Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=[O:7].[N+:13]([O-])([OH:15])=[O:14]>>[CH3:12][O:11][C:9]1[C:8]([N+:13]([O-:15])=[O:14])=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1)[CH:6]=[O:7]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: O=[N+]([O-])O
Product: COc1cc(C=O)c([N+](=O)[O-])c(OC)c1
Reaction time: 1 h
Yield: 64 %

Procedure:
The 3,5-Dimethoxybenzaldehyde (0.5 g, 3 mmol) was added to 70% nitric acid (0.88 mL, 14.44 mmol) at 0° C. in portion. After stirring for 1 hour, the reaction mixture was quenched and extracted by water and CH2Cl2. The organic layers were combined and evaporated to give a residue, which was purified by flash chromatography (EtOAc:n-hexane=1:2.5) to give the brown crystals, yield 64%. mp 104.0-104.6° C., 1H NMR (500 MHz, CDCl3) δ 3.93 (s, 3H), 3.93 (s, 3H), 6.76 (d, J=2.4 Hz), 6.96 (d, J=2.4 Hz, 1H), 9.94 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:8])=[CH:5][C:6]=1[CH3:7].CO[CH2:11][Cl:12]>C(O)(=O)C>[CH3:8][C:4]1[S:3][C:2]([CH3:1])=[C:6]([CH3:7])[C:5]=1[CH2:11][Cl:12]
Reactant: Cc1cc(C)c(C)s1
Reactant: COCCl
Solvent: CC(=O)O
Product: Cc1sc(C)c(CCl)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
24.6 G. of 2,3,5-trimethyl-thiophene, 14.8 g. of freshly distilled chloromethyl methyl ether and 52 g. of glacial acetic acid were combined in a glass pressure bottle and stirred at room temperature for 41/2 hours. The resulting reaction mixture was poured into ice water, stirred for 10 min. and extracted with benzene. The combined benzene extracts were washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The resulting 2,4,5-trimethyl-3-chloromethyl-thiophene was used for the next step without any further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:4][C:3]=1[CH2:12][O:13][C:14]1[CH:34]=[CH:33][C:17]([CH2:18][O:19]/[N:20]=[C:21](/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)\[CH2:22][CH2:23][C:24]([O-:26])=[O:25])=[CH:16][CH:15]=1.O.CO.Cl>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:4][C:3]=1[CH2:12][O:13][C:14]1[CH:34]=[CH:33][C:17]([CH2:18][O:19]/[N:20]=[C:21](/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)\[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:16][CH:15]=1
Reactant: Cc1oc(-c2cccs2)nc1COc1ccc(CO/N=C(\CCC(=O)[O-])c2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2cccs2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1
Yield: 84.9 %

Procedure:
E-4-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino)-4-phenylbutyrate (430 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (1.8 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-4-phenylbutyric acid (366 mg, yield 88%) as colorless crystals. m.p. 142-143° C.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[ClH:22].[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[OH:33])[CH2:27][CH2:28][NH2:29].C(O)CCC>Cl.O>[ClH:22].[C:13]1([N:6]([CH2:5][CH:4]2[C:30]3[C:26](=[CH:25][C:24]([OH:23])=[C:32]([OH:33])[CH:31]=3)[CH2:27][CH2:28][NH:29]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(CN(c1ccccc1)c1ccccc1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: Oc1cc2c(cc1O)C(CN(c1ccccc1)c1ccccc1)NCC2
Yield: 35.4 %

Procedure:
N,N-diphenylaminoacetaldehyde diethyl acetal (3.5 g) and 3,4-dihydroxyphenethylamine hydrochloride (2.1 g) were added to a mixture of n-butyl alcohol (35 ml), water (5 ml) and conc. hydrochloric acid (2 drops) and then the mixture was refluxed for 6.5 hours in a stream of nitrogen. The reaction mixture was concentrated to dryness and the residue was washed with acetone and collected by filtration to recover the starting material, 3,4-dihydroxyphenethylamine (1.2 g). The filtrate was concentrated to give 1-(N,N-diphenylaminomethyl)6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.5 g), oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[Cl-:9].[NH4+:10]>CO.C[O-].[Na+]>[ClH:9].[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]([NH2:10])=[NH:2]
Reactant: N#Cc1ccccn1
Reactant: [Cl-]
Reactant: [NH4+]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: N=C(N)c1ccccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.8 %

Procedure:
To a solution of 2-cyanopyridine (10-a) (Sigma-Aldrich) (100 g, 0.95 mol) in methanol (1.5 L) under nitrogen was added sodium methoxide (2.5 g, 44 mmol). The reaction mixture was stirred at room temperature for 24 hours. Ammonium chloride (53.5 g, 1 mol) was added to the reaction mixture. The mixture was stirred at room temperature for 4 h and the solvent was removed in vacuo. The residue was washed with ipropanol/ethyl acetate=1/10 and dried in vacuo to provide compound 10-b (100 g, 66%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[S:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:24]=[CH:25][CH:26]=2)=[CH:17]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:30]2[CH2:31][CH2:32][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:18]4[CH:19]=[CH:20][S:16][CH:17]=4)[CH:22]=3)[CH2:28][CH2:29]2)=[O:15])[CH:2]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: c1cc(-c2ccsc2)cc(N2CCNCC2)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCN(c2cccc(-c3ccsc3)c2)CC1
Yield: 37.4 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (303 mg, 1.13 mmol), 1-[3-(3-thienyl)phenyl]piperazine (250 mg, 1.02 mmol) and diisopropylethylamine (0.356 ml, 2.05 mmol) in dimethylsulfoxide (3.5 ml) was stirred at 70° C. for 3 days. Water was poured into the reaction solution, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the titled compound 139 mg (37.3%) as solid product.
Reaction SMILES: [CH:1]1([N:6]=[C:7]=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:9][C:10]1[C:11](=[O:17])[NH:12][C:13](=[O:16])[NH:14][CH:15]=1>N1C=CC=CC=1>[CH:1]1([NH:6][C:7]([N:14]2[CH:15]=[C:10]([F:9])[C:11](=[O:17])[NH:12][C:13]2=[O:16])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C=NC1CCCC1
Solvent: c1ccncc1
Product: O=C(NC1CCCC1)n1cc(F)c(=O)[nH]c1=O

Procedure:
Cyclopentylisocyanate, 5.67 g, was allowed to react with 5-fluorouracil, 4.6 g, in 17 g of pyridine at 90° C. for 2 hr, then the pyridine was evaporated and the residue was shaken with 100 ml of dichloromethane and 100 ml of hydrochloric acid water. The lower layer of the mixture was dried and exsiccated. The residue was recrystallized from ethanol and 8.3 g of 1-cyclopentylcarbamoyl-5-fluorouracil (melting point: 137° C.) was obtained (Compound No. 9) was obtained. NMR: 1.00-2.28 (6H b CH) 3.56-4.12 (1H b CH--NHCO) 8.40 (1H d C6 --H) 8.68-9.08 (1H b NHCO) 9.48 (1H b N3 --H).
Reaction SMILES: S([O-])(O[O-])(=O)=O.[K+].[K+].[CH3:9][O:10][C:11]1[C:16]2[NH:17][C:18](=[O:20])[S:19][C:15]=2[C:14]([CH2:21][CH2:22][NH:23][C:24](=[O:40])[CH2:25][CH2:26][S:27][CH2:28][C:29](=[O:39])[NH:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:13][CH:12]=1.[OH2:41].C[OH:43].O>>[CH3:9][O:10][C:11]1[C:16]2[NH:17][C:18](=[O:20])[S:19][C:15]=2[C:14]([CH2:21][CH2:22][NH:23][C:24](=[O:40])[CH2:25][CH2:26][S:27]([CH2:28][C:29](=[O:39])[NH:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:43])=[O:41])=[CH:13][CH:12]=1
Reactant: COc1ccc(CCNC(=O)CCSCC(=O)NCCc2ccccc2)c2sc(=O)[nH]c12
Reactant: O
Reactant: CO
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Product: COc1ccc(CCNC(=O)CCS(=O)(=O)CC(=O)NCCc2ccccc2)c2sc(=O)[nH]c12
Reaction time: 4 h

Procedure:
Potassium peroxymonosulphate (5.57 g) was gradually added to a solution of the compound from step c) (2.81 g) in methanol:water (6:4, 72 ml) cooled to 0°. The mixture was stirred for 4 hours, water added and the whole extracted with chloroform. A yellow solid precipitated from the aqueous layer and was removed by filtration, and washed (water and pentane) to give the subtitled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.Cl[CH:14]([F:16])[F:15].C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Na+].[Na+]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:14]([F:16])[F:15])=[C:6]([F:11])[CH:5]=1
Reactant: FC(F)Cl
Reactant: COC(=O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: COC(=O)c1ccc(OC(F)F)c(F)c1
Yield: 82.7 %

Procedure:
A solution of 3-fluoro-4-hydroxy-benzoic acid methyl ester (2 g, 11.75 mmol), chlorodifluoromethane (10.6 g, 122.6 mmol, 10.4 eq.) and K2CO3 (1.94 g, 14.1 mmol) was heated in an autoclave for 6 hrs. at 160° C. After cooling the mixture was treated with excess Na2CO3 and extracted with EtOAc. The organic phase was washed twice with satd. NaCl then dried and evaporated to afford the title compound (2.14 g, 83% yield) as an orange oil. MS: m/e=220 (M+).
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=O)CC1C=CC=CC=1.[O:13]=[C:14]1[CH:19]([CH2:20][C:21]([NH2:23])=O)[NH:18][C:17](=[O:24])[CH2:16][NH:15]1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:18]1[CH:19]([CH2:20][C:21]#[N:23])[C:14](=[O:13])[N:15]([C:10](=[O:12])[CH3:2])[CH2:16][C:17]1=[O:24])(=[O:27])[CH3:26]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)CC1NC(=O)CNC1=O
Product: CC(=O)N1CC(=O)N(C(C)=O)C(CC#N)C1=O

Procedure:
A method of preparing α-APM derivatives without using an expensive L-phenylalanine is provided, wherein 2,5-dioxopiperazine-3-acetamide is reacted with acetic anhydride to give N,N'-diacetyl-6-cyanomethyl-2,5-dioxopiperazine, which is then reacted with benzaldehyde in the presence of a strong base to give 1-acetyl-3-benzylidene-6-cyanomethyl-2,5-dioxopiperazine. This is treated with hydrazine to give 3-benzylidene-6-cyanomethyl-2,5-dioxopiperazine, which is then reduced to prepare 3-benzyl-6-cyanomethyl-2,5-dioxopiperazine, which is converted by reaction with methanol in the presence of a strong acid to an α-APM derivative for use as a sweetener.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:12][NH:13][CH3:14].[C-]#N.[K+].Cl.[CH3:19][NH:20]C>CO>[CH3:12][N:13]([CH3:14])[C:8]1([C:19]#[N:20])[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: CNC
Reactant: O=C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: CN(C)C1(C#N)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 65 h

Procedure:
200 g 1,4-dioxaspiro[4.5]decan-8-one were initially introduced into the reaction vessel, 1.68 l aqueous dimethylamine solution (40 per cent by volume), 200 ml methanol, 200 g potassium cyanide and 303 g dimethylamine hydrochloride were added in succession and the reaction mixture was stirred for 65 hours at room temperature. The white suspension obtained was extracted four times with 800 ml diethyl ether each time, the combined extracts were first concentrated and the residue was taken up in 500 ml methylene chloride, the organic phase was separated, dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. 265 g 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile were obtained as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[Br:9][C:10]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:13]([CH:14]=[O:15])=[C:12](F)[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CC(OC)(C)C>C(#N)C>[Br:9][C:10]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([N:4]2[CH2:5][CH:6]([CH3:8])[O:7][CH:2]([CH3:1])[CH2:3]2)[CH:11]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=Cc1cc([N+](=O)[O-])c(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: COC(C)(C)C
Product: CC1CN(c2cc(Br)c([N+](=O)[O-])cc2C=O)CC(C)O1
Temperature: 25 °C
Reaction time: 63 h
Yield: 63.6 %

Procedure:
A solution of cis-2,6-dimethylmorpholine (1.06 g, 9.20 mmol) in acetonitrile (40 mL) is added to a flask containing 4-bromo-2-fluoro-5-nitrobenzaldehyde (from Step 1) (2.0 g, 8.06 mmol) and potassium carbonate (3.92 g, 28.4 mmol). The resulting slurry is stirred at room temperature for 63 hours. The mixture is poured into MTBE (100 mL) and is washed with water (100 mL) followed by brine (100 mL). The organics are filtered through silica gel and concentrated to give 1.76 g of bright yellow solid. 1H NMR (DMSO-d6) δ 9.93, 8.44, 7.53, 3.74-3.81, 3.48, 2.78, 1.12.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH:25]5[CH2:29][NH:28][CH2:27][CH2:26]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.IC.[C:33](=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH:25]5[CH2:26][CH2:27][N:28]([CH3:33])[CH2:29]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC3CCNC3)cc2c1=O
Agent: [K+]
Solvent: CI
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC3CCN(C)C3)cc2c1=O
Yield: 39.7 %

Procedure:
N-Cyclopropyl-4-methyl-3-[4-oxo-6-(pyrrolidin-4-yloxy)quinazolin-3(4H)-yl]benzamide (0.18 g), iodomethane (0.031 ml) and potassium carbonate (0.246 g) were stirred in DMA (1 ml) for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate and the organic phase was washed with water and concentrated. The residue was dissolved in ethyl acetate (2 ml) and triturated with iso-hexane and the resulting solid was filtered and dried under vacuum at 40° C. There was thus obtained the title compound (0.074 g); NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.67 (m, 2H), 1.80 (m, 1H), 2.08 (m, 4H), 2.30 (m, 4H), 2.80 (m, 4H), 5.06 (s, 1H), 7.49 (m, 3H), 7.71 (d, 1H), 7.81 (s, 1H), 7.89 (d, 1H), 8.16 (s, 1H), 8.41 (s, 1H); Mass Spectrum: M+H+ 419.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][CH:2]12.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.CC#N>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:6]1[CH2:5][CH2:4][N:3]2[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][CH:2]2[CH2:1]1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: O=C1CCCC2CNCCN12
Solvent: CC#N
Solvent: ClCCl
Product: O=C1CCCC2CN(S(=O)(=O)c3ccccc3F)CCN12
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.3 %

Procedure:
To a solution of octahydro-pyrido[1,2-a]pyrazin-6-one (compound of Description 12, 20 mg, 0.13 mmol) in DCM (1 ml), TEA (16 mg, 0.16 mmol) and a solution of 2-fluoro-benzenesulfonyl chloride (25 mg, 0.13 mmol) in CH3CN (1 ml) were added at 0° C. After stirring 3 hours at room temperature, the solvent was evaporated. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography (from DCM to DCM/MeOH/32% NH4OH 95/5/0.5 respectively) to afford the title compound (18 mg, 44% yield).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:11])[N:4]([CH2:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[N:3]=1.[Cl:21][C:22]1[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][CH:23]=1>N1C=CC=CC=1>[Cl:21][C:22]1[S:26][C:25]([S:27]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[F:11])[N:4]([CH2:12][C:13]3[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=3)[N:3]=2)(=[O:29])=[O:28])=[CH:24][CH:23]=1
Reactant: N#Cc1cccc(Cn2nc(N)c3c(F)cccc32)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: c1ccncc1
Product: N#Cc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(F)cccc32)c1
Temperature: 0 °C

Procedure:
To a solution of 3-[(3-amino-4-fluoro-1H-indazol-1-yl)methyl]benzonitrile (for a preparation see Intermediate 37) (695 mg, 2.61 mmol) in anhydrous pyridine (3 mL) cooled in an ice/water bath was added 5-chloro-2-thiophenesulfonyl chloride (567 mg, 2.61 mmol) dropwise over 1 minute and the reaction mixture was stirred in the ice/water bath for 1 hour. The reaction mixture was partitioned between ethyl acetate (150 mL) and 2N hydrochloric acid (100 mL). The organic layer was separated, passed through a hydrophobic frit and evaporated in-vacuo to yield a dark red oil (1.264 g). The oil was dissolved in the minimum volume of dichloromethane, applied to a 100 g silica SPE cartridge and purified by chromatography on Flashmaster II using a 0-50% ethyl acetate in cyclohexane gradient over 60 min. Fractions 66-69 were combined and evaporated in-vacuo to yield a white foam (540 mg), which was further purified by chromatography on 100 g silica SPE cartridge on Flashmaster II using a 0-10% methanol in dichloromethane gradient over 60 min. Fractions 23-26 were evaporated in-vacuo to yield the title compound as a white foam (493 mg, 42%). LCMS (System B) RT=3.01 min, ES+ve m/z 447/449 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc2cccnc2n1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1ccc2cccnc2n1
Yield: 70.8 %

Procedure:
The title compound (0.28 g) was prepared from (S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.35 g) and 2-chloro-1,8-naphthyridine (0.19 g) according to the method of D30.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14](Br)[CH:13]=2)[O:9][N:8]=1.[CH:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22]>O1CCCC1.ClCCl.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>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([CH:21]=[CH2:22])[CH:15]=[C:16]([C:18]#[N:19])[CH:17]=2)[O:9][N:8]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1cc(Br)cc(-c2nc(-c3ccccn3)no2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 85 °C
Yield: 78.5 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole (1.005 g, 3.21 mmol) and Pd(PPh3)4 (369 mg, 0.32 mmol) in tetrahydrofuran (10 mL) was treated with vinyl tributyl tin (0.985 mL, 3.36 mmol). The reaction mixture was heated in a sealed tube at 85° C. for 18 hours. After cooling, the mixture was diluted with dichloromethane and water. The organic layer was dried by filtration through an EX-TUBE. Silica gel chromatography afforded 691 mg (78%) of 3-(pyrid-2-yl)-5-(3-cyano-5-vinylphenyl)-1,2,4-oxadiazole: 1H-NMR (CDCl3), δ (ppm): (s, 1H), 8.52 (s, 1H), 8.43 (s, 1H), 8.23 (d, 1H), 7.90 (m, 2H), 7.48 (m, 1H), 6.78 (dd, 1H), 5.98 (d, 1H), 5.55 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:16]O>C(OCC)(=O)C>[CH3:16][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH3:11]
Reactant: CO
Reactant: Cc1ccc(Br)cc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)ccc1C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
The compound of example 1 (20.3 g, 0.0944 mol) was dissolved in 150 mL methanol and cooled to 0° C. To this reaction mixture, thionyl chloride (28.07 g, 0.236 mol) was added slowly within 15-20 min. The reaction mixture was stirred at room temperature for 2-3 h. After completion of the reaction, MeOH was removed under vacuum. The oily material obtained was dissolved in ethyl acetate and washed with sodium bicarbonate, water and brine and dried over anhydrous sodium sulfate. The organic layer was concentrated to obtain the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24](=O)[CH2:25][CH3:26]>>[CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][N:14]([CH2:24][CH2:25][CH3:26])[CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cn2nc(-c3ccccc3)c3c2CCNCC3)cc1
Reactant: CCC=O
Product: CCCN1CCc2c(-c3ccccc3)nn(Cc3ccccc3)c2CC1

Procedure:
The title compound (0.05 g) was prepared from 1-benzyl-3-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 44, 0.09 g) and 23 μL of propionaldehyde as in Example 35. MS (ESI): exact mass calculated for C23H27N3, 345.22; found, m/z 346.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.56-7.54 (m, 2H), 7.47-7.28 (m, 6H), 7.21-7.19 (m, 2H), 5.44 (s, 2H), 3.70-3.66 (m, 2H), 3.41-3.07 (m, 8H), 1.86-1.76 (m, 2H), 1.03 (t, J=7.3 Hz, 3H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[N:7][CH:8]=1>C(O)(C)C.O1CCOCC1.C(O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Br)cn2)CC1
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Brc1ccc(N2CCCNCC2)nc1
Temperature: 70 °C
Yield: 117.1 %

Procedure:
6 ml of a solution of hydrogen chloride (6N) in isopropanol are added to a solution of 1.63 g (4.4 mmol) of 1,1-dimethylethyl 4-(5-bromo-2-pyridyl)-1,4-diazepane-1-carboxylate, obtained in step 11.1, in 12 ml of dioxane and 4 ml of ethanol. This reaction mixture is maintained at 70° C. for 3 hours. The mixture is allowed to cool to room temperature and is then concentrated under reduced pressure. 1.32 g of a white solid are obtained after crystallization from acetone. These crystals are taken up in 10 ml of dichloromethane and the reaction medium is basified to pH=14, by adding 28% ammonia solution. The organic phase is recovered by filtration through a hydrophobic cartridge and the filtrate is concentrated under reduced pressure. 0.96 g of product is obtained in the form of an oil, and is used without further purification in the following step.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:3]1.Cl.O[N:32]=[C:33]([NH2:36])[CH2:34][CH3:35]>>[CH3:1][C:2]1([CH3:29])[O:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:26]3[O:27][N:36]=[C:33]([CH2:34][CH3:35])[N:32]=3)[CH2:11]2)=[O:9])[CH2:3]1
Reactant: CC1(C)CN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CCO1
Reactant: CCC(N)=NO
Agent: Cl
Product: CCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOC(C)(C)C3)C2)n1

Procedure:
250 mg (0.410 mmol, 68% pure) of 1-[(2,2-dimethylmorpholin-4-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 208A) and 56.2 mg (0.451 mmol) of N′-hydroxypropanimidamide hydrochloride were reacted according to the General Method 1. Yield: 80.6 mg (42% of theory).