Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].I[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>CS(C)=O.[Cu]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=C(O)c1ccc(I)cc1
Agent: [Cu]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Temperature: 210 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution of 4.36 g of 4-methyl-phenol in 70 ml of dry dimethylsulfoxide under nitrogen with stirring is added 9.0 g of potassium t-butoxide. After stirring for 15 minutes, 0.1 g of copper metal is added followed by 10.0 g of 4-iodobenzoic acid. The reactants are stirred under nitrogen while heating at 210° C. for 18 hours. The cooled reaction mixture is extracted with chloroform (2×900 ml) and the remaining water acidified with 2N HCl (pH=3) with ice bath cooling, to give 8.1 g of the desired product. MS(M+H=229.0)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].F[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][N:21]=1)[C:17]#[N:18]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][N:21]=1)[C:17]#[N:18]
Reactant: N#Cc1ccnc(F)c1
Reactant: COc1ccc(CN)c(OC)c1
Product: COc1ccc(CNc2cc(C#N)ccn2)c(OC)c1

Procedure:
The title compound was prepared according to the method described for Preparation 20 using 2,4-dimethoxybenzylamine and 2-fluoroisonicotinonitrile.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]2[CH:43]=[CH:42][C:37]([C:38](OC)=[O:39])=[CH:36][CH:35]=2)=[CH:16][CH:15]=1.Cl>O1CCCC1.COCCOC>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]2[CH:35]=[CH:36][C:37]([C:38](=[O:39])[CH2:3][S:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)(=[O:6])=[O:5])=[CH:42][CH:43]=2)=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)c1ccccc1
Reactant: COC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: O=C(CS(=O)(=O)c1ccccc1)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1

Procedure:
A solution of 864 mg. of sodium hydride and 5.3 g. of methylphenylsulfone in 20 ml. of 1,2-dimethoxyethane is stirred at 60° C. for one hour under an atmosphere of argon. To this solution is added a solution of 5.0 g. of methyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate in 50 ml. of tetrahydrofuran and the reaction mixture is stirred at 60° C. for 1.5 hours. The mixture is cooled, poured onto ice, acidified with dilute hydrochloric acid to pH 3 and then extracted with chloroform. The organic layer is separated, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated to dryness. The crude solid is chromatographed on silica gel, eluting with methylene chloride to yield 4'-[13-(4-chlorophenyl)tridec-12-ynylamino]-2-(phenylsulfonyl)acetophenone.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5](#N)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>[O-2].[Cd+2].C(O)(=O)C>[CH2:6]([C:5]1[O:2][CH2:1][CH2:3][N:4]=1)[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC#N
Reactant: NCCO
Agent: [Cd+2]
Agent: [O-2]
Solvent: CC(=O)O
Product: CCCCCC1=NCCO1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A mixture of about 3.24 grams cadmium oxide, about 3.00 grams acetic acid, about 64.8 grams ethanolamine, and about 98.2 grams hexanenitrile is heated and stirred under nitrogen at about 120 degrees C. to 125 degrees C. for about two days. The liquid is decanted from the catalyst and distilled under vacuum. The fraction boiling at about 86 degrees C. to about 93 degrees C. at about 28 mmHg to about 30 mm Hg is collected.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].CN(P(N(C)C)(N(C)C)=O)C.[CH2:21]=[O:22]>C1(C)C=CC=CC=1.C([Mg]Br)C>[OH:22][C:21]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=1[CH:3]=[O:9]
Reactant: Cc1ccc(O)c(C)c1
Reactant: C=O
Agent: CC[Mg]Br
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(O)c(C=O)c1
Yield: 58.4 %

Procedure:
To a solution of 2,4-dimethylphenol (24.9 g, 204 mmole) in anhydrous toluene (75 mL) at 0° C. was added HMPA (35 mL) and then a solution of ethylmagnesium bromide (61 mL-3 M in ethyl ether, 0.183 mmole), keeping the temperature <10° C. Then paraformaldehyde (13 g, 0.43 mole) was added and the cooling was removed. The ethyl ether was removed by distillation and the mixture was refluxed. The mixture was quenched with 10% HCl and EtOAc was added. The EtOAc solution was washed twice with H2O, twice with aqueous NH4Cl, dried over Na2SO4 and concentrated in vacuo. Purification by silica chromatography (98:2 hexanes:EtOAc) gave 17.9 g (59% yield) of the product as a yellow oil: ESHRMS m/z 147.0619 (M−H, C9H9O2, Calc'd 147.0603).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[CH:13]1([Mg]Cl)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl-].[NH4+]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[OH:12]
Reactant: Cl[Mg]C1CCCCC1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C1(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 18.15 g of 5-chloroisatin in 45 ml of THF is cooled to +4° C., 200 ml of a 2M solution of cyclohexylmagnesium chloride in ether are added dropwise and the mixture is stirred for 3 hours at RT. 900 ml of a saturated solution of ammonium chloride are added and the solvents are concentrated under vacuum. The aqueous phase is extracted with AcOEt, the organic phase is washed with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated off under vacuum to give 4 g of the expected product after crystallization from a THF/AcOEt mixture.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH:10]=[CH:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.[C].[Pd]>[C:1]([C:5]1[N:6]=[C:7]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1csc(C=Cc2cccc(C(=O)O)c2)n1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)c1csc(CCc2cccc(C(=O)O)c2)n1
Yield: 92.6 %

Procedure:
3-[2-(4-tert-Butyl-2-thiazolyl)vinyl]benzoic acid (1.20 g, 4.18 mmol) was dissolved in tetrahydrofuran (24 ml), 10% palladium-carbon powder (0.2 g) was added to the solution, and the mixture was stirred at room temperature for 3 hours in an atmosphere of hydrogen. The reaction solution was filtered and the resulting filtrate was concentrated under reduced pressure. By crystallizing the resulting residue from diethyl ether-hexane, 3-[2-(4-tert-butyl-thiazolyl)ethyl]benzoic acid (1.12 g, 93%) was obtained.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)CCC.[C@@H:19]1([N:27]2[CH:31]=[C:30](I)[CH:29]=[C:28]2[N+:33]([O-:35])=[O:34])[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[CH2:20]1>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.CN(C=O)C>[C@@H:19]1([N:27]2[CH:31]=[C:30]([C:6]3[O:7][CH:8]=[CH:9][CH:10]=3)[CH:29]=[C:28]2[N+:33]([O-:35])=[O:34])[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[CH2:20]1
Reactant: O=[N+]([O-])c1cc(I)cn1[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2ccco2)cn1[C@H]1C[C@H](O)[C@@H](CO)O1
Yield: 76 %

Procedure:
2-(Tributylstannyl)furan (472 μL, 1.5 mmol) was added to a DMF (2.5 mL) solution containing 1-(2-deoxy-β-D-ribofuranosyl)-4-iodo-2-nitropyrrole (177 mg, 0.5 mmol) and bis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.025 mmol). The mixture was reacted at 100° C. for 30 minutes in a microwave machine (standard mode). The reaction solution was separated between ethyl acetate (50 mL) and water (50 mL). The organic layer was concentrated and purified by HPLC to yield 1-(2-deoxy-β-D-ribofuranosyl)-4-(furan-2-yl)-2-nitropyrrole (111 mg, 0.38 mmol, 76%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH3:13])[CH2:8][CH2:7]1)=[O:5].C(N(CC)C(C)C)(C)C.[F:23][C:24]([F:30])([F:29])[S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:13][CH:9]1[CH2:8][CH2:7][C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[C:11]([O:12][S:25]([C:24]([F:30])([F:29])[F:23])(=[O:27])=[O:26])[CH2:10]1
Reactant: CCOC(=O)C1CCC(C)CC1=O
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CC(C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a solution of ethyl 4-methyl-2-cyclohexanone-1-carboxylate (50 g, 0.27 mol) in dichloromethane (500 ml) at −10° C. was added N,N-diisopropylethylamine (52 ml, 0.3 mol) followed by dropwise addition of trifluoromethanesulphonyl chloride (57 ml, 0.3 mol) keeping the temperature between −5 and −100° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. TLC showed 80% reaction, it was cooled to −5° C. and more N,N-diisopropylethylamine (14 ml, 0.1 mol) was added followed by trifluoromethanesulphonyl chloride (15.5 ml, 0.1 mol) and the reaction mixture was stirred for 15 hours at room temperature. The mixture was washed with cold water (2×200 ml), cold saturated sodium bicarbonate (2×200 ml) and brine (1×200 ml). The organic layer was dried (MgSO4), filtered and evaporated to give the required product (85 g) as a colourless oil. 1H NMR (250 MHz, CDCl3) δ 1.04 (3H, d, J=6.5 Hz), 1.43 (3H, m), 1.73-2.09 (4H, m), 2.39-2.63 (3H, m), 4.25 (2H, m).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].I[CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC/C=C\CCCI
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCC/C=C\CCCOc1ccccc1C(=O)OC
Yield: 90 %

Procedure:
88 mg of 28 (578 μmol) and 77 mg of K2CO3 (557 μmol) are added to 140 mg of 13 (500 μmol) in anhydrous DMF (2 mL). After reaction for 8 hours at 90° C., the reaction medium is concentrated, taken up in DCM and then washed with water. 137 mg of a yellow oil are obtained, and are chromatographed on silica gel in pentane/ethyl acetate (40/1). 100 mg of a yellow oil are isolated, i.e. a yield of 66%.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1.[Cl-].[NH4+].Cl>C(OCC)C.C1COCC1>[OH:9][C:10]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13]1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2)C1
Temperature: -50 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
3.9 ml (11.7 mmol) of a 3M solution of phenylmagnesium bromide in diethyl ether are added dropwise to a solution, immersed in a bath at −50° C., containing 500 mg (2.92 mmol) of 3-oxo-1-(tert-butoxycarbonyl)azetidine in 10 ml of THF. The medium is stirred for 1 hour at −50° C. and hydrolysed by adding a saturated solution of ammonium chloride. After a return to ambient temperature, a 1N solution of hydrochloric acid is added, followed by extraction with ethyl acetate. The organic phase is dried and evaporated to dryness. The crude product obtained is purified on silica in a 7/3 heptane/ethyl acetate mixture. 253 mg in the form of a white powder are obtained with a yield of 35%.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][CH:33]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:38][C:35]3[CH:36]=[CH:37][C:32]([C:31]([OH:40])=[O:30])=[CH:33][CH:34]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COC(=O)c1ccc(C=O)cc1
Product: O=C(O)c1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
This compound was prepared according to the procedure of Example 66 from 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 4-formyl-benzoic acid methyl ester MS (ESI) m/z 511.
Reaction SMILES: C(N1C2C(=CC=CC=2)C(O)(CC(=O)C2C=CC=CN=2)C1=O)CCC.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH2:36][CH3:37])[C:30](=[O:38])[C:29]2=[O:39].[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([C:49](=[O:51])[CH3:50])=[CH:41]1>>[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([C:49](=[O:51])[CH2:50][C:29]2([OH:39])[C:28]3[C:32](=[CH:33][CH:34]=[C:26]([Cl:25])[CH:27]=3)[N:31]([CH2:35][CH2:36][CH3:37])[C:30]2=[O:38])=[CH:41]1
Reactant: CC(=O)c1c[nH]c2ccccc12
Reactant: CCCN1C(=O)C(=O)c2cc(Cl)ccc21
Agent: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Product: CCCN1C(=O)C(O)(CC(=O)c2c[nH]c3ccccc23)c2cc(Cl)ccc21

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 5-chloro-1-propylindoline-2,3-dione and commercially available 1-(1H-indol-3-yl)ethanone (purchased from Fisher Scientific). 1H-NMR δ 8.71 (bs, NH) 8.38 (m, 1H), 7.79 (d, 1H), 7.49 (d, 1H), 7.41 (m, 1H), 7.35-7.31 (m, 2H), 7.26 (m, 1H), 6.78 (d, 1H), 5.00 (bs, OH), 3.65 (m, 2H), 3.50 (d, 1H), 3.25 (d, 1H), 1.69 (m, 2H), 0.96 (t, 3H). calculated mass for C21H19ClN2O3, 382.11, observed, 383.1 (M+1).
Reaction SMILES: Cl[O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:11]([C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])=[CH2:12].C(N(C(C)C)C(C)C)C>CCOCC>[C:5]1([C:4]2[CH2:12][CH:11]([C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[C:15]([O:17][CH3:18])=[O:16])[O:2][N:3]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=Cc1ccccc1C(=O)OC
Reactant: ClON=Cc1ccccc1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1C1CC(c2ccccc2)=NO1
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a stirred solution of 9.4 g (0.0604 mol) of benzaldehyde chlorooxime and 10.76 g (0.0664 mol) of methyl o-vinyl-benzoate in 100 ml of ether at 0°-5° C. was added dropwise a solution of 7.81 g (0.0604 mol) of ethyldiisopropylamine in 35 ml of ether during 30 minutes. The mixture was stirred in an ice bath for 4 hours, diluted with another 400 ml of ether, extracted three times with water, and concentrated under vacuum to a solid. This solid was washed with 200 ml of hexane. The undissolved solid product, 14.21 g, had mp 90°-94° C. Crystallization of this from 100 ml of methanol gave 13.50 g (79%) of white solid, mp 93.5°-95° C.
Reaction SMILES: [OH-].[K+].CS(C)=O.[NH:7]1[CH:11]=[N:10][N:9]=[N:8]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:22][C:21]=2[S:29]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:31])=[O:30])=[CH:16][CH:15]=1>O>[CH2:25]([C:23]1[S:22][C:21]([S:29]([NH:32][C:33]([CH3:34])([CH3:35])[CH3:36])(=[O:30])=[O:31])=[C:20]([C:17]2[CH:16]=[CH:15][C:14]([CH2:13][N:8]3[N:9]=[N:10][CH:11]=[N:7]3)=[CH:19][CH:18]=2)[CH:24]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)Cc1cc(-c2ccc(CBr)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: c1nnn[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Cc1cc(-c2ccc(Cn3ncnn3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Reaction time: 0.08 h
Yield: 22.6 %

Procedure:
KOH (112.2 mg, 2.00 mmol, crushed pellets) was added to DMSO (10 mL, dried over 4 A molecular sieve) and stirred for 5 min. Tetrazole (28.0 mg, 0.4 mmol) was added to the mixture, which was then stirred for 2 h. 3-(4-Bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (130 mg, 0.292 mmol, see step (b) above) was added, the mixture was cooled briefly and stirred for an additional hour before water (50 mL) was added. The reaction mixture was extracted with ethyl acetate (250 mL) and the extract was washed with water (2×50 mL) and brine (0 mL). The organic phase was dried over MgSO4 and the solvent was removed in vacuo. The residue was purified on column chromatography using hexane:acetone (3:1) as eluent to give the sub-title compound (28.6 mg, 0.066 mmol, 23% yield).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C@@H:10]2[CH2:14][S:13][CH2:12][C@H:11]2[C:15]([OH:17])=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[F:58][C:59]1[CH:71]=[CH:70][C:62]([CH2:63][C@@H:64]2[CH2:69][CH2:68][CH2:67][NH:66][CH2:65]2)=[CH:61][CH:60]=1>ClCCl>[F:58][C:59]1[CH:60]=[CH:61][C:62]([CH2:63][C@@H:64]2[CH2:69][CH2:68][CH2:67][N:66]([C:15]([C@H:11]3[C@H:10]([NH:9][C@@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH3:8])[CH2:14][S:13][CH2:12]3)=[O:17])[CH2:65]2)=[CH:70][CH:71]=1
Reactant: C[C@@H](N[C@@H]1CSC[C@H]1C(=O)O)c1ccccc1
Reactant: Fc1ccc(C[C@@H]2CCCNC2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](N[C@@H]1CSC[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Reaction time: 0.08 h
Yield: 94 %

Procedure:
A cloudy solution of (3R,4S)-4-[(R)-1-phenyl-ethylamino]-tetrahydrothiophene-3-carboxylic acid (containing sodium chloride; 928 mg, 2.54 mmol) in dichloromethane (20 mL) was treated with benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (1.59 g, 3.05 mmol) and triethylamine (814 μL, 5.84 mmol) and stirred for 5 minutes. A solution of the (S)-3-(4-fluorobenzyl)-piperidine prepared above in dichloromethane (5 mL) was added and the mixture was stirred at room temperature. After 21.5 h, the mixture was diluted with dichloromethane, washed with water and saturated NaHCO3, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (55% ethyl acetate/hexanes) to provide the product as a gum (1.05 g, 94%).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O:20]1[CH:26]2[CH:21]1[CH2:22][CH:23]([C:27](OC)=[O:28])[CH2:24][CH2:25]2.N12CCN(CC1)CC2.C1(C)C=CC=CC=1>CO>[O:20]1[CH:26]2[CH:21]1[CH2:22][CH:23]([C:27]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:28])[CH2:24][CH2:25]2
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: COC(=O)C1CCC2OC2C1
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOC(=O)C1CCC2OC2C1
Yield: 90.4 %

Procedure:
To a 3-neck 100 mL flask equipped with an argon inlet, stir bar and distillation apparatus was added 1-octadecanol (5.03 g, 19 mmol, obtained from Sigma-Aldrich), methyl 3,4-epoxycyclohexanecarboxylate (ERL-4140, 8.69 g, 56 mmol, obtained from Dow Chemical Company), 1,4-diazabicyclo[2.2.2]octane (DABCO™, 1.02 g, 9.1 mmol, obtained from Sigma-Aldrich) and toluene (15 mL). The reaction mixture was refluxed until methanol ceased collecting in the receiving flask and the completion of the reaction was confirmed by 1H NMR spectroscopy. The still pot from the distillation was diluted with toluene (15 mL) and washed with brine (3×15 mL). The organic layer was separated, dried over MgSO4 and filtered. The solvent was removed in vacuo. The excess methyl 3,4-epoxycyclohexane carboxylate was removed via Kugelrohr distillation under reduced vacuum to give 6.78 g (87%) of a white solid (mp=32-34° C.) of octadecyl 3,4-epoxycyclohexanecarboxylate. 1H NMR (CDCl3, δ): 4.06 (td, J=6.7, 1.9 Hz, 2H), 3.25-3.14 (m, 2H), 2.55-2.45 (m, 1H), 2.31-1.26 (m, 38H), 0.88 (t, J=6.7 Hz, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[N:18]1([CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Br:10][C:11]1[CH:12]=[C:13]([NH:17][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([CH2:24][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:26][CH:27]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C(O)c1ccc(CN2CCCCC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Br)c1)c1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
DIEA (433 μl, 2.49 mmol) was added into a suspension of 3-bromobenzenamine (90.34 μl, 0.829 mmol), 4-(piperidin-1-ylmethyl)benzoic acid (200 mg, 0.912 mmol), BOP (477 mg, 1.08 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature under argon atmosphere overnight. The reaction mixture was loaded onto a 5 g silica loading cartridge. After solvent in the cartridge was dried out under vacuum, the cartridge was put on the ICSO system for purification (yield: 80%). MS (ESI+) m/z 373.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:15][O:16]C(Cl)Cl>ClCCCl.[N+](C)([O-])=O>[CH:15]([C:4]1[CH:3]=[C:2]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH:1][CH:5]=1)=[O:16]
Reactant: COC(Cl)Cl
Reactant: CCOC(=O)c1ccc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCCl
Product: CCOC(=O)c1cc(C=O)c[nH]1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a mixture of ethyl pyrrole-2-carboxylate (8.1 g, 58.3 mmol) and AlCl3 (15.5 g, 2 equiv) in 1,2-dichloroethane-nitromethane (1:1, 120 ml) was added α,α,-dichloromethyl methyl ether (6.4 mL, 2 equiv) dropwise at −20° C. Stirring was continued for 1 h at −20° C. and the reaction mixture was stored at −20° C. overnight. It was then poured into ice. Organic layer was separated and aqueous layer was extracted with DCM. The combined organic layers were washed with water, aqueous NH4OH and water and dried over Na2SO4. Evaporation of solvent afforded ethyl 4-formylpyrrole-2-carboxylate as a solid (8.8 g, 90%). 1H-NMR(CDCl3): δ 10.40 (1H, s), 8.95 (1H, s), 7.60 (1H, dd), 7.33 (1H, dd), 4.36 (2H, q), 1.39 (3H, t).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:12][C:10]1[CH:11]=[C:2]([NH:1][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)cc(NC2CCCCC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (1 g, 5.02 mmol) and cyclohexanone (2.45 g, 25 mmol) in methanol (10 mL), acetic acid (0.3 g, 5.02 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.63 g, 10.05 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford methyl 5-chloro-3-(cyclohexylamino)-2-methylbenzoate (1.2 g, 89.92%).