Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:38])[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].NC(CO)[CH2:41][OH:42]>>[Cl:36][C:8]1[CH:9]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])[C:11]([Cl:13])=[CH:12][C:7]=1[C:6]([NH:5][CH:4]([CH2:3][OH:38])[CH2:41][OH:42])=[O:37]
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: NC(CO)CO
Product: O=C(NC(CO)CO)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Yield: 72 %

Procedure:
The title compound was prepared in analogy to Example 1, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 2-amino-propane-1,3-diol (commercially available, CAS RN 534-03-2). The product was purified on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give the desired compound as a light brown foam (72%). MS (ESI): m/z=559.2 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:26]([O:62][CH3:63])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:60][CH3:61])[C@@H:36]([CH3:59])[C:37](=[O:58])[NH:38][C@H:39]([C:47]1[O:48][C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[N:50][N:51]=1)[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:69][CH2:70][CH2:71][C:72]([OH:74])=[O:73].C([BH3-])#N.[Na+].O1CCOCC1>O1CCOCC1.O>[C:72]([CH2:71][CH2:70][CH2:69][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:26]([O:62][CH3:63])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:60][CH3:61])[C@@H:36]([CH3:59])[C:37](=[O:58])[NH:38][C@H:39]([C:47]1[O:48][C:49]([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)=[N:50][N:51]=1)[CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:12])[CH3:13])([OH:74])=[O:73]
Reactant: O=CCCC(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
22.4 mg (24 μmol) N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]-amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetic acid salt (intermediate 21) was dissolved in 1.4 mL dioxane/water (1:1) and reacted with a 15% aqueous solution of 4-oxobutanoic acid in the presence of sodium cyanoborohydride by analogy with the synthesis according to Example 1. After lyophilization from dioxane, 8.2 mg (38% of the theoretical) of the title compound was obtained in the form of a white solid.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=1.[Br:16][C:17]1[CH:22]=[C:21]([C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]S(C(C)(C)C)=O)[CH:20]=[CH:19][N:18]=1.Cl>C1COCC1.CO>[Br:16][C:17]1[CH:22]=[C:21]([C:23]2([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([CH:13]4[CH2:15][CH2:14]4)[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:19][N:18]=1
Reactant: Brc1ccnc(C2CC2)c1
Reactant: CC(C)(C)S(=O)N=C(c1ccnc(Br)c1)c1cccc(F)c1C#N
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: NC1=NC(c2ccnc(Br)c2)(c2ccnc(C3CC3)c2)c2cccc(F)c21
Temperature: -100 °C
Reaction time: 0.33 h
Yield: 45.3 %

Procedure:
Under an atmosphere of argon, tert-butyllithium (1.7 M in pentane) (0.576 mL, 0.98 mmol) was added dropwise to anhydrous tetrahydrofuran (4.00 mL) at −100° C. 4-Bromo-2-cyclopropylpyridine (0.097 g, 0.49 mmol) in anhydrous THF (2.00 mL) was added dropwise to the mixture. The solution was stirred for 2 minutes before dropwise addition of a solution of N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (0.200 g, 0.49 mmol) in anhydrous THF (2.00 mL). The reaction was stirred at −100° C. for 20 minutes, then the temperature was raised to −78° C. over a period of 10 minutes. The reaction was stirred at −78° C. for another 60 minutes. MeOH (2.0 mL) was added dropwise at −78° C. followed by hydrogen chloride (1.25 M in methanol) (1.176 mL, 1.47 mmol). The cooling bath was removed and the reaction was left to stir at ambient temperature for 60 minutes. The solvents were evaporated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (×2), the organics were combined, dried (Na2SO4), filtered and evaporated. Purification by silica chromatography using 0 to 5% (3.5 M ammonia in methanol) in dichloromethane gave the title compound (0.094 g, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][NH:11][C:12]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][CH:3]=1.C1C(=O)N(Cl)C(=O)C1.C(O)(C(F)(F)F)=O>ClC1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCCSc1ccc(Cl)cc1)C1CCOCC1
Agent: O=C1CCC(=O)N1Cl
Solvent: Clc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(Sc2cnc(C3CCOCC3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution of N-{2-[(4-chlorophenyl)sulfanyl]ethyl}tetrahydro-2H-pyran-4-carboxamide (9.48 g, 31.6 mmol) in chlorobenzene (316 ml) was added NCS (8.44 g, 63.2 mmol) by portions and the reaction mixture was stirred at RT for 1 h. TFA (1.218 ml, 15.81 mmol) was added and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with DCM, washed with aq NaHCO3, dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (silica 2×330 g, 0 to 50% EtOAc in hexane), to give 5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2 H-pyran-4-yl)-1,3-oxazole (7.45 g) as a white solid. MS: M+H=296. H′NMR (400 MHz, CDCl3) δ: 7.27 (d, J=10.3 Hz, 2 H), 7.26 (s, 1 H), 7.17 (d, J=10.3 Hz, 2 H), 4.01 (dt, J=33, 12.2 Hz, 2 H), 3.51 (td, J=3.7, 12.2 Hz, 2 H), 3.10-3.00 (m, 1 H), 2.04-1.85 (m, 4 H).
Reaction SMILES: [OH-:1].[Na+].[C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[CH:19]1[CH:24]=CC=C[CH:20]=1>>[CH2:20]([O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH3:4])[CH:19]1[O:1][CH2:24]1
Reactant: [OH-]
Reactant: c1ccccc1
Reactant: CC(C)(c1ccccc1)c1ccccc1O
Agent: [Na+]
Product: CC(C)(c1ccccc1)c1ccccc1OCC1CO1

Procedure:
The cumylphenyl glycidyl ether was prepared as follows: a 3-liter flask equipped with a mechanical stirrer, thermometer, addition funnel, and external heating and cooling devices was charged sequentially with 1 liter of benzene, 1 liter of 4.5 wt. % aqueous sodium hydroxide and 1 mole of cumylphenol. The cumylphenol salt dispersion formed after mixing was cooled to 10°-15° C., mixed and maintained at 10°-15° C. during the addition of 1.1 moles of epichlorohydrin over a four hour period. After the addition of the chlorohydrin, the reaction mix was warmed to 50° C. for 8 hours. The two phases which formed were separated and the water phase discarded. The organic phase was thrice washed with cold water and the residual organic material fractionated. One hundred ninety grams (71 mole %) of a pale yellow oil having a boiling point at 5 mm Hg of 258°-263° C. was obtained. The oil had an Epoxide Number determined by MgCl2 -HCl titration of 3.72 meq/g, while the theoretical Epoxide Number for cumylphenol glycidyl ether is 3.73 meq/g.
Reaction SMILES: CN(C=O)C.[C:6](Cl)(=[O:10])[C:7](Cl)=O.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[C:21]#[N:22])C=[CH:13]1>ClCCl>[CH:6]([C:7]1[C:15]2[C:20](=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][CH:16]=2)[NH:12][CH:13]=1)=[O:10]
Reactant: N#Cc1cccc2cc[nH]c12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cccc2c(C=O)c[nH]c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
DMF (0.539 mL) in dry dichloromethane (30 mL) was added dropwise to a solution of oxalyl chloride (0.610 mL) in dry dichloromethane (30 mL) at 0° C. The resulting solution was stirred at 0° C. for 15 min. A solution of 1H-indole-7-carbonitrile (D2) (0.90 g) in dry dichloromethane (5 mL) was added to the reaction mixture. The reaction mixture was warmed to RT and stirred for 30 min. The solvent was evaporated. THF (20 mL) was added, followed by addition of aqueous NaOH (0.5 M, 50 mL). The biphasic mixture was allowed to stand for 10 min. EtOAc (100 mL) and water (70 mL) was added. The organic fraction was separated and was dried over anhydrous magnesium sulfate. The dried solution was concentrated to afford 3-formyl-1H-indole-7-carbonitrile (D3) as a light cream solid (0.75 g, 70%). δH (DMSO-d6, 400 MHz): 7.42 (1H, t), 7.79 (1H, dd), 8.43 (1H, dd), 8.48 (1H, s), 10.00 (1H, s), 13.02 (1H, br s). MS (ES): C10H6N2O requires 170; found 171.2 (M+H+).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([C:12]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][NH:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11]>O.C1COCC1.[Rh]>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH:16]1([C:12]2([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][NH:14][CH2:15]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCCCCC1(c2ccccc2)CNC1
Agent: [Rh]
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC1(C2CCCCC2)CNC1
Temperature: 80 °C
Reaction time: 23 h
Yield: 54.8 %

Procedure:
254 mg of rhodium-on-alumina at 5% are added to 652 mg (2.62 mmol) of 3-pentyl-3-phenylazetidine oxalate (cf.) in 13 ml of water and 6.5 ml of THF. The medium is placed under a hydrogen atmosphere at 6 bar of pressure and heated at 80° C. After 23 hours, the reaction medium is filtered through celite and the solvents are evaporated off. 0.43 g of 3-cyclohexyl-3-pentylazetidine oxalate is obtained with a yield of 64%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1ccc(Cl)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(CCCBr)cc1Cl
Reaction time: 2 h
Yield: 92.8 %

Procedure:
Compound 38-2 (2.82 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (4.02 g) and N-bromosuccinimide (2.71 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.42 g) as a colorless oil.
Reaction SMILES: C(O)(=O)C[C:3](CC(O)=O)([C:5]([OH:7])=[O:6])[OH:4].[C:14]([OH:22])(=O)[CH:15]([CH2:17][C:18]([OH:20])=O)[OH:16]>>[O:6]=[C:5]1[O:7][C@H:17]([C@H:15]([CH2:14][OH:22])[OH:16])[C:18]([OH:20])=[C:3]1[OH:4]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
The mixture as defined in claim 1 including citric acid, malic acid, an ascorbic acid and other organic acids inherent in fruits to give a titratable acid level of 0.15 to 0.8 percent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])[C:10]2[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=2)=[CH:4][CH:3]=1.[NH2:29][CH2:30][CH2:31][OH:32].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])[C:10]2[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:29][CH2:30][CH2:31][OH:32])=[O:17])=[N:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)O)ncc1C(Sc1ccc(F)cc1)c1c(F)ccc(F)c1F
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc(C(=O)NCCO)ncc1C(Sc1ccc(F)cc1)c1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
To a solution of 5-[[(4-fluorophenyl)thio](2,3,6-trifluorophenyl)methyl]-4-m ethylpyridine-2-carboxylic acid (163 mg, 0.40 mmol) obtained in Example 34 in methylene chloride (5 ml), 2-aminoethanol (0.027 ml, 0.44 mmol), 1-hydroxybenzotriazole (60 mg, 0.44 mmol), 4-methylmorpholine (0.048 ml, 0.44 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (84 mg, 0.44 mmol) were added at room temperature. After stirring for 3 hours at room temperature, the reaction mixture was washed with water and then with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=2:3 was concentrated under reduced pressure to obtain the title compound (175 mg, 0.39 mmol, 97%) as a colorless oily substance.
Reaction SMILES: [Br:1][CH2:2][CH:3]1[O:12][CH2:11][CH:10]2[CH:6]([O:7][C:8]([CH3:14])([CH3:13])[O:9]2)[CH2:5][O:4]1.Br[CH2:16]C1OCC(O)C(O)CO1.C(C(C)=O)C>>[Br:1][CH2:2][CH:3]1[O:12][CH2:11][CH:10]2[CH:6]([O:7][C:8]([CH2:14][CH3:16])([CH3:13])[O:9]2)[CH2:5][O:4]1
Reactant: OC1COC(CBr)OCC1O
Reactant: CC1(C)OC2COC(CBr)OCC2O1
Solvent: CCC(C)=O
Product: CCC1(C)OC2COC(CBr)OCC2O1
Yield: 82 %

Procedure:
4-Bromomethyl-9-ethyl-9-methyl-3,5,8, 10-tetraoxabicyclo[5.3.0]decane was prepared in a similar way to 4-bromomethyl-9,9-dimethyl-3,5,8, 10-tetraoxabicyclo [5.3.0]decane starting from 198.2 mmole (45 g ) of 2-bromomethyl-5,6-dihydroxy-1,3-dioxepane and 1.225 mol (88.3 g) of ethylmethylketone, fractional distillation giving 46 g (82% yield) from 95° to 100° C. (0.25 mbar).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])=[CH:4][C:3]=1[F:9]
Reactant: CCCCCCCCCCCCCBr
Reactant: Oc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCOc1ccc(Br)c(F)c1

Procedure:
This was prepared using a similar method to that described for compound 3. Quantities: compound 1 (4.02 g, 21.1 mmol), 1-bromotridecane (6.11 g, 23.2 mmol), potassium carbonate (5.22 g, 37.8 mmol) and butanone (115 ml).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:13][CH:12]1[C:22](=O)[NH:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=1)=O)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])(=O)C.[NH4+:40]>>[CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:19])[F:20])[CH2:13][CH:12]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=2)[N:40]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)NC(C(=O)N1CCN(CC(F)(F)F)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CCN(CC(F)(F)F)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 1.83 h
Yield: 53.2 %

Procedure:
{1-[2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-(2,2,2-trifluoro-ethyl)-piperazine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (192 mg, 0.34 mmol) was dissolved in m-Xylenes (2 mL) and heated at 135° C. Solid ammonium acetate (128 mg, 1.66 mmol) was added and the reaction was stirred at 135° C. After 110 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc w MeOH 10%/hexanes) to yield the product {1-[2-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2,2,2-trifluoro-ethyl)-piperazine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (98.7 mg, 0.181 mmol): LCMS-ESI+: calc'd for C22H27BrF3N5O3: 546.4 (M+). Found: 546.0/548.2 (M+H+).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][CH2:11]Cl)=[CH:5][CH:4]=1.[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=2[N:23]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:11][CH:10]=[CH:9][C:6]3[CH:7]=[N:8][C:3]([CH3:2])=[CH:4][CH:5]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1
Reactant: Cc1ccc(C=CCCl)cn1
Reactant: Nc1nc2c(s1)CCNCC2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cc1ccc(C=CCN2CCc3nc(N)sc3CC2)cn1
Yield: 30 %

Procedure:
Prepared from 3-(6-methyl-3-pyridyl)allyl chloride hydrochloride and 3 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 30% of theory, Melting point: 180°-184° C. (ether).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH:7]1[S:11][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:21]([CH3:30])[S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])=[N:9][CH2:8]1.Cl[CH2:32][C:33](Cl)=[O:34].[OH-].[Na+].Cl>C(O)C.O>[CH3:30][N:21]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][C:12]([C:10]1[S:11][CH:7]([CH2:6][CH2:5][N:4]3[CH2:3][CH2:2][O:1][CH2:32][C:33]3=[O:34])[CH2:8][N:9]=1)=[CH:20]2)[S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23]
Reactant: O=C(Cl)CCl
Reactant: CN(c1cccc2cc(C3=NCC(CCNCCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(c1cccc2cc(C3=NCC(CCN4CCOCC4=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 3 h
Yield: 41 %

Procedure:
To a solution of N-[2-(5-{2-[(2-hydroxyethyl)amino]ethyl}-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (220 mg) in ethanol (2 mL) and water (1 mL) were added chloroacetyl chloride (95 μL) and 8M aqueous sodium hydroxide solution (310 μL), and the mixture was stirred at the inside temperature of 20° C. or less for 3 hr. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (100 mg, yield 41%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-methanol (10:1, volume ratio).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][N:17]1[C:18](=[O:27])[C:19]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]2[C:21]1=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCO)OCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCCCON1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To a solution of 3-(benzyloxycarbonylamino)-1-propanol (4.0 g, 19 mmol), as prepared in the preceding step, N-hydroxyphthalimide (3.26 g, 20 mmol) and triphenylphosphine (5.25 g, 20 mmol) in tetrahydrofuran (80 mL) was added diethyl azodicaroxylate (3.5 g, 20 mmol). The reaction mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added, the solution washed with saturated NaHCO3 (2×100 mL) and brine (100 mL), and dried over Na2SO4. After evaporating the solvent, the residue was purified by flash column chromatography (methylene chloride to 4% ethyl acetate in methylene chloride) to give the title compound as a white solid (6.85 g, 100%). 1H-NMR (300 MHz, CDCl3) δ7.83 (m, 2H), 7.77 (m, 2H), 7.36 (m, 5H), 5.67 (br s, 1H), 5.12 (s, 2H), 4.28 (t, J=5.8 Hz, 2H), 3.51 (q, J=6.1 Hz, 2H), 1.99 (pentet, J=6.0 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:15]2[NH:19][CH:18]=[N:17][N:16]=2)=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1.O1CCCC1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C([O-])(O)=O.[Na+]>[Br:1][C:2]1[S:3][C:4]([C:15]2[N:19]=[CH:18][N:17]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)[N:16]=2)=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1
Reactant: C1=COCCC1
Reactant: Clc1ccc(Cc2nc(Br)sc2-c2nnc[nH]2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(Cc2nc(Br)sc2-c2ncn(C3CCCCO3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
In a 250 mL round bottomed flask were placed 3-[2-bromo-4-(4-chlorobenzyl)-1,3-thiazol-5-yl]-4H-1,2,4-triazole (0.7 g, 2 mmol) and tetrahydrofuran (50 mL, 600 mmol). To the mixture were added dihydropyran (2 mL, 20 mmol) and p-toluenesulfonic acid monohydrate (911.3 mg, 4.791 mmol). The mixture was refluxed for 2 h then was allowed to cool to rt and then a saturated aqueous solution of NaHCO3 (50 mL) was added. The resulting biphasic mixture was vigorously stirred for 30 min at rt. The aqueous phase was separated then was extracted with EtOAc (50 mL×2). The combined organic phases were dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica, elution with a 10%-80% mixture of EtOAc in hexane (linear gradient, 30 min) to afford 3-[2-bromo-4-(4-chlorobenzyl)-1,3-thiazol-5-yl]-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (778 mg; 67% six steps) as a yellow syrup which spontaneously solidified on standing at rt for 2 days. LC/MS (FA) ES+ 441. 1H NMR (d6-DMSO, 400 MHz): δ: 8.89 (1H, s), 7.28-7.34 (4H, m), 5.62 (1H, dd, J=2.8 and 9.6 Hz), 4.52 (2H, s), 3.92-3.96 (1H, m), 3.63-3.70 (1H, m), 1.91-2.14 (3H, m), 1.52-1.72 (3H, m)