Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC1C2C(=CC=C(C)C=2)N(CC)C1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([N:27]1[C:35]2[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=2)[C:29](=[O:37])[C:28]1=[O:38])[CH2:24][CH2:25][CH3:26]>>[C:1]([O:37][CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)[N:27]([CH2:23][CH2:24][CH2:25][CH3:26])[C:28]1=[O:38])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN1C(=O)C(=O)c2cc(Cl)ccc21
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Product: CCCCN1C(=O)C(OC(=O)c2ccccc2)c2cc(Cl)ccc21

Procedure:
Was made in an analogous fashion to 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate using 1-butyl-5-chloroindoline-2,3-dione. 1H NMR δ 8.11 (t, 2H), 7.60 (t, 1H), 7.44 (m, 3H), 7.33 (d, 1H), 6.82 (d, 1H), 6.10 (s, 1H), 3.73 (m, 2H), 1.72 (m, 2H), 1.44 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[C:10]3[S:15][C:16]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:17]([CH:18]=C)[C:9]2=3)=[CH:4][CH:3]=1.O.I([O-])(=O)(=O)=[O:28].[Na+].N1C(C)=CC=CC=1C>O1CCOCC1.[Os](=O)(=O)(=O)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[C:10]3[S:15][C:16]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:17]([CH:18]=[O:28])[C:9]2=3)=[CH:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1c(N2CCOCC2)sc2c1C(c1ccc(Cl)cc1)CNC2=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1c(N2CCOCC2)sc2c1C(c1ccc(Cl)cc1)CNC2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A suspension of 4-(4-chlorophenyl)-2-(morpholin-4-yl)-3-vinyl-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (209.0 mg, 0.5575 mmol, single enantiomer of unknown configuration) in 1,4-dioxane (8.46 mL) and water (2.12 mL, 117 mmol) was cooled to 0° C. To the mixture was added sodium metaperiodate (0.477 g, 2.23 mmol), 2,6-lutidine (0.258 mL, 2.23 mmol), and a solution of 4% osmium tetroxide in water (68.1 uL, 0.0112 mmol). The reaction was vigorously stirred at 0° C. for 1 h. After 1 h, the ice-water bath was removed, and the reaction was stirred at rt for an hour. The reaction mixture was filtered through a celite pad, and the pad was washed with EtOAc. The filtrate was washed with 1N HCl (×2), brine, dried over Na2SO4, and concentrated in vacuo. The crude mixture was purified using column chromatography on silica gel (40 g ISCO column, continuous gradient 100% hexanes to 100% EA over 60 minutes) to give the title compound (176 mg orange oil, 84%). Final purification of 26 mg of this material by HPLC gave 16 mg pure product as a white solid. LCMS: (FA) ES+ 377, 379. 1H NMR (400 MHz, DMSO) δ 9.52 (s, 1H), 7.59 (d, J=4.5 Hz, 1H), 7.39-7.34 (m, 2H), 7.10-7.05 (m, 2H), 4.67 (d, J=4.4 Hz, 1H), 3.92 (dd, J=12.9, 5.1 Hz, 1H), 3.81-3.70 (m, 4H), 3.47-3.36 (m, 2H), 3.36-3.26 (m, 3H overlapping with H2O peak).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([C:13]2[O:17][N:16]=[C:15]([CH2:18]OS(C)(=O)=O)[CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[NH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35](=[O:46])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]([F:45])([F:44])[F:43])[CH2:31][CH2:30]1)=[O:28].O>CN(C=O)C>[C:7]1([C:13]2[O:17][N:16]=[C:15]([CH2:18][NH:25][CH2:26][C:27]([N:29]3[CH2:30][CH2:31][N:32]([C:35](=[O:46])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]([F:45])([F:43])[F:44])[CH2:33][CH2:34]3)=[O:28])[CH:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)OCc1cc(-c2ccccc2)on1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CNCc1cc(-c2ccccc2)on1)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 40 °C
Yield: 9.3 %

Procedure:
K2CO3 (201 mg, 1.46 mmol) was added to a stirred solution of methanesulfonic acid 5-phenyl-isoxazol-3-ylmethyl ester (200 mg, 0.73 mmol) and 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (257 mg, 0.73 mmol) in DMF (4 mL). The resulting mixture was heated at 40° C. for 1 hr. Cold water was then added and the resulting precipitate was isolated by filtration. The crude solid was purified by column chromatography using (silica gel of 60-120 mesh and 2% MeOH in CHCl3 as eluent) to afford 32 mg (9.2% yield) of 2-[(5-phenyl-isoxazol-3-ylmethyl)-amino]-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone. LCMS Purity: 96.53%. 1H NMR (DMSO-d6): δ 9.85 (s, 2H), 7.96-7.82 (m, 3H), 7.82-7.74 (t, 1H), 7.3 (d, 1H), 6.64-6.48 (d, 1H), 4.0-3.9 (d, 2H), 3.9-3.8 (m, 1H), 3.76-3.56 (m, 2H), 3.56-3.4 (m, 4H), 3.56-3.26 (bs, 1H), 3.2 (d, 2H), 2.49-2.29 (bs, 1H).
Reaction SMILES: [CH3:1][C@@:2]([C:6]([OH:8])=[O:7])([CH2:4][SH:5])[NH2:3].[CH3:9][C:10]([CH3:12])=O>CO>[CH3:9][C:10]1([CH3:12])[NH:3][C:2]([CH3:1])([C:6]([OH:8])=[O:7])[CH2:4][S:5]1
Reactant: CC(C)=O
Reactant: C[C@](N)(CS)C(=O)O
Solvent: CO
Product: CC1(C)NC(C)(C(=O)O)CS1
Temperature: 56 °C

Procedure:
2.00 g of 2,2,4-trimethylthiazolidine-4-carboxamide hydrochloride prepared by the method described in Justus Liebigs Ann. Chem. (1966), 697, 140-157, was dissolved in 10 ml of 36% concentrated hydrochloric acid. The obtained solution was then heated to reflux at 105° C. for 1 hour, followed by concentration and drying. The thus obtained white solid was washed with isopropanol to obtain 1.62 g of 2-methylcysteine hydrochloride. This compound was converted into an aqueous solution, and the solution was passed through an anion exchange resin for desalinization. Thereafter, it was evaporated to dryness to obtain 1.27 g of 2-methylcysteine. The total amount of the obtained 2-methylcysteine was dissolved in 5 ml of methanol, and thereafter, 5 ml of acetone was added thereto, followed by heating to reflux at 56° C. Four hours later, the heating was terminated, and the reaction solution was concentrated and dried. The obtained white solid was then washed with acetone to obtain 1.32 g of 2,2,4-trimethylthiazolidine-4-carboxylic acid. The yield was found to be 80 mol % relative to the 2-methylcysteine hydrochloride as the raw material. The obtained 2,2,4-trimethylthiazolidine-4-carboxylic acid had the following physical properties:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][P:11]([CH2:16][C:17]([OH:19])=O)([O:13][CH2:14][CH3:15])=[O:12])[CH3:9].[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH2:32][CH:33]1[CH2:35][CH2:34]1)[N:27]=[CH:26][N:25]=[C:24]2[NH:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([Cl:44])[CH:38]=1.O>CN(C)C=O>[Cl:44][C:39]1[CH:38]=[C:37]([NH:36][C:24]2[C:23]3[C:28](=[CH:29][C:30]([O:31][CH2:32][CH:33]4[CH2:34][CH2:35]4)=[C:21]([NH:20][C:17]([CH2:16][P:11]([O:10][CH2:8][CH3:9])([O:13][CH2:14][CH3:15])=[O:12])=[O:19])[CH:22]=3)[N:27]=[CH:26][N:25]=2)[CH:42]=[CH:41][C:40]=1[F:43]
Reactant: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Reactant: CCOP(=O)(CC(=O)O)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.77 ml of triethylamine, 3.43 g of diethoxyphosphorylacetic acid, and 5.62 g of benzotriazol-1-yl-N-tetramethyluronium tetrafluoroborate are added successively to 5.00 g of 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxyquinazoline in 25 ml of N,N-dimethylformamide. The reaction mixture is stirred for one hour at ambient temperature; 250 ml of water is then added and the mixture is extracted with 250 ml of ethyl acetate/methanol (10:1). The organic phase is washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated by evaporation. The residue in the flask is crystallized by stirring with diethylether.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([CH3:37])=[CH:29]2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:37][C:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:28]([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:21]=2)=[O:27])[CH:29]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cn(C(=O)c2cc(Cl)ncn2)c2ccccc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
227 mg (0.78 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one dihydrochloride were added to 200 mg (0.74 mmol) (6-chloropyrimidin-4-yl)-(3-methyl-indol-1-yl)-methanone and 413 μL (2.40 mmol) DIPEA in 5 mL DMF. The reaction mixture was stirred overnight at RT and then purified by preparative HPLC. The product fractions were combined and concentrated by rotary evaporation using the rotary evaporator. The residue was taken up in methanol and purified through a silica gel column. The product fractions were combined and concentrated by rotary evaporation using the rotary evaporator.
Reaction SMILES: C(OC(=O)NCC1CCNCC1)(C)(C)C.C(OC(=O)[NH:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30](=[O:49])[NH:31][C:32]2[S:33][C:34]3[C:40]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:39][CH:38]=[C:37]([O:47][CH3:48])[C:35]=3[N:36]=2)[CH2:26][CH2:25]1)(C)(C)C.FC(F)(F)C(O)=O.[CH3:58][S:59](Cl)(=[O:61])=[O:60].N1C=CC=CC=1>>[CH3:48][O:47][C:37]1[C:35]2[N:36]=[C:32]([NH:31][C:30]([N:27]3[CH2:26][CH2:25][CH:24]([CH2:23][NH:22][S:59]([CH3:58])(=[O:61])=[O:60])[CH2:29][CH2:28]3)=[O:49])[S:33][C:34]=2[C:40]([N:41]2[CH2:42][CH2:43][O:44][CH2:45][CH2:46]2)=[CH:39][CH:38]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)N3CCC(CNC(=O)OC(C)(C)C)CC3)nc12
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)N3CCC(CNS(C)(=O)=O)CC3)nc12

Procedure:
Using piperidin-4-ylmethyl-carbamic acid tert-butyl ester, [1-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylcarbamoyl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester was prepared as white solid. Subsequent deprotection with trifluoroacetic acid and reaction with methanesulfonyl chloride/pyridine under standard conditions afforded the title compound as white crystals in 44% overall yield. MS: m/e=482([M−H+]−).
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[Cl:14][CH2:15][CH:16]([OH:25])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC(C)=O.[Cr]>[Cl:14][CH2:15][C:16]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:25]
Reactant: OC(CCl)COc1ccccc1
Agent: O=[Cr](=O)=O
Agent: [Cr]
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCl)COc1ccccc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 49.7 %

Procedure:
8 N Jones reagent (100 ml.) was added dropwise to a stirred solution of 1-chloro-2-hydroxy-3-phenoxypropane (28.3 g.) in acetone (100 ml.) during 1 hour while maintaining the reaction temperature at 20° C. The mixture was then stirred for 4 hours, and then sufficient water was added to dissolve the precipitated chromium salts. The mixture was extracted three times with diethyl ether and the combined ethereal extracts were dried over sodium sulphate, concentrated under reduced pressure, dried again over sodium sulphate, and concentrated further and distilled, to give 1-chloro-3-phenoxyacetone (13.9 g.), b.p. 150°-155° C./20 mm.Hg.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][CH2:5][CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:9][C:8](=[O:19])[NH:7]1.C[O:22][C:23](=[O:40])[CH2:24][CH:25]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[CH:26]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1.Cl>[OH-].[Na+]>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([CH:25]([CH:26]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27]2)[CH2:24][C:23]([OH:40])=[O:22])=[CH:37][CH:36]=1.[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH:10]2[CH2:9][C:8](=[O:19])[NH:7][CH:6]2[CH2:5][CH2:4][C:3]([OH:20])=[O:2])=[CH:12][CH:13]=1
Reactant: COC(=O)CC(c1ccc(OC)cc1)C1CCC(=O)N1
Reactant: COC(=O)CCC1NC(=O)CC1c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(CC(=O)O)C2CCC(=O)N2)cc1
Product: COc1ccc(C2CC(=O)NC2CCC(=O)O)cc1

Procedure:
A solution of 132.3 g of 3-(4-methoxyphenyl)-5-oxo-2-pyrrolidinepropanoic acid methyl ester and β-(4-methoxyphenyl)-5-oxo-2-pyrrolidinepropanoic acid methyl ester in 480 ml of 1 N aqueous sodium hydroxide solution is heated to 60° C. for four hours. Excess aqueous hydrochloric acid (3 N, 170 ml) is added and the solution concentrated under reduced pressure to give β-(4-methoxyphenyl)-5-oxo-2-pyrrolidinepropanoic acid and 3-(4-methoxyphenyl)-5-oxo-2-pyrrolidinepropanoic acid. The acids are dissolved in 300 ml of acetic anhydride, and the solution is heated to 90° C. The solution is filtered hot and the filtrate concentrated in vacuo. The oil is dissolved in chloroform, treated with activated carbon, filtered and concentrated. The oil is chromatographed on silica gel (200-400 mesh) (elution with chloroform) to give cis-and trans-dihydro-1-(4-methoxyphenyl)-1H-pyrrolizine-3,5(2H,6H)-dione as a white solid with a mp 125°-127° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:25])=O>ClCCl.CCOCC>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([Cl:25])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: Cn1cccc1C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1cccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 mg (4 mmol) of 1-methyl-2-pyrrolecarboxylic acid in 5 ml of dichloromethane are introduced into a round-bottomed flask and under a nitrogen stream. There are added, dropwise, 790 μl (4 mmol) of dicyclohexylamine and, 30 minutes later, 290 μl (4 mmol) of thionyl chloride. The medium is stirred for 1 hour at room temperature and then heated for 2 hours at 50° C. The mixture is then diluted with ether and the precipitate is filtered off. The filtrate is evaporated off and a brown oil is obtained.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[CH3:59][C:60]1[CH:68]=[C:67]([CH3:69])[CH:66]=[C:65]([CH3:70])[C:61]=1[C:62](Cl)=[O:63]>>[CH3:57][CH:56]([CH3:58])[C@H:51]([N:46]1[CH2:45][C:44]2[C:48](=[CH:49][C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:62](=[O:63])[C:61]4[C:65]([CH3:70])=[CH:66][C:67]([CH3:69])=[CH:68][C:60]=4[CH3:59])=[CH:40][CH:39]=3)=[CH:42][CH:43]=2)[C:47]1=[O:50])[C:52]([O:54][CH3:55])=[O:53]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4c(C)cc(C)cc4C)cc3)cc2C1=O
Yield: 77 %

Procedure:
The compound of example 153 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2,4,6-trimethyl benzoyl chloride.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][C:30]=1[Cl:39])[C:12]([C:14]1[S:28][C:17]2[C:18]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O1CCCC1.O.O.[OH-].[Li+]>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([C:29]1[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]=1[Cl:39])[C:12]([C:14]1[S:28][C:17]2[C:18]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(N(CCO[Si](C)(C)C(C)(C)C)C(=O)c2cc3c(s2)-c2c(C)cccc2OCC3)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2c1-c1sc(C(=O)N(CCO[Si](C)(C)C(C)(C)C)c3ccc(C(=O)O)cc3Cl)cc1CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of methyl 4-(N-(2-(tert-butyldimethylsilyloxy)ethyl)-10-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoate (0.250 g, 0.436 mmol) in tetrahydrofuran (10.2 mL, 126 mmol) and water (10.2 mL, 566 mmol) was added lithium hydroxide, monohydrate (0.0732 g, 1.74 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, acidified with 1M HCl, and extracted with DCM (3×). The combined organics were dried (Na2SO4), filtered and concentrated to give 4-(N-(2-(tert-butyldimethylsilyloxy)ethyl)-10-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoic acid (yield 60%). MS: (ESI+) 559.1
Reaction SMILES: [CH3:1]OC(OC)OC.[CH3:8][C:9]1([CH3:17])[O:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[O:10]1.[CH3:18][O:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][N:25]2[C:29]([NH2:30])=[CH:28][C:27]([CH3:31])=[N:26]2)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][N:25]2[C:29]([NH:30][CH:1]=[C:12]3[C:13](=[O:15])[O:14][C:9]([CH3:17])([CH3:8])[O:10][C:11]3=[O:16])=[CH:28][C:27]([CH3:31])=[N:26]2)=[CH:32][CH:33]=1
Reactant: COc1ccc(Cn2nc(C)cc2N)cc1
Reactant: COC(OC)OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: COc1ccc(Cn2nc(C)cc2NC=C2C(=O)OC(C)(C)OC2=O)cc1
Temperature: 25 °C

Procedure:
A stirred mixture of trimethoxymethane (118 mL, 1077 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) (15.5 g, 108 mmol) was heated under reflux for 1 hour. A suspension of 1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-5-amine (23.4 g, 108 mmol; prepared according to the procedure described by Misra, R. N.; et al. Bioorg. Med. Chem. Lett. 2003, 13, 1133-1136) in trimethyl orthoformate (110 mL, 1075 mmol) was added at once, and the dark orange reaction was refluxed for 3 hours under N2. After cooling to room temperature, the reaction was concentrated in vacuo, using toluene (3×100 mL) to azeotrope residual trimethyl orthoformate. The resulting deep orange residue was triturated/sonicated with diethyl ether (200 mL). The resulting peach colored solid was filtered, washing with diethyl ether (3×50 mL). Yield: 28.0 g, 70%. 1H NMR (400 MHz, DMSO-d6) δ 11.13 (d, J=11 Hz, 1H), 8.06 (d, J=11 Hz, 1H), 7.10 (d, J=9 Hz, 2H), 6.87 (d, J=9 Hz, 2H), 6.32 (s, 1H), 5.19 (s, 2H), 3.70 (s, 3H), 2.14 (s, 3H), 1.65 (s, 6H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:53][CH2:54][C@H:55]1[CH2:60][CH2:59][CH2:58][CH2:57][C@H:56]1[OH:61]>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][C:9]([C:10]([NH:53][CH2:54][C@@H:55]3[CH2:60][CH2:59][CH2:58][CH2:57][C@@H:56]3[OH:61])=[O:12])=[CH:8][N:7]=2)[CH2:2][CH2:3]1
Reactant: NC[C@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@@H]1CCCC[C@@H]1O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.4 %

Procedure:
6-Cyclopropylmethoxy-5-(4-fluoro-phenyl)-nicotinic acid (0.50 g, 2 mmol) was dissolved in DMF (20 mL). To the solution was added TBTU (0.62 g, 2 mmol), N,N-diisopropylethyl amine (1.5 mL, 9 mmol) and cis-2-aminomethyl-1-cyclohexanol (317 mg, 2 mmol). The reaction mixture was stirred for 18 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 585 mg of the title compound as a colorless solid, MS (ISP) 399.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:40]=[CH:39][C:35]([CH:36]=[N:37][OH:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:38]/[N:37]=[CH:36]/[C:35]2[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:42])[F:41])=[CH:40][CH:39]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: ON=Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCO/N=C/c2ccc(C(F)(F)F)cc2)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Yield: 77.6 %

Procedure:
This compound was produced using similar methods as those used in Step 5, example 27, starting with 4-(3-bromo-propoxy)-2-(4-trifluoromethoxy-benzoylamino)-benzoic acid methyl ester (0.46 g, 0.97 mmol), 4-trifluoromethyl-benzaldehyde oxime (0.19 g, 1.01 mmol) and cesium carbonate (1.26 g, 3.86 mmol) in acetone (35 mL). The crude material was purified by flash chromatography through silica gel using diethyl ether/hexanes (0/100 gradient to 10/90) to give 2-{[4-(trifluoromethoxy)benzoyl]amino}-4-{3-[({(1E)-[4-(trifluoromethyl)phenyl]methylidene}amino)oxy]propoxy}benzoic acid methyl ester (0.44 g, 78%) as a white solid. 1H NMR (500 MHz, DMSO-d6); δ 11.92 (s, 1H), 8.38 (s, 1H), 8.32 (d, 1H), 8.05 (d, 2H), 7.97 (d, 1H), 7.80-7.21 (AA′BB′, 4H), 7.60 (d, 2H), 6.82 (dd, 1H), 4.34 (t, 2H), 4.21 (t, 2H), 3.87 (s, 3H), 2.18 (m, 2H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.[C:12]([NH:16][C:17]1[O:18][C:19]([C:26](Cl)=[O:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=1)([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[CH3:13][C:12]([NH:16][C:17]1[O:18][C:19]([C:26]([NH:4][CH2:3][CH2:1][OH:2])=[O:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=1)([CH3:15])[CH3:14]
Reactant: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)Cl)o1
Reactant: NCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)NCCO)o1
Yield: 34.3 %

Procedure:
By the procedure of Example 38, a stirred mixture of 50 ml methylene chloride, 0.70 g (11.46 mmol) of ethanolamine, 1.27 g (12.61 mmol) of triethylamine, and 3.1 g (11.46 mmol) of 2-(tert-butylamino)-4-trifluoromethyl-5-oxazolecarbonyl chloride, was reacted for 64 hours at ambient temperature. The product was separated and then recrystallized to yield 1.16 g of a yellow solid product (m.p.=154°-156° C.) identified in Table 1.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][C:14]2=[O:17])=[CH:10][CH:9]=1.[C:18]([O:22]C)(=O)[CH:19]=[CH2:20].[OH-].[K+]>C1COCC1.O>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][C:13]3([CH2:20][CH2:19][C:18](=[O:22])[CH2:2][CH2:1]3)[C:14]2=[O:17])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: C=CC(=O)OC
Reactant: O=C1CCc2ccc(Br)cc21
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.6 %

Procedure:
Potassium tert-butoxide (7.50 g, 66.81 mmol) was added in portions to 6-bromo-2,3-dihydro-1H-inden-1-one (11.75 g, 55.67 mmol) and methyl acrylate (11.05 mL, 122.5 mmol) in THF (55 mL) under cooling in an ice-bath. The mixture was stirred for 1.5 h at r.t. Water (80 mL) and KOH (3.12 g, 55.7 mmol) was added and the mixture was heated to 75° C. and then at 60° C. overnight. The mixture was cooled to 0° C., and the formed precipitate was filtered off and dried in vacuo to give the title compound (11.69 g, 72% yield). 1H NMR (500 MHz, CDCl3) δ ppm 1.83-1.92 (m, 2 H), 2.15-2.27 (m, 2 H), 2.40-2.50 (m, 2 H), 2.71 (dt, 2 H), 3.17 (s, 2 H), 7.39 (d, 1 H), 7.75 (dd, 1 H), 7.92 (d, 1 H); MS (ES+) m/z 293 [M+H]+.