Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[C:32](Cl)=[O:33]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:32](=[O:33])[C:31]3[CH:30]=[C:29]([Cl:28])[CH:37]=[C:36]([Cl:38])[CH:35]=3)=[CH:15][CH:14]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Nc1ccc(C(=O)N2CCCc3cc(F)ccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2CCCc3cc(F)ccc32)cc1)c1cc(Cl)cc(Cl)c1
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
6-Fluoro-1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline (0.15 g) is dissolved in dichloromethane (10 ml) and thereto is added triethylamine (0.31 ml). To the mixture is added dropwise a solution of 3,5-dichlorobenzoyl chloride (0.14 g) in dichloromethane (2.0 ml) under ice-cooling, and the mixture is stirred for 30 minutes under ice-cooling, and further, at room temperature for 1 hour. To the mixture are added triethylamine (0.31 ml) and 3,5-dichlorobenzoyl chloride (0.14 ml). The mixture is stirred at room temperature for 4 hours. The reaction mixture is washed with water, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:5→1:4), and recrystallized from ethyl acetate/n-hexane to give 6-fluoro-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.12 g) and 6-fluoro-1-{4-[bis-(3,5-dichlorobenzoyl)amino]benzoyl}-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[CH3:27][NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[CH3:36].[CH3:38][N:39]([CH3:51])[C:40]1[CH:41]=[C:42]([CH:48]=[CH:49][CH:50]=1)[C:43](OCC)=[O:44]>O1CCCC1>[CH3:27][NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[CH2:36][C:43](=[O:44])[C:42]1[CH:48]=[CH:49][CH:50]=[C:40]([N:39]([CH3:38])[CH3:51])[CH:41]=1
Reactant: CNC(=O)c1cccnc1C
Reactant: CCOC(=O)c1cccc(N(C)C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1cccnc1CC(=O)c1cccc(N(C)C)c1
Reaction time: 2 h

Procedure:
263 ml. of 1.6 M.n-butyl lithium in hexane (420 mmol.) were slowly added to a solution of 58.7 ml. (420 mmol.) of diisopropylamine in 200 ml. of dry tetrahydrofuran stirred at -10° C. under nitrogen. To the resulting solution of lithium diisopropylamide, a solution of 30 g. (200 mmol.) of 2-methylnicotinic acid N-methylamide (Compound XII) in 200 ml. of dry tetrahydrofuran was slowly added at -20°--30° C. The resulting red reaction mixture was stirred under nitrogen at -20°--30° C. for an additional two hours. Then, a solution of 38.6 g. (200 mmol.) of ethyl 3-dimethylaminobenzoate in 100 ml. of dry tetrahydrofuran was slowly added at -20°--30° C. with stirring under nitrogen. Stirring under nitrogen was continued for 1 hour at the same temperature. The reaction mixture was then quenched with 250 ml. of saturated sodium chloride solution and extracted three times with ethyl acetate. The ethyl acetate phases were combined, washed four times with water, once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to a thick oil (55.6 g.) which was dissolved in a small amount of isopropanol and chromatographed on silica gel using 5% isopropanol/chloroform as the eluant. The last major fraction to be eluted (approx. 24 g.) was rechromatographed on silic gel using 2% isopropanol/chloroform as the eluant. The largest fraction contained the crude product (17.2 g.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[N:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.I[CH:13]([CH3:15])[CH3:14]>>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:13]([CH3:15])[CH3:14])[CH:9]=[N:10][C:5]2=[C:4]([Cl:11])[CH:3]=1
Reactant: CC(C)I
Reactant: Clc1cc(Cl)c2nc[nH]c2n1
Product: CC(C)n1cnc2c(Cl)cc(Cl)nc21

Procedure:
Following the procedure of Example 15b, 5,7-dichloro-3H-imidazo[4,5-b]pyridine (J. Med. Chem., 2007, 50, 828-834) (0.118 g, 0.624 mmol) was reacted with 2-iodopropane. The crude product mixture was purified by silica gel chromatography (25 to 35% ethyl acetate in hexane eluant) to afford a mixture of the title compound (major) and an isomeric product as a solid. MS m/z 230.2 (M+1).
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[CH3:14][N:15]([CH3:36])[CH2:16][CH2:17][N:18]1[C:34](=[O:35])[C:33]2[C:32]3[C:31]4[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=4[NH:25][C:24]=3[CH:23]=[CH:22][C:21]=2[C:19]1=[O:20]>[C].[Pd].C(Cl)(Cl)Cl>[CH3:14][N:15]([CH3:36])[CH2:16][CH2:17][N:18]1[C:34](=[O:35])[C:33]2[C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]=3[CH:23]=[CH:22][C:21]=2[C:19]1=[O:20]
Reactant: CN(C)CCN1C(=O)c2ccc3[nH]c4c(c3c2C1=O)CCCC4
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CN(C)CCN1C(=O)c2ccc3[nH]c4ccccc4c3c2C1=O
Temperature: 25 °C
Yield: 56.3 %

Procedure:
3.6 g of diphenyl ether and 70 mg of 10% palladium-carbon were added to 180 mg of N-(2-dimethylaminoethyl)-5,6,7,8-tetrahydrocarbazole-3,4dicarboximide. The mixture was refluxed in a nitrogen stream for 15 minutes, and then cooled to room temperature. Thereto was added 40 ml of chloroform. The resulting insoluble material was removed by filtration. The filtrate was mixed with 25 ml of water. The mixture was adjusted to pH 1.0 with 6N hydrochloric acid. The aqueous layer was separated, washed with 10 ml of chloroform, and mixed with 20 ml of chloroform. The mixture was adjusted to pH 7.5 with an aqueous saturated sodium hydrogencarbonate solution. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from ethanol to obtain 100 mg (yield: 56%) of N-(2-dimethylaminoethyl)-carbazole-3,4-dicarboximide as yellow needles.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][N:25]([CH3:35])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:34][C:31]2[CH:30]=[CH:29][C:28]([CH2:27][CH2:26][N:25]([CH3:24])[CH3:35])=[CH:33][CH:32]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: CN(C)CCc1ccc(O)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(CCN(C)C)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 4-[2-(dimethylamino)ethyl]phenol: 1H-NMR (CDCl3) δ 8.53 (1H, d, J=2.6 Hz), 8.23 (1H, d, J=7.5 Hz), 8.13 (1H, d, J=2.8 Hz), 8.02–7.98 (2H, m), 7.43 (2H, d, J=8.3 Hz), 7.33–7.30 (2H, m), 7.11–7.06 (2H, m), 5.39–5.30 (1H, m), 3.90 (3H, s), 2.87–2.82 (2H, m), 2.63–2.58 (2H, m), 2.33 (6H, s), 1.59 (3H, d, J=7.0 Hz).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:12])[CH3:9].[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>ClCCl>[CH2:8]([O:10][C:11]([C:13]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:16][N:15]([C:36]([CH:33]2[CH2:35][CH2:34]2)=[O:37])[CH2:14]1)=[O:12])[CH3:9]
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)C2CC2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
Triethylamine (0.37 mL, 2.7 mmol) was added to a stirred solution of 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 65) (300 mg, 0.87 mmol) in dichloromethane (10 mL) and the resulting mixture cooled to 0° C. Cyclopropanecarbonyl chloride (0.08 mL, 0.87 mmol) was added and the reaction mixture stirred at room temperature for 16 hours. The mixture was partitioned between water (50 mL) and dichloromethane (50 mL). The organic layer was separated, washed brine (50 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 15% ethyl acetate in hexane to afford the title compound as a pale yellow solid (305 mg, 85%).
Reaction SMILES: CC([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](C(C)C)[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.[CH:33](C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.C1(C(C)C(O)=O)C=CC=CC=1>>[O:15]=[C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=1)[CH:13]([C:5]1[CH:4]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:33]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)O
Agent: CC(C(=O)O)c1ccccc1
Product: CC(C)c1ccc(C(=O)C(C)c2ccccc2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with α-phenylpropionic acid, mp 142°-144° C.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-:12].[Na+].[Na+].O>CC(C)=O>[CH3:8][C:7]([CH3:10])([CH3:9])[C:6]#[C:5][CH:4]=[CH:3][CH2:2][OH:12]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)C#CC=CCBr
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)C#CC=CCO

Procedure:
To 5.24 g (26.0 mmol) of an approximately 3:1 mixture of the E and Z isomers of 1-bromo-6,6-dimethyl-2-hepten-4-yne was added sodium carbonate (5.52 g, 52.0 mmol) 80 ml of acetone and 170 ml of water. This mixture was heated to reflux for 3 hours. After cooling, most of the acetone was removed in vacuo and the mixture was extracted with ethyl ether three times. The combined ether layer was dried with sodium sulfate and concentrated to afford 3.97 of 6,6-dimethyl-2-hepten-4-yn-1-ol.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[S:5]([O-:9])([O-:8])(=[O:7])=[S:6].[Na+:10].[Na+].C(O)C>O>[CH2:1]([O:8][S:5]([O-:9])(=[O:7])=[S:6])[CH:2]=[CH2:3].[Na+:10]
Reactant: C=CCBr
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCOS(=O)([O-])=S

Procedure:
A mixture of allyl bromide (100 g), sodium thiosulphate (212.5 g), ethanol (90 ml) and water (40 ml) was stirred and heated to reflux for 15 minutes, giving a homogeneous solution. The solution was allowed to cool somewhat, and ethanol and water were then evaporated under vacuum. The solid residue was added to absolute ethanol, and the solvent was then evaporated under vacuum to remove more water. The residue was stirred with hot ethanol (800 ml), and the suspension thus obtained was filtered. On cooling, the filtrate deposited a white solid (109.2 g). The NMR spectrum of the sold showed that it consisted of 80% by weight of sodium allylthiosulphate, 11% by weight of water and 9% by weight of inorganic salt.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([CH3:12])([CH3:11])[C:7](=O)[CH2:8]Br)[CH3:2].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[S:21])=[CH:18][CH:17]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([CH3:12])([C:7]1[N:22]=[C:20]([C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:25])([F:14])[F:26])=[CH:24][CH:23]=2)[S:21][CH:8]=1)[CH3:11])[CH3:2]
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CC(C)(C)C(=O)CBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(C)(C)c1csc(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
500 mg (1.99 mmol) of 5-bromo-3,3-dimethyl-4-oxo-pentanoic acid ethyl ester, 408.6 mg (1.99 mmol) of 4-trifluoromethyl-thiobenzamide and 403 mg (3.98 mmol) of triethylamine in 10 ml of toluene were stirred at 80° C. for 2 h. After evaporation, water and dichloromethane were added, the organic phase was separated, washed with water, dried, and evaporated. The product was purified by chromatography (silica gel, n-heptane/ethyl acetate 8:1). Yield: 498.5 mg.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[N+:17]([O-])=O.CN(C=O)C.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCCCCC>[NH2:17][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:8]=1[Cl:7])[C:12]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:14]
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Nc1cc(C(=O)Nc2ccccc2)ccc1Cl
Yield: 68.9 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (2.5 mL, 28.66 mmol), 4-chloro-3-nitrobenzoic acid (4.02 g, 19.94 mmol), DMF (1.0 mL, 12.92 mmol), and aniline (3.6 mL, 39.51 mmol) to afford the product (3.39 g) after trituration in hexane; m.p. 194-197° C. after recrystallization from ethyl acetate.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:35][CH2:36][N:31]([C:28]3[CH:29]=[CH:30][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:26][CH:27]=3)[CH2:32][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CC(C)c1ccc(N2CCNCC2)cc1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccc(C(C)C)cc3)CC2)c(OC)nc1C
Yield: 68 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-isopropylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: N[C@@H]1CCN(CCCO[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)C1.[NH:25]1[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C[C:40](=[O:43])[CH2:41][CH3:42]>>[OH:30][C@@H:27]1[CH2:28][CH2:29][N:25]([CH2:42][CH2:41][CH2:40][O:43][C:21]2[CH:22]=[C:17]([C:14]3[CH:13]=[CH:12][CH:11]=[CH:16][CH:15]=3)[CH:18]=[CH:19][C:20]=2[C:23]#[N:24])[CH2:26]1
Reactant: O[C@@H]1CCNC1
Reactant: CCC(C)=O
Reactant: N#Cc1ccc(-c2ccc(OCCCN3CC[C@@H](N)C3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: N#Cc1ccc(-c2ccccc2)cc1OCCCN1CC[C@@H](O)C1
Yield: 69 %

Procedure:
4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile (200 mg, 0.74 mmol), (3R)-3-pyrrolidinol (70 mg, 0.81 mmol), potassium carbonate (152 mg) and potassium iodide (183 mg) in 25 mL of 2-butanone were heated at 110° C. for 72 hours. The mixture was evaporated under reduced pressure and the residue was purified by chromatography (CHCl3:MeOH:NH4OH, 9:1:0.1) to provide the title compound (69% yield).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:27](Cl)(=O)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>C(Cl)(Cl)Cl>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][CH2:21][N:20]1[C:19]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]=2[N:8]=[C:44]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH3:27]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)c1ccc(NCCCN(C)C)c(N)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2cc(C(=O)OCC)ccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
Triethylamine (1.05 ml) was added to a solution containing ethyl 3-amino-4-{[3-(dimethylamino)propyl]amino}benzoate (1.83 g) in chloroform (20 ml), and then stearoyl chloride (2.07 g) was added thereto while being cooled with ice. After being stirred for 4 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (5.00 ml) was added to a solution containing the residue (3.95 g) in ethanol (30 ml). After being stirred for 3 hours at 90° C., the reaction mixture was neutralized with 5N sodium hydroxide aqueous solution (12 ml) and concentrated. The residue, with ethyl acetate added thereto, was washed with water and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (3.28 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=20:1-10:1), thereby yielding the entitled compound (2.99 g) as orange solid.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C@@:10]2([C:20]([OH:22])=[O:21])[CH2:15][C@H:14]([OH:16])[CH:13]3[CH:11]2[C@H:12]3[C:17]([OH:19])=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](Cl)(=O)[CH3:24].[CH2:27](O)[CH3:28]>>[C:1]1([C@H:7]([NH:9][C@@:10]2([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][C@H:14]([OH:16])[CH:13]3[CH:11]2[C@H:12]3[C:17]([O:19][CH2:27][CH3:28])=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: CC(=O)Cl
Reactant: C[C@@H](N[C@@]1(C(=O)O)C[C@H](O)C2C1[C@H]2C(=O)O)c1ccccc1
Product: CCOC(=O)[C@H]1C2C1[C@](N[C@H](C)c1ccccc1)(C(=O)OCC)C[C@@H]2O
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a suspension of 2-[((1R)-1-phenylethyl)amino](2S,4S,6R)-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid (4 g, 13 mmol) in 48 mL of ethanol at room temperature is added acetyl chloride (11.2 mL, 157 mmol) via an addition funnel such that a gentle reflux is maintained. The resulting mixture is allowed to stir another 16 hours at reflux and upon cooling to room temperature is concentrated in vacuo to a solid residue. The solid is treated slowly with a solution of sodium bicarbonate (6.6 g) in 100 mL of water followed by washing with ethyl acetate (2×100 mL). The combined organics are dried (MgSO4), filtered, and concentrated in vacuo to give 4.7 g (99%) of the title compound as a solid. Column chromatography on silica gel eluting with CH2Cl2/MeOH (95:5) followed by crystallization from Et2O provides an analytically pure sample of the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([CH3:14])[NH:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C1C=CC(I(OC(C(F)(F)F)=O)OC(C(F)(F)F)=O)=CC=1>FC(F)(F)C(O)C(F)(F)F>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:9]2[C:8]3[C:12](=[CH:13][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[NH:11][C:10]=2[CH3:14])=[CH:18][CH:17]=1
Reactant: Fc1ccc(S)cc1
Reactant: Cc1cc2ccc(S(C)(=O)=O)cc2[nH]1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: Cc1[nH]c2cc(S(C)(=O)=O)ccc2c1Sc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
A solution of 6-methanesulfonyl-2-methyl-1H-indole (207 mg, 1 mmol) in 6 mL of hexafluoroisopropanol was treated with 4-fluorothiophenol (2 mmol) followed by addition of PIFA (1.5 mmol). The dark colored solution was stirred for 30 minutes followed by partitioning between EtOAc and water. Purification by TLC (2:1 hexane/EtOAc) afforded 145 mg of 3-(4-fluoro-phenylsulfanyl)-6-methanesulfonyl-2-methyl-1H-indole, 101, MS: 336 ([M+H]+).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].Br.C(O)(=O)C>C(OC(=O)C)C.CO>[NH2:13][S:12]([C:9]1[CH:10]=[CH:11][C:3]([OH:2])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6])(=[O:14])=[O:15]
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: NS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Reaction time: 8 h

Procedure:
A mixture of 2-methoxy-5-sulfamoylbenzoic acid (58 g, 0.25 mole), 48% hydrobromic acid (150 ml), and acetic acid (150 ml) was heated to reflux for five hours. The progress of reaction was checked by thin layer chromatography (silica gel, 7:2:1 ethylacetate/methanol/29% ammonium hydroxide). Upon cooling, a solid crystallized out which was collected by filtration, and rinsed with cold water. This solid was dissolved in hot water (≤85° C.) and filtered through Celite® and recrystallized from the cool filtrate. Some of the recrystallized material was crystallized once more by dissolving in methanol, filtering, and mixing with excess amount of 1,1,1-trichloroethane. The mixture was evaporated to remove most of the methanol, and the resulting crystallizing mixture was stirred in ice bath. The solid was collected by filtration and rinsed with 1,1,1-trichloroethane, vacuum pumped at room temperature overnight to give a white solid, mp 234°-235° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[Cl:6][CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:10]>C1COCC1>[Cl:6][CH2:7][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)([OH:10])[CH2:3][CH:2]=[CH2:1]
Reactant: C=CC[Mg]Br
Reactant: O=C(CCCl)c1ccc(F)cc1
Solvent: C1CCOC1
Product: C=CCC(O)(CCCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.3 %

Procedure:
A 250-mL flask was charged with anhydrous CeCl3 (5.58 g, 22.6 mmol) and THF (40 mL). The mixture was vigorously stirred for 3.5 h at rt. The suspension was then cooled to −78° C. and a solution of allylmagnesium bromide (1.0 M in THF, 21 mL, 21.0 mmol) was added. After stirring for 2 h at −78° C., a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (2.522 g, 13.5 mmol) in THF (30 mL) was added via cannula. The reaction mixture was allowed to slowly warm to 8° C. while stirring overnight (18 h). The reaction was then quenched with satd aq NaHCO3, extracted with EtOAc, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (3.0049 g, 97%) as an oil. LC-MS Method 1 tR=1.79 min, m/z 213, 211 (M-OH)+; 1H NMR (400 MHz, CDCl3) δ 7.37-7.32 (m, 2H), 7.07-7.02 (m, 2H), 5.57-5.47 (m, 1H), 5.20-5.19 (m, 1H), 5.16 (m, 1H), 3.59-3.52 (m, 1H), 3.24-3.18 (m, 1H), 2.70 (dd, J=13.8, 5.9 Hz, 1H), 2.50 (dd, J=13.8, 8.5 Hz, 1H), 2.29 (t, J=7.9 Hz, 2H), 2.22 (s, 1H); 19F NMR (376 MHz, CDCl3) δ −116.52 (m).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:19]([CH3:20])=NON=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CC[C@H](OC(=O)C(F)(F)F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH2:53][C:54]1C=CC=C[C:55]=1[S:60]([CH3:63])(=[O:62])=[O:61]>>[C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:19]=[CH:20][CH:53]=[CH:54][C:55]=3[S:60]([CH3:63])(=[O:62])=[O:61])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccccc1CBr
Reactant: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Agent: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nn(Cc3ccccc3S(C)(=O)=O)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 1-(bromomethyl)-2-(methylsulfonyl)benzene and isolated as white solid. MS (m/e): 431.3 (MH+).