Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4](=[CH:7][CH2:8][CH:9]1[CH2:14][CH:13]2[C:11]([CH3:15])([CH2:12]2)[C:10]1([CH3:17])[CH3:16])[CH:5]=[O:6].CC(C)=O>O.C(O)C>[CH3:3][C:4](=[CH:7][CH2:8][CH:9]1[CH2:14][CH:13]2[C:11]([CH3:15])([CH2:12]2)[C:10]1([CH3:17])[CH3:16])[CH2:5][OH:6]
Reactant: CC(C=O)=CCC1CC2CC2(C)C1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Solvent: O
Product: CC(=CCC1CC2CC2(C)C1(C)C)CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
0.5 g (10 mmol) of sodium borohydride dissolved in 5 ml of water was added portionwise to the solution of 5.0 g (24 mmol) of 2-methyl-4-(1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)but-2-enal in 20 ml of ethanol maintained at 0° C. Stirring was continued for 1 hour at 0-5° C., then acetone was added to destroy the excess of hydride. The reaction mixture was poured on 100 ml of water, extracted with 2×100 ml of ether, dried (MgSO4) and evaporated in vacuo. Kugelrohr distillation of the residue at 160° C./0.1 Torr gave 4.5 g (90% yield) of 2-methyl-4-(1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)but-2-en-1-ol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Br[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:14]([NH:13][C:9]1[CH:8]=[C:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:2][CH2:3]2)[CH:12]=[CH:11][CH:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)OC(C)(C)C)CC2)c1
Yield: 431.2 %

Procedure:
A solution of N1-[3-(4-piperidyl)phenyl]acetamide (550 mg, 0.210 mmol), tert-butyl N-(3-bromopropyl)carbamate (550 mg, 0.230 mmol), K2CO3 (1.10 g, 0.890 mmol), diisopropylethyl amine (1.50 mL) and a few crystals of KI in dioxane (20 mL) was heated at reflux temperature for 2 days. The precipitated salts were removed by filtration, concentrated in vacuo and the crude product was chromatographed, giving the desired product (340 mg): 1H NMR (CDCl3) δ 8.15 (s, 1H), 7.47–7.44 (m, 2H), 7.22 (t, 1H, J=7.8 Hz), 6.94 (d, 1H, J=7.8 Hz), 5.53 (b, 1H), 3.23 (b, 6H), 2.80–1.60 (m, 9H), 2.20 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:22][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:19]([OH:21])=O)=[CH:11][C:12]=3[C:13]3(OCCC[O:14]3)[C:5]2=[N:4][CH2:3]1.[O:24]([CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]1([CH3:23])[CH2:22][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:19]([N:33]4[CH2:34][CH2:35][CH2:36][C@H:32]4[CH2:31][O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:21])=[CH:11][C:12]=3[C:13](=[O:14])[C:5]2=[N:4][CH2:3]1
Reactant: c1ccc(OC[C@@H]2CCCN2)cc1
Reactant: CC1(C)CN=C2N(C1)c1ccc(C(=O)O)cc1C21OCCCO1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CN=C2C(=O)c3cc(C(=O)N4CCC[C@H]4COc4ccccc4)ccc3N2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution of 3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole]-8′-carboxylic acid (0.090 g, 0.284 mmol) in CH2Cl2 (7 mL) was added (2S)-2-(phenoxymethyl)pyrrolidine (0.75 g, 0.427 mmol), DCC (0.082 g, 0.039 mmol), HOBT (0.038 g, 0.281 mmol) and Et3N (0.045 mL, 0.277 mmol) and the solution stirred overnight at rt. The reaction was filtered through 1 cm of silica gel washing with EtOAc. The filtrate was dried over Na2SO4, filtered, concentrated and purified on silica gel eluting with acetone/hexane (30/70). The resulting white foam was dissolved in CH2Cl2 (1.5 mL) and methanesulfonic acid (1 mL) was added and the solution was stirred at rt overnight. The reaction was poured onto ice, basified to pH 11 with ammonium hydroxide and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, concentrated and purified on Biotage Si 12+M cartridge silica gel eluting with acetone/hexane (35/65) to give the title compound as a yellow foam (0.021 g, 20%). NMR (400 Mz, DMSO-d6): consistent. MS (ES+) m/z 418.3 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.N[CH:13]([CH2:21][NH:22][C:23]1[C:28]([CH3:29])=[C:27]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:32][CH2:31]2)[N:26]=[CH:25][N:24]=1)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>ClCCl.N1C=CC=CC=1>[CH3:29][C:28]1[C:23]([NH:22][CH2:21][CH:13]([C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:24][CH:25]=[N:26][C:27]=1[N:30]1[CH2:35][CH2:34][CH:33]([C:36]2[CH:45]=[CH:44][C:43]3[CH2:42][CH2:41][CH2:40][NH:39][C:38]=3[N:37]=2)[CH2:32][CH2:31]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1c(NCC(N)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)C(CNc2ncnc(N3CCC(c4ccc5c(n4)NCCC5)CC3)c2C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
40 mg (0.233 mmoles) of 4-methoxy-benzoyl chloride in solution in 3 ml of dichloromethane is added to a mixture of 109 mg (0.233 mmoles) of tert-butyl 2-amino-3-{5-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate in solution in 6 ml of dichloromethane and 650 ml of pyridine. The reaction mixture is stirred at ambient temperature for 1 hour. Then, the solvent is evaporated off under reduced pressure (2 kPa) and the residue is chromatographed on silica gel with the following eluent ethyl acetate-dichloromethane 50-50, ethyl acetate-dichloromethane/methanol (95/5) 50-50 then finishing with ethyl acetate-dichlorornethane/methanol (9/1) 50-50. 98 mg of expected product is obtained.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].F[C:17]1[CH:18]=[CH:19][C:20](I)=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23]>>[N:12]1[N:11]([C:5]2[CH:4]=[CH:3][CH:2]=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])[N:15]=[CH:14][CH:13]=1.[N:12]1([C:20]2[CH:19]=[CH:18][CH:17]=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])[CH:13]=[CH:14][N:15]=[N:11]1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: O=C(O)c1cc(F)ccc1I
Product: O=C(O)c1ccccc1-n1ccnn1
Product: O=C(O)c1ccccc1-n1nccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 1, substituting 2-iodobenzoic acid for 5-fluoro-2-iodo-benzoic acid. Two products were formed in this reaction, 2-[1,2,3]triazol-2-yl-benzoic acid and 2-[1,2,3]triazol-1-yl-benzoic acid, as a result of the tautomeric forms of 1,2,3-triazole. 1H NMR (400 MHz, CD3OD): 7.91 (s, 2H), 7.85-7.82 (m, 1H), 7.75 (dd, J=8.1, 1.0 Hz, 1H), 7.69 (td, J=7.7, 1.5 Hz, 1H), 7.60-7.55 (m, 1H).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].CN(CCN(C)C)C.[Li]CCCC.[Cl:40]N1C(=O)CCC1=O>C1COCC1.C(OCC)C.O>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[C:19]2[CH:20]=[C:21]([F:26])[C:22]([Cl:40])=[C:23]([F:25])[CH:24]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](CCc2c(F)cccc2-c2cc(F)cc(F)c2)CC1
Reactant: O=C1CCC(=O)N1Cl
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](CCc2c(F)cccc2-c2cc(F)c(Cl)c(F)c2)CC1
Reaction time: 0.5 h

Procedure:
A solution of 0.1 m of 1-(trans-4-n-propylcyclo-hexyl)-2-(3,3′, 5′-trifluorobiphenylyl)ethane and 0.1 m of TMEDA in 300 ml of THF is treated dropwise at about -65° with 0.1 m of n-BuLi (1.5 M in hexane). The mixture is stirred at this temperature for a further 30 minutes, and 0.2 m of N-chlorosuccinimide in 70 ml of THF is then slowly added. When the addition is complete, the mixture is allowed to warm to −20° and is hydrolyzed using H2O. The product is dissolved completely by adding diethyl ether. Extractive work-up and purification by chromatography and crystallization give l-(trans-4-n-propylcyclohexyl)-2-(4′-chloro-3,3′, 5′-trifluorobiphenylyl)ethane.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.BrCCCC[C:22]1[CH:32]=[CH:31][CH:30]=[C:24]2[C:25]([NH:27][C:28](=[O:29])[C:23]=12)=[O:26]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:16][CH2:2][CH2:3][CH2:4][N:27]4[C:28](=[O:29])[C:23]5=[CH:22][CH:32]=[CH:31][CH:30]=[C:24]5[C:25]4=[O:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2c(CCCCBr)cccc21
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 47.1 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.5 g, 25 mmol), 4-bromobutylphthalimide (8.0 g, 28.3 mmol, 1.13 eq), K2CO 3 (4.55 g, 32 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours. At the end of the reaction, the mixture was filtered. The insolubles were washed with dichloromethane (200 ml). The organic solution was concentrated gradually to allow cystallization. The crude crystals (5.9 g) were collected. The mother liquor was concentrated to a solid (5.5 g). Purification was by flash chromatography over a silica gel column. The product (3.8 g) thus purified was recrystallized from ethanol (70 ml) to give 2.48 g of N-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl]phthalimide as white crystals,
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].CO[CH:17]1[CH2:21][CH2:20][CH:19](OC)O1>C(O)(=O)C.O1CCOCC1>[N:1]1([C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=2)[C:5]([OH:7])=[O:6])[CH:17]=[CH:21][CH:20]=[CH:19]1
Reactant: Nc1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(O)c1cc(-n2cccc2)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 3-amino-5-(trifluoromethyl)benzoic acid (2.0 g) and 2,5-dimethoxytetrahydrofuran (1.52 ml) in a mixture of acetic acid (10 ml) and 1,4-dioxane (10 ml) was stirred at 100° C. for 2 hours. After cooling to room temperature, the mixture was concentrated and purified with column chromatography (silica gel, 50 ml, methanol:dichloromethane=10:90) to give crude solid. The solid was recrystallized from ethyl acetate (5.0 ml) and hexane (200 ml) to give 3-(pyrrol-1-yl)-5-(trifluoromethyl)-benzoic acid (1.72 g) as a powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].C(N1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])(OCC)=O>O1CCCC1.C(N(CC)CC)C>[C:19]1(=[O:28])[N:7]([CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(CN)cc1OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)c3ccccc3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a stirred solution of 3,4-dimethoxybenzylamine (0.836 grams, 5.00 mmol) and N-carbethoxyphthalimide (1.10 grams, 5.00 mmol) in 20 milliliters of tetrahydrofuran was added 1 drop of triethylamine and the mixture stirred overnight. After 24 hours at room temperature, the mixture was refluxed for 16 hours, then allowed to cool to room temperature without stirring. Crystals formed on cooling. The mixture was filtered, the solid dried in vacuo to afford 0.89 grams (60%) of 1-phthalimido-1-(3′,4′-dimethoxyphenyl)methane as small white needles: mp 160-161° C.; 1H NMR (CDCl3/TMS) δ 7.8 (m, 2H), 7.7 (m, 2H), 7.03 (m, 2H), 6.8 (m, 1H), 4.78 (s, 2H), 3.88 (s, 3H, OCH3), 3.84 (s, 3H, OCH3); 13C NMR (CDCl3/TMS) δ 168.0, 148.9, 148.7, 133.9, 132.1, 129.0, 123.3, 121.3, 112.1, 111.1, 55.9, 41.4. Anal. Calcd for C17H15NO4. Theory: C, 68.68; H, 5.09; N, 4.71. Found: C, 68.49; H, 4.99; N, 4.67.
Reaction SMILES: [SH:1][CH:2]([CH2:10][CH2:11][SH:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+]>O>[S:12]1[CH2:11][CH2:10][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[S:1]1
Reactant: O=C(O)CCCCC(S)CCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCCC1CCSS1
Reaction time: 2.5 h
Yield: 75.3 %

Procedure:
8.0 grams (0.038 mole) of 6,8-dimercapto octanoic acid were added to 1.54 grams (0.038 mole) of sodium hydroxide in 90 ml of water and the solution formed adjusted to pH 9 with dilute aqueous sodium hydroxide. The solution was extracted twice, each time with 30 ml of methyl tertiary butyl ether, the aqueous solution separated off and the residual ether removed in a vacuum. The solution was diluted with 200 ml of water, 7 mg of iron (III) sulfate added and oxygen led in with stirring at room temperture. After 2.5 hours the reaction solution had reached a pH of 12.4, the supply of oxygen was ended and the precipitated iron salt filtered off. The clear yellow solution was acidified with 10% hydrochloric acid at 5° C., to 10° C., further stirred for 1 hour at pH 1 and the precipitated crude product filtered off. The precipitate was washed with water, dried in a vacuum and recrystallized from ethyl acetate/hexane. After drying there were obtained 5.9 grams (75% of theory) of 1,2-dithiolane-3-pentanoic acid as yellow crystals having a melting point of 61° C. to 62° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36].O>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-c2nn(CCCC(=O)O)c3ncccc23)cc(C(C)(C)C)c1O
Temperature: 60 °C
Reaction time: 21 h
Yield: 67.6 %

Procedure:
To a solution of 9.7 g of the compound of Example 1 in 70 ml of dimethylformamide are added 5.5 g of potassium carbonate and 6 g of ethyl 4-chlorobutyrate, and the mixture is stirred at 60° C. for 21 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The extract is washed with water, dried and concentrated. To a solution of the residue in 100 ml of 80 % methanol is added 3 g of potassium hydroxide, and the mixture is stirred at room temperature for two hours. After completion of the reaction, the methanol is distilled off under reduced pressure and the residue is dissolved into water and the aqueous solution is acidified with dilute hydrochloric acid. The precipitated crystals are collected by filtration and then recrystallizing from ethanol to give 8.3 g of 4-[3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl]butyric acid as pale yellow crystals, melting at 192°-194° C.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=O)C1C=CC=CC=1.[NH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:47]([O:46][C:44]([N:41]1[CH2:42][CH2:43][CH:38]([N:37]2[CH2:17][CH2:16][C@@H:15]([CH2:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:22][C:21]=3[Cl:35])[C:14]2=[O:36])[CH2:39][CH2:40]1)=[O:45])([CH3:50])([CH3:48])[CH3:49]
Reactant: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1
Yield: 58 %

Procedure:
Treat a solution of (R)-4-((R)-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde (Preparation 10) (4.0 g, 7.6 mmol) and 4-Amino-1N-Boc-piperidine (1.5 g, 7.6 mmol) in CH2Cl2 (100 mL) with acetic acid (0.4 mL, 7.6 mmol) and stir the reaction 1 hr at room temperature. Treat the reaction with sodium triacetoxyborohydride (3.2 g, 15 mmol) and stir overnight at room temperature. Quench the reaction with water and separate the organic layer. Wash the organic with brine, dry over MgSO4, filter, and remove the solvent. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 2.35 g (58%) of desired product. MS (m/e): 555 (M+Na+).
Reaction SMILES: [CH:1]1([C:6]([NH:8][CH:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.ClC(=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH:1]1([C:6]([NH:8][CH:9]([CH2:13][CH3:14])[C:10](=[O:12])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCC(NC(=O)C1CCCC1)C(=O)O
Reactant: CCOC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(CC)NC(=O)C1CCCC1
Temperature: 25 °C

Procedure:
1.6 g (8 mmol) 2-[(cyclopentylcarbonyl)amino]butanoic acid are suspended in 30 ml tetrahydrofurane and heated to reflux together with 1.91 g (24 mmol) pyridine and a bit of N,N-dimethylaminopyridine. While heating at reflux, 2.19 g (16 mmol) ethyl chloro(oxo)acetate are added dropwise. The reaction mixture is heated at reflux until no more evolution of gas can be observed. After cooling down to room temperature, the reaction mixture is added to ice water and the organic phase extracted with ethyl acetate. The dried organic phase is evaporated to dryness in vacuo, dissolved in ethanol and the solution directly used for the next reaction.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)(=[O:4])=[O:3]
Reactant: OCCc1c(-c2cccnc2)[nH]c2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1c(-c2cccnc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (2.50 ml) is added dropwise to a solution of 7.5 g 3-(2-hydroxyethyl)-2-(3-pyridyl)-indole and 10.0 ml of triethylamine in 150 ml of methylene chloride at -10°. This mixture is stirred at room temperature for 0.5 hour and poured into 600 ml of ice water. The resulting slurry is extracted with methylene chloride and the extract is washed with saturated sodium bicarbonate solution, dried over MgSO4 and evaporated in vacuo to give 3-(2-methylsulfonyloxyethyl)-2-(3-pyridyl)-indole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].[CH2:23]([O:30][C:31]1[C:32](Cl)=[N:33][S:34][N:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH2:23]([O:30][C:31]1[C:32]([O:22][C:3]2[CH:4]=[C:5]([N:9]3[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]3=[O:21])[C:6]([F:8])=[CH:7][C:2]=2[Cl:1])=[N:33][S:34][N:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: Clc1nsnc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3nsnc3OCc3ccccc3)c(Cl)cc2F)c1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 28.8 %

Procedure:
To a solution of 0.60 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol and 0.50 g of 4-benzyloxy-3-chloro-1,2,5-thiadiazole in 8 ml of dimethyl sulfoxide, 0.25 g of potassium carbonate was added, and stirred for 30 minutes at 50° C., and for 3 hours at 100° C. The reaction solution was poured into dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, then, saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.27 g of 4-benzyloxy-3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-1,2,5-thiadiazole (purity: 44%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3I)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:22]1[CH:30]2[CH:25]([CH2:26][NH:27][CH2:28][CH2:29]2)[CH2:24][N:23]1C(OC(C)(C)C)=O.[ClH:38]>>[Cl-:38].[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:27]2[CH2:28][CH2:29][CH:30]3[CH2:22][NH2+:23][CH2:24][CH:25]3[CH2:26]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cccc(F)c1)c1cnc2c(I)cccc2c1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CC2CCNCC2C1
Product: O=S(=O)(c1cccc(F)c1)c1cnc2c(N3CCC4C[NH2+]CC4C3)cccc2c1
Product: [Cl-]

Procedure:
0.072 g of 5-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)octahydro-1H-pyrrolo[3,4-c]pyridin-2-ium chloride were prepared by analogy to the methods of Examples 27 and 28 by coupling of 3-(3-fluorophenylsulfonyl)-8-iodoquinoline with commercially available tert-butyl hexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate and subsequent deprotection of the tert-butyl-oxycarbonyl derivative with HCl in isoproanol.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C@@H:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][S:21]([OH:24])(=[O:23])=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14](F)[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1.[Cl:29]C1C=C2C(B3OC(C)(C)C(C)(C)O3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.FC1C=C2C(B3OC(C)(C)C(C)(C)O3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.C(O)(C(F)(F)F)=O>C(#N)C.O>[Cl:29][C:14]1[CH:15]=[C:16]2[C:8]([C:5]3[N:4]=[C:3]([NH:18][C@@H:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][S:21]([OH:24])(=[O:23])=[O:22])[C:2]([F:1])=[CH:7][N:6]=3)=[CH:9][NH:10][C:11]2=[N:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: CC(C)(C)[C@@H](CS(=O)(=O)O)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Agent: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](CS(=O)(=O)O)Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F

Procedure:
Sulfonic acid, 10, was synthesized in a manner similar to Compound 11, using 5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine instead of boronate ester, 7a, as the starting material: 1H NMR (400 MHz, MeOD) δ 8.44 (s, 1H), 8.34 (dd, J=9.2, 2.6 Hz, 1H), 8.22 (d, J=5.7 Hz, 1H), 8.13 (s, 1H), 5.16 (d, J=4.1 Hz, 1H), 3.46-3.33 (m, 2H), 1.10 (d, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% TFA, C18) m/z 412.19 (M+H) retention time=1.91 minutes.