Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[CH:5]1([CH2:9]Br)[CH2:8][CH2:7][CH2:6]1>>[CH:5]1([CH2:9][NH:4][CH2:3][CH2:2][OH:1])[CH2:8][CH2:7][CH2:6]1
Reactant: NCCO
Reactant: BrCC1CCC1
Product: OCCNCC1CCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclobutylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dimethylphenyl isothiocyanate to give 2-(2,3-dimethylphenylimino)-3-(cyclobutylmethyl)-1,3-thiazolidine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[C:5]2I.[CH3:17][Sn](C)(C)C>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.C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[C:5]2[CH3:17]
Reactant: COC(=O)c1ccc(I)c2cc(O)ccc12
Reactant: C[Sn](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C)c2cc(O)ccc12
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A resealable tube was charged with methyl 6-hydroxy-4-iodo-1-naphthoate (0.302 g, 0.920 mmol), toluene (5.0 ml), tetramethyltin (0.40 g, 0.30 mL, 2.2 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.042 g, 0.036 mmol). The system was purged with argon and the tube was sealed. The mixture stirred at 90° C. for 24 h and was cooled to RT. The mixture was partitioned between EtOAc and water. The aqueous phase was separated and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford an orange solid. This material was purified via column chromatography on silica gel (eluting with 0-50% ethyl acetate-hexane) to afford methyl 6-hydroxy-4-methyl-1-naphthoate as an orange brown solid. MS (ESI, pos. ion) m/z: 217.1 (M+H). Mass Calc'd for C13H12O3: 216.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:8][CH:9]=2)[C:4]([S:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[N:3]1.[CH2:38]([NH2:40])[CH3:39]>C1COCC1>[CH2:38]([NH:40][CH2:13][CH2:12][O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[N:3]=[C:4]2[S:25]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:26])=[O:27])[CH3:39]
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3C)cc1
Solvent: C1CCOC1
Product: CCNCCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2C
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.413 g, 0.770 mmol) and 2.0 M ethylamine in THF (10 mL, 20 mmol) in THF (10 mL) was stirred at 80° C. in a sealed tube for 16.5 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated. The residue was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 80° C. in vacuo for 20 minutes to give ethyl-{2-[1-methyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-amine as a dark yellow solid (0.292 g, 92.7%). This was dissolved in chloroform and methanol, and ethereal hydrochloride was added. The mixture was concentrated and dried for 25 hours at 83° C. in vacuo to give the hydrochloride as a beige solid (0.227 g) MP 276-7° C.dec.; Mass Spectrum (+EI, [M+H]+) m/z 410. 1HNMR (500 MHz, DMSO-d6): δ8.95 (s, br, 2H), 8.75 (d, 1H, J=8.79 Hz), 8.52 (dd, 1H, J=7.45 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.30 Hz), 8.04 (d, 1H, J=7.57 Hz), 7.71-7.75 (m, 2H), 7.56-7.66 (m, 2H), 7.36 (d, 1H, J=2.07 Hz), 7.22 (dd, 1H, J=9.15 Hz and 2.31 Hz), 4.30-4.33 (m, 2H), 4.05 (s, 3H), 3.33-3.34 (m, 2H), 2.99-3.05 (m, 2H), 1.19-1.23 ppm (m, 3H). Elemental Analysis for C22H23N3O3S.1.00 mol HCl.0.40 mol H2O: Calcd: C, 58.31; H, 5.52; N, 9.27; Found: C, 58.62; H, 5.54; N, 9.11.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([O:20][CH2:21][C:22](OCCCC)=[O:23])=[CH:13][C:12]=2[F:29])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[N:3]([C:11]2[C:12]([F:29])=[CH:13][C:14]3[O:20][CH2:21][C:22](=[O:23])[NH:17][C:15]=3[CH:16]=2)[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: CCCCOC(=O)COc1cc(F)c(-n2nc3c(c2Cl)CCCC3)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1COc2cc(F)c(-n3nc4c(c3Cl)CCCC4)cc2N1
Yield: 82.1 %

Procedure:
A suspension of 3-chloro-2-(2-fluoro-4-butyloxycarbonylmethoxy-5-nitrophenyl)-4,5,6,7-tetrahydro-2H-indazole (10 g) and iron powders (10 g) in acetic acid was refluxed for 5 hours. After completion of the reaction, the reaction mixture was filtered by the use of celite, and the filtrate was combined with water and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by column chromatography using a mixture of hexane and ethyl acetate as an eluent to give 3chloro-2-[7-fluoro-2H-1,4-benzoxazin-3(4H )-on-6yl]-4,5,6,7-tetrahydro-2H-indazole (6.2 g). nD29.0 1.5628.
Reaction SMILES: [CH2:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:2][CH3:3].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O.O>[CH2:1]([C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:2][CH3:3]
Reactant: CCCC(C(=O)OCC)C(=O)OCC
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 97.2 %

Procedure:
Diethyl prop-1-ylmalonate (70.23 g) was added dropwise to a stirred suspension of sodium hydride (8.35 g) in dimethylformamide (400 ml) under an atmosphere of nitrogen at 10° to 15° C. Following the addition, the mixture was allowed to stir at room temperature until effervescence ceased. The resulting clear solution was cooled again and ethyl bromoacetate (58.06 g) was added. The mixture was heated at 70° C. for 2 hours then allowed to cool, diluted with water, and extracted with ether. The extracts were washed with water, dried over magnesium sulphate, and concentrated to give almost pure diethyl 2-prop-1-yl-2-ethoxycarbonylsuccinate (97.35 g, 97%) as a pale yellow liquid.
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].[N-:16]=[N+:17]=[N-:18].[Na+].O>CN(C=O)C>[C:1]1([CH2:11][C:12]2[NH:18][N:17]=[N:16][N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1cccc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(Cc3nnn[nH]3)cccc2c1
Temperature: 125 °C
Reaction time: 16 h

Procedure:
A mixture of the above acetonitrile (5.40 g, 32 mmol), ammonium chloride (2.59 g, 48 mmol) and sodium azide (3.15 g, 48 mmol) in N,N'-dimethylformamide (100 ml) was stirred at 125° C. for 16 hours. After cooling the mixture was poured into water (300 ml) and extracted with ethyl acetate (2×150 ml) The combined organic phases were washed with water (100 ml) and evaporated in vacua. The residue was crystallised from diethyl ether (20 ml), filtered off and washed with diethyl ether affording 1.86 g (27%) of the title compound as a solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[CH2:7]([C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])=[CH:18][CH:17]=2)[C:13]2[CH:30]=[C:31]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH:32]=[C:33]([CH3:34])[C:12]=2[N:11]=1)[CH2:8][CH3:9].O>CN(C)C=O>[CH2:7]([C:10]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:3]=[N:2][N:1]=3)=[CH:20][CH:21]=2)[C:13]2[CH:30]=[C:31]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH:32]=[C:33]([CH3:34])[C:12]=2[N:11]=1)[CH2:8][CH3:9]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 140 °C
Reaction time: 24 h

Procedure:
4.3 g (66 mMol) of sodium azide and 3.5 g (66 mMol) of ammonium chloride are added to a solution of 1.60 g (3.3 mMol) of 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl in 50 ml of dimethylformamide and the mixture is stirred for 24 hours at 140° C. Then water is added and the precipitate is removed by suction filtering. The crude product thus obtained is purified by chromatography over silica gel (300 g of silica gel, methylene chloride +6% ethanol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].Cl[C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1.O>CS(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:14]2[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Cc1cc(C)nc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)nc(Oc2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
27.8 g (0.2 mole) of 4-nitro-phenol were dissolved in 100 ml of dimethylsulphoxide. After addition of 11.2 g (0.2 mole) of powdered potassium hydroxide, the mixture was stirred at room temperature for 30 minutes and 28.5 g (0.2 mole) of 2-chloro-4,6-dimethyl-pyrimidine were then added. The mixture was heated at 120° C. for 6 hours and then cooled, stirred with one liter of water and filtered off with suction. The crystals filtered off with suction were dried in air. 38 g (77.5% of theory) of 2-(4-nitrophenoxy)-4,6-dimethyl-pyrimidine were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=O)[O:13][C:14](=[O:21])[C:15]=2[C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:3]1.C[N:24](C=O)C.N>O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:13])[NH:24][C:14](=[O:21])[C:15]=2[C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3ccsc3)C(=O)OC2=O)c2ccccc21
Reactant: CN(C)C=O
Agent: N
Solvent: O
Product: Cn1cc(C2=C(c3ccsc3)C(=O)NC2=O)c2ccccc21
Temperature: 140 °C

Procedure:
0.28 g of 3-(1-methyl-3-indolyl)-4-(3-thienyl)furan-2,5-dione was treated with 10 ml of DMF and 40 ml of 33% aqueous ammonia. The mixture was heated at 140° C. for 4 hours. The cooled solution was poured into 150 ml of water and the resulting precipitate was filtered off and dried to give 0.15 g of 3-(1-methyl-3-indolyl)-4-(3-thienyl)-1H-pyrrole-2,5-dione, m.p. 211°-212° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:14][NH:15][C:16]([NH:18][CH3:19])=[O:17])[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[BH4-].[Na+]>CO>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][NH:5][C:4]([NH:14][NH:15][C:16]([NH:18][CH3:19])=[O:17])=[N:3]1
Reactant: CNC(=O)NNc1nnc(-c2ccccc2)c(C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC(=O)NNC1=NC(C)C(c2ccccc2)=NN1
Yield: 64.8 %

Procedure:
5-Methyl-3-(4-methylsemicarbazido)-6-phenyl-1,2,4-triazine (3.8 g) was reacted with sodium borohydride (1.5 g) in methanol. The precipitates in the reaction mixture were collected by filtration, washed with water and with methanol, and then dissolved in dimethyl sulfoxide. To the solution was added water. The resultant precipitates were collected by filtration, washed with water and ethanol, and then dried to give pale yellow powder of 5-methyl-3-(4-methylsemicarbazido)-6-phenyl-2,5-dihydro-1,2,4-triazine (2.48 g), mp 214° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[C:37]([NH:40][CH2:41][CH2:42][NH2:43])(=[O:39])[CH3:38]>>[C:37]([NH:40][CH2:41][CH2:42][NH:43][C:23](=[O:24])[CH:22]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:7]1[CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)NCCN
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCCNC(C)=O)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with N-acetylethylendiamine.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:18][C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]2[NH:25]C(=O)OC(C)(C)C)=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1)#[N:2]>C(O)(C(F)(F)F)=O>[NH2:25][C@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[NH:18][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=2)[C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Nc2ccc(C#N)cc2)n1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)cnc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
The crude tert-butyl (1S,2R)-2-(5-cyano-6-(4-cyanophenylamino)pyrazin-2-ylamino)cyclohexylcarbamate (166 mg) was dissolved in TFA (5 mL). After being stirred at room temperature for 30 min, the mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2S)-2-aminocyclohexylamino)-3-(4-cyanophenylamino)pyrazine-2-carbonitrile (40 mg).
Reaction SMILES: [O:1]=[C:2]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[CH:3]([CH:13]1[CH2:18][N:17](C(OC(C)(C)C)=O)[CH:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:15][CH2:14]1)[O:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].C(Cl)Cl.C(O)(C(F)(F)F)=O>>[C:5]([O:4][CH:3]([CH:13]1[CH2:14][CH2:15][CH:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:17][CH2:18]1)[C:2](=[O:1])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:6])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(OC(=O)c2ccccc2)C(=O)c2ccccn2)CCC1c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OC(C(=O)c1ccccn1)C1CCC(c2ccccc2)NC1)c1ccccc1

Procedure:
tert-Butyl 5-{2-oxo-1-[(phenylcarbonyl)oxy]-2-(pyridin-2-yl)ethyl}-2-phenylpiperidine-1-carboxylate (29 mg, 0.058 mmol) was stirred in 4:1 DCM/TFA (5 ml) at room temperature for 3 h. Then the volatiles were removed under vacuum, and the resulting residue was purified by reverse phase HPLC (0.05% TFA-water-acetonitrile) to give the title compound. LC-MS m/e 401.19 [M+1]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:10])[C:8]#[CH:9].[N+:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1F)([O-:13])=[O:12].O>CC(C)=O>[CH2:7]([NH:10][C:15]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=1[N+:11]([O-:13])=[O:12])[C:8]#[CH:9]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: C#CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C#CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
To a suspension of potassium carbonate (1.0 g) in acetone (10 ml) was added 2-propyn-1-amine (0.26 g, 473×10-3 mole). 2,4-Dinitrofluorobenzene (1.32 g, 7.10×10-3 mole) was gradually added with stirring and the reaction mixture was refluxed two hours. After cooling it was poured into excess water and filtered. Recrystallization of the crude solid from ethanol afforded yellow needles; m.p. 151°-152° C. Yield: 0.99 g (95%). IR (KBr): 3367 (NH), 3268 (=CH), 1618, 1590, 1333 and 1311 cm-1 (Ar--NO2).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])[CH3:2].[OH-].[Na+].[C:13]1([CH2:19][CH2:20]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)CS(C)(=O)=O
Reactant: BrCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccccc1)S(C)(=O)=O
Reaction time: 0.25 h

Procedure:
6.648 g of methylsulphonyl-acetic acid ethyl ester are added dropwise at -30°, within 30 minutes, to 1.745 g of sodium hydroxide dispersion (55% in oil) in 40 ml of DMF. The solution is subsequently stirred for 15 minutes, then heated and, within 150 minutes, under reflux, 7.4 g of 2-phenylethyl bromide in 10 ml of DMF are added dropwise thereto. The reaction mixture is then stirred for 20 minutes, acidified with 12 ml of glacial acetic acid and concentrated by evaporation. The residue is taken up in ethyl acetate, washed with water, dried over magnesium sulphate, concentrated by evaporation and purified by flash chromatography on 700 g of silica gel 60 (eluant D). 1H-NMR (DMSO-d6): 1.35 ppm (t, 3H), 2.6-2.9 (m, 2H); 3.75 (dxd, 1H); 4.25 (q, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:14]=1[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18]>>[NH2:20][CH2:19][C:16]1[C:17]([NH2:18])=[N:8][C:7]([C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:9][C:15]=1[C:14]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:13]=1[Cl:12]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: COc1ccc(C(=N)N)cc1
Product: COc1ccc(-c2nc(N)c(CN)c(-c3ccc(Cl)cc3Cl)n2)cc1

Procedure:
The title compound, MS: m/e=375.3 (M+H+), was prepared from 4-methoxybenzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:8]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][O:29][C:26]2[CH:25]=[CH:24][C:23]([S:20]([CH:8]3[CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]3[CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)(=[O:22])=[O:21])=[CH:28][CH:27]=2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)C1CCN(Cc2ccc(C)cc2)C(S(=O)(=O)c2ccc(OCc3ccc(Cl)cc3)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(CN2CCC(C(=O)O)CC2S(=O)(=O)c2ccc(OCc3ccc(Cl)cc3)cc2)cc1

Procedure:
[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylic acid was prepared starting from [4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylic acid ethyl ester (7.9 g, 124 mmol) dissolved in THF:Methanol (50:50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.6 g (61%); off white solid, mp 204° C.; MS: 514.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](Cl)=[O:5].[CH2:12]([NH:14][CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)([OH:21])[C:17]([F:20])([F:19])[F:18])[CH3:13]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([N:14]([CH2:12][CH3:13])[CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1)([OH:21])[C:17]([F:18])([F:20])[F:19])=[O:5]
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: Cc1cccc(Cl)c1C(=O)Cl
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1c(C)cccc1Cl

Procedure:
Prepared similarly to Example 56 from 2-chloro-6-methylbenzoylchloride and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-2-propanol. Purification by mass directed autopreparation (System B) resulted in separation of atropisomers of the title compound:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.C(N(CC)CC)C.[C:21](C(CC(N)=O)C(N)=O)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>CN(C=O)C>[C:25]1([CH2:24][O:23][C:21]([NH:1][CH2:2][CH:3]2[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]2)=[O:22])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Reactant: NC(=O)CC(C(N)=O)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(CNC(=O)OCc2ccccc2)C1
Reaction time: 18 h
Yield: 64 %

Procedure:
To a solution of 1,1-dimethylethyl 3-(aminomethyl)-1-azetidinecarboxylate (5.0 g, 26.84 mmole) in DMF (40 mL) was added triethylamine (4.9 mL, 34.9 mmole) and Cbz-succinamide (8.7 g, 34.9 mmole). After 18 hours, the reaction solution was concentrated under vacuum and redissolved in EtOAc (250 mL). The organic solution was washed with H2O (2×150 mL), brine (100 mL) and dried over Na2SO4 and concentrated. The remaining residue was purified on silica (hexanes/EtOAc, 1:1) to give the title compound (5.5 g, 64%) as a light yellow oil: LC-MS (ES) m/e 321 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1.[CH3:30][OH:31]>C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[CH3:30][O:31][CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: CO
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: -10 °C

Procedure:
2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (1.10 g) was dissolved in methylene chloride (12 ml) and to this solution was added methanol (3 ml). And to the solution was added silver fluoroborate (0.45 g) under stirring under cooling at -10° C and the mixture was stirred for 2 hours at the same temperature. After the reaction was completed, the reaction mixture was filtered and the filtrate was washed with sodium bicarbonate aqueous solution and then with water, dried over magnesium sulfate and thereafter concentrated. The residue was subjected to column chromatography on silica gel (25 g) and eluted with chloroform. The eluate was separated into fractions of about 20 ml and the first and second fractions were collected. After distilling off the solvent, the residue was dried to give oily 2,2,2-trichloroethyl 2-methoxymethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate.