Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1[OH:24].C[Si](C)(C)N[Si](C)(C)C.C[Si](C)(C)Cl>O1CCCC1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C@@H:12]([OH:13])[CH2:11][C@H:10]1[OH:24]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: C1CCOC1
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Temperature: -10 °C

Procedure:
Refer to Chart F, wherein E is --CH=CH--, R2, R4, and R6 are methyl, R7 is (CH3)3Si--, V is --CH=CH--(CH2)3 --, W is 1-pentyl, and ~ is alpha or beta. A solution of PGE2, methyl ester, 15-methyl ether (Example 1, 1.0 g.) in 20 ml. of dry tetrahydrofuran (THF) is stirred with 3 ml. of hexamethyldisilazane and 0.6 ml. of trimethyl chlorosilane for 20 hrs. at about 25° C., with protection from moisture. The mixture is concentrated under reduced pressure, then taken up in 50 ml. of dry benzene and again concentrated. The residue is dissolved in 150 ml. of cold methanol and treated, with stirring, with a cold (-10° C) solution of sodium borohydride (2.8 g.) in 150 ml. of methanol, maintaining the temperature below about 10° C. After 10 minutes of additional stirring, there is added 5 ml. of acetone and sufficient acetic acid to neutralize the mixture. The mixture is concentrated under reduced pressure to about 75 ml. Water (about 75 ml.) is added to hydrolyze the trimethylsilyl group thereafter stirring at about 25° C. for 3 hrs. When the trimethylsilyl group is removed, as shown by TLC, the mixture is concentrated under reduced pressure to remove most of the methanol. The remaining solution is extracted with ethyl acetate, and the combined ethyl acetate extracts are washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is taken up in a minimum amount of dichloromethane and subjected to silica gel chromatography, eluting with 50-100% ethylacetate-Skellysolve B (isomeric hexanes). Those fractions shown to contain the 9α-hydroxy title compound free of starting compound and by-products by TLC are combined to yield the PGF2α -type Formula-VII title compound. Mass spectral peaks at 382, 364, 350, 346, and 332; infrared spectral absorptions at 3410, 1735, 1660, 1435, 1365, 1315, 1240, 1215, 1195, 1170, 1090, and 970 cm.-1 ; NMR peaks at 5.42 (multiplet), 3.9 (multiplet), 3.64, 3.49, 3.21, and 0.9 (triplet) 6.
Reaction SMILES: [CH3:1][C:2]1[C:29]([CH3:30])=[CH:28][C:5]2[NH:6][C:7](=S)[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1.O.[NH2:32][NH2:33].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CCC>[CH3:1][C:2]1[C:29]([CH3:30])=[CH:28][C:5]2[N:6]=[C:7]([NH:32][NH2:33])[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: NN
Reactant: Cc1cc2c(cc1C)NC(=S)CC(c1ccc(-n3c(C)nc4cnccc43)cc1)=N2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCCO
Product: Cc1cc2c(cc1C)N=C(c1ccc(-n3c(C)nc4cnccc43)cc1)CC(NN)=N2
Temperature: 100 °C

Procedure:
A mixture of 2,3-dihydro-7,8-dimethyl-4-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-1H-[1,5]benzodiazepine-2-thione (411 mg, 1.0 mmol), hydrazine hydrate (60 mg, 1.2 mmol) and p-toluenesulphonic acid (10 mg) in n-butanol (5 ml) was heated at 100° C. for 1.5 hours. The solvent was removed under reduced pressure and the crude product was used directly for Examples 29-31.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[NH:10]([C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncc(Br)c(Nc2ccccc2)n1

Procedure:
A solution of 5-bromo-2,4-dichloropyrimidine (6.84 g, 30.0 mmol), aniline (2.79 g, 30.0 mmol) and N,N-diisopropylethylamine (3.87 g, 30.0 mmol) in n-butanol (75 ml) was heated under relux for 4 hours. Volatile material was removed by evaporation and the residue was dissolved in DCM (100 ml). The solution was washed with water (3×100 ml) and saturated brine (100 ml) and dried. Volatile material was removed by evaporation and the residue was purified by column chromatography, eluting with 15% ethyl acetate/isohexane, to give the product as an oil which solidifed on standing (5.12 g, 60%). NMR: 7.1 (t, 1H), 7.4 (t, 2H), 7.55 (d, 2H), 8.4 (s, 1H), 9.2 (br s, 1H); MS (MH+): 284, 286, 288.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Br:24])[NH2:20].[CH:27](=O)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CO>[CH2:27]([NH:20][C:19]1[CH:21]=[CH:22][C:23]([Br:24])=[C:17]([C:16]([F:15])([F:25])[F:26])[CH:18]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCC=O
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCNc1ccc(Br)c(C(F)(F)F)c1
Reaction time: 1 h
Yield: 53 %

Procedure:
Sodium triacetoxyborohydride (4 g) was added to a solution of 3-trifluoromethyl-4-bromoaniline (1.5 g) and decanal (4 mL) in methanol (90 mL). After stirring for 1 h the solution was partitioned between water and petroleum ether. The organic extract was concentrated under reduced pressure and the residue was purified via flash column chromatography using petroleum ether as eluent to give N-Decyl-4-broma-3-trifluoromethylaniline (4) (1.2 g, 53%). 1H NMR (CDCl3) δ 7.44 (d, 1H, ArH); 6.92 (d, 1H, ArH); 6.61 (dd, 1H, ArH); 3.11 (t, 2H, NCH2); 0.80 (t, 3H, CH2CH3). TLC (silica gel): Rf=0.35 (petroleum ether).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2C(=O)C3=CC=CC=C3C2=O)=[CH:6][C:5]=1[F:21])#[N:2]>CO.O.NN>[C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[F:21])#[N:2]
Reactant: N#CCc1ccc(N2C(=O)c3ccccc3C2=O)cc1F
Agent: NN
Solvent: O
Solvent: CO
Product: N#CCc1ccc(N)cc1F
Yield: 76.3 %

Procedure:
To a solution of the compound (164 mg) obtained in Example 250 in methanol (5 ml), hydrazine monohydrate (0.057 ml) was added and heated under reflux for 3 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=6:4) to give 67 mg of the titled compound (yield, 76%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[S:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[NH:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27]([CH3:32])=[CH:26]3)[CH:14]=1>>[CH3:32][C:27]1[NH:28][C:29]2[C:25]([CH:26]=1)=[CH:24][C:23]([NH:22][C:19]1[CH:18]=[CH:17][N:16]=[C:15]3[CH:14]=[C:13]([C:6]4[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=4)[S:21][C:20]=13)=[CH:31][CH:30]=2
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cc1cc2cc(Nc3ccnc4cc(Br)sc34)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5ccc(C=O)cc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 4-formylbenzeneboronic acid and (2-bromo-thieno[3,2-b]pyridin-7-yl)-(2-methyl-1H-indol-5-yl)-amine by a procedure analogous to example 17. RP18-HPLC RT: 5.391 minutes; API MS: 384.29 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([O:24][CH2:25][CH3:26])[C:19]([O:21]CC)=[O:20])=[CH:13][CH:12]=2)[C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2.O.[OH-].[Li+]>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([O:24][CH2:25][CH3:26])[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=2)[C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2
Reactant: CCOC(=O)C(Cc1ccc(NCCCN2CCOc3ccccc32)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCOC(Cc1ccc(NCCCN2CCOc3ccccc32)cc1)C(=O)O
Yield: 67.9 %

Procedure:
Ethyl 3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate (700 mg, 0.98 mmol) obtained in example 1, was hydrolyzed using lithium hydroxide monohydrate (123 mg, 2.9 mmol), in methanol-water at RT till all the starting material was consumed (4 to 5 h). The reaction mixture was diluted with water, acidified with dil. HCl to adjust the pH to ˜4-5 and then extracted with ethyl acetate. The ethyl acetate layer was dried over Na2SO4 and concentrated on rotavapour. The residue was chromatographed using methanol and chloroform to yield the title compound as viscous liquid (256 mg, yield 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si](C)(C)C)=[CH:4][C:3]=1[O:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: COc1cc(C#C[Si](C)(C)C)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#Cc1ccc(Cl)c(OC)c1
Yield: 93.2 %

Procedure:
Using the procedure of Step C of Preparation 14, 8 g of the product of Step A and 0.46 g of potassium carbonate were reacted to obtain 5.2 g of the expected product.
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[N+:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1O)([O-:31])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@@H:2]([O:1][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N+:29]([O-:31])=[O:30])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3ccccc3[N+](=O)[O-])c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.5 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-nitrophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (2.37 mg, 34.5% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.84 (d, 1H), 7.90 (m, 1H) 7.45 (m 1H), 7.30–7.20 (m, 5H), 7.20 (m, 2H), 6.98 (m, 2H), 6.89 (apparent d, 1H, J=7.7 Hz), 5.62 (apparent dd, 1H, J=4.1, 8.9 Hz), 3.10 (m, 2H), 2.60 (m, 2H), 2.53 (m, 2H), 2.30–2.10 (m, 6H), 1:90 (m, 2H), 1.25 (d, 6H, overlapped); ESMS m/e: 502.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:10].[CH:11](O)=O.Cl.[OH-].[NH4+]>O>[CH3:9][C:6]1[C:7]2[NH:8][CH:11]=[N:1][C:2]=2[C:3]([CH3:10])=[CH:4][CH:5]=1
Reactant: O=CO
Reactant: Cc1ccc(C)c(N)c1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C)c2[nH]cnc12
Temperature: 25 °C

Procedure:
A mixture of 2,3-diamino-p-xylene (5.1 g), formic acid (88%, 200 mL) and 12N HCl (20 mL) is heated to reflux for 3 hours. The resulting mixture is cooled to room temperature and rotary evaporated. The residue is diluted with water (100 mL), then basified with ammonium hydroxide (28-30%). The suspension is extracted with ethyl acetate (3×100 mL). The combined extracts are dried over MgSO4 and rotary evaporated to afford 4,7-dimethylbenzimidazole as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[Mg].C([C@@H]1CC[C@@H](C)C[C@H]1O[C:22](=[O:36])[C:23]([O:25][C@@H:26]1[CH2:31][C@H:30]([CH3:32])[CH2:29][CH2:28][C@H:27]1[CH:33]([CH3:35])[CH3:34])=[O:24])(C)C.[NH4+].[Cl-]>C1COCC1.CCCCCCC.CCOCC>[O:36]=[C:22]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1)[C:23]([O:25][C@@H:26]1[CH2:31][C@H:30]([CH3:32])[CH2:29][CH2:28][C@H:27]1[CH:33]([CH3:34])[CH3:35])=[O:24]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Reactant: C=Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=Cc1ccc(C(=O)C(=O)O[C@@H]2C[C@H](C)CC[C@H]2C(C)C)cc1
Temperature: 25 °C
Yield: 47.1 %

Procedure:
A Grignard reagent prepared from 4-bromostyrene (2.75 g, 15.0 mmol) and magnesium (0.39 g, 16.0 mmol) in THF (20 mL) was added dropwise (during a period of 20 min) to a stirred solution of bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxalate (5.00 g, 13.7 mmol) in THF (15 mL) at −60° C. The mixture was left warming to room temperature and poured into a mixture of ice (200 g) and a saturated solution of NH4Cl (10 mL). Extraction with diethyl ether (2×), washing with water (3×), drying (Na2SO4) and concentrating afforded 6.42 g of the crude compound as an oil. Repetitive column chromatography (SiO2, heptane/ether 7:3 and heptane/ether 95:5) gave 2.03 g (47%) of an oil.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:19])[C@:15]([NH2:18])([O:16][CH3:17])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:20]([S:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1)[CH2:21][CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[O:7])(C)(C)C.C(N(CC)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)C>C(Cl)Cl>[C:15]([NH:18][C@:15]1([O:16][CH3:17])[C:14](=[O:19])[N:13]2[C:8]([C:6]([OH:5])=[O:7])=[C:9]([CH:20]([S:28][C:29]3[NH:30][N:31]=[N:32][N:33]=3)[CH2:21][CH2:22][NH:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH2:10][S:11][C@H:12]12)(=[O:16])[C@@H:14]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[OH:19]
Reactant: CO[C@@]1(N)C(=O)N2C(C(=O)OC(C)(C)C)=C(C(CCNS(C)(=O)=O)Sc3nnn[nH]3)CS[C@@H]21
Reactant: CCN(CC)c1ccccc1
Solvent: ClCCl
Product: CO[C@@]1(NC(=O)[C@H](O)c2ccccc2)C(=O)N2C(C(=O)O)=C(C(CCNS(C)(=O)=O)Sc3nnn[nH]3)CS[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.04 g (2 mmol) of 7β-amino-7α-methoxy-3-[1-(2-methanesulfonamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 0.30 g (2 mmol) of N,N-diethylaniline in 100 ml of dry methylene chloride is stirred at 0°-5° while 0.56 g (2 mmol) of D-O-dichloroacetylmandeloyl chloride in 10 ml of methylene chloride is added dropwise over 10 minutes. The mixture is stirred in the cold for 30 minutes when warmed to room temperature and stirred for an additional 30 minutes. The solution is washed with 50 ml of cold dilute hydrochloric acid and 50 ml of cold 5% aqueous sodium bicarbonate, dried and evaporated to dryness. The residue is dissolved in a mixture of 10 ml of trifluoroacetic acid and 2 ml of m-dimethoxybenzene and stirred at ambient temperature for 2 hours. The excess trifluoroacetic acid is evaporated under vacuum and the residue is partitioned between 50 ml of ether and 50 ml of water and adjusted to pH 9.3-9.5 with 5% aqueous sodium carbonate. The organic phase is separated and discarded. The aqueous phase is stirred at pH 9.3-9.5 for 30 minutes, extracted with 50 ml of ethyl acetate which is discarded, layered with fresh ethyl acetate and adjusted to pH 1.5 with dilute hydrochloric acid. The aqueous layer is extracted with three 50 ml portions of ethyl acetate and the combined extracts are dried and evaporated to a small volume. Petroleum ether is added dropwise to precipitate the title compound which is collected by filtration and dried.
Reaction SMILES: [F:1][S:2]([C:5]1[S:6][C:7](Cl)=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)(=[O:4])=[O:3].C1N2CN3CN(C2)C[N:15]1C3.S(=O)(=O)(O)O>CO>[F:1][S:2]([C:5]1([NH2:15])[CH2:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][S:6]1)(=[O:4])=[O:3]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)F)sc1Cl
Agent: O=S(=O)(O)O
Solvent: CO
Product: NC1(S(=O)(=O)F)CC([N+](=O)[O-])=CS1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The 2-fluorosulphonyl-4-nitro-5-chlorothiophene (20.4 parts), was added to methanol (240 parts) with hexamine (22.5 parts). Heated to reflux and stirred under these conditions for 4 hours. Cooled to room temperature and poured onto 10% sulphuric acid solution (250 parts). The product was extracted out with ethyl acetate, separated and dried over magnessium sulphate, then screened and concentrated to yield the product 2-fluorosulphonyl-4-nitro-2-aminothiophene (16 parts).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]([NH:9][C@@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12])=O)[S:5][CH:6]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:3]=[C:4]([C:7](=[S:25])[NH:9][C@@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12])[S:5][CH:6]=1
Reactant: C[C@H](NC(=O)c1nc(Br)cs1)C(F)(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: C[C@H](NC(=S)c1nc(Br)cs1)C(F)(F)F
Yield: 87.4 %

Procedure:
To a solution of (S)-4-bromo-N-(1,1,1-trifluoropropan-2-yl)thiazole-2-carboxamide (50 g, 1.0 eq.) in toluene (1000 ml) was added Lawesson's Reagent (100 g, 1.5 eq.). It was refluxed overnight. TLC and LCMS showed the reaction was complete. It was concentrated and the residue was purified by column to obtain 46 g (88% y) of (S)-4-bromo-N-(1,1,1-trifluoropropan-2-yl)thiazole-2-carbothioamide.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[CH:16][N:17]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=1.[F:33][C:34]1[C:39]([S:40]Cl)=[C:38]([F:42])[C:37]([F:43])=[C:36]([F:44])[C:35]=1[F:45]>CCCCCC.C1(C)C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]=[C:16]([S:40][C:39]3[C:38]([F:42])=[C:37]([F:43])[C:36]([F:44])=[C:35]([F:45])[C:34]=3[F:33])[N:17]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2ncn(C3CCCCO3)c2-c2ccc(OC)cc2)cc1
Reactant: Fc1c(F)c(F)c(SCl)c(F)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc(Sc3c(F)c(F)c(F)c(F)c3F)n(C3CCCCO3)c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under agitation and using argon as the protective gas, 15 ml of about 1.6N n-butyllithium in hexane, diluted with 30 ml of toluene, is added dropwise at -5° to 0° to a solution of 8.83 g of 4,5-bis(4-methoxyphenyl)-1-(tetrahydropyran-2-yl)imidazole in a mixture of 75 ml of absolute tetrahydrofuran and 75 ml of toluene. After 20 minutes, the pentafluorophenylsulfenyl chloride solution is added dropwise to the reaction mixture, maintaining the temperature between -5° and 0° by cooling. After 2 hours' stirring at room temperature, the solution is diluted with 200 ml of ethyl acetate, washed with sodium bicarbonate solution; the organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is purified by chromatography on aluminum oxide, neutral, activity stage II, with hexane/ethyl acetate. Recrystallization from ethyl acetate/hexane yields 8.86 g of 4,5-bis(4-methoxyphenyl)-1-(tetrahydropyran-2-yl)-2-(pentafluorophenylthio)imidazole, mp 156°-158°.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:7][CH2:6]1)=[O:4].C1C[O:25][CH2:24]C1>>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][N:12]2[C:13](=[O:21])[C:14]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:20][C:24]2=[O:25])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](CNC(=O)c2ccccc2N)CC1
Reactant: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](Cn2c(=O)[nH]c3ccccc3c2=O)CC1
Temperature: 25 °C

Procedure:
To a solution of 1,1-carbonyldiimidazole (17 g, 103.5 mmol) in THF (200 mL), trans-4-[(2-Amino-benzoylamino)-methyl]-cyclohexanecarboxylic acid methyl ester (15 g, 51.72 mmol) was added and the reaction was heated to reflux temperature for 16 hours. The mixture was allowed to cool down to room temperature and the solvent was removed under reduced pressure. The residue was washed with 100 mL of H2O and the precipitate was filtered. The tiled compound (15.9 g, yield 97%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:13])[CH3:12])=[O:4].[N:20]([CH:23]1[CH2:28][CH:27]([CH3:29])[CH2:26][CH2:25][CH:24]1[C:30](Cl)=[O:31])=[N+:21]=[N-:22].CC1CCC(C(Cl)=O)=CC1.C([O-])(O)=O.[Na+]>ClCCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:9]=1[N:10]([C:30]([CH:24]1[CH2:25][CH2:26][CH:27]([CH3:29])[CH2:28][CH:23]1[N:20]=[N+:21]=[N-:22])=[O:31])[CH:11]([CH3:13])[CH3:12])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)C
Reactant: CC1CCC(C(=O)Cl)C(N=[N+]=[N-])C1
Agent: CC1CC=C(C(=O)Cl)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1N=[N+]=[N-])C(C)C
Temperature: 90 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
To a solution of 3-Isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (227 mg, 0.824 mmol) in 1,2-dichloroethane (2.5 ml) was added the 2:1 mixture of 2-Azido-4-methyl-cyclohexanecarboxylic acid chloride and 4-Methyl-cyclohex-1-enecarboxylic acid chloride (182 mg, 0.906 mmol) dissolved in 1,2-dichloroethane (0.5 ml). The resulting solution was stirred for 18 h at 90° C. and then cooled to room temperature. It was then diluted with ethyl acetate (10 ml) and a solution of saturated NaHCO3 (10 ml). The aqueous phase was separated and washed with ethyl acetate (2×10 ml) and the combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0% to 20% EtOAc/Hexane) to obtain 178 mg (49%) of 3-[(2-Azido-4-methyl-cyclohexanecarbonyl)-isopropyl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([O:12][C:13]2[C:14]([F:38])=[C:15]([CH2:20][NH:21][C:22]([C:24]3[N:28](COCC[Si](C)(C)C)[CH:27]=[N:26][C:25]=3[Cl:37])=[O:23])[CH:16]=[CH:17][C:18]=2[Cl:19])[CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([C:5]1[CH:6]=[C:7]([O:12][C:13]2[C:14]([F:38])=[C:15]([CH2:20][NH:21][C:22]([C:24]3[NH:28][CH:27]=[N:26][C:25]=3[Cl:37])=[O:23])[CH:16]=[CH:17][C:18]=2[Cl:19])[CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCCCc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To a solution of N-({3-[(3-butyl-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (148 mg, 0.246 mmol) in DCM (5 ml) was added TFA (3.0 ml) and the reaction mixture was stirred at rt for 2 hours. The reaction mixture was neutralized with saturated sodium bicarbonate, diluted with EtOAc, and the organic layer was separated. The solvent was evaporated and the crude material was purified via silica gel chromatography to give N-({3-[(3-butyl-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (94 mg, 0.200 mmol, 81% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.69 (s, 1H), 7.24-7.37 (m, 2H), 6.90 (s, 1H), 6.56-6.66 (m, 2H), 4.62 (s, 2H), 2.53 (t, 2H), 1.51 (qd, 2H), 1.20-1.35 (m, 2H), 0.88 (t, 3H). LC-MS (ES+) m/z 469.93, [M+H].