Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Se](=O)=[O:13]>O1CCOCC1.O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][N:7]=2)[C:2]([CH:1]=[O:13])=[CH:3][CH:4]=1
Reactant: Cc1ccnc2ncccc12
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccnc2ncccc12
Temperature: 80 °C
Yield: 77.3 %

Procedure:
4-Methyl-[1,8]naphthyridine (0.743 g, 5.15 mmol) was dissolved in dioxane (32 mL) and water (4 mL). Selenium dioxide (1.14 g, 103 mmol) was added, and the solution was heated to 80° C. for 1 h. Subsequently more selenium dioxide (0.020 g, 1.80 mmol) was added, the solution heated for 30 min, and then allowed to cool to RT. The solution was passed through a syringe filter to remove solids, and poured into a solution of water : satd. aq. NaHCO3 (1:1) (60 mL). The organic layer was separated and the remaining aqueous extracted with DCM (2×100 mL) and (1×50 mL). The organic fractions were combined, dried over Na2SO4, filtered, and concentrated under vacuum. The product was purified (SGC using MeCN:hexanes in 1:1 ratio) to yield the title compound (0.63 g). MS (ESI+) for m/z 159 (M+H)+. 1H NMR (CDCl3) δ 10.39 (s, 1H), 9.39-9.37 (m, 2H), 9.16 (d, 1H), 7.85 (d, 1H), 7.61 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:9]=[N:10][O:11][C:12]=2[CH:13]2[CH2:15][CH2:14]2)=[O:7])=[C:4]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:3]=1.[O-]CC.[Na+].O>C(O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=[O:7])[CH:8]([C:9]#[N:10])[C:12]([CH:13]2[CH2:15][CH2:14]2)=[O:11])=[C:4]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Cl)ccc1C(=O)c1cnoc1C1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1cc(Cl)ccc1C(=O)C(C#N)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 4-[4-chloro-2-(methylsulphonyl)benzoyl]-5-cyclopropylisoxazole (2.2 g) in ethanol was added to a solution of sodium ethoxide in ethanol (prepared from sodium (0.2 g) and ethanol). The mixture was stirred at room temperature for 2 hours then poured into water and acidified to pH 1. It was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was recrystallised from ethyl acetate and cyclohexane to give 1-[4-chloro-2-(methylsulphonyl)phenyl]-2-cyano-3-cyclopropylpropan-1,3-dione, COMPOUND 612, (1.7 g) as a light brown solid, m.p. 116° C.
Reaction SMILES: CO[C:3](OC)([CH3:29])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[NH:12][S@@](C(C)(C)C)=O.O1CCOCC1.C(OC)(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.Cl>[CH3:29][CH:3]1[CH2:4][C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[NH:12]1
Reactant: COC(C)(Cc1ccccc1C(N[S@](=O)C(C)(C)C)c1ccc(C(F)(F)F)cc1)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCCl
Solvent: COC(OC)OC
Product: CC1Cc2ccccc2C(c2ccc(C(F)(F)F)cc2)N1
Reaction time: 0.33 h

Procedure:
(R)—N-((2-(2,2-Dimethoxypropyl)phenyl)(4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamide (6.650000 g, 15 mmol) was dissolved in 150 mL of DCE and hydrogen chloride, 4.0 m solution in 1,4-dioxane (11 mL, 44 mmol) was added. Stirring was continued for 20 min and trimethyl orthoformate (8.0 mL, 73 mmol) and sodium triacetoxyborohydride (11 g, 51 mmol) were added. TLC-analysis showed a complex product mixture but LCMS showed the formation of some desired product along with a lot of fully aromatized product. The crude was semi-purified via glass colm chrom and used w/o further clean up in the next steps. MS (ESI, positive ion) m/z: 292.0 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:15]([O-])=O)=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][O:13][CH3:14])[C:6]#[N:7]>[Pd].C(O)C>[NH2:15][C:4]1[C:3]([O:2][CH3:1])=[C:10]([O:11][CH2:12][O:13][CH3:14])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: COCOc1ccc(C#N)c([N+](=O)[O-])c1OC
Agent: [Pd]
Solvent: CCO
Product: COCOc1ccc(C#N)c(N)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To 5% palladium on activated carbon 6.00 g under argon atmosphere was added a solution of 3-methoxy-4-(methoxymethoxy)-2-nitrobenzonitrile 6.00 g (25.2 mmol) in ethanol 50 mL and stirred under hydrogen atmosphere at room temperature for 8 hours. The reaction mixture was filtrated and the filtrate was concentrated in vacuo. Silica gel chromatography (n-hexane/AcOEt=4/1) afforded the title compound 2.83 g as white solid. Yield 53.9%.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][C:7](Br)=[C:8]([CH3:32])[C:9]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]2[CH:20]=[CH:21][C:22]3[N:28]([CH3:29])[C:27](=[O:30])[O:26][CH2:25][CH2:24][C:23]=3[CH:31]=2)[N:12]=1)=[O:4].[CH3:34]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([CH3:34])=[C:8]([CH3:32])[C:9]=1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]2[CH:20]=[CH:21][C:22]3[N:28]([CH3:29])[C:27](=[O:30])[O:26][CH2:25][CH2:24][C:23]=3[CH:31]=2)[N:12]=1)=[O:4]
Reactant: CB(O)O
Reactant: CNC(=O)c1sc(Br)c(C)c1Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CNC(=O)c1sc(C)c(C)c1Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl
Yield: 4.6 %

Procedure:
A solution of 5-bromo-3-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-4-methyl-thiophene-2-carboxylic acid methylamide (50 mg, 0.09 mmol), methylboronic acid (16.4 mg, 0.27 mmol), 2 M aqueous potassium phosphate solution (2 mL) and tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.004 mmol) in 1,4-dioxane (2 mL) was heated at 100° C. for 24 hours. The mixture was cooled and extracted with methylene chloride. The organic layer was washed with brine, dried over by sodium sulfate, and concentrated. Chromatography with preparative TLC (methylene chloride and methanol (40:1)) followed by semipreparative HPLC gave of 5-methyl-3-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-4-methyl-thiophene-2-carboxylic acid methylamide (2 mg, 5%): 1H NMR (300 MHz, CDCl3) δ 8.1 (s, 1H), 7.44 (d, 1H), 7.33 (d, 1H), 7.0 (d, 1H), 6.53 (q, 1H), 4.48 (t, 2H), 3.38 (s, 3H), 2.94 (d, 3H), 2.83 (t, 2H), 2.43 (s, 3H), 1.95 (s, 3H); MS (m/e): 487.3 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[N+]([O-])([O-])=O.[Ag+:14]>O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Ag:14]
Reactant: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: c1ccc2[nH]nnc2c1
Solvent: O
Product: [Ag]

Procedure:
In 3,000 ml of water were dissolved 28 g of gelatin and 13.2 g of benzotriazole, and the solution was kept at 40° C. while stirring. To the solution was added 100 ml of an aqueous solution of 17 g of silver nitrate over 2 minutes. Excess salts were sedimented and removed from the resulting emulsion by pH-adjustment. Thereafter, the emulsion was adjusted to a pH of 6.30 to obtain a silver benzotriazole emulsion. The yield of the emulsion was 400 g.
Reaction SMILES: C(O[C:4](=[O:9])[CH2:5][C:6]([CH3:8])=O)C.[CH3:10][CH:11]([NH:19][NH2:20])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1>C(O)C>[CH3:8][C:6]1[NH:20][N:19]([CH:11]([CH3:10])[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:4](=[O:9])[CH:5]=1
Reactant: Cc1ccc(C(C)NN)cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CCO
Product: Cc1ccc(C(C)n2[nH]c(C)cc2=O)cc1

Procedure:
26 g of acetoacetic acid ethyl ester were dissolved in 20 ml of absolute ethanol. 30.0 g of α-methyl-4-methylbenzylhydrazine in a little absolute ethanol were slowly added to this solution under nitrogen. After the exothermic reaction had subsided, the mixture was heated for 2 hours under reflux. On cooling, the crude product crystallized out and was purified by recrystallization from methanol. Melting point 144°- 146°C; yield 28 g (65% of theory).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Cl)=[CH:5][CH:4]=1.[I-:11].[Na+].[CH2:13]([N:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>CC(C)=O>[I-:11].[I:11][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N+:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:5][CH:4]=1
Reactant: ClCc1ccc(CCl)cc1
Reactant: CCCCN(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCC[N+](CCCC)(CCCC)Cc1ccc(CI)cc1
Temperature: 25 °C

Procedure:
To a mixture of α,α'-dichloro-p-xylene (50 g, 28.6 mmol) and sodium iodide (8.6 g, 57 mmol) in acetone (100 mL) was added tri-n-butylamine (3.7 g, 20.0 mmol). The reaction mixture was stirred at room temperature under argon for several days after which time TLC examination showed completion of the reaction. The reaction mixture was filtered and the solvent was removed under reduced pressure to give an oily residue. The residue was washed with pentane several times and dried to give a yellow solid. The product was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[C:15]2[CH:16]=[CH:17][N:18]=[CH:19][C:20]=2[CH:21]=[C:22](Br)[CH:23]=1)(=[O:13])=[O:12])(C)(C)C.[F:26][CH:27]([F:37])[C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.CO.O.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]>[NH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[C:15]2[CH:16]=[CH:17][N:18]=[CH:19][C:20]=2[CH:21]=[C:22]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([CH:27]([F:37])[F:26])[CH:33]=2)[CH:23]=1)(=[O:12])=[O:13]
Reactant: OB(O)c1cccc(C(F)F)c1
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc(Br)cc2cnccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: COCCOC
Solvent: O
Product: NCCNS(=O)(=O)c1cc(-c2cccc(C(F)F)c2)cc2cnccc12
Temperature: 82 °C
Yield: 88.3 %

Procedure:
Dissolve [2-(7-bromo-isoquinoline-5-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (0.13 g, 0.30 mmol) and 3-(difluoromethyl)phenylboronic acid (0.057 g, 0.33 mmol) in DME-methanol (8:1, 10 ml). To the mixture, add K3PO4 (0.13 g, 0.60 mmol), and PdCl2(dppf) (0.012 g, 0.015 mmol). Heat this mixture at 82° C. overnight. Cool the reaction mixture, dilute with water and extract with EtOAc. Wash with brine and evaporate to dryness. Purify by silica gel chromatography to give the desired compound (0.10 g, 71% yield): 1H NMR (CDCl3): δ9.39 (s, 1H), 8.66 (m, 2H), 8.43 (d, J=5.7 Hz, 2H), 7.86 (m, 2H), 7.61 (m, 2H), 6.76 (t, J=52.1 Hz, 1H), 5.00 (br s, 1H), 3.18 (m, 2H), 3.03 (m, 2H), 1.37 (s, 9H); ESIMS: m/z 478 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:14]([C:15](=[O:21])[C:16]2[S:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][C:5]2[CH2:6][CH:7]([C:9]([O:11][CH3:12])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:22].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrN1C(=O)CCC1=O.Cl>C(Cl)(Cl)(Cl)Cl.CS(C)=O.O>[Cl:1][C:2]1[C:14]([C:15](=[O:21])[C:16]2[S:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][C:5]2[CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:22]
Reactant: COC(=O)C1Cc2cc(C(=O)c3cccs3)c(Cl)c(Cl)c2O1
Agent: Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CS(C)=O
Product: COC(=O)c1cc2cc(C(=O)c3cccs3)c(Cl)c(Cl)c2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylate (3.6 g., 0.01 mole) in carbon tetrachloride (100 ml.) containing a few crystals of benzoyl peroxide is treated with N-bromosuccinimide (1.8 g., 0.01 mole) then refluxed for one hour. The reaction mixture is cooled, filtered free of succinimide and the solvent distilled at reduced pressure to leave a yellow residual oil comprised of a mixture of methyl 2(and 3)-bromo-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylate which is dissolved in dimethylsulfoxide (25 ml.) treated with 1,5-diazobicyclo(4.3.0)-5-nonene (1.3 g., 0.01 mole), stirred at 25° C. for two hours in an inert atmosphere, diluted with water (100 ml.) and acidified with hydrochloric acid to give methyl 6,7-di chloro-5-(2-thenoyl)benzofuran-2-carboxylate wich melts at 184°-7° C. after recrystallization from acetonitrile-H2O.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]([CH3:22])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH2:19][CH2:20][NH2:21])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]([CH3:22])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH2:19][CH2:20][NH:21][C:33]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:34])=[O:9])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1OCCCN
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1OCCCNC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a solution of 4-nitro-N-methyl-N-[2-(3-aminoprop-1-yloxy)phenyl]benzamide (422 mg) and triethylamine (130 mg) in dichloromethane (10 ml) was added phenyl chloroformate (201 mg) and the solution was stirred at 0° C. for 30 minutes. The reaction mixture was diluted with dichloromethane and then the organic solution was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution and brine. Drying, filtering and removal of solvents afforded a crude product. The crude product was chromatographed on silica gel (eluent; 1% methanol in chloroform) to give 4-nitro-N-methyl-N-[2-(3-phenoxycarbonylaminoprop-1-yloxy)phenyl]benzamide (383 mg) as a slightly yellow oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][C:5]1([C:11](O)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2].C1(C(O)=O)CCCCC1.S(Cl)([Cl:27])=O.C(C(CC)CC1(C(OC(C2(CC(CC)CC)CCCCC2)=O)=O)CCCCC1)C>C(N(CC)CC)C>[CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][C:5]1([C:11]([Cl:27])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2]
Reactant: CCC(CC)CC1(C(=O)O)CCCCC1
Reactant: O=S(Cl)Cl
Agent: CCC(CC)CC1(C(=O)OC(=O)C2(CC(CC)CC)CCCCC2)CCCCC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C1CCCCC1
Product: CCC(CC)CC1(C(=O)Cl)CCCCC1
Temperature: 50 °C
Yield: 92.9 %

Procedure:
A mixture of 103.0 mmol 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid, 38.9 mmol cyclo-hexanecarboxylic acid and 396 μL triethylamine (2.84 mmol=0.02 eq. relative to the sum of both acids) was warmed to 50° C. 12.4 mL (170.3 mmol=1.2 Eq. relative to the sum of both acids) of thionyl chloride was added during 18 minutes at a temperature of 40-54° C. (reaction is endothermic, vigorous gas evolution) and the reaction mixture was kept at 54-55° C. After 1 hr reaction was complete (0.03% 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid and no 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid anhydride). After removing volatile components in vacuo (60° C. bath, 3.5-4.3 mbar followed by 120° C. bath, 10-11 mbar) 25.44 g of residue was obtained (assay 92.9% 1-(2-ethyl-butyl)-cyclohexanecarbonyl chloride, yield 99.4%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].B>C1COCC1>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1c(Br)cc(F)cc1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: Nc1c(Br)cc(F)cc1CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
To a 0.5M suspension of 2-amino-3-bromo-5-fluorobenzoic acid in THF in an ice bath was slowly added borane (1.0M/THF, 3 eq). The reaction mixture was stirred at ambient temperature for 24 h. The mixture was recooled to 0° C. and quenched with methanol and concentrated to remove solvent. The residue was taken into ethyl acetate and organic phase was washed with water, saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to give yellow solid in 90% yield. ES/MS m/z 220/222 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:13]#[N:14])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C1(C)C=CC=CC=1.S(Cl)([Cl:24])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:13]#[N:14])[C:10]=1[O:11][CH3:12])[C:5]([Cl:24])=[O:6]
Reactant: COc1c(Cl)cc(C(=O)O)cc1C#N
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(Cl)cc(C(=O)Cl)cc1C#N
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-chloro-5-cyano-4-methoxybenzoic acid (932 mg), toluene (9.3 mL), N,N-dimethylformamide (0.03 mL) and thionyl chloride (0.38 mL) were added, and the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (993 mg) as a brown solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].CC(O)=O.[CH3:9][C:10]([CH3:21])([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:11]=[CH2:12]>CC(OC(C)=O)=O>[CH3:9][C:10]([CH3:21])([CH:11]=[CH2:12])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: C=CC(C)(C)CCc1ccccc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: C=CC(C)(C)CCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
In a flask, was loaded fuming HNO3 (18.7 mL, 90%, d=1.5), HOAc (18 mL), Ac2O (14 mL), which was allowed to cool back to room temperature before proceeding. This solution was added dropwise to 3,3-dimethyl-5-phenyl-1-pentene (45.8 g, 0.263 mol), which was prepared using the procedure of Reike and coworkers referenced as 12 in the manuscript, in Ac2O (120 mL). The reaction was kept between 0 and −5° C. during the addition. After the addition, the mixture was stirred at 0° C. for 12 h. The reaction mixture was poured into crushed ice (300 g) The product was extracted with ethyl ether (3×200 mL) and the combined organic layers were washed with portions of saturated NaHCO3 (˜300 mL total) until no gas formed on addition of the basic aqueous solution. The organic solution was filtered, and the separated solids were washed with ether (50 mL). The combined aqueous layers were extracted with ether (3×200 mL). The combined ether solutions were dried with MgSO4. The volatiles were removed in vacuo providing the product as a yellow oil in 97% yield (55.95 g) as a mixture of isomers. GC/FID analysis displayed an ortho:para ratio of 49:51. The compound was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@@:10]([CH2:47][CH:48]=O)([CH2:34][CH2:35][O:36][Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:28][CH2:29]3)(=[O:25])=[O:26])[C:11](=[O:33])[C@@:10]([CH2:47][CH2:48][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)([CH2:34][CH2:35][O:36][Si:37]([CH:38]([CH3:40])[CH3:39])([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:43])[CH3:42])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](CC=O)(CCO[Si](C(C)C)(C(C)C)C(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C1COCCN1
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@](CCO[Si](C(C)C)(C(C)C)C(C)C)(CCN2CCOCC2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
N—((S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-(2-oxoethyl)-3-(2-((triisopropylsilyl)oxy)ethyl)piperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide (Example 408, Step F) and morpholine were combined according to a procedure similar to the one described in Example 91, Step F. Purification by chromatography on silica gel (eluent: 50 to 100% EtOAc/DCM, gradient elution over 15 min) provided the title compound as a clear, colorless glass.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[C@@H:17]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]4[O:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[C:24]=4[CH:34]=3)[CH2:16][N:15]([S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C@@H:14]([CH2:45][C:46]([OH:48])=[O:47])[CH2:13]2)=[CH:8][CH:7]=1>CCOCC.CO>[CH3:3][O:47][C:46](=[O:48])[CH2:45][C@H:14]1[CH2:13][C@H:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:11][CH:10]=2)[C@@H:17]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]3[O:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[C:24]=3[CH:34]=2)[CH2:16][N:15]1[S:35]([C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=1)(=[O:36])=[O:37]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)OC)C[C@@H]3c3ccc(OC)cc3)cc21
Reaction time: 3.5 h

Procedure:
4 ml of a solution of diazomethane in ether (0.2M) are added dropwise to a solution of 0.12 g of [(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetic acid (from example 25f) in 2 ml of methanol at 0° C. The reaction mixture is worked up after 3.5 hours by quenching with solid magnesium sulfate to decompose any excess diazomethane, filtering and concentrating under reduced pressure to afford the crude title compound as a pale yellow solid with was used in the next step without any further purification. Rf=0.78 (EtOAc); Rt=5.26.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]1[C:14]2[N:15]=[CH:16][S:17][C:13]=2[CH:12]=[CH:11][CH:10]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].[Pd].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>[C:2]1([C:9]2[C:14]3[N:15]=[CH:16][S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: Clc1cccc2scnc12
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: c1ccc(-c2cccc3scnc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
a 500 mL 2-neck round-bottomed flask was equipped with a reflux condenser and replaced by nitrogen. 70 mL of THF that was dried with Mg metal (0.11 mol) was added to the above flask and then, 1-bromobenzene (0.10 mol) was added in a dropwise fashion. The reaction was significantly exodermic and thus a cooling bath was equipped to reduce the temperature inside the reactor less than 50° C. It was agitated for 2 hours at room temperature, zinc chloride (0.1 μmol) was added with 100 mL of THF, and further agitated for 2 hours to obtain a slurry-phase reaction mixture. Another flask was replaced by nitrogen and then 0.10 mol of 4-chlorobenzothiazole derivative, 0.10 mol of Pd, and 3 mol % of Pd(PPh3)4 were dissolved in 100 mL of THF. The prepared solution was added to the reaction mixture and then agitated 60° C. for 24 hours. After the reaction is complete, the resulting product was placed on a silica gel column to remove an inorganic slurry, and then a THF solution was concentrated under vacuum to obtain 4-phenylbenzo[d]thiazole using column chromatography at a yield of 91%.