CH:44][C:45]([S:52]([CH3:55])(=[O:54])=[O:53])=[C:46]([CH:47]([O:50][CH3:51])[O:48][CH3:49])[C:38]=2[Cl:37])[CH:27]=[N:26]1)[CH3:24]
Reactant: CCn1nccc1O
Reactant: COC(OC)c1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(O)C#N
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C(OC)OC)c2Cl)c1O
Temperature: 25 °C

Procedure:
To ethyl acetate in a volume of 50 ml, was dissolved 2-chloro-4-methanesulfonyl-3-dimethoxymethylbenzoic acid in an amount of 3.0 g (9.7 mmol), and to the resulting solution, were added DCC in an amount of 2.2 g (10.7 mmol) and 1-ethyl-5-hydroxypyrazole hydrochloride in an amount of 1.4 g (9.7 mmol) while cooling with ice and the mixture was subsequently stirred for a night at an ambient temperature. Insoluble product precipitated was filtrated, and the filtrate was condensed under reduce pressure. The residue obtained was then dissolved in chloroform in a volume of 30 ml, and the resulting solution was stirred for 6 hours at an ambient temperature following to an addition of acetone cyanohydrin in an amount of 0.25 g (2.9 mmol) and triethylamine in an amount of 2.0 g (20 mmol) thereto. The reacted-mixture was washed with 1-N hydrochloric acid and then with saturated saline solution, dried over anhydrous magnesium sulfate and subjected to distillation for eliminating the solvent therein. The crystals remained were washed with methanol to obtain 1-ethyl-5-hydroxy-4-(2-chloro-4-methanesulfonyl-3-dimethoxymethylbenzoyl)pyrazole in an amount of 1.6 g. The melting point of this compound is in a range of from 168° to 170° C.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH2:26][CH3:27])C(O)=O)=[CH:18][CH:17]=1)([O-:15])=[O:14].[CH:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)=[CH:30][CH:29]=1.CO>C(Cl)Cl>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:26][CH2:27][C:1]([O:41][C:38]2[CH:39]=[CH:40][C:35]([NH:34][C:31]3[CH:30]=[CH:29][CH:28]=[CH:33][CH:32]=3)=[CH:36][CH:37]=2)=[O:2])=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: Oc1ccc(Nc2ccccc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CO
Product: O=C(CCCc1ccc([N+](=O)[O-])cc1)Oc1ccc(Nc2ccccc2)cc1
Reaction time: 3 h
Yield: 89 %

Procedure:
0.98 g (6.02 mmol) of 1,1′-carbonyldiimidazole is slowly added at 20° C. to a solution of 1.25 g (5.96 mmol) of 4-nitrophenylbutyric acid in 25 ml CH2Cl2. The reaction mixture is agitated for 30 minutes before the addition of 1 g (5.42 mmol) of 4-hydroxydiphenylamine. After agitation for 3 hours, the reaction is stopped by the addition of 3 ml of MeOH and the solvent is evaporated under vacuum. The evaporation residue is purified on a silica column (eluent: Heptane/AcOEt: 100/0 to 80/20). A yellow solid is obtained with a yield of 89%.
Reaction SMILES: [CH:1]([CH:3]([OH:11])[CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)=[CH2:2].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:28]([Si:32](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:31])([CH3:30])[CH3:29]>ClCCl.CN(C)C=O>[CH3:31][C:28]([Si:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[O:11][CH:3]([CH:1]=[CH2:2])[CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)([CH3:29])[CH3:30]
Reactant: C=CC(O)CCC1OCCO1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(CCC1OCCO1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.8 %

Procedure:
A solution of α-ethenyl-1,3-dioxolane-2-propanol (49.4 g, 315 mmole) in dichloromethane (175 ml) was treated sequentially with dimethylaminopyridine (5.72 g, 47 mmole) and triethylamine (52.8 ml, 380 mmole) followed by (dropwise) a solution of t-butylchlorodiphenylsilane (89.5 g, 332 mmole) in dimethylformamide (150 ml). The reaction was stirred under argon for 48 hours (25° C.), poured into 2.5 L of ice water and extracted with ethyl acetate (1.2 L). The organic extracts were wsashed with water (2×1 L), brine (1 L), dried (sodium sulfate), filtered, and concentrated in vacuo to 130 g of viscous yellow oil. The crude product was dissolved in ether, filtered from a small amount of suspended material, concentrated in vacuo, and chromatographed (Waters, Prep 500 L.C., 10% ethyl acetate:hexane) to afford 106 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][C:13]([OH:15])=O)[C:8]([CH3:11])=[CH:9][N:10]=1.[F:24][C:25]([F:34])([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:26][NH2:27]>>[F:34][C:25]([F:24])([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:26][NH:27][C:13](=[O:15])[CH2:12][N:7]1[C:8]([CH3:11])=[CH:9][N:10]=[C:5]([NH:4][CH2:3][C:2]([F:1])([F:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:6]1=[O:16]
Reactant: NCC(F)(F)c1ccncc1
Reactant: Cc1cnc(NCC(F)(F)c2ccccn2)c(=O)n1CC(=O)O
Product: Cc1cnc(NCC(F)(F)c2ccccn2)c(=O)n1CC(=O)NCC(F)(F)c1ccncc1

Procedure:
7-1 was prepared from [3-(2,2-difluoro-2-pyridin-2-ylethylamino)-6-methyl-2-oxo-2H-pyrazin-1-yl]-acetic acid and 2,2-difluoro-2-(4-pyridyl)ethyl amine essentially according to the procedure of Example 1, Step K. Mass Spectrum: Found: (M+1) 465.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)=[C:4]([F:21])[CH:3]=1.[CH:22]([O:24][CH2:25][CH2:26][O:27][NH2:28])=[CH2:23].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:22]([O:24][CH2:25][CH2:26][O:27][NH:28][C:18]([C:17]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:21])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[CH:11]2)=[O:20])=[CH2:23]
Reactant: C=COCCON
Reactant: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(Br)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1ccc2[nH]ncc2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
To a solution of 4-(4-bromo-2-fluorophenylamino)-1H-indazole-5-carboxylic acid (115 mg, 0.33 mmol) and O-(2-vinyloxy-ethyl)-hydroxylamine (51 mg, 0.49 mmol) in DMF (3 mL) was added EDCI (69 mg, 0.36 mmol), HOBt (49 mg, 0.36 mmol) and DIPEA (61 μL, 0.36 mmol). The reaction mixture was stirred at room temperature for 4 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-10% methanol in DCM) to yield the title compound as a pale yellow solid (96 mg, 67%). LCMS (Method B): RT=3.43 min, [M−H]−=433/435.
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:14]1[CH2:16][C@H:15]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O.[CH:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:17]1([C@@H:15]2[CH2:16][C@H:14]2[NH:5][CH2:6][CH2:7][CH:8]2[CH2:9][CH2:10][N:11]([CH2:25][C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=3)[CH2:12][CH2:13]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(N(CCC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(O)c1ccc(CN2CCC(CCN[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(2-(piperidin-4-yl)ethyl)acetamide (126 mg, 0.370 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added 4-formylbenzoic acid (66.7 mg, 0.444 mmol) and sodium triacetoxyborohydride (157 mg, 0.740 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was quenched with water (2 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was dissolved into methanol (2 ml) and 1N NaOH aqueous solution (2 mL) was added. The mixture was stirred at room temperature for 1 h and concentrated. The residue was treated with MeOH (3 mL) and filtered. The filtrate was purified using reverse-phase HPLC under the acidic conditions. The resulting TFA salt of the product was treated with 1N HCl and concentrated. The residue was further dried under vacuum to give 87 mg of product as white solid (HCl salt). MS: (M+H)+=379.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (q, 1H), 1.46-1.67 (m, 5H), 1.82 (br. s., 2H), 2.87 (br. s., 3H), 3.05 (br. s., 2H), 3.30 (br. s., 2H), 4.34 (d, J=3.79 Hz, 2H), 7.10-7.40 (m, 5H), 7.74 (d, J=8.08 Hz, 2H), 8.00 (d, J=7.83 Hz, 2H), 9.53 (br. s., 2H).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4]1.I[CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1.O>CN(C=O)C.C(OCC)(=O)C>[O:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[O:16][CH2:15][CH2:14][N:9]1[CH:10]=[CH:11][C:6]2[CH:5]=[CH:4][O:3][C:7]=2[C:8]1=[O:12]
Reactant: ICCOC1CCCCO1
Reactant: O=c1[nH]ccc2ccoc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2occc2ccn1CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
Sodium hydride (60% in oil, 138 mg, 3.5 mmol) was suspended in DMF (10 ml). A DMF solution (5 ml) of 6H-furo[2,3-c]pyridin-7-one (310 mg, 2.3 mmol) was added thereto at 0° C., and stirring was conducted at the same temperature for 1 hour. A DMF solution (5 ml) of 2-(2-iodoethoxy)tetrahydropyran (1175 mg, 4.6 mmol) was added thereto, and stirring was conducted at room temperature overnight. Water was added to the reaction mixture and extraction with ethyl acetate was performed. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1). The purified product was concentrated under reduced pressure to thereby obtain 450 mg (yield: 74%) of 6-[2-(tetrahydropyran-2-yloxy)ethyl]-6H-furo[2,3-c]pyridin-7-one as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][C:26](C)([CH3:29])[CH2:27][OH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][C@@H:26]([CH3:29])[CH2:27][OH:28])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(N)CO
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)N[C@@H](C)CO)cn1
Yield: 94 %

Procedure:
As described for example 254, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) was converted, using L-alaminolinstead of 2-amino-2-methyl-1-propanol, to the title compound (110 mg, 94%) which was obtained as a white solid. MS: m/e=402.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:15][CH3:16])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].[CH2:19]=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([N:15]([CH3:19])[CH3:16])[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CNC1(c2ccc(Cl)cc2)CCC(=O)CC1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)C1(c2ccc(Cl)cc2)CCC(=O)CC1
Reaction time: 2 h
Yield: 59 %

Procedure:
A reaction solution consisting of 5.68 gm. (0.0201 mole) 4-(p-chlorophenyl)-4-methylaminocyclohexanone, ethylene ketal (prepared in Part G, above), 22 ml. 37 percent formalin (aqueous formaldehyde), and 75 ml. methanol is heated at the reflux temperature for 4 hours, after which heating the solution is allowed to cool and then chilled in an ice-bath. Small portions of sodium borohydride are cautiously added with stirring to a total of 2.89 gm. (0.076 mole). Stirring is continued for 2 hours at 25° C. when the solution is concentrated by removing most of the solvent under reduced pressure. The concentrate is diluted with a mixture of 100 ml. methylene chloride and 20 ml. water. The aqueous phase that separates is discarded, and the organic phase is washed successively with water and then with brine. The methylene chloride solvent is then removed by evaporation under reduced pressure. The residue thus obtained is dissolved in the formalin and methanol as initially, heated at the reflux temperature, cooled in an ice bath, and treated again with the sodium borohydride as previously. Following the same work-up as described, the crude 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal free base obtained following the removal of the methylene chloride is dissolved in a small amount of diethyl ether, and the ether solution is treated with 3 N hydrogen chloride in ether. A precipitate forms which is recrystallized from methylene chloride and ethyl acetate to give 3.96 gm. (59% yield) of object compound 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride having a melting point at 261° to 262° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.Cl.[CH3:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:19]=1>>[ClH:1].[CH3:9][C:10]1[CH:15]=[C:14]([NH:16][C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:19]=1
Reactant: Cc1cc(N)ccc1NC1=NCCCCC1
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)Nc1ccc(NC2=NCCCCC2)c(C)c1

Procedure:
The title compound was prepared by the method of Example 16 using ethyl chloroformate and 1.0 g (3.1 mmole) of the product compound of Example 15. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([NH:17][S:18]([C:21]2[S:22][C:23]([Cl:26])=[CH:24][CH:25]=2)(=[O:20])=[O:19])[CH2:15][OH:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:26][C:23]1[S:22][C:21]([S:18]([NH:17][C@@H:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:15][OH:16])(=[O:19])=[O:20])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(CO)NS(=O)(=O)c2ccc(Cl)s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(N[C@H](CO)C1CCNCC1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.6 %

Procedure:
To a solution of 4-[1-(5-chloro-thiophene-2-sulfonylamino)-2-hydroxy-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (0.204 g, 0.48 mmol (see example 209)) dissolved in dichloromethane (2 mL) at 0° C. was added trifluoroacetic acid (0.5 mL). The reaction was allowed to warm to 25° C. and stir overnight. The mixture was then concentrated and dichloromethane was added and evaporated 6 times to yield a crude solid. Purification by HPLC (C-18 column, (21×75 mm) with elution system 60-100% acetonitrile-water+0.1% TFA, 20 min gradient) gave the product as an oil (0.0166 g, 11%). MS (ESI) m/z 325 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][S:9]([CH2:12][C:13]#[N:14])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[F:15][C:16]([S:19][CH2:20][CH2:21]OS(C(F)(F)F)(=O)=O)([F:18])[F:17]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][S:9]([CH:12]([CH2:21][CH2:20][S:19][C:16]([F:18])([F:17])[F:15])[C:13]#[N:14])(=[O:10])=[O:11])=[CH:4][CH:3]=1
Reactant: O=S(=O)(OCCSC(F)(F)F)C(F)(F)F
Reactant: N#CCS(=O)(=O)Cc1ccc(Cl)nc1
Product: N#CC(CCSC(F)(F)F)S(=O)(=O)Cc1ccc(Cl)nc1

Procedure:
Compound II-7 was prepared from (6-chloro-pyridin-3-ylmethanesulfonyl)-acetonitrile and trifluoro-methanesulfonic acid 2-trifluoromethylsulfanyl-ethyl ester as described for compound II-1.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13](=[C:15]3C(=O)O[C:18](C)([CH3:22])[O:17][C:16]3=[O:24])[OH:14])[CH2:10][CH2:9][N:8]2[C:25]([O:27][CH3:28])=[O:26])=[CH:4][CH:3]=1>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@H:7]2[CH2:12][C@H:11]([C:13](=[O:14])[CH2:15][C:16]([O:17][CH2:18][CH3:22])=[O:24])[CH2:10][CH2:9][N:8]2[C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@H:7]2[CH2:12][C@@H:11]([C:13](=[O:14])[CH2:15][C:16]([O:17][CH2:18][CH3:22])=[O:24])[CH2:10][CH2:9][N:8]2[C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1
Reactant: COC(=O)N1CCC(C(O)=C2C(=O)OC(C)(C)OC2=O)CC1Cc1ccc(Cl)cc1
Solvent: CCO
Product: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(Cl)cc2)C1
Product: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(Cl)cc2)C1
Reaction time: 1.5 h
Yield: 13 %
Yield: 24 %

Procedure:
Methyl 2-(4-chlorobenzyl)-4-((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)(hydroxy)-methyl)piperidine-1-carboxylate (7.00 g, 16 mmol) was dissolved in EtOH (100 mL) to give a yellow solution. The mixture was warmed up to almost reflux and stirred for 90 min. The solvent was evaporated and the residue was purified via Biotage (heptane:ethyl acetate, gradient 20%->70% ethyl acetate, 7 CV, 340 g column, two runs) to yield trans-methyl 2-(4-chlorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (780 mg, 13%) and cis-methyl 2-(4-chlorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.45 g, 24%) Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.14-1.31 (m, 3H), 1.56-1.95 (m, 4H), 2.59-3.08 (m, 4H), 3.43 (d, 2H), 3.59 (d, 3H), 3.80-3.95 (m, 1H), 4.00-4.22 (m, 3H), 7.05-7.11 (m, 2H), 7.18-7.24 (m, 2H). MS m/z 382, 384 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.26 (t, 3H), 1.39-1.99 (m, 4H), 2.46-3.06 (m, 4H), 3.35-3.72 (m, 5H), 3.95-4.32 (m, 3H), 4.40-4.72 (m, 1H), 6.99-7.37 (m, 4H). MS m/z 382, 384 (M+H)+
Reaction SMILES: [I:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[C:18]([OH:21])(=O)[CH3:19].[C:22](OC(=O)C)(=[O:24])[CH3:23]>CCOCC>[C:22]([O:10][C@@H:9]1[C@@H:11]([CH2:12][O:13][C:18](=[O:21])[CH3:19])[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([I:1])[C:3](=[O:17])[NH:4][C:5]2=[O:16])[CH2:8]1)(=[O:24])[CH3:23]
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Solvent: CCOCC
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(I)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Yield: 102.8 %

Procedure:
To 5-iodo-2′-deoxyuridine (2.1) (70.8 g, 200 mmol, 1 eq) in an 500 mL Erlenmeyer flask was added acetic acid (72 g, 68.7 mL, 1200 mmol, 6 eq) and acetic anhydride (51 g, 47.1 mL, 500 mmol, 2.5 eq). In a test tube at 0° C., the catalyst for the reaction was prepared by adding HClO4 (0.5 mL) over acetic anhydride (2 mL). Five drops of the catalyst were added into the Erlenmeyer flask at 0° C. with stirring. The reaction mixture was brought to room temperature and stirred for 4 hours where upon a thick white precipitate formed. The Erlenmeyer flask was filled with ether and stirred vigorously for 30 minutes. The white precipitate was filtered and the white cake was washed with ether (500 mL). The product was dried in the vacuum oven overnight to afford (2.2) (90.1 g, 95%) 1H-NMR (CDCl3) δ (ppm) 9.40 (bs, 1H, exchangeable, NH), 7.78 (s, 1H, H-6), 6.18 (dd, J=8.10 Hz, 1H, H-1′), 5.05 (m, 1H, H-3′), 4.07-4.25 (m, 3H, H-4′, 5′), 2.35 (m, 1H, H-2′b), 1.85-2.12 (m, 7H, 2×CH3, H-2′a)