Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].C(O[C:24](=[O:40])[CH:25]([CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)C.[C:41]12([NH:51][C:52](=[O:55])[CH2:53]Br)[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]3)[CH2:42]1)[CH2:48]2>C1COCC1>[C:41]12([N:51]3[C:52](=[O:55])[CH2:53][C:25]([CH2:26][C:27]4[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=4)([CH2:33][C:34]4[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=4)[C:24]3=[O:40])[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]3)[CH2:42]1)[CH2:48]2
Reactant: O=C(CBr)NC12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)C(Cc1ccncc1)Cc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1CC(Cc2ccncc2)(Cc2ccncc2)C(=O)N1C12CC3CC(CC(C3)C1)C2
Temperature: -25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
To a distilled THF solution (30 ml) at -78° C. under a nitrogen atmosphere containing diisopropylamine (1.13 ml, 8.032 mmol distilled from sodium metal) was added butyllithium (BuLi) (8.032 mmol). The solution was allowed to warm to approximately -25° C., recooled to -78° C. and stirred for 1 hour. The lithium diisopropylamide (LDA) solution was added (via cannula) to a separate flask containing 3-pyridin4-yl-2-pyridin-4-ylmethyl-propionic acid ethyl ester (2.056 g, 8.032 mmol) in THF (30 ml) at -78° C. The red mixture was allowed to warm to approx. -25° C., recooled to -78° C., and stirred for 1 hour. To this lithium enolate solution was added (via cannula) a solution of N-adamantan-1-yl-2-bromo-acetamide (2.186 g, 8.032 mmol) in THF (10 ml) at -78° C. The mixture was kept at -78° C. for 16 hours, warmed to ambient temperature and stirred for two additional hours. The mixture was quenched with EtOAc, washed with an equal volume of H2O and brine, dried (Na2SO4) and concentrated in vacuo to a brown oil. The crude mixture was chromatographed on silica gel (1:1 acetone:hexane) to afford 475 mg (14%) of the title compound as a white solid, which was recrystallized from isopropyl ether, mp 137°-138.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][C:47]=1[F:48])[NH2:44]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:44][C:43]3[CH:45]=[CH:46][C:47]([F:48])=[C:41]([F:40])[CH:42]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: Nc1ccc(F)c(F)c1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4ccc(F)c(F)c4)C3)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.1 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (146 mg, 0.428 mmol), EDC (115 mg, 0.599 mmol), and HOBT (81 mg, 0.599 mmol) in DMF (8 mL was added 3,4-difluoroaniline (77 mg, 0.599 mmol), and the reaction mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (95 mg) as a yellow solid. LC-MS (ES) m/z=453 [M+H]+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13]([NH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([CH3:27])[CH:21]=[CH:20]2)(=[O:15])=[O:14]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:12][S:13]([NH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N+:23]([O-:9])=[C:22]([CH3:27])[CH:21]=[CH:20]2)(=[O:14])=[O:15]
Reactant: Cc1ccc2cc(NS(C)(=O)=O)ccc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc2cc(NS(C)(=O)=O)ccc2[n+]1[O-]
Reaction time: 17 h

Procedure:
m-Chloroperbenzoic acid ("MCPBA") (5.2 g) was added portionwise to a solution of 6-methanesulphonamido-2-methylquinoline (6 g) in methylene chloride and stirring was continued for 17 hours. The reaction mixture was then diluted with aqueous sodium bicarbonate and the organic layer was separated. The aqueous layer was extracted with methylene chloride. The combined organic layers were washed with aqueous sodium bicarbonate, dried (MgSO4) and evaporated in vacuo to give a solid which was recrystallised from ethanol to give the title compound, yield 1.6 g, m.p. 241°-243°.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:20]=[CH:19][C:18]([C:21]4[CH:30]=[N:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]=4)=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Br:31]N1C(=O)CCC1=O>CN(C)C=O>[Br:31][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:30]=[N:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:19][CH:20]=2)=[C:14]2[C:5]=1[CH:4]=[CH:3][CH:2]=[CH:1]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(-c3ccc(-c4cnc5ccccc5n4)cc3)c3ccccc3cc2c1
Solvent: CN(C)C=O
Product: Brc1c2ccccc2c(-c2ccc(-c3cnc4ccccc4n3)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 520.9 %

Procedure:
Dissolving 2.2 g (6.2 mmol) of 2-(4-anthracen-9-yl-phenyl) quinoxaline obtained in the foregoing step (2) into 20 milliliter of N,N-dimethylformamide, and adding 1.2 g (6.7 mmol) of N-bromosuccinimide, stirred at room temperature for 8 hours. After completion of the reaction, precipitated solids were separated by filtration and washed with water and methanol, thereby obtaining 14.9 g of 2-[4-(10-bromo-anthracen-9-yl)-phenyl]-quinoxaline (yield: 78%).
Reaction SMILES: Br[CH2:2][C:3](Br)([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])[CH3:4].[NH:14]1[CH:18]=[N:17][CH:16]=[N:15]1.O>CN(C=O)C>[N:14]1([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=2[F:12])=[CH2:4])[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: CC(Br)(CBr)c1ccc(F)cc1F
Reactant: c1nc[nH]n1
Solvent: CN(C)C=O
Solvent: O
Product: C=C(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 29.9 %

Procedure:
5 g (15.9 mmol) of 1,2-dibromo-2-(2,4-difluorophenyl) propane VIII and 3.3 g (48 mmol) of 1,2,4-triazole in DMF was refluxed for 15 hours. The reaction mixture was cooled down to room temperature, water (40 mL) was added and product was extracted with EtOAc (2×50 mL). The EtOAc phase was washed with water and dried (Na2SO4). Evaporation of the solvent under reduced pressure and purification of the residue on a silica gel column with ethyl acetate as the eluent, furnished the title compound (1.05 g, 30%).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N+:9]([C:12]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:13]=1[OH:26])([O-])=O.C(O)C>O>[NH2:9][C:12]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:13]=1[OH:26]
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(OCc2ccccc2)ccc1O
Temperature: 25 °C

Procedure:
Sodium dithionite (174.11 g, 10 moles) in water (400 ml) was dropwise added to the nitrophenol ((a), 93.0 g, 0.38 mole) in refluxing ethanol. The resulting solution was refluxed for further 3 hours, then cooled at room temperature and filtered. The obtained solution was concentrated at a final volume of 100 ml; Water (100 ml) was added and the separated amine ((b), 72.0 g, 88%) was recovered as brown powder.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].CC(OC)(C)C>O.CC(O)C>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.) in water (0.75 ml) and propan-2-ol (7.5 ml). The mixture was heated to reflux and 1 ml of propan-2-ol was added. After 2 h the mixture was cooled to room temperature and stirred for 2 h. MTBE (60 ml) was dripped into the solution over 20 min and it was stirred for another 1.5 h. The product was isolated by filtration under nitrogen, washed with MTBE and dried at 50° C. in a vacuum oven for 24 h to obtain 1.9 g (62%) of fluvastatin sodium Form VII.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH2:4][CH2:5][NH:6][CH2:7][CH2:8][C:9]=1[C:10]#[N:11].[CH2:12](I)[CH3:13]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:12]([N:6]1[CH2:7][CH2:8][C:9]([C:10]#[N:11])=[C:3]([Cl:2])[CH2:4][CH2:5]1)[CH3:13]
Reactant: N#CC1=C(Cl)CCNCC1
Reactant: CCI
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CCC(Cl)=C(C#N)CC1
Reaction time: 8 h

Procedure:
7.1 gm (0.037 mol) of 4-chloro-5-cyano-2,3,6,7-tetrahydro-1H-azepine hydrochloride were dissolved in 170 ml of chloroform by addition of 28.5 ml of triethylamine. Then, 8.6 gm (0.055 mol)=4.9 ml of ethyl iodide were added dropwise at the boiling point, while stirring, and the mixture was refluxed for 4 hours. To complete the reaction, another 10 ml of triethylamine and 2.5 ml of ethyl iodide were added, and the mixture was boiled further. After a total of 10 hours the reaction was finished. After standing overnight, the mixture was concentrated by evaporation in vacuo. The residue was chromatographed on a silica-gel column (chloroform/methyl alcohol/ammonia=9:1:0.1). After the corresponding fractions had been concentrated by evaporation, the mixture was evaporated in vacuo.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]3[C:15]([CH3:32])=[CH:16][C:17](OS(C(F)(F)F)(=O)=O)=[C:18]([CH:23]=3)[C:19]([O:21][CH3:22])=[O:20])=[CH:9][CH:8]=2)[C:4]([CH3:33])=[N:3]1.[CH2:34](C([Sn])=C(CCCC)CCCC)[CH2:35]CC.[Cl-].[Li+].[F-].[K+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]3[C:15]([CH3:32])=[CH:16][C:17]([CH:34]=[CH2:35])=[C:18]([CH:23]=3)[C:19]([O:21][CH3:22])=[O:20])=[CH:9][CH:8]=2)[C:4]([CH3:33])=[N:3]1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COC(=O)c1cc(Cc2ccc(-c3cn(C)nc3C)nc2)c(C)cc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Product: C=Cc1cc(C)c(Cc2ccc(-c3cn(C)nc3C)nc2)cc1C(=O)OC
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 5-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (0.26 g) in DMF (5.5 mL) were added tributylvinyltin (0.24 mL), trans-dichlorobis(triphenylphosphine)palladium(II) (0.02 g) and lithium chloride (0.17 g), and the mixture was stirred at 90° C. for 1.5 hr under argon atmosphere. To the reaction mixture was added aqueous potassium fluoride solution, and the precipitated insoluble substance was removed by filtration through Celite. The filtrate was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.18 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13]>>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(Br)c1
Reactant: O=C(CCl)C(F)(F)F
Product: O=C(CSc1cccc(Br)c1)C(F)(F)F

Procedure:
Prepared according to the procedure described in Example 6, Step 1, using the following starting materials: 3-bromothiophenol and 3-chloro-1,1,1-trifluoropropane-2-one.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:25]=[CH:24][C:14]([CH2:15][NH:16]C(=O)OC(C)(C)C)=[CH:13][CH:12]=2)=[O:9])[CH:3]=1.[CH2:26]([NH:29][CH2:30][CH:31]1[CH2:33][CH2:32]1)[CH2:27][CH3:28]>>[NH2:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:4]2[CH:3]=[C:2]([N:29]([CH2:30][CH:31]3[CH2:33][CH2:32]3)[CH2:26][CH2:27][CH3:28])[N:7]=[CH:6][N:5]=2)=[O:9])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)c2cc(Cl)ncn2)cc1
Reactant: CCCNCC1CC1
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CN)cc2)ncn1

Procedure:
Following the general method as outlined in Example 72 (Steps 1 and 2), starting from tert-butyl (4-{[(6-chloropyrimidin-4-yl)carbonyl]amino}benzyl)carbamate (Intermediate 22) and N-propylcyclopropanemethylamine (Aldrich), the title compound was obtained as a beige solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6]([CH:7]=[O:8])[C@:5]1([CH3:21])[C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]([CH:18]([CH3:20])[CH3:19])[CH:10]=1.CC12C(C)(C)C(C(OC[C@@H]3[C@@H](COC)[C@]3(C)C3C=C(C(C)C)C=C(C(C)C)C=3)=O)(CC1)OC2=O>>[CH3:1][O:2][CH2:3][C@@H:4]1[C@@H:6]([CH:7]=[O:8])[C@@:5]1([CH3:21])[C:9]1[CH:10]=[C:11]([CH:18]([CH3:19])[CH3:20])[CH:12]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1
Reactant: COC[C@@H]1[C@H](C=O)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Agent: COC[C@@H]1[C@@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Product: COC[C@@H]1[C@@H](C=O)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Yield: 87 %

Procedure:
Following a procedure similar to that for the preparation of Intermediate 45 but using Intermediate 44a as the starting material afforded the title compound (14 mg, 87% yield) as a colorless oil:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C:17]2[C:12](=[C:13]([C:18]3[S:22][C:21]([C:23]4[CH:24]=[CH:25][C:26](F)=[C:27]([CH:30]=4)[C:28]#[N:29])=[N:20][N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:32][CH:33]([CH3:35])[O-:34].[Na+]>CC(O)C>[Si:1]([O:8][C@@H:9]1[C:17]2[C:12](=[C:13]([C:18]3[S:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([O:34][CH:33]([CH3:35])[CH3:32])=[C:27]([CH:30]=4)[C:28]#[N:29])=[N:20][N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)[O-]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCc2c(-c3nnc(-c4ccc(F)c(C#N)c4)s3)cccc21
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4O[Si](C)(C)C(C)(C)C)s2)cc1C#N
Temperature: 60 °C
Yield: 76.3 %

Procedure:
Prepared using General Procedure 2: To a solution of (S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile (21 mg, 0.04 mmol) in IPA (2 mL) was added sodium isopropoxide (5 mg, 0.06 mmol). The reaction mixture was heated at 60° C. for 2 h. Upon cooling, the solvent was evaporated and the product was purified by a silica gel column chromatography (EA/hexanes) to afford (S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile (15 mg, 68%). LCMS-ESI (m/z) calculated for C28H34N2O2SSi: 491.7, found 492.2 [M+H]+, tR=5.17 min (Method 1).
Reaction SMILES: [C:1]([S:14]([NH2:17])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[Na+].Cl[CH2:21][C:22]([O:24][Na:25])=[O:23]>O>[C:1]([S:14]([NH:17][CH2:21][C:22]([O:24][Na:25])=[O:23])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:11])[F:12])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: NS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(CCl)O[Na]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)O[Na]
Temperature: 98 °C
Yield: 70 %

Procedure:
A 1 L 3-necked round bottom flask equipped with a mechanical stirrer, thermocouple, reflux condenser and heating mantle was charged with C4F9SO2NH2 (58 g; 0.20 moles; as prepared above), NaOH (8.7 g; 0.22 moles; pellets) and water (60 mL) and heated at 98° C. for 45 minutes. Upon cooling to 76° C., ClCH2CO2Na (25 g; 0.22 moles, Sigma-Aldrich) was added and the temperature was then increased to 100° C. and maintained for 18 hours. Water was then added (200 mL) and a white solid appeared. The upper liquid phase was decanted off and discarded leaving the white solid, to which water (250 mL) was added. Water was removed to yield C4F9SO2N(H)CH2CO2Na (53.1 g ; 74% yield).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[N:8]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].[O-]S([O-])(=O)=O.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]3[O:14][CH2:15][CH2:16][O:17]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Brc1cccc(C2OCCO2)n1
Reactant: Br[Mg]C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: c1cc(C2CC2)nc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a stirred solution of 0.5 M zinc chloride in THF (9.1 mL, 4.55 mmol) under N2, cooled to −78° C. was added dropwise a solution of 0.5 M cyclopropylmagnesium bromide in THF (9.1 mL, 4.55 mmol). The reaction mixture was warmed to RT and stirred for 1 h. The resulting zincate was transferred via syringe to a sealed tube containing a solution of 2-bromo-6-(1,3-dioxolan-2-yl)pyridine of Step B (694.3 mg, 3.03 mmol) and Pd(PPh3)4 in dry THF (3 mL). The reaction mixture was degassed, sealed and heated at 120° C. for 2 h. The reaction mixture was cooled to RT and partitioned between ethyl acetate (100 mL) and saturated aqueous NH4Cl (50 mL). The phases were separated. The aqueous phase was extracted with ethyl acetate (15 mL). The combined organic phases were dried (MgSO4), filtered and concentrated. The resulting residue was dissolved in CH2Cl2, adsorbed onto silica gel and purified on a Biotage 40S column with SIM using 10% ethyl acetate in hexane as the eluent to afford 538.2 mg (2.82 mmol, 93%) of the desired product as a bright yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].S(Cl)(Cl)=O.Cl.[Al+3].[Cl-].[Cl-].[Cl-]>C1(C)C=CC=CC=1.C(=S)=S>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12](=[O:14])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCC(c1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: S=C=S
Solvent: Cc1ccccc1
Product: O=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 48 %

Procedure:
A solution of 4-(3,4-dichlorophenyl)-4-phenylbutanoic acid (228 g., 0.74 mole) in toluene (1.2 l.) was treated with thionyl chloride (66 ml., 0.90 mole) and the resulting solution heated at reflux for 75 minutes, with provision made for trapping HCl gas given off from the refluxing reaction solution. The reaction solution was then evaporated under vacuum to about 230 g. of a light brown oil. The oil was dissolved in carbon disulfide (360 ml.) and the resulting solution added to a well stirred suspension of AlCl3 (1.5 kg., 12.5 moles) in carbon disulfide (1.20 l.), with the mixture held below 8° C. during the addition period, forming a brown mass. After the addition was completed, the reaction mixture was stirred for about 16 hours at room temperature and then slowly poured on ice (vigorous reaction). The resulting suspension was extracted with ethyl acetate (2×4 l.). The combined extract was washed with water, washed with saturated aqueous sodium bicarbonate solution, dried and evaporated under vacuum to a residue, which was crystallized from hexane (500 ml.) to yield the named product (104.1 g., 48% yield, m.p. 99°-101° C., elemental analysis calculated: 66.00% C; 4.16% H; found: 66.06% C; 4.23% H).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].N12CCCN=C1CCCCC2.CC1C=CC([C:24]2[C:25]([F:53])=[C:26]([CH:30]=[C:31]([Cl:52])[C:32]=2[O:33][C:34]2[CH:35]=[N:36][C:37]([O:44][CH2:45][C:46]([F:51])([F:50])[CH:47]([F:49])[F:48])=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=2)[C:27]([O-])=[O:28])=CC=1>C(#N)C>[Cl:52][C:31]1[C:32]([O:33][C:34]2[CH:35]=[N:36][C:37]([O:44][CH2:45][C:46]([F:51])([F:50])[CH:47]([F:48])[F:49])=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=2)=[CH:24][C:25]([F:53])=[C:26]([CH:30]=1)[C:27]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:28]
Reactant: Cc1ccc(-c2c(F)c(C(=O)[O-])cc(Cl)c2Oc2cnc(OCC(F)(F)C(F)F)c(C(F)(F)F)c2)cc1
Reactant: CS(N)(=O)=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(OCC(F)(F)C(F)F)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.9 %

Procedure:
Methanesulphonamide (89.54 mg, 0.94 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL, 1.03 mmol) were added to 4-methylphenyl-5-chloro-4-(6-(2,2,3,3-tetrafluoropropoxy)-5-(trifluoromethyl)pyridin-3-yloxy)-2-fluorobenzoate (Preparation 263, 475 mg, 0.86 mmol) in acetonitrile (5 mL) and the reaction mixture was stirred for 18 hours at room temperature. The reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate and water, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase chromatography (acetonitrile/water both with 0.1% formic acid) to give the title compound as a white solid (303 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:13])=O>C1COCC1.CN(C=O)C>[Br:1][C:2]1[O:6][C:5]([C:7]([Cl:13])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Br)o1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Br)o1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-bromo-2-furoic acid (2.1 g, 6.856 mmol) in THF (20 mL) was added oxalyl chloride (0.66 mL, 7.541 mmol). 2 drops of DMF were then added to the reaction mixture, with bubbles of CO observed to come out vigorously. Oxalyl chloride ((COCl)2) (0.1 mL) was then added. The reaction mixture was stirred at room temperature for 10 min and at 90° C. for 10 min. Solvent and excess (COCl)2 were taken off under vacuum to yield 5-bromo-furan-2-carbonyl chloride as a pale yellow crystalline solid.
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1/[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:9]/1=[O:10])C.O.[NH2:19]N>C1(C)C=CC=CC=1>[OH:10][C:9]12[CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH:5]1[CH:4]=[N:2][NH:19]2
Reactant: CN(C)/C=C1/CN(C(=O)OC(C)(C)C)CC1=O
Reactant: NN
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2C=NNC2(O)C1
Temperature: 5 °C
Reaction time: 10 h

Procedure:
To a solution of tert-butyl (3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate (58.2 kg, 242 mol) in toluene (251 kg) at 35-45° C. was added hydrazine hydrate (14.6 kg, 290 mol) via drop-wise addition over 2 h. The mixture was then stirred for 10 h at this temperature. The batch was then cooled to 0-10° C. and the slurry stirred for 6 h. This slurry was then filtered and the cake washed with n-heptane. The solids were then dried under vacuum overnight at 35-50° C. to give tert-butyl 6a-hydroxy-3a,4,6,6a-tetrahydropyrrol[3,4-c]pyrazole-5(1H)-carboxylate.