Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=[O:4])[CH:2]=[CH2:3].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=1.N12CCN(CC1)CC2>>[OH:24][CH:23]([C:19]1[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=1)[C:2](=[CH2:3])[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=1)=[O:4]
Reactant: C=CC(=O)OCc1cccc(C(F)(F)F)c1
Reactant: O=Cc1cccnc1
Agent: C1CN2CCN1CC2
Product: C=C(C(=O)OCc1cccc(C(F)(F)F)c1)C(O)c1cccnc1
Reaction time: 8 h
Yield: 52 %

Procedure:
A mixture of 62 mg (0.27 mmol) of 3-(trifluoromethyl)phenylmethyl acrylate, 29 mg (0.27 mmol) of pyridine-3-carboxaldehyde, and 30 mg (0.27 mmol) of 1,4-diazabicyclo [2.2.2]octane (DABCO) was thoroughly shaken on a Vortex mixer, and then stored at 0° C. overnight. The product was purified by preparative HPLC (prep HPLC) using a Gilson 210 HPLC/fraction handler to give 47 mg (0.14 mmol; 52% yield) of the desired Baylis-Hillman adduct, 3-(trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-3-pyridinepropanoate. 1H NMR (CDCl3): δ 5.18 (s, 2H), 5.63 (1H), 5.98 (1H), 6.45 (1H), 7.70 (d of t, 1H), 8.49 (d of d, 1H), and 8.56 ppm (d, 1H). MS m/z: 338.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][C:3]=1[CH3:13]>C(O)C.[Pd]>[F:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([NH2:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(F)c(C)cc1N
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of 1-fluoro-5-methoxy-2-methyl-4-nitro-benzene (5.5 g, 29.3 mmol) and 10% Pd—C (1.56 g) in ethanol (300 mL, 0.1 M) was hydrogenated at 1 atm. After stirring overnight, the solution was flushed through a pad of silica gel using 400 mL of ethanol as the eluant. The filtrate was concentrated under reduced pressure to afford 4-fluoro-2-methoxy-5-methyl-phenylamine (4.5 g, 99%) as a pale purple solid: mp 108–110° C.; Rf 0.35 (30% ethyl acetate in heptane); 1H NMR (DMSO-d6, 300 MHz) δ 6.62 (d, J=11.4 Hz, 1 H), 6.43 (d, J=7.8 Hz, 1 H), 3.70 (s, 3 H), 2.02 (d, J=1.8 Hz, 3 H); ESI-LC/MS m/z calcd for C8H10FNO: 155.1; Found 156.0 (M+1)+. Anal. calcd for C8H10FNO: C, 61.92; H, 6.50. Found: C, 61.64; H, 6.53.
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[F-].[Cs+].[N:22]1([CH2:28][CH2:29][O:30][C:31]2[CH:59]=[CH:58][C:34]([O:35][C:36]3[C:45](OS(C(F)(F)F)(=O)=O)=[CH:44][CH:43]=[C:42]4[C:37]=3[CH:38]=[CH:39][C:40]([O:54][C:55](=[O:57])[CH3:56])=[CH:41]4)=[CH:33][CH:32]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[CH3:60][S:61]([C:64]1[CH:69]=[CH:68][C:67](OS(C(F)(F)F)(=O)=O)=[CH:66][C:65]=1[O:78][CH3:79])(=[O:63])=[O:62]>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH3:60][S:61]([C:64]1[CH:69]=[CH:68][C:67]([C:45]2[C:36]([O:35][C:34]3[CH:58]=[CH:59][C:31]([O:30][CH2:29][CH2:28][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:32][CH:33]=3)=[C:37]3[C:42](=[CH:43][CH:44]=2)[CH:41]=[C:40]([O:54][C:55](=[O:57])[CH3:56])[CH:39]=[CH:38]3)=[CH:66][C:65]=1[O:78][CH3:79])(=[O:63])=[O:62]
Reactant: CC(=O)Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)ccc1S(C)(=O)=O
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: COc1cc(-c2ccc3cc(OC(C)=O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)ccc1S(C)(=O)=O
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 32.4 %

Procedure:
Combine Pd(OAc)2 (46 mg, 0.20 mmol), tricyclohexylphosphine (95 mg, 0.34 mmol), and CsF (1.85 g, 12.26 mmol) in CH3CN (20 mL) under N2. Stir the reaction mixture for 5 minutes. Add acetic acid 5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-6-trifluoromethanesulfonyloxy-naphthalen-2-yl ester (730 mg, 1.36 mmol) and bis(neopentyl glycolate)diboron (460 mg, 2.04 mmol) to the reaction mixture. Heat to 90° C. and stir for about 5 minutes. Add trifluoro-methanesulfonic acid 4-methanesulfonyl-3-methoxy-phenyl ester (500 mg, 1.5 mmol) and continue to heat the mixture for two hours. Cool to room temperature, add water (100 mL), and extract the aqueous layer with CH2Cl2 (3×100 mL). Combine the organic layers and dry with Na2SO4, filter and concentrate. Purify by flash column chromatography (silica gel, 0 to 5% MeOH/CH2Cl2) to give 260 mg of the title compound (33%): mass spectrum (ion spray): m/z=590.4 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(O)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: O=C1CCC(O)(c2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC=C(c2ccc(F)cc2)CC1
Yield: 96 %

Procedure:
To 17 ml. of well stirred trifluoroacetic acid, 0.16 g. of 4-(p-fluorophenyl)-4-hydroxycyclohexanone (obtained as in Example 3) is added. At the end of about 5 minutes the mixture is poured into an excess of aqueous sodium bicarbonate solution. The solid material is collected on a filter and recrystallized from petroleum ether to give a 96% yield of 4-(p-fluorophenyl)-3-cyclohexen-1-one melting at 44.5° to 46.5° C.
Reaction SMILES: [C:1]1([C:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)([OH:11])[CH2:8][CH2:9]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:18]#[N:19].[Na+]>CS(C)=O>[C:1]1([C:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)([OH:11])[CH2:8][CH2:9][C:18]#[N:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(CCCl)(c1ccccc1)C1CCCCC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCC(O)(c1ccccc1)C1CCCCC1
Temperature: 140 °C
Yield: 78.8 %

Procedure:
A mixture of 1-phenyl-1-cyclohexyl-3-chloro-1-propanol (3.8 g) and sodium cyanide (0.69 g) in 11 ml of dimethyl sulphoxide (DMSO) was heated at 140° C. for 3 hours. The mixture was poured into ice, then the water was extracted with ether. The solvent was removed and the residue triturated with diisopropylic ether to afford 2.7 g of 1-phenyl-1-cyclohexyl-3-cyano-1-propanol. M.p. 97°-101° C.
Reaction SMILES: [I:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:13])[CH:11]=[CH2:12])=[C:4]([CH3:14])[CH:3]=1.CN(C)C=O.[NH:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27](=[O:41])[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:22][CH2:21]1>C(O)(C)C>[I:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([CH2:11][CH2:12][N:20]2[CH2:21][CH2:22][CH:23]([O:26][C:27](=[O:41])[NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:24][CH2:25]2)=[O:13])=[C:4]([CH3:14])[CH:3]=1
Reactant: C=CC(=O)Nc1cc(C)c(I)cc1C
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1I
Temperature: 50 °C
Reaction time: 24 h
Yield: 93.2 %

Procedure:
To a solution of N-(4-iodo-2,5-dimethylphenyl)acrylamide (32.2 g, 107 mmol) in a 6:1 v/v mixture of N,N-dimethylformamide and isopropanol (700 mL) was added biphenyl-2-ylcarbamic acid piperidin-4-yl ester (36.3 g, 123 mmol). The resulting mixture was heated at 50° C. for 24 hours and then at 80° C. for 24 hours. The reaction mixture was then cooled to room temperature and concentrated under vacuum. The residue was dissolved in dichloromethane (1 L) and this solution was washed with 1N aqueous hydrochloric acid (500 mL), water (500 mL), brine (500 mL) and saturated aqueous sodium bicarbonate solution (500 mL). The organic layer was then dried over anhydrous magnesium sulfate and filtered. Ethanol (400 mL) was added and the resulting mixture was concentrated under vacuum to a volume of about 400 mL, at which time a precipitate had formed. The precipitate was filtered and dried to afford biphenyl-2-ylcarbamic acid 1-[2-(4-iodo-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (59.6 g, 84% purity, 79% yield). m/z: [M+H+] calcd for C29H32IN3O3 598.49; found 598.5.
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:8])[CH2:6][NH2:7].C(O[C:12](=O)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[CH:16]=1)C>C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:12]2[NH:7][CH2:6][CH2:5][N:8]=2)=[CH:16][C:17]=1[F:22]
Reactant: CCOC(=O)COc1ccc(Cl)c(F)c1
Reactant: NCCN
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Fc1cc(OCC2=NCCN2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To dry toluene (4 ml) under an inert atmosphere at 0° C. was added a toluene solution of trimethylaluminium (3.44 ml, 6.88 mmol, 2 M solution). A solution of ethylenediamine (0.46 ml, 6.88 mmol) in toluene (1.5 ml) was then added dropwise and the reaction mixture was then allowed to warm to room temperature and stirred for 1 h at this temperature before being re-cooled to 0° C. To this mixture was added dropwise a solution of (4-chloro-3-fluoro-phenoxy)-acetic acid ethyl ester (0.80 g, 3.44 mmol) in toluene (3 ml). The reaction mixture was then heated at 95° C. for 45 min and then cooled first to room temperature and finally to 0° C. The mixture was quenched by dropwise addition of methanol (1 ml) and when all gas evolution had ceased the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was triturated in ether to yield a white solid (0.73 g, 92%) which was collected by filtration; MS (ISP): 231.2, 229.3 ([M+H]+.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-])=O.C(N(CC)CC)C.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](Cl)=[O:24]>C(O)C.[Pd]>[NH:6]1[CH:5]=[C:4]([NH:1][C:23](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: O=C(Cl)c1ccccn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Nc1cn[nH]c1)c1ccccn1
Reaction time: 3 h

Procedure:
A solution of 4-nitro-1H-pyrazole (2.5 g, 22 mmol) in ethanol (80 mL) was added to a Parr vessel under an argon atmosphere. Carefully into the vessel, 10% Pd/C (0.2 g) was added. The vessel was sealed and H2 was added to a pressure of 40 psi. The vessel was shaken for 3 hours and then the catalyst removed by filtration. The catalyst was washed with ethanol and the combined filtrates where evaporated to dryness under reduced pressure. The residue was dissolved in THF (350 mL), treated with triethyl amine (6.9 mL, 49 mmol) and cooled on an ice bath under an argon atmosphere. Picolinoyl chloride hydrochloride (3.94 g, 22.3 mmol) was added in one portion. When the reaction was complete, the solvent was removed under reduced pressure and the residue dissolved in dichloromethane. The solution was extracted with water, NaHCO3 sat, dried, and the solvent removed under reduced pressure. The crude residue was re-crystallized from ethyl acetate to afford N-(1H-pyrazol-4-yl)picolinamide. (2.19 g, 52%). 1H NMR (DMSO-d6) δ 10.88 (s, 1 H), 8.7 (s, 1 H), 8.12 (m, 2 H), 8.04 (m, 1 H,), 7.96 (s, 1 H), 7.65 (m, 1 H). MS: m/z=189[M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C@H:4]2[C:11](=[O:12])[N:10]3[C@H:6]([CH2:7][O:8][C@@H:9]3[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:5]2[CH:19]=1>CCO.[Pd]>[CH3:1][CH:2]1[CH2:19][C@@H:5]2[C@@H:6]3[N:10]([C:11](=[O:12])[C@@H:4]2[CH2:3]1)[C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:8][CH2:7]3
Reactant: CC1=C[C@@H]2[C@H]3CO[C@H](c4ccccc4)N3C(=O)[C@@H]2C1
Agent: [Pd]
Solvent: CCO
Product: CC1C[C@@H]2[C@H]3CO[C@H](c4ccccc4)N3C(=O)[C@@H]2C1
Reaction time: 1.5 h

Procedure:
A solution of (1R,3aS,3bS,6aR)-5-methyl-1-phenyl-3a,3b,6,6a-tetrahydro-3H-2-oxa-7a-aza-cyclopenta[a]pentalen-7-one (Jao E. et al Tetrahedron Letters, 2003, 44, 5033-5035) (2.34 g) in EtOH (23 mL) was treated with Pd/C 10% (456 mg) and stirred under hydrogen (1 bar) for 1.5 h. After filtration through celite and removal of the solvents the title compound was obtained as an oil, which was used without further purification.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([NH:10][C:11]3[N:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH:13]=O)[CH:7]=[CH:6][C:5]=12.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])[CH:20]=1.[Li+].CC([N-]C(C)C)C>>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([N:10]3[C:11]4[C:12](=[CH:15][CH:16]=[CH:17][N:18]=4)[CH:13]=[C:28]([CH2:27][CH2:26][CH2:25][C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[C:29]3=[O:30])[CH:7]=[CH:6][C:5]=12
Reactant: O=Cc1cccnc1Nc1ccc2nsnc2c1
Reactant: CCOC(=O)CCCCc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=c1c(CCCc2cccnc2)cc2cccnc2n1-c1ccc2nsnc2c1
Yield: 48 %

Procedure:
The procedure of Example 1 was repeated using 2-(2,1,3-benzothiadiazol-5-ylamino)nicotinaldehyde (1.0 eq., prepared in Synthetic Example 1a)), ethyl 5-(pyridin-3-yl)pentanoate (1.5 eq., prepared in Synthetic Example 3) and LDA (1.5 eq.) to obtain 1-(2,1,3-benzothiadiazol-5-yl)-3-[3-(pyridin-3-yl)propyl]-1,8-naphthyridin-2(1H)-one (yield, 48%). The product was purified through flash column chromatography and recrystallization (mp 173.5–174.5° C./DMF).
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([O-:12])=[O:11])=[C:7]([N:13]([CH:23]2[CH2:28][CH2:27][P:26]([O:30][CH3:31])(=[O:29])[CH2:25][CH2:24]2)[C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1.[Li+].[OH-].Cl>CO.C1COCC1>[CH3:32][C:2]([CH3:1])([CH3:33])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([CH:23]2[CH2:28][CH2:27][P:26]([O:30][CH3:31])(=[O:29])[CH2:25][CH2:24]2)[C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1
Reactant: COP1(=O)CCC(N(c2cc(C#CC(C)(C)C)sc2C(=O)[O-])C(=O)[C@H]2CC[C@H](C)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COP1(=O)CCC(N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(1-methoxy-1-oxo-1λ5-phosphinan-4-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylate (36 mg, 0.07 mmol) was dissolved in 1 mL of methanol and 1 mL of THF, and to the solution was added 0.2 mL of 1 N LiOH. The reaction mixture was stirred at room temperature for 5 hours, and then cooled to 0° C. and neutralized with 0.4 mL of 0.5 N HCl. After removal of solvent, the residue was purified by HPLC (Gemini column; 5% acetonitrile:water, 5 min; 5-100% acetonitrile:water, 18 min; 100% acetonitrile, 6 min; both solvents containing 0.1% trifluoroacetic acid), resulting in 20 mg (57%) of the title compound. MS (m/z): 494.2 [M+H]+; HPLC retention time: 4.144 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: N(OC(C)(C)C)=O.[F:8][C:9]1[C:15]([CH3:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([CH3:19])[C:10]=1N>CN(C)C=O>[F:18][C:13]1[C:14]([F:17])=[C:15]([CH3:16])[C:9]([F:8])=[CH:10][C:12]=1[CH3:19]
Reactant: Cc1c(N)c(F)c(C)c(F)c1F
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Product: Cc1cc(F)c(C)c(F)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A solution of t-butyl nitrite (4.56 g) in anhydrous dimethylformamide (26.5 ml) is stirred with heating at 50°-52° C. and thereto a solution of 2,4,5-trifluoro-3,6-dimethylaniline (4.24 g) in anhydrous dimethylformamide (40 ml) is added dropwise at 50°-52° C. over a period of 30 minutes. The mixture is further stirred at the same temperature for 30 minutes. After cooling, the mixture is poured into ice-water, extracted with diethyl ether, and the extract is washed with water, and then with diluted hydrochloric acid and dried. The diethyl ether is distilled off under atomospheric pressure and the residue is concentrated and distilled under atomospheric pressure to give 2,3,5-trifluoro-4-methyltoluene (1.9 g), as yellow oil, b.p. 120°-125° C.
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:5]=[C:6]([N+:19]([O-])=O)[C:7]2[O:13][CH2:12][CH2:11][C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:9][C:8]=2[CH:18]=1>CO.O.[Fe]>[Cl:3][C:4]1[CH:5]=[C:6]([NH2:19])[C:7]2[O:13][CH2:12][CH2:11][C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:9][C:8]=2[CH:18]=1
Reactant: COC(=O)C1=Cc2cc(Cl)cc([N+](=O)[O-])c2OCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)C1=Cc2cc(Cl)cc(N)c2OCC1
Reaction time: 6 h
Yield: 55.1 %

Procedure:
To a suspension of iron (reduced, 13.6 g) and ammonium chloride (1.6 g) in a mixture of methanol (140 ml) and water (50 ml) was added methyl 2,3-dihydro-7-chloro-9-nitro-1-benzoxepin-4-carboxylate (13.8 g) in portions under reflux. The reaction mixture was stirred for 6 hours under reflux. The iron powder was filtered off and the solvent was removed by concentration. The residue was diluted with ethyl acetate. The organic solvent was washed successively with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel using chloroform as an eluent. The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 2,3-dihydro-7-chloro-9-amino-1-benzoxepin-4-carboxylate (6.8 g).
Reaction SMILES: [C-:1]#[N:2].[Na+].[N+:4]([C:7]1[CH:25]=[CH:24][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22]Cl)=[O:12])=[CH:9][CH:8]=1)([O-:6])=[O:5].O>CS(C)=O>[N+:4]([C:7]1[CH:25]=[CH:24][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][C:1]#[N:2])=[O:12])=[CH:9][CH:8]=1)([O-:6])=[O:5]
Reactant: O=C(NCCc1ccccc1CCl)c1ccc([N+](=O)[O-])cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccccc1CCNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 74.5 %

Procedure:
Sodium cyanide (2.9 g) was dissolved in 100 ml of dimethylsulfoxide, and with stirring at room temperature, 15.5 g of 1-(4-nitrobenzoyl)amino-2-(2-chloromethylphenyl)ethane was gradually added. The reaction was performed at room temperature for 10 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed in water, and dried. The solvent was distilled off, and the residue was recrystallized from ethanol to afford 11.2 g of 1-(4-nitrobenzoyl)amino-2-(2-cyanomethylphenyl)ethane having a melting point of 118.6° to 119.1° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[CH:9]([F:11])[F:10].[CH2:12]([S-:14])[CH3:13].[Na+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:14][CH2:12][CH3:13])=[CH:4][C:3]=1[CH:9]([F:11])[F:10]
Reactant: Fc1ccc(Br)c(C(F)F)c1
Reactant: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCSc1ccc(Br)c(C(F)F)c1
Yield: 28.4 %

Procedure:
1-Bromo-2-(difluoromethyl)-4-fluorobenzene (Preparation 50, 772 mg, 3.43 mmol) and sodium ethanethiolate (352.7 mg, 3.77 mmol) in DMSO (5 mL) was heated at 50° C. for 18 hours. On cooling, water (70 mL) was added to the reaction mixture, the product was extracted with EtOAc (20 mL×3). The combined organic layers were concentrated to give the crude product, which was purified by silica gel column chromatography eluting with heptane to afford the title compound as a colourless oil (260 mg, 28%).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:5][CH2:4][CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1])(=[O:18])=[O:17]
Reactant: CC(C)(C)CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3,3-dimethyl-1-butanol (2 ml) in dichloromethane (48 ml), under nitrogen, was added triethylamine (4.64 ml) and the resulting solution cooled to 0/C. Methanesulphonylchloride (1.28 ml) was then added dropwise via syringe and stirring continued for 18 h as the reaction warmed to room temperature. The reaction was then concentrated onto silica and purified by flash chromatography to give the title compound as a yellow oil.
Reaction SMILES: [CH3:1][NH2:2].[CH:3]12[O:8][CH:7]1[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2>C(OC(C)C)(C)C>[OH:8][CH:3]1[CH:7]([NH:2][CH3:1])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Solvent: CC(C)OC(C)C
Product: CNC1CN(C(=O)OC(C)(C)C)CC1O
Yield: 96 %

Procedure:
Aqueous methylamine solution (40% solution, 812 mL, 3.8 mol) was added to the epoxide 3 (140 g, 0.65 mol) at room temperature and the reaction was stirred until complete. The excess methylamine was removed by distillation under reduced pressure. To the residue obtained, diisopropyl ether (800 mL) was added and the mixture stirred for about 30 min. The solid was filtered, washed with diisopropyl ether (200 mL), then dried to give compound 4 (135 g).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:16][CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].[C:27](OC)(=[O:32])[C:28]([O:30][CH3:31])=[O:29].C(=O)=O>O1CCCC1>[CH3:31][O:30][C:28](=[O:29])[C:27]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:16][CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[O:32]
Reactant: COC(=O)C(=O)OC
Reactant: CC(C)(C)[Si](C)(C)OCCCn1ccc2c(Br)cccc21
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1cccc2c1ccn2CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
Add tert-butyl lithium (88.1 ml, 149.8 mmol, 1.7 M in hexane) to a solution of 4-Bromo-[3-(tert-butyldimethylsilyloxy)propyl]-1H-indole (22.0g, 59.92 mmol) in anhydrous tetrahydrofuran (100 ml) at −78° C. Stir the reaction at −78° C. for 20 min. Transfer the mixture into a solution of dimethyl oxalate (24.8g, 209.72 mmol) in tetrahydrofuran (400ml) at −40° C. via a dry-ice cooled cannula. Upon complete addition, stir the reaction at −78° C. for 15 minutes and slowly warm to room temperature. Quench the reaction with saturated aqueous ammonium chloride and extract into ethyl acetate. Combine the organic layers, dry over magnesium sulfate, and concentrate under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate: hexane gradient 100% hexane to 15% ethyl acetate:hexane over 90 minutes) gives the title compound, as a light brown oil.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:12](=[CH:13][CH:14]=1)[CH:11]1[CH2:15][CH:7]2CN[CH2:10]1)([O-])=O.[CH2:16](N(CC)CC)[CH3:17].C(Cl)Cl.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>O>[CH3:16][CH:17]=[CH:5][CH:4]=[CH:14][CH:13]=[CH:12][CH2:6][CH2:7][CH2:15][CH2:11][CH3:10]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc2c(c1)C1CNCC2C1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC=CC=CC=CCCCCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 108.4 %

Procedure:
In a 30 ml reaction vial 4-nitro-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (195 mg, 0.955 mmol), Triethylamine (0.40 mL, 2.9 mmol) were charged to methylene chloride (10 mL, 200 mmol). The reaction was cooled to 0° C. and the methanesulfonyl chloride (81 uL, 1.0 mmol) added dropwise with a syringe. The reaction was allowed to stir at 0° C. for 30 minutes. The reaction was poured into water (20 ml) and saturated sodium bicarbonate solution (20 ml) and the layers separated. The aqueous was washed with another 2×10 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to yield 10-methanesulfonyl-4-nitro-10-aza tricycle[6.3.1.0*2,7*]dodeca-2,4,6-triene (170 mg, 63%) as a brown oil that was used crude in the next reaction. 1H-NMR (CDCl3) δ 8.17 (d, J=6.1 Hz, 1H), 8.13 (s, 1H), 7.39 (d, J=8.1 Hz, 1H), 3.77-3.68 (m, 2H), 3.41-3.28 (m, 4H), 2.52-2.42 (m, 1H), 2.30 (s, 3H), 1.92 (d, J=11.1 Hz), LC/MS (ESI+): 283 (M+H).