Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O:13][CH3:14].[Cl:15][C:16]1[N:21]=[C:20]([NH2:22])[C:19]([CH3:23])=[CH:18][N:17]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:15][C:16]1[N:21]=[C:20]([NH:22][CH2:2][C:3]2[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=2[O:13][CH3:14])[C:19]([CH3:23])=[CH:18][N:17]=1
Reactant: Cc1cnc(Cl)nc1N
Reactant: COc1ccc(S(C)(=O)=O)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(S(C)(=O)=O)cc1CNc1nc(Cl)ncc1C
Temperature: 100 °C

Procedure:
2-(Bromomethyl)-1-methoxy-4-(methylsulfonyl)benzene VI-1 (1 g, 3.6 mmol, prepared by Procedure H) was added to a stirred solution of 2-chloro-5-methylpyrimidin-4-amine (1 g, 6.9 mmol) and K2CO3 (1 g, 7.2 mmol) in acetonitrile (10 mL) and heated overnight at 100° C. The mixture was filtered, concentrated in vacuo and purified by flash chromatography (ethyl acetate/petrol) to afford 2-chloro-N-(2-methoxy-5-(methylsulfonyl)benzyl)-5-methylpyrimidin-4-amine as a yellow solid. LC-MS (Method C) RT=0.93 min (ES+) 342.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19](O)=[O:20])=[C:16]4[CH2:22][CH2:23][CH2:24][CH2:25][C:15]=34)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=O)C([Cl:33])=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:28])([F:29])[F:27])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19]([Cl:33])=[O:20])=[C:16]4[CH2:22][CH2:23][CH2:24][CH2:25][C:15]=34)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Yield: 98 %

Procedure:
Stir a mixture of 3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (600 mg, 1.2 mmol), 2 drops DMF in oxalyl dichloride (5 mL) at ambient temperature for 3 hours. Remove the solvent under vacuum to afford 3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carbonyl chloride as a yellow solid (615 mg, 98%).
Reaction SMILES: C([N:8]([CH2:54][C@@H:55]([C:64]1[CH:73]=[CH:72][C:71]([O:74]CC2C=CC=CC=2)=[C:70]2[C:65]=1[CH:66]=[CH:67][C:68](=[O:82])[NH:69]2)[O:56][Si:57]([C:60]([CH3:63])([CH3:62])[CH3:61])([CH3:59])[CH3:58])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:21]=[C:22]([CH2:26][NH:27][C:28]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH:35]([O:38][C:39](=[O:53])[NH:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH2:34][CH2:33]3)=[O:29])[CH:23]=[CH:24][CH:25]=2)=[O:19])=[CH:13][CH:12]=1)C1C=CC=CC=1>CCO.CC(O)=O.[Pd]>[Si:57]([O:56][C@H:55]([C:64]1[CH:73]=[CH:72][C:71]([OH:74])=[C:70]2[C:65]=1[CH:66]=[CH:67][C:68](=[O:82])[NH:69]2)[CH2:54][NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]([C:20]2[CH:21]=[C:22]([CH2:26][NH:27][C:28]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH:35]([O:38][C:39](=[O:53])[NH:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH2:34][CH2:33]3)=[O:29])[CH:23]=[CH:24][CH:25]=2)=[O:19])=[CH:15][CH:16]=1)([C:60]([CH3:63])([CH3:61])[CH3:62])([CH3:59])[CH3:58]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCc1ccc(NC(=O)c2cccc(CNC(=O)CCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)c2)cc1)Cc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(NC(=O)c2cccc(CNC(=O)CCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)c2)cc1)c1ccc(O)c2[nH]c(=O)ccc12
Reaction time: 8 h
Yield: 75.9 %

Procedure:
A solution of biphenyl-2-ylcarbamic acid 1-[2-({3-[4-(2-{benzyl-[(R)-2-(8-benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)-2-(tert-butyldimethylsilanyloxy)ethyl]-amino}ethyl)phenylcarbamoyl]phenyl}methylcarbamoyl)ethyl]piperidin-4-yl ester (1.74 g, 1.56 mmol) in EtOH (12.2 mL) and AcOH (0.122 mL) was flushed with nitrogen for 3 min. Palladium on carbon (10%, ˜50% water, 0.18 g) was added and the reaction mixture was flushed with hydrogen for 4 min. The mixture was stirred under a hydrogen atmosphere (balloon) overnight and then filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-15% MeOH in DCM) to give the title compound (1.11 g, 76% yield) as a thick brownish liquid.
Reaction SMILES: C([Li])CCC.C(OP([CH2:14][C:15]([OH:17])=[O:16])(OCC)=O)C.[Cl:18][C:19](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:20]=O.Cl>O1CCCC1>[Cl:18][C:19](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:20]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: O=CC(Cl)=Cc1ccccc1
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C=CC(Cl)=Cc1ccccc1
Temperature: -65 °C
Reaction time: 0.67 h
Yield: 75.9 %

Procedure:
Butyllithium (50 mL of 2.5 N solution) was added to 250 mL of anhydrous tetrahydrofuran (THF) at −65° C. A solution of diethylphosphonoacetic acid (11.4 g) in 90 mL of anhydrous THF was added dropwise to the stirred solution at −65° C. The resulting solution was stirred at −65° C. for an additional 40 minutes and then a solution of α-chloro-cinnamaldehyde (10.0 g) in 60 mL of anhydrous THF was added to the reaction at −65° C. over a period of 95 minutes. The reaction was stirred for one hour, allowed to warm to room temperature and then stirred overnight. The reaction was then acidified with 5% hydrochloric acid (48 mL) to a pH of 3.9. The aqueous layer was extracted with 50 mL of ether twice and with 50 mL of ethyl acetate once. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material was dissolved in 30 mL of hot methanol and then refrigerated overnight. The crystals formed were filtered and dried under vacuum to afford 9.2 g of the desired 4-chloro-5-phenyl-2,4-pentadienoic acid. 1H NMR (acetone-d6, 300 MHz), δ(ppm) 7.86 (d, 2H), 7.60 (d, 1H), 7.45 (m, 3H), 7.36 (broad s, 1H), 6.32 (d, 1H).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][N:5]1[C@H:14]2[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:25]([F:28])([F:27])[F:26])[C:7]=2[C:6]1=[O:29].O.[OH-].[Li+]>C1COCC1>[C:21]([O:20][C:18]([N:16]1[CH2:17][C@H:13]2[C@@H:14]([N:5]([CH2:4][C:3]([OH:30])=[O:2])[C:6](=[O:29])[C:7]3[C:8]([C:25]([F:27])([F:26])[F:28])=[CH:9][CH:10]=[CH:11][C:12]=32)[CH2:15]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)CN1C(=O)c2c(cccc2C(F)(F)F)[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N(CC(=O)O)[C@H]2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of (3aR,9bS)-tert-butyl 4-(2-methoxy-2-oxoethyl)-5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 18, Part A (105 mg, 0.25 mmol) in 4 mL of THF and 2 mL of water was added lithium hydroxide (12 mg, 0.49 mmol). The resulting mixture was allowed to stir at ambient temperature for 2 h. The reaction was quenched with 10 mL of 1N HCl and extracted with ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated in vacuo to afford 100 mg (98%) of the title compound. LRMS (ESI): 415.20 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:17])[N:6]([CH3:16])[C:7](=[O:15])[NH:8]2.[Cl:18]N1C(=O)CCC1=O>>[Cl:18][C:10]1[CH:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[C:4]2[C:9]=1[NH:8][C:7](=[O:15])[N:6]([CH3:16])[C:5]2=[O:17]
Reactant: COc1ccc2[nH]c(=O)n(C)c(=O)c2c1OC
Reactant: O=C1CCC(=O)N1Cl
Product: COc1cc(Cl)c2[nH]c(=O)n(C)c(=O)c2c1OC
Yield: 67 %

Procedure:
Following the procedure employed in Example 11, treatment of 5,6-dimethoxy-3-methylquinazolin-2,4(1H, 3H)-dione 1/4 hydrate with N-chlorosuccinimide gives the title compound after isopropanol crystallization in 67% yield, mp 224°-227° C.
Reaction SMILES: [CH3:1][C:2]([OH:15])([CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:28])[CH2:24][CH2:25][CH2:26]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(C)CC(=O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23](=[O:28])[CH2:24][CH2:25][CH2:26][N:12]2[CH2:13][CH2:14][CH:9]([C:2]([OH:15])([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:10][CH2:11]2)=[CH:21][CH:22]=1
Reactant: CC(O)(c1ccccc1)C1CCNCC1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CC(O)(c1ccccc1)C1CCN(CCCC(=O)c2ccc(F)cc2)CC1

Procedure:
The mixture of 2 g of α-methyl-α-(4-piperidyl)-benzyl alcohol, 1.95 g of 4'-fluoro-4-chlorobutyrophenone, 2 g of sodium carbonate (anhydrous), a crystal of sodium iodide and 150 ml of 4-methyl-2-pentanone are stirred and refluxed for 72 hours. The reaction mixture is filtered to remove the inorganic salts and the filtrate evaporated under reduced pressure. Diethyl ether is added to the residue and the resulting solution extracted with 5% aqueous hydrochloric acid. The aqueous solution is made basic with ammonia and extracted with diethyl ether. The extract is then dried and evaporated under reduced pressure to afford the 4'-fluoro-4-[4-(α-hydroxy-α-methylbenzyl)-piperidino]- butyrophenone of the formula ##STR5## Recrystallization from isopropanol yields the above compound melting at 55°-57° and isolated as a solvate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][Si](C(C)(C)C)(C)C)=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.Cl[C:28]1[O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1>C1COCC1>[O:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: Clc1nc2ccccc2o1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Oc1ccc(-c2nc3ccccc3o2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-t-butyldimethylsilyloxybenzene (8.3 g; 29 mmol) in THF (60 ml) at -78° C. is added a solution of butyllithium in hexane (14 ml; 35 mmol) over 10 minutes. This is allowed to stir 1 hour and 2-chlorobenzoxazole (4 ml; 35 mmol) is added dropwise over 5 minutes.-After stirring 15 minutes, the reaction is allowed to warm to 0° C. and is quenched with MeOH. This is then poured into 1N HCl and after stirring 1 hour is extracted with ethyl acetate. The organic extracts are dried (MgSO4) and then concentrated to yield 4-(benzoxazol-2-yl)phenol which is used directly in Step C.
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=O)C3C(=CC=CC=3)C=2C=CC=1.C=O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:16][NH:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C=O
Agent: CC[SiH](CC)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CN[C@@H](CC(C)C)C(=O)O
Reaction time: 22 h
Yield: 117.1 %

Procedure:
A suspension of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-leucine (1.67 g, 5 mmol) in toluene(100 ml) was charged with paraformaldehyde (1 g, 33.3 mmol) and 4-toluenesulfonic acid (100 mg, catalytic). The mixture was refluxed for 30 minutes in a Dean Stark apparatus for azeotropic distillation. The solution was washed with a saturated solution of sodium bicarbonate (×2), dried over magnesium sulfate and evaporated. The resulting oil in a 1:1 mixture of chloroform:trifluoroacetic acid (50 ml), at room temperature, was charged with triethylsilane (2.38 ml, 15 mmol). Stirring was continued for 22 hr. The solvents were removed in vacuum and the oil was crystallized from a mixture of ether:hexane. Recrystalyzation from EtOAc:hexane afforded 0.85 g (46%) of the product as a colorless solid, mp 101°-3° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][CH:27]([NH2:38])[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:38][CH:27]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[CH3:26])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CC(N)c1cccc2ccccc12
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), R-(+)-1-(1-naphthyl)ethylamine (0.570 g, 3.33 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-{1-(1-naphthyl)ethyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.950 g, 64.7% yield).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1.Cl[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]#[N:21]>O>[CH:8]1([O:12][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[C:20]#[N:21])[CH2:11][CH2:10][CH2:9]1
Reactant: N#Cc1ccncc1Cl
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccncc1OC1CCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.6 %

Procedure:
A mixture of mineral oil free NaH (0.86 g, 21.4 mmol) and DMF (15 ml) was cooled in an ice-bath and cyclobutanol (1.6 ml, 20.5 mmol) was added in one portion. The mixture was slowly warmed to room temperature and was stirred for 45 minutes. The mixture was once again cooled in an ice-bath and 3-chloro-4-cyanopyridine (2.6 g, 18.6 mmol) was added in one portion. The mixture was warmed to room temperature and was stirred for 3 hours. Water (10 ml) was added and the solvent was removed in vacuo. Water (225 ml) was aded to the residue and the mixture was extracted with ether (3×100 mL). The combined organic layers were dried over anhydrous MgSO4, treated with charcoal and removed in vacuo to afford 3.0 g (95%) of 3-cyclobutyloxy-4-cyanopyridine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br[CH2:31]/[CH:32]=[CH:33]/[C:34]([O:36][CH3:37])=[O:35]>>[CH3:37][O:36][C:34](=[O:35])/[CH:33]=[CH:32]/[CH2:31][N:19]1[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=2[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]3)/[S:21][C:20]1=[O:22]
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: COC(=O)/C=C/CBr
Product: COC(=O)/C=C/CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(2E)-4-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]but-2-enoic acid methyl ester was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and methyl 4-bromocrotonate following General Procedure S.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](/[C:6](=[CH:14]\[C:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=3[Cl:24])[N:17]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:16]=2[C:36]([O:38][CH2:39][CH3:40])=[O:37])/[C:7]([O:9]C(C)(C)C)=[O:8])=[CH:2]1.FC(F)(F)C(O)=O>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][C:3](/[C:6](=[CH:14]\[C:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=3[Cl:24])[N:17]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:16]=2[C:36]([O:38][CH2:39][CH3:40])=[O:37])/[C:7]([OH:9])=[O:8])=[CH:2]1
Reactant: CCOC(=O)c1c(/C=C(/C(=O)OC(C)(C)C)c2ccsc2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(/C=C(/C(=O)O)c2ccsc2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.75 h

Procedure:
Combine (E)-2-(thien-3-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoic acid, t-butyl ester and trifluoroacetic acid (10 mL). After 45 min, evaporate in vacuo to obtain a residue. Dissolve the residue in ethyl acetate and extract with water. Evaporate the organic layer in vacuo to obtain a residue. Triturate with pentane containing a small amount of ether to give a solid. Recrystallize the solid from cyclohexane/ethyl acetate, filter, and dry to give the title compound: mp 197-200° C. (dec); 1H NMR (CDCl3) δ 8.00 (s, 1H), 7.95 (d, 1H, J=1.7 Hz), 7.74 (d, 2H, J=8.5 Hz), 7.27 (d, 2H, J=8.5 Hz), 7.25 (d, 1H, J=1.7 Hz), 7.08 (d, 1H, J=2.8 Hz), 7.08 (d, 1H, J=3.6 Hz), 6.81 (dd, 1H, J=3.6, 2.8 Hz), 4.22 (q, 2H, J=7.2 Hz), 2.40 (s, 3H), 1.28 (t, 3H, J=7.2 Hz); 1H NMR (DMSO-d6) δ 13.07 (br s, 1H), 7.88 (d, 1H, J=1.7 Hz), 7.74 (d, 2H, J=8.4 Hz), 7.66 (s, 1H), 7.57 (d, 1H, J=1.7 Hz), 7.44 (d, 2H, J=8.4 Hz), 7.27 (dd, 1H, J=5.0, 2.9 Hz), 7.09 (dd, 1H, J=2.9, 1.2 Hz), 6.63 (dd, 1H, J=5.0, 1.2 Hz), 4.11 (q, 2H, J=7.1 Hz), 2.36 (s, 3H), 1.14 (t, 3H, J=7.1 Hz). Elemental Analysis calculated for C25H19Cl2NO6S2 : C, 53.20; H, 3.39; N, 2.48. Found: C, 52.80; H, 3.19; N, 2.29.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][CH2:4]/[N:5]=[CH:6]\[C:7]1[S:11][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[N:9][CH:8]=1.[SH:27][C@@H:28]([CH2:32][C:33]([OH:35])=[O:34])[C:29](O)=[O:30]>C1(C)C=CC=CC=1>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([C:10]2[S:11][C:7]([CH:6]3[N:5]([CH2:4][CH2:3][C:2]([CH3:26])([CH3:25])[CH3:1])[C:29](=[O:30])[C@H:28]([CH2:32][C:33]([OH:35])=[O:34])[S:27]3)=[CH:8][N:9]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)CC/N=C\c1cnc(C2CCN(C(=O)OC(C)(C)C)CC2)s1
Reactant: O=C(O)C[C@H](S)C(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)CCN1C(=O)[C@H](CC(=O)O)SC1c1cnc(C2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 110 °C
Yield: 100.3 %

Procedure:
A mixture of (Z)-tert-butyl 4-(5-((3,3-dimethylbutylimino)methyl)thiazol-2-yl)piperidine-1-carboxylate (290 mg, 0.76 mmol, 1 eq) and (S)-2-mercaptosuccinic acid (138 mg, 0.92 mmol, 1.2 eq) in toluene (20 mL) was heated at 110° C. for 18 hr. The excess solvent was concentrated in vacuo and the solids were collected by filtration. The solids were washed with water, toluene and dried to give 2-((5S)-2-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)thiazol-5-yl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid (390 mg, 90% yield). (M+1) 512. 1H NMR (CDCl3) δ 7.15 (m, 1H), 5.68 (m, 1H), 4.58-4.11 (m, 3H), 3.62 (m, 1H), 3.39-3.09 (m, 2H), 2.93-2.74 (m, 3H), 2.09 (m, 2H), 1.71-1.64 (m, 2H), 1.47 (s, 9H), 1.44 (m, 1H), 0.85 (s, 9H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:11][CH:12]([CH3:14])[O-:13].[CH3:15][CH:16]([CH3:18])[O-:17].[CH3:19][CH:20]([CH3:22])[O-:21].Cl[Ti+3:24]>CCOCC>[CH3:11][CH:12]([CH3:14])[O-:13].[CH3:15][CH:16]([CH3:18])[O-:17].[CH3:19][CH:20]([CH3:22])[O-:21].[CH3:1][C:2]1[CH:3]=[C:4]([Ti+3:24])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc([Mg]Br)c1
Reactant: Cl[Ti+3]
Agent: CC(C)[O-]
Solvent: CCOCC
Product: Cc1cc(C)cc([Ti+3])c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 10 mmoles of 3,5-dimethylphenylmagnesium bromide in 10 mL of ether was cooled to -78° C. under nitrogen and to this was added 10 mL of a 1M solution of chlorotitanium triisopropoxide. The solution was stirred at -78° C. for 30 minutes and used in the next step.
Reaction SMILES: [C:1](OC([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:13][C:14]([NH2:16])=[NH:15].[OH-].[Na+]>CC(C)=O.O>[NH2:15][C:14]([NH:16][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[NH:13]
Reactant: N=C(N)N
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(=N)N
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A solution of tert-butyl dicarbonate (57.3 g, 263 mmol) in acetone (500 mL) was added to a solution of guanidine hydrochloride (100 g, 1050 mmol) and sodium hydroxide (84 g, 2100 mmol) in water (400 mL) at 0° C. The mixture was stirred at RT for 2 hrs. The acetone was removed by rotary evaporation and the remaining suspension was extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate and the solvent was evaporated to give 1,1-dimethylethyl [amino(imino)methyl]carbamate (42 g, 100%). 1H NMR (400 MHz, chloroform-d) δ ppm 6.08 (br. s., 4H), 1.44 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](Cl)=[O:14])=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:22][N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28]([O:30][CH3:31])=[O:29].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:22][N:23]1[CH:27]=[C:26]([C:13]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:14])[CH:25]=[C:24]1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1cccn1C
Reactant: COc1ccc(C(=O)Cl)c2ccccc12
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)c1cc(C(=O)c2ccc(OC)c3ccccc23)cn1C
Reaction time: 1 h
Yield: 50 %

Procedure:
4-Methoxy-naphthoic acid chloride (35 g; prepared by action of phosphorous pentachloride on the acid of m.p. 250° C.) followed by methyl 1-methyl-pyrrole-2-carboxylate (22 g) are dissolved in 1,2-dichloroethane (400 ml). To the stirred solution, at about -20° C., is slowly added anhydrous aluminium chloride (23 g). After one hour, the resulting material is poured over 1 kg crushed ice. The organic phase is decanted off and the aqueous phase is extracted with chloroform (500 ml). The organic solution is then dried and the solvents are evaporated off. The solid residue (28 g) is washed with isopropyl ether (200 ml), to give methyl 1-methyl-4-(4-methoxy-1-naphthoyl)-pyrrole-2-carboxylate, m.p.=162° C., in a yield of 50%.
Reaction SMILES: [OH-:1].[K+].C([O:5][C:6](=[O:43])[C:7]([CH3:42])([CH3:41])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([N+]#[C-])(S(C1C=CC(C)=CC=1)(=O)=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24]CC)=[O:23])C>O.C(O)C>[CH3:41][C:7]([CH3:42])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:1])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([OH:24])=[O:23])[C:6]([OH:5])=[O:43]
Reactant: [C-]#[N+]C(CCCCCCC(C)(C)C(=O)OCC)(CCCCCCC(C)(C)C(=O)OCC)S(=O)(=O)c1ccc(C)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCCCCC(=O)CCCCCCC(C)(C)C(=O)O)C(=O)O
Yield: 57.3 %

Procedure:
To a solution of KOH (85%, 8.4 g, 127.3 mmol) in deionized water (3.6 mL) and ethanol (11.5 mL) was added 208i (15.0 g, 25.3 mmol) and the mixture was heated to reflux for 7 h. The reaction mixture was diluted with water (40 mL) and extracted with MTBE (2×30 mL). The aqueous layer was cooled with an ice-bath and the pH was adjusted to 1 by addition of 5 N sulfuric acid (45 mL). The aqueous layer was extracted with MTBE (3×30 mL) and the combined organic layers were washed with brine (50 mL), dried over anhydrous MgSO4, and concentrated in vacuo to give a crude oil (12.5 g). Purification by chromatography (silica gel, ethyl acetate/hexanes=10% to 100%) and recrystallization from MTBE/hexanes (4 mL/50 mL) yielded 210i (5.37 g, 57%) as a white powder. Mp 74.5-76.0° C. 1H NMR (CDCl3): δ (ppm): 12.40-11.20 (br, 2H), 2.39 (t, J=7.3, 4H), 1.62-1.48 (m, 8H), 1.38-1.22 (m, 12H), 1.11 (s, 12H). 13C NMR (CDCl3=77.02 ppm): δ (ppm): 211.88, 184.93, 42.70, 42.19, 40.63, 29.63, 29.09, 24.96, 24.83, 23.83. HRMS (LSIMS, gly): Calcd for C21H39O5 (MH+): 371.2797, found: 371.2804.