Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:7]=2S[C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2]>[Ni]>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH:5]([C:6]1[CH:7]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=1)[NH:4][C:1](=[O:3])[CH3:2]
Reactant: COC(=O)c1sc2cc(C(F)(F)F)ccc2c1NC(C)=O
Agent: [Ni]
Product: COC(=O)CC(NC(C)=O)c1ccc(C(F)(F)F)cc1
Yield: 92.8 %

Procedure:
Methyl 3-acetamido-6-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (0.7014 g, 2.21 mmol) was reductively desulfurized using Raney nickel to yield the title compound as a clear oil (0.5961 g, 2.05 mmol, 92.6%); TLC: Rf=0.52 (Solvent I), 0.86 (Solvent L); IR (cm−1): 3340 (NH), 1736 (ester C═O), 1654 (amide C═O); 1H nmr (DMSO-d6): δ 8.45 (d, 1H, J=8.0 Hz), 7.59 (d, 2H, J=8.3 Hz), 7.49 (d, 2H, J=8. J z), 5.25 (q, 1H, J=7.6, 15 Hz), 3.55 (s, 3H), 2.75 (m, 2H), 1.82 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:15](=[O:26])[C:16]4[C:21]([C:22](=[O:25])[C:23]=3Cl)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:27].[K+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][CH:11]([C:14]3[C:15](=[O:26])[C:16]4[C:21]([C:22](=[O:25])[C:23]=3[OH:27])=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1C(Cl)=C(C2CCC(c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1C(O)=C(C2CCC(c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21

Procedure:
The product of stage (b) was suspended in 10 ml of boiling methanol and 0.55 g of potassium hydroxide in 5.5 ml of water was added dropwise over 15 mins. The mixture was refluxed until a dark red solution formed, (after ca. 6 hrs) when 2 ml of concentrated hydrochloric acid was cautiously added dropwise. The mixture was cooled and filtered, and the solid residue washed thoroughly with water. The water washings were re-acidified and filtered. The combined solid residues (500 mg) mp 200°-209°, were recrystallised from acetonitrile to give the title product as the trans-isomer (300 mg) m.p. 216°-219° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](F)(F)F)[C:3]=1[CH2:4][N:5]1[C:10]([CH3:11])=[C:9](I)[C:8](=[O:13])[NH:7][C:6]1=[O:14].[Cl:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1.[OH-].[Na+].C(O)(=O)C>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=1[C:9]1[C:8](=[O:13])[NH:7][C:6](=[O:14])[N:5]([CH2:4][C:3]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:2]=2[F:1])[C:10]=1[CH3:11]
Reactant: Cc1c(I)c(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reactant: COc1cccc(B2OC(C)(C)C(C)(C)O2)c1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(-c2c(C)n(Cc3c(C)cccc3F)c(=O)[nH]c2=O)c1Cl
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
Compound 1b (80 g, 0.19 mol), 7a (60.22 g, 0.22 mol), HP(t-Bu)3BF4 (13.01 g, 44.85 mmol), and Pd2(dba)3 (13.69 g, 14.95 mmol) were charged to the reaction vessel and purged with an inert atmosphere. Degassed THF (560 mL) was added followed by NaOH (31.45 g, 0.56 mol) in degassed water (128.8 mL) and the reaction warmed to 45° C. After 2 hours acetic acid (56 mL) was added and stirred for 15 minutes. After settling, the layers were separated and the organic layer was filtered through celite, rinsing with hot THF (2×160 mL). The filtrate was concentrated in vacuo to a slurry, to which was added N-acetyl cysteine (15.84 g) as a solution in water (160 mL) and ethanol (640 mL) and stirred for 2 hours at 75° C. under an inert atmosphere. The slurry was cooled to RT, and the solids filtered off, washed with ethanol:water (8:2, 2×160 mL) to give 5-(2-chloro-3-methoxy-phenyl)-1-(2-fluoro-6-methyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 7b as a white solid (58.6 g, 0.13 mol, 70%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:15][O:16][CH2:17][S:18][CH3:19])[C:10]([O:12]CC)=[O:11])[N:8]=1)=[O:2].[OH-].Cl>CO>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:15][O:16][CH2:17][S:18][CH3:19])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: CCOC(=O)C(=NOCSC)c1csc(NC=O)n1
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CSCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 30 °C
Reaction time: 2.5 h
Yield: 51.9 %

Procedure:
A mixture of ethyl 2-(2-formamidothiazol-4-yl)-2-methylthiomethoxyiminoacetate (syn isomer, 2.4 g.), 1N aqueous soidum hydroxide (23.8 ml.) and methanol (19.8 ml.) was stirred at 30° C. for 2.5 hours. The resultant solution was adjusted to pH 7 with 10% hydrochloric acid and methanol was distilled off in vacuo. The aqueous solution was adjusted to pH 1 with 10% hydrochloric acid under ice cooling, and extracted with ethyl acetate three times. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give 2-(2-formamidothiazol-4-yl)-2-methylthiomethoxyiminoacetic acid (syn isomer, 1.13 g.), mp. 157° C. (dec.).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24](=[O:35])[C@H:25]([NH:27]C(=O)OC(C)(C)C)[CH3:26])=[CH:19][CH:18]=1>ClCCl>[CH3:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[C:10]=1[O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24](=[O:35])[C@@H:25]([CH3:26])[NH2:27])=[CH:19][CH:18]=1
Reactant: Cc1cccc(C)c1Oc1ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C)c1Oc1ccc(NC(=O)[C@@H](C)N)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 50 mL round-bottomed flask 1,1-dimethylethyl [(1R)-2-({6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}amino)-1-methyl-2-oxoethyl]carbamate (Intermediate 43, 282 mg) was dissolved in dichloromethane (2 mL) to give a yellow solution. Trifluoroacetic acid (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at room temperature. After 20 min, the solvent was evaporated under vacuum affording a yellow oil that was charged on a 5 g SCX cartridge. It was then flushed with 25 mL of MeOH followed by 25 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as a yellow oil which solidified (173.8 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[CH:5]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[C:6]([CH3:11])[CH:5]=1)=[O:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2)c(C)c1
Temperature: 80 °C
Yield: 67.2 %

Procedure:
A mixture of 250 mg (1.09 mmol) of 4-bromo-3-methyl-benzoic acid methyl ester, 204 mg (1.31 mmol) of 4-chlorophenylboronic acid, 1.06 g (3.27 mmol) of cesium carbonate (Cs2CO3) and PdCl2(dppf) catalyst (5 mol %) was flushed with argon. To this mixture was added 3 mL of 1,4-dioxane and the reaction mixture was heated to 80° C. overnight. The mixture was then cooled to rt, and filtered through a pad of Celite while rinsing the pad with ethyl acetate. The filtrate was washed with brine, dried over sodium sulfate and concentrated to give a residue which was chromatographed on silica gel (5% ethyl acetate in hexane) to afford 191 mg (67%) of desired 4′-chloro-2-methyl-biphenyl-4-carboxylic acid methyl ester, as an oil as indicated by 1H NMR; LC-MS calcd for C15H13ClO2 [M++H]+: 261.07, found: 261.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Cl:9][C:7]1[CH:6]=[C:4]([CH:3]=[C:2]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[CH:8]=1)[NH2:5]
Reactant: C1COCCN1
Reactant: Nc1cc(Cl)cc(Br)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(Cl)cc(N2CCOCC2)c1
Temperature: 65 °C
Reaction time: 2.3 h

Procedure:
To a stirred solution of 3-bromo-5-chloroaniline (1.00 g, 4.84 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.185 g, 0.39 mmol), Pd2dba3 (0.177 g, 0.194 mmol) and morpholine (0.464 g, 5.33 mmol) in tetrahydrofuran (9.7 mL) was added LHMDS in THF (19.37 mL, 19.37 mmol). The resulting mixture was heated to 65° C. and stirring continued for 2.3 h. The reaction was cooled to rt and then poured into water (100 mL) and extracted with EtOAc (2×150 mL) and DCM (2×150 mL). The combined organic layers were dried over magnesium sulfate and the crude product was purified on silica gel (0 to 100% DCM in EtOAc) to give 3-chloro-5-morpholinoaniline. Mass Spectrum (ESI) m/e=213.1 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[NH2:13])(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]2[N:28]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[N:30]=[C:23]2[N:22]=1.S(Cl)(Cl)(=O)=O.[OH-].[Na+]>C(Cl)Cl.C(#N)C>[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]2[N:28]=[C:29]([S:31]([NH:13][C:7]3[C:8]([Cl:12])=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:32])=[O:33])[N:30]=[C:23]2[N:22]=1
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)nc2n1
Reactant: CC(=O)OCc1cccc(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(=O)OCc1cccc(Cl)c1NS(=O)(=O)c1nc2nc(C)cc(C)n2n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 13.1 %

Procedure:
A solution of 1.30 gm (6.50 mmol) of 2-amino-3-chlorobenzyl acetate, 4.11 gm (52.0 mmol) of pyridine and 5.0 ml of acetonitrile was treated with 1.61 gm (6.50 mmol) of 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonyl chloride and the resulting mixture stirred at 25° C. for 120 hours. An additional 0.53 gm (2.2 mmol) of the sulfonyl chloride was added and stirring at 25° C. continued for an additional 24 hours. The mixture was filtered and the filtrate evaporated to provide a brown oil. The oil was then dissolved in 40 ml of methylene chloride and stirred with 25 ml of 0.5M NaOH. After 5 minutes, the aqueous phase was separated, washed with ether and acidified with 3N HCl. A light brown solid was collected, washed with water, dried and recrystallized from acetonitrile to provide 0.35 gm (13%) of the desired product as a solid, mp 214° -217° C., containing approximately 10% of an impurity. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [C:1]1([C@H:7]([OH:11])[CH2:8][C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C1COCC1>[C:1]1([C@H:7]([OH:11])[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC[C@@H](O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: NCC[C@@H](O)c1ccccc1

Procedure:
To a THF solution of (R)-3-phenyl-3-hydroxypropanenitrile was slowly added borane THF complex at room temperature and then the resulting solution was refluxed for 2.5 h. After cooling to room temperature methanolic HCl was added to the reaction mixture. Methanol and methyl borate were removed by distillation and the reaction mixture neutralized with sodium hydroxide (5N). Extraction of the mixture with dichloromethane,followed by concentration provided the crystalline (R)-3-phenyl-3-hydroxypropylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:26])[C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:25])(=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:26])[C:15]2[CH:16]=[CH:17][C:18]([S:21](=[O:25])(=[O:24])[NH:22][CH3:23])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CNS(=O)(=O)c1ccc(C(O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 79.6 %

Procedure:
To a solution of 4-[hydroxy-(4-methylsulfamoyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 33) (530 mg, 1.38 mmol) in CH2Cl2 (10 ml) were added PCC (900 mg, 4.1 mmol) followed by SiO2 (1.5 g). The resultant mixture was stirred at room temperature overnight to give 4-(4-methylsulfamoyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (420 mg, 80%) as a colourless oil after purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([O:12]CC)=[O:11])=[CH:5][N:4]=1.[OH-].[Na+].Cl>O1CCOCC1>[CH3:1][S:2][C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([OH:12])=[O:11])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CSc1ncc(C(=O)O)c(=O)[nH]1
Temperature: 85 °C
Yield: 60.8 %

Procedure:
A solution of ethyl 3,4-dihydro-2-methylthio-4-oxopyrimidine-5-carboxylate (C. W. Todd, J. H. Fletcher and D. S. Tarbell, J. Am. Chem. Soc. (1943), 65, 350-4) (1.95 g) in dioxan (15 ml) was treated with aqueous NaOH (0.73 g in 15 ml) and heated at 85° C. overnight. After cooling, the solution was acidified with 2N HCl to pH3 and the white solid filtered off and dried under vacuum to give title compound (1.03 g). MS (−ve ion chemical ionisation) m/z 185 ([M−H]−, 70%), 141 (100%).
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11](O)=[O:12])[C:4]=2[O:3]1.CN(C)C=O.S(Cl)([Cl:22])=O>ClCCCl>[F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([Cl:22])=[O:12])[C:4]=2[O:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc2c1OC(F)(F)O2
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc2c1OC(F)(F)O2
Yield: 106 %

Procedure:
2,2-Difluoro-1,3-benzodioxole-4-carboxylic acid (15.0 g) was dissolved in 1,2-dichloroethane and N,N-dimethylformamide and thionyl chloride (10.6 g) added. The mixture was heated under reflux for 1 hour, and the solvent evaporated in vacuo. The residue was dissolved in toluene and re-evaporated to yield 2,2-difluoro-1,3-benzodioxol-4-oyl chloride (17.35 g).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.FC(F)(F)S(O[C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:27]=1[O:34][CH3:35])(=O)=O.[Cl-].[Li+]>CN(C=O)C.C(OCC)C.O.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>[CH3:35][O:34][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][C:26]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[C:32]#[N:33]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COc1cc(C#N)ccc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc(C#N)ccc1-c1ccccn1
Temperature: 100 °C

Procedure:
A solution of 2-(tributylstannyl)pyridine (18 g of 80% pure, 39.2 mmol) and 4-cyano-2-methoxyphenyl trifluoromethanesulfonate (9.2 g, 32.7 mmol) were dissolved in DMF (65 mL) and treated with lithium chloride (1.39 g, 32.7 mmol) and Pd(PPh3)4 (1.9 g, 1.6 mmol), then degassed by bubbling argon through the solution for 15 min. The reaction mixture was heated to 100° C. while under an atmosphere of argon for 12 h. The cooled reaction mixture was diluted with diethyl ether (100 mL) and water (100 mL). The organic layer was separated and washed with a 1M solution of sodium hydroxide (50 mL) and brine (50 mL), then dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:9 to 1:1) to afford 3-methyoxy-4-pyridin-2-ylbenzonitrile.
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)=[C:9]([F:30])[CH:8]=1.[CH3:31][C:32]([CH3:55])([CH2:37][O:38][C:39]1[CH:44]=[C:43]([CH3:45])[C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][N:40]=1)[C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[F:30][C:9]1[CH:8]=[C:7]([C:42]2[C:43]([CH3:45])=[CH:44][C:39]([O:38][CH2:37][C:32]([CH3:31])([CH3:55])[C:33]([O:35][CH3:36])=[O:34])=[N:40][CH:41]=2)[CH:12]=[CH:11][C:10]=1[C:13]1[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1
Reactant: COC(=O)C(C)(C)COc1cc(C)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)c(F)c2)cn1
Temperature: 60 °C
Reaction time: 5 h
Yield: 102.3 %

Procedure:
N,N-dimethylformamide (4 mL) was added to 2-(4-bromo-2-fluorophenyl)-4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (500 mg), methyl 2,2-dimethyl-3-{[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}propanoate (477 mg) and palladium chloride (dppf) methylene chloride complex (46 mg), and after adding 2N aqueous sodium carbonate solution (1.71 mL) to the mixture, the atmosphere was replaced with nitrogen and the resulting mixture was stirred at 60° C. for 5 hours. To the reaction mixture were added ethyl acetate and water, and the liquids were separated. The organic layer was separated, washed with a saturated brine, and the residue obtained by concentrating the mixture under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5 to 82:18) to obtain methyl 3-[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate (677 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4](F)[C:3]=1[N+:10]([O-:12])=[O:11].C(N(CC)CC)C.[F:20]C1C=C(F)C=CC=1N>[C].[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:20])[C:5]([Cl:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Nc1ccc(F)cc1F
Reactant: O=[N+]([O-])c1c(F)ccc(Cl)c1F
Agent: [Pd]
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Yield: 94 %

Procedure:
A solution of 2,6-difluoro-5-chloronitrobenzene (2.0g., 1.03 × 10-2 mole) and triethylamine (2.1g., 2.06 × 10-2 mole) was hydrogenated over 10% palladium carbon catalyst for 18 minutes at room temperature and for an additional 4 hours at 60° C. The catalyst was removed by filtration and washed twice with methanol, using 16 ml. of each wash. The solvent was evaporated and the residue was treated with dichloromethane. The resulting mixture was washed with 15 ml. of water, 70 ml. of ammonium hydroxide solution and then 15 ml. of water, and dried over Na2SO4. Evaporation of the remaining solvent gave 1.25 g. of a yellow oil, a yield of 94%. Gas chromatography established the reaction product to contain 89.5% 2,4-difluoro-aniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:14](=O)[CH2:15][CH3:16])=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6](O)=[O:7].O.[NH2:19][NH2:20]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:5]2[C:4]=1[C:14]([CH2:15][CH3:16])=[N:19][NH:20][C:6]2=[O:7]
Reactant: CCC(=O)c1c(OC)cc(OC)cc1C(=O)O
Reactant: NN
Solvent: O
Product: CCc1n[nH]c(=O)c2cc(OC)cc(OC)c12

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 3,5-dimethoxy-2-propionylbenzoic acid with hydrazine hydrate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([CH2:52][O:53][CH3:54])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:54][O:53][CH2:52][C:49]1[CH:50]=[CH:51][C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:47][CH:48]=1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: COCc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (220 mg) was added toluene/ethanol/water (10/1/1, 6 ml) and then were added 4-(methoxymethyl)phenyl borate (86 mg) and potassium carbonate (123 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (19 mg), and the mixture was stirred at 90° C. for 9 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-(4-methoxymethylphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 80) (99 mg).
Reaction SMILES: CN.[NH4+].[C:4]([CH:6]([CH3:12])[CH2:7][CH2:8][C:9]([O-])=[O:10])#[N:5].[CH3:13]C1CNC(=O)CC1.CC(CCC(O)=O)C(O)=O>[Pd].O>[CH3:13][N:5]1[CH2:4][CH:6]([CH3:12])[CH2:7][CH2:8][C:9]1=[O:10]
Reactant: CC(C#N)CCC(=O)[O-]
Reactant: CC1CCC(=O)NC1
Agent: [Pd]
Agent: CC(CCC(=O)O)C(=O)O
Agent: CN
Solvent: O
Product: CC1CCC(=O)N(C)C1
Temperature: 160 °C
Yield: 72.8 %

Procedure:
Into a 100 mL graduated cylinder was placed 54.4 mL of an aqueous reaction mixture containing 1.84M 4-cyanopentanoic acid ammonium salt (0.1 mole 4-cyanopentanoic acid ammonium salt, produced by the enzymatic hydrolysis of 2-methylglutaronitrile; Example 9, filtered product mixture from reaction #5), then 25.8 ml of 40 wt. % methylamine (9.31 g methylamine, 0.3 mole) was added and the final volume adjusted to 100 mL with distilled water. The final concentrations of 4-cyanopentanoic acid ammonium salt and methylamine were 1.0M and 3.0M, respectively. To the resulting solution was added 0.636 g (5 wt. %/wt. of 4-cyanopentanoic acid) of 5% Pd on carbon powder, and the resulting mixture charged to a 300-mL 314 SS Autoclave Engineers EZE-Seal stirred autoclave equipped with a Dispersimax® turbine-type impeller. After flushing the reactor with nitrogen, the contents of the reactor were stirred at 1000 rpm and heated at 160° C. under 500 psig of hydrogen gas for 4 h. Samples (ca. 1.5 mL) were removed via a sampling tube over the course of the reaction for analysis. After cooling to room temperature, analysis of the final reaction mixture by gas chromatography indicated a 72.8% yield of 1,5-dimethyl-2-piperidone, 3.5% 5-methyl-2-piperidone, 19.9% 2-methylglutaric acid, and no 4-cyanopentanoic acid ammonium salt remaining.