Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:18])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]([CH3:17])([CH3:16])[C:14]#[CH:15])[CH2:9][CH2:8]1)=[O:6])[CH3:3]>C(O)C.[Pt]=O>[CH3:3][C:2]([CH3:18])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]([CH3:17])([CH3:16])[CH2:14][CH3:15])[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: C#CC(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Pt]
Solvent: CCO
Product: CCC(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
A flask is charged with platinum oxide (250 mg) and absolute ethanol (20 ml) and is stirred under a hydrogen atmosphere (balloon) for 1 hr. Then a solution of 1-(1,1-dimethylethoxycarbonyl)-4-(1,1-dimethylprop-2-ynyl)piperazine (PREPARATION 68, 1.77 g) in absolute ethanol (20 ml) is added, and the mixture is stirred under hydrogen (balloon) for 4 hr, filtered, and concentrated. The residue is chromatographed on silica gel (70-230 mesh, 80 g), eluting with ethyl acetate/hexane (25/75), and the appropriate fractions (Rf =0.32, TLC, ethyl acetate/hexane, 25/75) are pooled and concentrated to give the title compound, NMR (CDCl3) 3.38, 2.46, 1.46-1.38, 0.97 and 0.84.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)(=[O:8])=[O:7]>C(O)C.CC(O)=O.[Pd]>[NH2:15][C:11]1[CH:10]=[C:9]([S:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:18])[CH3:1])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)CCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)CCNS(=O)(=O)c1cccc(N)c1
Yield: 99.7 %

Procedure:
A solution of 3 (0.8 g) in ethanol (10 mL) was subjected to catalytic hydrogenation (10% Pd/C, Degussa, 0.8 g, 3 drops of AcOH, 1 atm.) overnight. To work up, the solids were filtered the filtrate was dried under vacuum to afford 4 as a solid (0.71 g) which was used in the next step without further purification.
Reaction SMILES: CC1C2C=C(/C(/C)=C/[C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=3)C=CC=2SCCC1.[Na].[OH-].[Na+].Cl>C(O)C.O>[C:19]([OH:21])(=[O:20])[C:18]1[CH:24]=[CH:25][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)CCCS3)cc1
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccccc1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
A solution of 1.2 g of ethyl p-[(E)-2-(2,3,4,5-tetrahydro-5-methyl-1-benzothiepin-7-yl)propenyl]benzoate in 30 ml of ethanol was treated with 5 ml of water which contained 0.8 g of sodium hyohoxide (NaOH). The reaction mixture was stirred at 35° C. overnight, poured on to ice, acidified with HCl and extracted with ether. The organic phase was washed with water, dried and concentrated. After recrystallization from ethyl acetate, there were obtained 885 mg of p-[(E)-2,3,4,5-tetrahydro-5-methyl-1-benzothiepin-7-yl)-ropenyl]benzoic acid in the form of white crystals of melting point 186° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH2:17])=[CH:12][C:11]=1[OH:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([C:24]1[CH:36]=[C:35]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])[CH:34]=[CH:33][C:25]=1[O:26][CH:27]([CH2:31][CH3:32])[C:28](Cl)=[O:29])([CH2:22][CH3:23])([CH3:21])[CH3:20].N1C=CC=CC=1>C(OCC)(=O)C>[C:1]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:28](=[O:29])[CH:27]([O:26][C:25]2[CH:33]=[CH:34][C:35]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])=[CH:36][C:24]=2[C:19]([CH2:22][CH3:23])([CH3:21])[CH3:20])[CH2:31][CH3:32])=[CH:12][C:11]=1[OH:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Cl
Reactant: Nc1cc(O)c(NC(=O)c2ccccc2)cc1Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(O)c(NC(=O)c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 100 of ethyl acetate was dissolved 15 g (57×10-3 mole) of 2-benzamido-4-chloro-5-aminophenol, and then 21 g of 2-(2,4-di-t-amylphenoxy)butanoic acid chloride and 5 g of pyridine were added thereto and the mixture was stirred at room temperature for 3 hours. After the reaction, a solvent was distilled off, and the residue was separated and purified through column chromatography and recrystallized from n-hexane to obtain the title compound. Yield: 14.1 g, FD-Mass: 564, melting point: 190° to 191° C.
Reaction SMILES: [CH:1]1([NH:7][S:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][N:22]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NN>CO>[CH:1]1([NH:7][S:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][NH2:22])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(S(=O)(=O)NC2CCCCC2)c2ccccc12
Agent: NN
Solvent: CO
Product: NCc1ccc(S(=O)(=O)NC2CCCCC2)c2ccccc12
Yield: 61.6 %

Procedure:
To a solution of 4-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-naphthalene-1-sulfonic acid cyclohexylamide (G-4) (1.6 g, 3.57 mmol) in methanol (30 mL) was added hydrazine (2 mL). The resultant solution was stirred at room temperature overnight. A precipitate was formed and filtered. The solid was further washed with small amount of methanol. The filtrate was collected and solvent was removed in vacuo. Flash chromatography of the residue with Flash column (MeOH/CH2Cl2: 5-10%) gave the title compound (42) as white solid (0.7 g). 1H NMR (300 MHz, DMSO) δ 8.68 (d, 1H), 8.24 (d, 1H), 8.13 (d, 1H), 7.60 (m, 3H), 5.00 (s, 1H), 4.39 (s, 2H), 3.10 (s, 1H), 2.03 (m, 2H), 1.59 (m, 4H), 1.08 (m, 4H); LC/MS m/z 319 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[N:27]3[CH2:30][C:29](C(OCC)=O)([C:31]([O:33]CC)=[O:32])[CH2:28]3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]>CO.[OH-].[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[N:27]3[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CN([C@@H]2CCc3c(-c4noc(-c5ccc(OC(C)C)c(C#N)c5)n4)cccc32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N3CC(C(=O)O)C3)no2)cc1C#N
Temperature: 50 °C
Reaction time: 15 h
Yield: 33.1 %

Procedure:
To a stirred solution of crude (R)-diethyl 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3,3-dicarboxylate (93 mg, 0.17 mmol) in MeOH (2 mL) was added 6 N NaOH (5 drops). The resulting solution was heated to 50° C. in a closed vial. After 24 h the solution was concentrated, dissolved in water, neutralized with 1N HCl, and heated at 100° C. After 15 h, additional 1N HCl was added, and the mixture was stirred at 105° C. for 24 h. The mixture was diluted with water and extracted with DCM and EA. The organic layers were combined, dried over Na2SO4, and purified by preparative HPLC to provide 25 mg (33%) of (R)-1-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid 202. LCMS-ESI (m/z) calculated for C25H24N4O4: 444.5. found 445.2 [M+H]+, tR=2.55 min. Compound 203 was made in an analogous fashion.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12](N)=[CH:11][CH:10]=2)=[CH:6][C:5]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[NH:18][C:17]2=[O:27])=[C:4]([F:28])[CH:3]=1.S(=O)(=O)(O)[OH:30].N([O-])=O.[Na+].NC(N)=O>O.[Cu-]=O>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:30])=[CH:11][CH:10]=2)=[CH:6][C:5]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[NH:18][C:17]2=[O:27])=[C:4]([F:28])[CH:3]=1
Reactant: Nc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c(F)cc2Cl)cc1
Reactant: O=S(=O)(O)O
Agent: O=[Cu-]
Agent: NC(N)=O
Agent: O=N[O-]
Solvent: O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(Oc2ccc(O)cc2)c(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3-[4-Chloro-2-fluoro-5-(4-aminophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydro-pyrimidine-2,4-dione (2.0 g) was mixed with hot 30% sulfuric acid (5 ml) and ice/water (5.0 g) was added. The mixture kept at 10° C. while a solution of sodium nitrite (0.45 g) in water (5 ml) was slowly introduced at the bottom of the stirred mixture. After stirring for 10 minutes, urea (0.1 g) was added, followed by a solution of copper(2)nitrate (18.0 g) in water (170 ml), and copper(1)oxide (0.7 g). The mixture was stirred for 10 minutes, extracted with diethyl ether (50 ml×3), and dried over sodium sulfate. The crude product was purified by column chromatography (hexane:ethyl acetate, 4:1) to give 3-[4-chloro -2-fluoro-5-(4-hydroxyphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-31), (1.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH2:9]([Mg]Br)[CH3:10]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([OH:8])[CH2:9][CH3:10])[S:5][CH:6]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1cc(Br)cs1
Solvent: C1CCOC1
Product: CCC(O)c1cc(Br)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
30 g (157 mmol) of 4-bromo-2-thiophenecarboxaldehyde are dissolved in 200 mL of anhydrous THF. 104 mL (312 mmol) of 3.0 M ethylmagnesium bromide are added slowly and the medium is stirred for 2 hours at room temperature. After the usual treatment, an orange-coloured oil is obtained (m=33.5 g; Y=96%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([O:18][C:19]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:20])=[CH:17][C:11]2=[N:10]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:39]Br>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:39])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([O:18][C:19]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:20])=[CH:17][C:11]2=[N:10]1
Reactant: Cc1ccc(O)c(-n2nc3ccc(OC(C)(C)CC(C)(C)C)cc3n2)c1
Reactant: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)CC(C)(C)Oc1ccc2nn(-c3cc(CBr)ccc3O)nc2c1
Temperature: 25 °C

Procedure:
2-(2′-hydroxy-5′-bromomethyphenyl)-5-tert-octyloxybenzotriazole was prepared from the bromination of 2-(2′-hydroxy-5′-methyphenyl)-5-tert-octyloxybenzotriazole using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 8.236 g (0.0223 mol) 2-(2′-hydroxy-5′-methyphenyl)-5-tert-octyloxy benzotriazole and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mol) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2-(2′-hydroxy-5′-methyphenyl)-5-tert-octyloxybenzotriazole was kept in oil-bath with temperature 50° C. Nitrogen was bubbled through the solution for creating inert atmosphere. Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop, from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature. Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2′-hydroxy-5′-bromomethyphenyl)-5-tert-octyloxybenzotriazole was 7.8 g (81%).
Reaction SMILES: [Si:1]([O:18][C:19]1[C:24]2[CH2:25][CH2:26][CH2:27][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:29][C:23]=2[CH:22]=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si](OC1C2CCC=C(C(OC)=O)CC=2C=CC=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[C:14]([Si:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[O:18][C:19]1[C:24]2[CH2:25][CH2:26][CH2:27][CH:28]([C:30]([O:32][CH3:33])=[O:31])[CH2:29][C:23]=2[CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1=Cc2cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2CCC1
Agent: [Pd]
Agent: COC(=O)C1=CCCc2c(cccc2O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Solvent: CCOC(C)=O
Product: COC(=O)C1CCCc2c(cccc2O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of a mixture of methyl 1-(tert-butyldiphenylsilyloxy)-8,9-dihydro-7H-benzocycloheptene-6-carboxylate and methyl 1-(tert-butyldiphenylsilyloxy)-8,9-dihydro-5H-benzocycloheptene-6-carboxylate (1.50 g) in EtOAc (60 ml) was added 10% Pd-C (wet) (300 mg). The mixture was stirred under hydrogen atmosphere at room temperature for 7 hours. After removal of Pd-C by filtration, the filtrate was evaporated to give methyl 1-(tert-butyldiphenyl-silyloxy)-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylate (1.51 g) as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[S:9][CH:10]=[CH:11][C:4]=2[CH2:3]1.[Br:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](F)=[CH:15][CH:14]=1>>[Br:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([O:8][CH:6]2[CH2:7][N:2]([CH3:1])[CH2:3][C:4]3[CH:11]=[CH:10][S:9][C:5]2=3)=[CH:15][CH:14]=1
Reactant: CN1Cc2ccsc2C(O)C1
Reactant: Fc1ccc(Br)c2ccccc12
Product: CN1Cc2ccsc2C(Oc2ccc(Br)c3ccccc23)C1

Procedure:
The same method as in Example 1 was conducted using 5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 14) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 1-bromo-4-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].CC[N:14](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.N>C(Cl)Cl.O.CCOC(C)=O>[NH2:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:14])=[O:6]
Reactant: Nc1cccc(C(=O)O)c1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1cccc(N)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-amino-2-chlorobenzoic acid (5.8 mmol) in 12 mL DCM were added 3.0 mL DIPEA, HOBT (7.0 mmol) and EDC.HCl (7.0 mmol) followed by the addition of 0.67 mL of a solution of NH3 in water (13M). The mixture was stirred at RT overnight, EtOAc was then added and the mixture was extracted with water, sat. aq. NaHCO3 solution and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to obtain the desired compound as yellow solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1)[CH3:4].[OH-].[Li+].Cl.[CH3:18]O>O>[CH2:1]([O:2][CH:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH3:4])[CH3:18]
Reactant: COC(=O)c1ccc(C(C)OC)cc1
Reactant: CO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCOC(C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
To the solution of methyl 4-(1-methoxyethyl)benzoate (181 mg, 0.95 mmol) in methanol and water (50 mL/10 mL) was added lithium hydroxide (50 mg, 2.1 mmol), the solution was stirred at room temperature for 12 hours. Then the solution was acidified by hydrogen chloride (1 N/mol) pH to 6, extracted with dichloromethane (50 mL*3), evaporated the solvent to give 4-(1-ethoxyethyl)benzoic acid (166 mg, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:28])[NH:21][C:22]([CH3:27])=[CH:23][C:24]=1[CH2:25][CH3:26].Cl.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:28])[NH:21][C:22]([CH3:27])=[CH:23][C:24]=2[CH2:25][CH3:26])=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: CCc1cc(C)[nH]c(=O)c1CN
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Br)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Product: CCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 82 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (400 mg, 1.41 mmol) and 3-(aminomethyl)-4-ethyl-6-methyl-2(1H)-pyridinone.HCl (401 mg, 1.98 mmol) in DMSO (15 mL). 1-hydroxy-7-azabenzotriazole (308 mg, 2.26 mmol) was added and the resulting mixture was degassed with nitrogen for 10 minutes. N-methylmorpholine (0.64 ml, 5.79 mmol) and EDC (433 mg, 2.26 mmol) were added, the vessel was sealed, and the mixture was stirred at room temperature for 2 days. The mixture was poured onto 10 mL of ice-water and solids crashed out. 10% K2CO3 was added to adjust the pH˜8-9 and the contents were stirred for 10 min and then allowed to stand for another 10 min. Solids were filtered and air-dried. DMF along with some water were added and solids that precipitated were filtered. DCM was added and the contents purified by SiO2 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH). The collected product was suspended in EtOAc along with some hexanes. Solids that precipitated were filtered and dried to afford the title compound as a white solid (504 mg, 82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 8.63 (t, J=4.80 Hz, 1H) 8.37 (s, 1H) 8.20 (s, 1H) 7.70 (d, J=1.26 Hz, 1H) 5.93 (s, 1H) 5.06 (quin, J=6.57 Hz, 1H) 4.37 (s, 1H) 4.35 (s, 1H) 2.52-2.58 (m, 2H) 2.14 (s, 3H) 1.47 (s, 3H) 1.45 (s, 3H) 1.10 (t, J=7.58 Hz, 3H); LC-MS (ES) m/z=431.0/433.0
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[N:5][CH:4]=1)=[O:2].P([O-])(O)(O)=[O:21].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][CH:8]([C:6]2[S:7][C:3]([C:1]([OH:21])=[O:2])=[CH:4][N:5]=2)[CH2:9]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(C=O)s2)C1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(C(=O)O)s2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
tert-Butyl 3-(5-formylthiazol-2-yl)pyrrolidine-1-carboxylate (3.65 g, 12.93 mmol) was suspended in water (35 ml) and t-butanol (60 ml). Sodium dihydrogenphosphate (2.094 g, 17.45 mmol) was added, followed by 2-methylbut-2-ene (5.34 ml, 50.4 mmol). After 5 minutes, sodium chlorite (2.92 g, 32.3 mmol) was added in portions over about 5 minutes (mildly exothermic). The reaction was stirred for 1 hour at room temperature, then additional 2-methyl-2-butene (2 mL) was added. After stirring for 2 hours at room temperature, the reaction was concentrated and water (100 mL) was added. The mixture was adjusted to pH 2 by addition of 1N hydrochloric acid, then extracted dichloromethane. The organic extracts were dried over sodium sulfate, filtered and concentrated to provide the title compound.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([O:15][C:16]2[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:8][C:6]([C:9]1[CH:10]=[C:11]([O:15][C:16]2[CH:17]=[C:18]([CH3:24])[C:19]([N:20]=[C:1]=[S:2])=[CH:21][C:22]=2[CH3:23])[CH:12]=[CH:13][CH:14]=1)([CH3:5])[CH3:7]
Reactant: Cc1cc(Oc2cccc(C(C)(C)C)c2)c(C)cc1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(Oc2cccc(C(C)(C)C)c2)c(C)cc1N=C=S
Reaction time: 2 h

Procedure:
Thiophosgene (0.38 ml) is added to a two-phase mixture at room temperature of 4-((3-(1,1-dimethyl-ethyl)phenyl)oxy)-2,5-dimethylaniline (1.35 g) in toluene (6 ml) and sodium bicarbonate (840 mg) in water (6 ml). The reaction mixture obtained is stirred for 2 h and the phases are then separated by settling. The aqueous phase is extracted with toluene and the combined organic phases are then washed with water, dried (magnesium sulphate) and then concentrated to give the title product.
Reaction SMILES: [C:1]([CH:4]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=2)[N:7]([C:20]2[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=2)[C:6](=[O:29])[C:5]1=O)(=O)[CH3:2].Cl.[CH:32]1([NH:35][NH2:36])[CH2:34][CH2:33]1.CC(O)=O>O1CCOCC1>[CH:32]1([N:35]2[C:5]3[C:6](=[O:29])[N:7]([C:20]4[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=4)[CH:8]([C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=4)[C:4]=3[C:1]([CH3:2])=[N:36]2)[CH2:34][CH2:33]1
Reactant: NNC1CC1
Reactant: CC(=O)C1C(=O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1cccc(OC(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1nn(C2CC2)c2c1C(c1cccc(OC(F)(F)F)c1)N(c1cc(C)c(=O)n(C)c1)C2=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 17.8 %

Procedure:
To a solution of 4-acetyl-1-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(3-(trifluoromethoxy)-phenyl)pyrrolidine-2,3-dione (Step 91.1) (50 mg, 0.118 mmol) in Dioxane (1 mL) were added cyclopropylhydrazine hydrochloride (Step 17.2) (25.7 mg, 0.237 mmol) and TEA (0.082 mL, 0.592 mmol) and the resulting mixture was heated up and stirred at 120° C. for 2 hr. AcOH was added to acidify the reaction mixture and stirred at 100° C. for 30 min. The reaction was cooled down to RT and concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with a saturated aq. NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (CH2Cl2/(CH2Cl2/MeOH 19:1 NH3) 0-100%) to afford the title product (10 mg, 0.021 mmol, 18.1% yield) as yellow foam. tR: 1.03 min (LC-MS 2); ESI-MS: 459 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (d, J=6.3 Hz, 2H) 1.24 (br. s., 3H) 1.93 (s, 6H) 3.37-3.39 (m, 1H) 3.81 (br. s., 1H) 6.13 (s, 1H) 7.22-7.57 (m, 5H) 7.76 (br. s., 1H).