Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6](CC1C=CC(OC)=CC=1)[C:5]2([CH3:22])[CH3:21].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>CC#N.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2([CH3:22])[CH3:21]
Reactant: COc1ccc(CN2C(=O)c3ccc(F)cc3C2(C)C)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC1(C)NC(=O)c2ccc(F)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
To a stirred solution of 5-fluoro-2-(4-methoxy-benzyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one (3.8 g, 12.7 mmol) in MeCN (80 ml) and H2O (40 mL) was added CAN (20.9 g, 38.1 mmol) at 0° C. After stirring for 2 hours at 0° C., the reaction mixture was diluted with EtOAc and washed with brine. The organic layers were dried over anhy. Na2SO4, filtered and concentrated in vacuo to provide a crude product, which was purified by column chromatography to give tile product (1.03 g, yield 45%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:36])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:35])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[CH:23]=[CH:24]/[CH:25]=[C:26](/[CH:28]=[CH:29]/[CH:30]=[C:31](/[CH:33]=O)\[CH3:32])\[CH3:27])\[CH3:22].[OH-:37].[K+].[OH2:39]>C(O)CC>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:36])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:35])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[CH:23]=[CH:24]/[CH:25]=[C:26](/[CH:28]=[CH:29]/[CH:30]=[C:31](/[CH:33]=[CH:4]/[C:3]([C:2]([OH:39])([CH3:7])[CH3:1])=[O:37])\[CH3:32])\[CH3:27])\[CH3:22]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C=C(\C)C=O)C(C)(C)CCC1
Reactant: O
Reactant: [OH-]
Agent: [K+]
Solvent: CCCO
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C=C(C)/C=C/C(=O)C(C)(C)O)C(C)(C)CCC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 97.8 %

Procedure:
10.12 g of β-apo-4'-carotenal are suspended in 50 ml of n-propanol under argon in a 350 ml sulphonation flask fitted with a stirrer, thermometer, cooler and dosage pump. Then, 9.6 ml of 50% potassium hydroxide solution are added. The red-violet, thin suspension is now heated to 70° C. internal temperature. Then, a solution of 7.72 g of cyclocarbonate in 20 ml of n-propanol is dosed in using the dosage pump within one hour at 70° C. The mixture is stirred at 70° C. for 5 hours under control by thin-layer chromatography and HPLC. Almost all of the β-apo-4'-carotenal has reacted after this time according to HPLC. 70 ml of water are added to the mixture and the red-brown, thin reaction mixture is heated to reflux and stirred at an internal temperature of 89.3° C. Thereafter, the oil bath is removed and the mixture is cooled to 22° C. using a water bath and stirred for 30 minutes. The crystals are subsequently filtered off under suction and washed in succession twice with 50 ml of n-propanol each time and three times with 50 ml of water each time. After filtering off the crystals these are dried for 16 hours at 50° C. under reduced pressure. In this manner there are obtained 11.09 g (97.8% of theory) of 2'-dehydroplectaniaxanthin as brown crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]=O)[CH:4]=[N:3]1.[NH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:38]=[CH:37][C:19]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:38]=[CH:37][C:19]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:21])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:4]=[N:3]1
Reactant: Cc1c(C=O)cnn1C
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1c(CN2CCC(c3ccc(C(=O)Nc4ccccc4NC(=O)OC(C)(C)C)cc3)CC2)cnn1C
Reaction time: 2.5 h
Yield: 83.8 %

Procedure:
1,5-Dimethyl-1H-pyrazole-4-carbaldehyde (114 mg, 0.92 mmol) was added to a solution of tert-butyl 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate (289 mg, 0.73 mmol) in dichloromethane (6 ml) followed by acetic acid (50 μl, 0.87 mmol). The reaction mixture was allowed to stir under nitrogen for 2.5 hours. Sodium triacetoxyborohydride (233 mg, 1.10 mmol) was added and the reaction mixture allowed to stir, at ambient temperature, for 18 hours (overnight). Saturated aqueous sodium bicarbonate solution (10 ml) was then added to the reaction and allowed to stir for 15 minutes. The organic phase was separated and the aqueous phase re-extracted with dichloromethane (10 ml). The combined organics were washed with water, dried over magnesium sulphate and evaporated to dryness to afford the product as a colourless gum (308 mg, 84%), which was used without further purification; Mass Spectrum: M+H+504.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[Cu](C#N)[C:12]#[N:13].N>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:9])[C:7]=1[F:8])[C:12]#[N:13]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: N#C[Cu]C#N
Agent: N
Solvent: CN1CCCC1=O
Product: N#Cc1cc(F)c(F)c(F)c1
Temperature: 150 °C
Reaction time: 4 h
Yield: 67.2 %

Procedure:
To 50 ml of N-methylpyrrolidone were added 10 g of 3,4,5-trifluorobromobenzene and 8.5 g of copper cyanide, and the mixture obtained was stirred at 150° C. for 4 hours. Then, aqueous ammonia was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 5.0 g of 3,4,5-trifluorobenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:20])[C:11]3[N:12]([C:14]([C:17]([OH:19])=O)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.O[NH:22][C:23]([C:25]1[S:26][C:27]([S:30](=[O:33])(=[O:32])[NH2:31])=[CH:28][CH:29]=1)=[NH:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:20])[C:11]3[N:12]([C:14]([C:17]4[O:19][N:24]=[C:23]([C:25]5[S:26][C:27]([S:30]([NH2:31])(=[O:33])=[O:32])=[CH:28][CH:29]=5)[N:22]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cn2c(C(=O)O)cnc12
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(-c3nc(-c4ccc(S(N)(=O)=O)s4)no3)cnc12

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-8-methyl-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.33) (143 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (MeOH/diethyl ether) as an off-white solid (159 mg, 67%). MS (ISN) 470.0 [(M−H)−]; mp 271° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20](F)[C:17]=1[C:18]#[N:19].[C:25]([O:29][CH3:30])(=[O:28])[CH2:26][SH:27].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[NH2:19][C:18]1[C:17]2[C:16]([O:15][CH2:14][CH2:13][CH2:12][N:3]3[C:2](=[O:1])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:4]3=[O:11])=[CH:23][CH:22]=[CH:21][C:20]=2[S:27][C:26]=1[C:25]([O:29][CH3:30])=[O:28]
Reactant: N#Cc1c(F)cccc1OCCCN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1sc2cccc(OCCCN3C(=O)c4ccccc4C3=O)c2c1N

Procedure:
A mixture of EXAMPLE 14A (0.5 g, 1.54 mmol), methyl thioglycolate (217 μL, 2.31 mmol), and sodium carbonate (653 mg, 6.16 mmol), was heated in methanol (7.7 mL) at 70° C. for 21 hours. The mixture was cooled, diluted with water, and the precipitate filtered and dried. The crude product was purified by flash chromatography on silica gel using a gradient of 0-2% methanol in dichloromethane to provide the title compound as an 85% pure mixture with unreacted EXAMPLE 14A. 1H NMR (DMSO-d6) δ 7.79-7.88 (m, 5H), 7.33-7.44 (m, 2H), 6.97 (s, 1H), 6.86 (dd, J=7.8, 1.0 Hz, 1H), 4.23 (t, J=5.8 Hz, 2H), 3.80 (t, J=6.8 Hz, 2H), 3.77 (s, 3H), 2.17 (quin, J=6.1 Hz, 2H).
Reaction SMILES: Cl.[O:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH2:18]([O:20][C:21]([C:23]1[NH:24][C:25]([CH3:33])=[C:26]([S:29](Cl)(=[O:31])=[O:30])[C:27]=1[CH3:28])=[O:22])[CH3:19].O>C(Cl)Cl>[CH2:18]([O:20][C:21]([C:23]1[NH:24][C:25]([CH3:33])=[C:26]([S:29]([N:5]2[CH2:6][CH2:7][CH2:8][O:2][CH2:3][CH2:4]2)(=[O:30])=[O:31])[C:27]=1[CH3:28])=[O:22])[CH3:19]
Reactant: C1CNCCOC1
Reactant: CCOC(=O)c1[nH]c(C)c(S(=O)(=O)Cl)c1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c(C)c(S(=O)(=O)N2CCCOCC2)c1C
Yield: 101 %

Procedure:
To [1,4]oxazepane hydrochloride (400 mg) in DCM (45 mL) was added DIEA (2.70 mL) followed by 4-chlorosulfonyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (1.05 g). The mixture was stirred for 1 h at RT after which water was added and the resulting two phases were separated. The organic phase was washed two times with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated to give crude) 3,5-dimethyl-4-([1,4]oxazepane-4-sulfonyl)-1H-pyrrole-2-carboxylic acid ethyl ester (970 mg) which was used directly in the following step.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[Cl:6][CH2:7][CH2:8][N:9]=[C:10]=[O:11]>C(OCC)C>[CH2:1]([NH:5][C:10]([NH:9][CH2:8][CH2:7][Cl:6])=[O:11])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C=NCCCl
Reactant: CC(C)CN
Solvent: CCOCC
Product: CC(C)CNC(=O)NCCCl
Temperature: -5 °C
Reaction time: 2 h

Procedure:
Isobutylamine (7.3 g, 0.1 mol) was dissolved in 20 ml of diethyl ether and cooled to less than 5° C. Chloroethyl isocyanate (10.5 g, 0.1 mol) dissolved in 15 ml of ether was added maintaining a temperature between 0° and 5° C. with vigorous stirring. Stirring continued an additional 2 hrs. the mixture was cooled to -5° C., and the product (4.1 g, 46%) was filtered and dried in vacuo for 18 hrs. over KOH, MP 79.5° C. (decomposes). IR analysis showed peaks at 1630/cm (C=O) and 1585/cm (N--C=O). NMR: Doublet at 0.9 ppm (J=6.4 Hz), multiplet (1H) at 2.1 ppm, quartet (2H) at 2.9 ppm (J=6.4 Hz), multiplet (4H) at 3.5 ppm.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][CH3:4].[NH2:22][CH2:23][CH:24]([OH:40])[CH2:25][O:26][C:27]1[C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1>>[CH:30]1[C:31]2[NH:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:39]=2[C:27]([O:26][CH2:25][C@@H:24]([OH:40])[CH2:23][NH:22][CH:18]2[CH2:19][CH2:20][N:15]([S:12]([C:9]3[CH:8]=[CH:7][C:6]([C:2]([CH3:1])([CH3:5])[CH2:3][CH3:4])=[CH:11][CH:10]=3)(=[O:14])=[O:13])[CH2:16][CH2:17]2)=[CH:28][CH:29]=1
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)N2CCC(=O)CC2)cc1
Reactant: NCC(O)COc1cccc2[nH]c3ccccc3c12
Product: CCC(C)(C)c1ccc(S(=O)(=O)N2CCC(NC[C@H](O)COc3cccc4[nH]c5ccccc5c34)CC2)cc1

Procedure:
The title compound was prepared from 4-(1,1-dimethyl-propyl)-benzenesulfonyl-piperidin-4-one and 1-amino-3-(9H-carbazol-4-yloxy)-propan-2-ol according to the reductive amination procedure of Intermediate 21 as an off-white solid; 1H′NMR (DMSO) δ 0.55-0.63 )m, 3H), 1.27 (d, J=6.9 Hz, 6H), 1.40-1.46 (m, 2H), 1.58-1.65 (m, 2H), 1.81(m, 2H), 2.38-2.45 (m, 2H), 2.63-2.82 (m, 2H), 3.07-3.13 (m, 2H), 3.51-3.54 (m, 1H), 3.90 (m, 1H), 4.08-4.13 (m, 2H), 4.66 (d, J=3.78 Hz, 1H), 5.07 (bs, 1H), 6.64 (d, J=7.95 Hz, 1H), 7.04-7.11 (m, 2H), 7.20-7.35 (m, 2H), 7.43 (d, J=8.07 Hz, 1H), 7.54-7.67 (m, 4H), 8.15 (d, J=7.71 Hz, 1H), 11.25 (s, 1H); MS (ES) m/z: 550.1 (MH+); HRMS for C31H39N3O4S: 550.2751
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[Cl:8][C:9]1[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19].C(N(CC)CC)C.O>C1COCC1>[OH:4][CH2:3][C:2]([NH:1][S:14]([C:12]1[S:13][C:9]([Cl:8])=[C:10]([N+:18]([O-:20])=[O:19])[CH:11]=1)(=[O:16])=[O:15])([CH2:5][OH:6])[CH3:7]
Reactant: CC(N)(CO)CO
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(CO)(CO)NS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 19.8 %

Procedure:
To a stirred solution of 2-amino-2-methyl-1,3-propanediol (0.44 g, 4.2 mmol) in THF (10 ml) was added at room temperature 5-chloro-4-nitrothiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) and triethylamine (0.58 ml, 4.2 mmol). The light yellow suspension was stirred at room temperature for 17 h, poured into water (100 ml) and extracted with dichloromethane (3×75 ml). The combined organic layers were washed with water (100 ml) and brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate) and subsequent crystallization from ethyl acetate/hexane to yield 5-chloro-4-nitro-thiophene-2-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (0.25 g, 20%) as a light brown solid. Mp 133° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][C:10]#[N:11])([CH3:4])([CH3:3])[CH3:2].[N:13]([Sn](CCCC)(CCCC)CCCC)=[N+:14]=[N-:15].C(Cl)Cl.CC(O)C>C1(C)C=CC=C(C)C=1>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][C:10]1[NH:15][N:14]=[N:13][N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC#N
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1cccc(C)c1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1nnn[nH]1
Temperature: 25 °C

Procedure:
(2-Cyano-ethyl)-carbamic acid tert-butyl ester (59.5 g, 0.35 mol) is dissolved in dry m-xylene 460 ml) and stirred at room temperature. Azidotributyltin (140 g, 0.42 mol) is added and the reaction mixture is heated to 115° C. overnight. On cooling to room temperature, the reaction mixture is quenched with 2M NaOH (500 ml), the layers are separated and the aqueous phase is acidified with 6M HCl to pH 2 resulting in a thick precipitate. DCM (500 ml) is added followed by IPA (50 ml) resulting in clear layers, the organic layer is separated and the aqueous is re-extracted with 9:1 DCM/IPA (2×250 ml). The organic layers are combined, washed with brine (500 ml), dried over MgSO4, filtered and concentrated in vacuo. The resulting solid is triturated with iso-hexanes (250 ml), stirred for 1 hour at room temperature then a further 1 hour at 5-10° C., filtered and dried under vacuum to afford the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[S:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([Cl:13])[N:12]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH2:17]([NH:24][C:8]1[S:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([Cl:13])[N:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1sc(NCc2ccccc2)nc1Cl
Temperature: 25 °C
Yield: 95.7 %

Procedure:
7.0 g (0.051 mol) of anhydrous potassium carbonate are added to a solution of 12.0 g (0.06 mol) of 2,4-dichloro-5-nitrothiazole in 50 ml of acetonitrile. A mixture of 5.35 g (0.05 mol) of benzylamine and 50 ml of acetonitrile is then added dropwise at 15° C. to 20° C. in the course of about half an hour and the mixture is subsequently stirred at room temperature for a further hour. It is then heated at the reflux temperature for 15 minutes, cooled to room temperature and stirred into about 500 ml of ice-water and the precipitate is filtered off, washed with water and dried. To remove excess 2,4-dichloro-5-nitrothiazole, the product is stirred into 80 ml of petroleum ether at room temperature, filtered off, washed with petroleum ether and dried. 12.9 g (95.7% of theory) of 2-benzylamino-4-chloro-5-nitrothiazole of melting point 195° C. to 196° C. (decomposition) are obtained.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[S:16][CH:17]=2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[OH:5][S:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[S:16][CH:17]=2)=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(-c2nc(-c3ccc(O)cc3)cs2)cc1OC
Reactant: O=S(=O)(O)Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(-c3ccc(OS(=O)(=O)O)cc3)cs2)cc1OC
Temperature: 50 °C
Reaction time: 12 h

Procedure:
2 ml of chlorosulfonic acid was dropwise added to 40 ml of pyridine at room temperature. The mixture was stirred at 50° C. for 12 hours. Thereto was added 0.33 g of 4-(4-hydroxyphenyl-2-(3,4-dimethoxyphenyl)thiazole. The mixture was stirred at 50° C. for 6 hours and then at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure. The residue was mixed with water and the resulting crystals were collected by filtration. The resulting 4-(4-hydroxysulfonyloxyphenyl)-2-(3,4-dimethoxyphenyl)thiazole pyridinium salt was suspended in 3 ml of methanol. Thereto was added 5 ml of a 0.1N aqueous potassium hydroxide solution. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was dissolved in water. The solution was treated with 0.5 g of an ion exchange resin (Dowex 50Wx8). The filtrate was concentrated to obtain 0.04 g of 4-(4-hydroxysulfonyloxyphenyl)-2-(3,4-dimethoxyphenyl)thiazole.
Reaction SMILES: C(OC(=O)C([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH:24]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C@H:17]2[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]2)=[O:15])=[N:10][CH:9]=1)C)C.C1(N[C@H]2CC[C@H](C)CC2)CCCCCC1.NC1SC=NC=1.C([O:55][C:56](=[O:60])[CH:57](S)[CH3:58])C>>[CH:24]1([N:16]([C@H:17]2[CH2:18][CH2:19][C@H:20]([CH3:23])[CH2:21][CH2:22]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:58][CH2:57][C:56]([OH:60])=[O:55])=[CH:9][N:10]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)C(C)S
Reactant: CCOC(=O)C(C)Sc1cnc(NC(=O)N(C2CCCCCC2)[C@H]2CC[C@H](C)CC2)s1
Agent: C[C@H]1CC[C@H](NC2CCCCCC2)CC1
Agent: Nc1cncs1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCCCCC2)CC1

Procedure:
{2-[3-Cycloheptyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester prepared as described in general procedure (A) using cycloheptyl-(trans-4-methyl-cyclohexyl)-amine and 5-aminothiazole-2-mercaptopropionic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:9]O)[N:3]=[CH:2]1.S(Cl)([Cl:22])=O>O1CCOCC1>[NH:1]1[CH:5]=[C:4]([CH2:6][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:9][Cl:22])[N:3]=[CH:2]1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CN(CCO)Cc2c[nH]cn2)cc1
Solvent: C1COCCO1
Product: COc1ccc(CN(CCCl)Cc2c[nH]cn2)cc1
Temperature: 60 °C

Procedure:
To a solution of 2-(((1H-imidazol-4-yl)methyl)(4-methoxybenzyl)amino)ethanol (Step B, 14.5 g, 55.55 mmol) in anhydrous dioxane (100 mL) was added thionyl chloride (16.5 mL, 222.2 mmol) over a 10 minute period. The reaction mixture was heated at 60° C. for 3 hours, cooled to room temperature and partitioned under reduced pressure. The contents of the flask were azeotroped with dioxane (2×100 mL) and toluene (2×100 mL). The white solid c that separates out is filtered and used as such for the subsequent step without further purification (19.0 g).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4](C2C=CC(S(C)(=O)=O)=CC=2)[CH2:3]1.Cl[C:19]1[CH:24]=[CH:23][C:22]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:3]1
Reactant: C[C@@H]1CN(c2ccc(S(C)(=O)=O)cc2)CCN1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(F)(F)F
Product: C[C@@H]1CN(c2ccc(S(=O)(=O)C(F)(F)F)cc2)CCN1

Procedure:
The title compound was prepared following the procedure of Intermediate 26, but starting from 1-chloro-4-(trifluoromethanesulfonyl)benzene. Purification by flash chromatography (CHCl3/MeOH) gave the title compound as a pale yellow solid. M+(ESI): 309.2. HPLC (Condition A), Rt: 2.3 min (HPLC purity: 99.5%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12](=[O:14])[CH3:13].[Br-:16].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C(Cl)Cl.CO.C([O-])(O)=O.[Na+].O>[Br:16][CH2:13][C:12]([C:7]1[S:8][C:9]([CH3:11])=[C:10]2[C:6]=1[CH2:5][C@H:4]1[C:2]([CH3:15])([CH3:1])[C@H:3]12)=[O:14]
Reactant: [Br-]
Reactant: CC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1sc(C(=O)CBr)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a solution of (1aS,5aR)-1-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-ethanone (275 mg, 1.25 mmol) in DCM (7 mL) and methanol (3.5 mL) is added phenyltrimethyl-ammoniumbromid-dibromid (570 mg, 1.5 mmol) and the reaction mixture is stirred at rt for 30 min. Another portion of phenyltrimethyl-ammoniumbromid-dibromid (600 mg, 1.6 mmol) is added and stirring is continued for 1 h before the mixture is diluted with sat. aq. NaHCO3 (5 mL) and water (25 mL) and extracted twice with DCM (2×20 mL). The organic extracts are dried over Na2SO4 and evaporated to give crude 2-bromo-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-ethanone (250 mg) as a brownish oil; LC-MS: tR=1.06 min, [M+3]+=300.99.
Reaction SMILES: [OH:1][C:2]1([C:16]2[S:17][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)[N:22]=3)=[CH:19][N:20]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14]C)=[O:13])[CH:5]=[CH:4][C:3]1=2.[OH-:39].[K+].C1C[O:44]CC1>CO.CS(C)=O>[F:36][C:35]([F:38])([F:37])[C:33]([OH:44])=[O:39].[OH:1][C:2]1([C:16]2[S:17][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:32]=[CH:31][N:30]=4)[N:22]=3)=[CH:19][N:20]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]1=2
Reactant: [OH-]
Reactant: COC(=O)c1ccc2c(c1)CCCC2(O)c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Reactant: C1CCOC1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C3(O)CCCc4cc(C(=O)O)ccc43)s2)c1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 45 %

Procedure:
To a solution of (rac)-methyl 5-hydroxy-5-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]-5,6,7,8-tetrahydronaphthalene-2-carboxylate (250 mg, 0.462 mmol) in THF (1.9 mL) was added potassium hydroxide (40% solution in water, 1.3 mL, 9.25 mmol), and the reaction was stirred at rt for three days. The reaction was diluted with methanol (2 mL) and DMSO (2 mL), barrier filtered, and purified via reverse-phase HPLC (C18 column, water-acetonitrile, TFA modifier) to yield (rac)-5-hydroxy-5-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid, trifluoroacetate salt as a light brown solid (133.8 mg, 0.209 mmol, 45% yield). MS ESI calcd for C26H21F3N4O3S [M+H]+ 527, found 527. 1H NMR (500 MHz, DMSO) δ 10.21 (s, 1H), 8.63 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 8.23 (s, 1H), 7.72 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.36 (s, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.21 (d, J=5.1 Hz, 1H), 7.10 (s, 1H), 2.92-2.83 (m, 2H), 2.41-2.33 (m, 1H), 2.31 (s, 3H), 2.16-2.07 (m, 1H), 2.04-1.90 (m, 2H) ppm.