Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[NH:11][C:10]([C:18]([OH:20])=O)=[CH:9]2.[CH2:21]([S:28][CH:29]([CH:32]([O:35][CH3:36])[O:33][CH3:34])[CH2:30][NH2:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CCCCCC.C(OCC)(=O)C.CN(C)C=O>[CH2:21]([S:28][CH:29]([CH:32]([O:33][CH3:34])[O:35][CH3:36])[CH2:30][NH:31][C:18]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=2[N+:15]([O-:17])=[O:16])=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(OC)C(CN)SCc1ccccc1
Reactant: COCCOc1cc([N+](=O)[O-])c2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1cc([N+](=O)[O-])c2[nH]c(C(=O)NCC(SCc3ccccc3)C(OC)OC)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.5 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-nitro-1H-indole-2-carboxylic acid (4.7 g), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (4.9 g), 1H-1,2,3-benzotriazol-1-ol (3.4 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (4.9 g) and N,N-dimethylformamide (150 mL) was stirred at room temperature for 15 hr. The reaction solution was concentrated under reduced pressure, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=20:80-80:20) to give the title compound (6.8 g, yield 97%) as a orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[O:23][C:22]2[CH2:21][CH2:20][NH:19][CH:18]([CH3:24])[C:17]=2[CH:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[O:23][C:15]([CH3:14])=[CH:16][C:17]=4[CH:18]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: Cc1cc2c(o1)CCNC2C
Product: Cc1cc2c(o1)CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2C
Yield: 10 %

Procedure:
In close analogy to the procedure described in Example 11, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,4-Dimethyl-4,5,6,7-tetrahydro-furo[3,2-c]pyridine to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH2:30][OH:31])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:39]([O:41][CH2:42][CH2:43][Br:44])=[O:40].Cl>ClCCl.O>[CH2:1]([O:8][C@H:9]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:30][O:31][C:39]([O:41][CH2:42][CH2:43][Br:44])=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCCBr
Reactant: CCCCCCCCCCCCCCCCCCOC[C@H](CO)OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOC[C@H](COC(=O)OCCBr)OCc1ccccc1
Temperature: 0 °C

Procedure:
A solution of 0.5 g of (S)-2-O-benzyl-1-O-octadecyl glycerine in 25 ml of dichloromethane is treated with 0.3 ml of pyridine and cooled to 0° C. The solution is treated with 0.2 ml of 2-bromoethyl chloroformate, stirred at room temperature, treated with 10 ml of water and acidified to pH 3 with 1N hydrochloric acid. The organic phase is washed with water, dried and evaporated. The residue is chromatographed on silica gel while eluting with ether/n-hexane (1:1). There is obtained (R)-2-O-benzyl-1-[(2-bromoethoxy)carbonyl]-3-O-octadecylglycerine in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([F:22])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.CC(OC)(C)C.Cl[Pd]Cl>[ClH:1].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[C:15]([F:22])[CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(=O)c1ccnc(-c2ccc(Cl)cc2F)c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 102.5 %

Procedure:
Methyl 2-chloroisonicotinate (4 g, 23.31 mmol), 4-chloro-2-fluorophenylboronic acid (6.10 g, 34.97 mmol), potassium carbonate (2.416 g, 17.48 mmol) and PdCl2 (dppf) (0.506 g, 0.70 mmol) were mixed in methanol (30 mL) in two separate 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. Water and DCM were added and the phases were separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a dark-orange solid. The solid was dissolved in MTBE and stirred for 15 minutes, then filtered. The orange MTBE layer was treated with hydrogen chloride (4 M in dioxane, 5.83 mL, 23.31 mmol) and stirred for 1 h at room temperature. The precipitate was collected by filtration to yield methyl 2-(4-chloro-2-fluorophenyl)isonicotinate hydrochloride (7.22 g, quant.) as a slightly orange solid. MS m/z 266 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:14][CH2:13][C@H:12]3[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][N:11]3[CH2:10]2)=[CH:5][C:4]=1[O:26][CH3:27])#[N:2].[ClH:28]>O1CCOCC1>[ClH:28].[CH3:27][O:26][C:4]1[CH:5]=[C:6]([C@@H:9]2[O:14][CH2:13][C@H:12]3[CH2:15][NH:16][CH2:17][CH2:18][N:11]3[CH2:10]2)[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: COc1cc([C@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3CO2)ccc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc([C@H]2CN3CCNC[C@@H]3CO2)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (3S,9aR)-3-(4-cyano-3-methoxyphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (520 mg, 1.39 mmol) was dissolved in 10 Ml of 4 M HCl in dioxane and stirred at room temperature for 8 h. The mixture was concentrated to ¼ the original volume and diluted with 10 Ml of diethyl ether. The precipitate was filtered and dried under high vacuum to offer the title amine HCl salt: 1H NMR (DMSO-d6, E (trans) isomer, 500 MHz) δ 7.76 (d, J=8.0 Hz, 1H), 7.25 (s, 1H), 7.11 (d, J=7.9 Hz, 1H), 5.0 (bs, 1H), 4.17 (bs, 1H), 3.94 (s, 3H), 3.85-3.60 (bs, 2H), 3.62-3.34 (m, 6H), 1.69 (bs, 2H); LC/MS: (IE, m/z) [M+1]+=274.
Reaction SMILES: [C:1]1([CH:7]([N:14]2[CH2:17][CH:16]([C:18]#[N:19])[CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[Na]>O1CCCC1>[NH2:19][CH2:18][CH:16]1[CH2:15][N:14]([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:17]1
Reactant: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 65.6 %

Procedure:
A solution of 1-(1,1-diphenylmethyl)azetidine-3-carbonitrile (7.8 g, 31.4 mmol) in 30 mL of tetrahydrofuran was slowly added to a suspension of lithium aluminium hydride (4.0 g, 105 mmol) in tetrahydrofuran under nitrogen and the resulting mixture was stirred under reflux for one hour. On cooling, the mixture was treated dropwise with water (4 mL), aqueous sodium hydroxyde (4 mL, 4N), and water (12 mL) and filtered. The filtrate was concentrated under reduced pressure to yield 3-(aminomethyl)-1-(1,1-diphenylmethyl)azetidine as a white solid (5.2 g, 73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([OH:17])[CH:16]=[C:12]2[C:11]([CH3:18])=[N:10][N:9]=1.[Br:19]Br>C(O)(=O)C.O>[Br:19][C:16]1[C:15]([OH:17])=[N:14][N:13]2[C:12]=1[C:11]([CH3:18])=[N:10][N:9]=[C:8]2[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: BrBr
Reactant: Cc1nnc(-c2ccccc2F)n2nc(O)cc12
Solvent: CC(=O)O
Solvent: O
Product: Cc1nnc(-c2ccccc2F)n2nc(O)c(Br)c12
Yield: 94.5 %

Procedure:
To a stirred solution of 7-(2-fluorophenyl)-2-hydroxy-4-methylpyrazolo[1,5-d][1,2,4]triazine (1.48 g, 6.06 mmol) in glacial acetic acid (20 ml) was added, dropwise, bromine (0.343 ml, 6.66 mmol) and the mixture was stirred at room temperature for 20 min. The mixture was then diluted with water (80 ml) and the resulting solid was collected by filtration, washed with water and dried at 60° C. under vacuum to afford 1.85 g (94%) of the title compound as a cream solid: 1NMR (360 MHz, DMSO-d6) δ 2.88 (3H, s), 7.42-7.47 (2H, m), 7.67-7.76 (2H, m); MS (ES+) m/e 323/325 [M+H]+.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)[NH:10][C:11]2[O:12][CH2:13][C:14]([F:41])([F:40])[C@:15]3([N:39]=2)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:25]=C(C4C=CC=CC=4)C4C=CC=CC=4)[CH:23]=2)[S:18][CH2:17][CH2:16]3)=CC=1.FC(F)(F)C(O)=O.Cl>ClCCl>[F:41][C:14]1([F:40])[C@@:15]2([C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH2:25])[CH:23]=3)[S:18][CH2:17][CH2:16]2)[N:39]=[C:11]([NH2:10])[O:12][CH2:13]1
Reactant: COc1ccc(C(NC2=N[C@@]3(CCSc4ccc(N=C(c5ccccc5)c5ccccc5)cc43)C(F)(F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(CCSc3ccc(N)cc32)C(F)(F)CO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.9 %

Procedure:
A solution of (R)—N2-(bis(4-methoxyphenyl)(phenyl)methyl)-N6′-(diphenylmethylene)-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4′-thiochroman]-2,6′-diamine (613 mg, 815 μmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (930 mg, 8.15 mmol). The orange colored solution was stirred at room temperature for 15 hours. Thereafter, the reaction mixture was diluted with dichloromethane (10 ml) and washed with a 1M-solution of sodium carbonate (5 ml). The organic layer was separated, dried over sodium sulphate and evaporated. The resulting yellow oil was dissolved in dioxane (8 ml), then hydrochloric acid (4N in dioxane, 2.04 ml) was added dropwise. A precipitate was formed, which dissolved after addition of hydrochloric acid (4N in dioxane, 2.0 ml). The orange colored solution was stirred at room temperature for 15 hours. For the workup, the solution was evaporated at reduced pressure and the residue dissolved in ethyl acetate (30 ml). The organic layer was washed with hydrochloric acid (1N, 8 ml), the aqueous layer was separated and adjusted to pH 9 by addition of sodium hydroxide (2N). Thereafter, the aqueous layer was extracted with ethyl acetate (3×30 ml), the organic layers combined and dried over sodium sulphate. After evaporation at reduced pressure, the (R)-5,5-difluoro-5,6-dihydro spiro[[1,3]oxazine-4,4′-thiochroman]-2,6′-diamine (230 mg, 89% yield) was obtained as a yellow solid pure enough to be used in the next step without further purification. MS (ISP): m/z=286.1 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22]>C1(C)C=CC=CC=1.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]>[C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([CH:21]=[CH2:22])=[CH:18][CH:19]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1ccc(Cl)nc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 3-(1-BOC-2-(S)-azetidinylmethoxy)-6-chloropyridine (1.8 g, 6.04 mmol) in toluene (25 mL) was added vinyltributyltin (2.7 mL, 9.06 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (180 mg). After heating at reflux for 16 h, the resulting mixture was cooled to room temperature and the solvent was removed. The residue was chromatographed (silica gel; hexane/EtOAc, 10:1) to afford the title compound (1.49 g, 85%): 1H NMR (CDCl3, 300 MHz) δ 1.40 (s, 9H), 2.25-2.30 (m, 2H), 3.85-3.90 (m, 2H), 4.16 (m, 1H), 4.35 (m, 1H), 4.54 (m, 1H), 5.35 (dd, 1H, J=1.0, 12.0 Hz), 6.05 (dd, 1H, J=1.0, 18.0 Hz), 6.80 (dd, 1H, J=12.0, 18.0 Hz), 7.20-7.26 (m, 2H), 8.35 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 291 (M+H)+, 319 (M+NH4)+.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1.Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH3:24])[N:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C@H:9]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH3:24])[N:16]=2)[CH2:10]1
Reactant: C[C@H]1CCCN1[C@H]1CCNC1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
To a solution of (2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl dihydrochloride (0.596 g, 2.64 mmol,) in acetonitrile (25 mL) was added 2-chloro-5-nitro-6-picoline (0.685 g, 3.96 mmol,) and powdered potassium carbonate (1.45 g, 10.6 mmol), then heated to 65° C. for 4.0 hr, then at 45° C. for 16 hr. The reaction mixture was then allowed to cool to room temperature and filtered through a 10.0 g Varian Bond Elut SCX (stong cation-exchange) cartridge eluting with 50 mL of (1:1) methanol in dichloromethane, 25 mL of methanol, followed by 7N ammonia in methanol (50 mL). The filtrate was concentrated under vacuum, to afford 0.633 g (82%) of the title compound.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]([CH3:4])[CH3:3].Cl[C:8]1[C:9]2[N:24]=[C:23]([C:25]3[CH:30]=[C:29]([CH3:31])[C:28]([O:32][CH3:33])=[C:27]([CH3:34])[CH:26]=3)[O:22][C:10]=2[N:11]=[C:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:13]=1.C(OCC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:12]2[N:13]=[C:8]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:9]3[N:24]=[C:23]([C:25]4[CH:26]=[C:27]([CH3:34])[C:28]([O:32][CH3:33])=[C:29]([CH3:31])[CH:30]=4)[O:22][C:10]=3[N:11]=2)=[CH:20][CH:19]=1
Reactant: COc1c(C)cc(-c2nc3c(Cl)nc(Cc4ccc(Cl)cc4)nc3o2)cc1C
Reactant: CC(C)C[Mg]Br
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1c(C)cc(-c2nc3c(CC(C)C)nc(Cc4ccc(Cl)cc4)nc3o2)cc1C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
Under argon and at 0° C., 2.0 ml of a 2.0 M solution of isobutylmagnesium bromide in tetrahydrofuran were slowly added dropwise to a degassed solution of 1.50 g of 7-chloro-5-(4-chlorobenzyl)-2-(4-methoxy-3,5-dimethylphenyl)oxazolo[5,4-d]pyrimidine and 65 mg of iron(III) acetylacetonate in 20 ml of dry tetrahydrofuran. After 15 min at 0° C., diethyl ether was added to the reaction mixture, and 10% strength aqueous citric acid solution was added with ice cooling. The phases were separated, and the aqueous phase was extracted twice with diethyl ether. The combined organic phases was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. From the crude product, 0.80 g (51%) of the title compound was isolated after reprecipitation from acetonitrile.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[NH2:9][CH:10]([CH2:15][CH:16]=[CH:17][CH2:18][O:19][C:20](=[O:22])[CH3:21])[C:11]([O:13][CH3:14])=[O:12].C>O1CCOCC1>[N:9]([CH:10]([CH2:15][CH:16]=[CH:17][CH2:18][O:19][C:20](=[O:22])[CH3:21])[C:11]([O:13][CH3:14])=[O:12])=[C:2]=[O:1]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C(N)CC=CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)C(CC=CCOC(C)=O)N=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of methyl 2-amino-6-acetyloxy-4-hexenoate, prepared as described by D. Ferroud, J. P. Genet, and R. Kiolle in Tetrahedron Letters, 1986, 27, 23-26, and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give methyl 2-isocyanato-6-acetyloxy-4-hexenoate.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:15][CH2:16][CH2:17][Cl:18]>[OH-].[Na+].CC(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][N:5]1[CH2:6][CH2:7][C:2]([OH:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:4]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: OC1(c2ccccc2)CCN(CCCCl)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-hydroxy-4-phenylpiperidine (35.4 g, 0.2 mole) in 50 ml of 20% NaOH and 250 ml of acetone was cooled at <15° and 1-bromo-3-chloropropane (31.4 g, 0.2 mole) was added dropwise. The mixture was stirred at room temperature for 18 hours and concentrated in vacuo at <40°. The concentrate was converted to the HCl salt with HCL(g)/2-PrOH and concentrated in vacuo to an oil. The oil crystallized in hot acetone and the solid salt was collected and dried. The salt was warmed in 2-PrOH, cooled and filtered to remove 8 g of quaternary salt. mp >260°. The filtrate was warmed and diluted with ethyl acetate to obtain the desired salt. Yield 13 g (22.5%), m.p. 173°-6° (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([Cl:10])[N:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+].Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:10][C:4]1[N:3]=[C:2]([NH2:1])[C:7]([C:8]2[NH:13][N:12]=[N:11][N:9]=2)=[CH:6][N:5]=1
Reactant: N#Cc1cnc(Cl)nc1N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)ncc1-c1nnn[nH]1
Temperature: 100 °C
Yield: 43.1 %

Procedure:
Into a sealed tube were added 4-amino-2-chloro-pyrimidine-5-carbonitrile (837 mg, 5.4 mmol), sodium azide (7.1 mmol, 1.3 eq.), triethylamine hydrochloride (7.1 mmol, 1.3 eq.) and 14 mL of toluene. The tube was tightly capped and the reaction was stirred and heated to 100° C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate, transferred to a separatory funnel and extracted three times with water. The aqueous extractions were combined and acidified to a pH of 4 with concentrated HCl. The precipitate was collected by filtration, washed with acetonitrile, and dried under vacuum to afford 460 mg of the product, which was used without further purification. MS (EI) for C5HClN7: 198 (M+H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1.O1CCCC1.[CH:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]=[C:38]=[S:39])([CH3:30])[CH3:29]>ClCCl>[CH:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([C:11]2[N:12]=[CH:13][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=3)[N:10]=2)=[CH:15][CH:16]=1)=[S:39])([CH3:30])[CH3:29]
Reactant: CC(C)c1ccccc1N=C=S
Reactant: Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)c1ccccc1NC(=S)Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 65 °C

Procedure:
To 4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)aniline (0.496 g, 1.63 mmol) in a 25 mL vial equipped with a stir bar, Vigreux column, and nitrogen inlet was added tetrahydrofuran (4.08 mL) followed by 1-isopropyl-2-isothiocyanatobenzene (0.826 ml, 4.89 mmol). The reaction was heated to 65° C. overnight. The reaction was cooled to room temperature. The reaction mixture was diluted with dichloromethane and washed with water. The aqueous layer was extracted with dichloromethane (2×). The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography using 0-20% ethyl acetate/B, where B=1:1 dichloromethane/hexanes as eluent provided a white solid. The solid was dried at 55° C. at about 25 in. Hg providing the title compound as a white solid (0.361 g, 46%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:8][C:9](=[O:26])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=2[O:24][CH3:25])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@H]1CCCC[C@H]1NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound, colorless oil, MS: m/e=568.1 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and N-tert-butoxycarbonyl-4-piperidone.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[C:4]([CH:11]([CH3:13])[CH3:12])[CH:3]=1.[B-](F)(F)(F)[F:15].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N>[F:15][C:3]1[C:4]([CH:11]([CH3:13])[CH3:12])=[C:5]([C:9]#[N:10])[C:6](=[O:8])[NH:7][C:2]=1[CH3:1]
Reactant: F[B-](F)(F)F
Reactant: Cc1cc(C(C)C)c(C#N)c(=O)[nH]1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Cc1[nH]c(=O)c(C#N)c(C(C)C)c1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
To a stirred solution of 6-methyl-2-oxo-4-(propan-2-yl)-1,2-dihydropyridine-3-carbonitrile (225 mg, 1.277 mmol) in MeCN (6 mL) was added Selectfluor (620 mg, 1.75 mmol). The reaction mixture was stirred at 50° C. for 3 h. Alter cooling to 23° C., the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (50% to 100% EtOAc-heptane to obtain the titled compound (90 mg, 36%). 1H NMR (400 MHz, CDCl3) δ ppm 3.39 (m, 1H), 2.44 (d, J=3.1 Hz, 3H), 1.41 (dd, J=7.0, 3.1 Hz, 6H); LCMS E-S (M+H)=195.2.
Reaction SMILES: ClCC([O:5][C@@H:6]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:25]2[C@@H:24]([O:30][C:31](=[O:34])[CH2:32][Cl:33])[CH2:23][C@@:22]2([CH3:35])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:16]2([O:21][CH2:20][CH2:19][O:18]2)[CH3:17])[CH2:7]1)=O.C(=O)(O)[O-].[Na+]>CO>[Cl:33][CH2:32][C:31]([O:30][C@H:24]1[CH2:23][C@@:22]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C@@H:15]2[C:16]2([O:18][CH2:19][CH2:20][O:21]2)[CH3:17])[C@H:11]2[C@H:25]1[C@:26]1([CH3:29])[C@@H:8]([CH2:9][CH2:10]2)[CH2:7][C@H:6]([OH:5])[CH2:28][CH2:27]1)=[O:34]
Reactant: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](OC(=O)CCl)CC[C@]5(C)[C@H]4[C@@H](OC(=O)CCl)C[C@]23C)OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)CC[C@]5(C)[C@H]4[C@@H](OC(=O)CCl)C[C@]23C)OCCO1

Procedure:
A solution of 3α,11β-bischloroacetoxy-20,20-ethylenedioxy-5α-pregnane (1 g) in refluxing methanol was stirred whilst a saturated solution of sodium bicarbonate (2.5 ml) was added. The mixture was refluxed until reaction was judged complete (by t.l.c), most of the solvent was evaporated in vacuo and water was added. The crude product was collected by filtration and purified by preparative t.l.c. (ethyl acetate-petroleum ether 1:1) and crystallization from ethyl acetate-petroleum ether to give title compound m.p. 194°-202°, [α]D +44° (c 0.1).