Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([P:7]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8]C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:22](=O)[CH3:23].[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:30][CH:31]=1>ClC1C=CC=CC=1>[C:26]1([CH3:25])[CH:27]=[CH:28][C:29]([S:32]([NH:35][CH:22]([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])[O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:23])(=[O:34])=[O:33])=[CH:30][CH:31]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CC=O
Reactant: c1ccc(OP(Oc2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(C)P(=O)(Oc2ccccc2)c2ccccc2)cc1
Yield: 79 %

Procedure:
A mixture of 0.15 mole each of diphenyl phenylphosphonite, acetaldehyde, and p-toluenesulfonamide in 100 g of chlorobenzene is stirred and warmed at 103°-115° C. for 1 hr, and the solvent and by-product phenol are removed by concentration of the reaction mixture to 120° at 0.5 mm. Ether is stirred into the residue, causing separation of 49.4g (79% yield) of solid product. Recrystallization twice from chlorobenzene gives a white solid: mp 178°-181°; 31P nmr (DMSO-d6)- 37.7 ppm.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29].O>C(O)C>[CH2:26]([NH:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in ethanol (5 mL) was added potassium carbonate (321 mg, 2.32 mmol) and butylamine (170 mg, 2.32 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (358 mg, 99.1% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[F:10][C:11]1[C:16](B(O)O)=[CH:15][C:14]([Br:20])=[CH:13][N:12]=1>C(#N)C.[F-].[K+]>[Br:20][C:14]1[CH:15]=[C:16]([C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][C:5]=2[NH2:8])[C:11]([F:10])=[N:12][CH:13]=1
Reactant: OB(O)c1cc(Br)cnc1F
Reactant: Nc1cnc(Cl)cc1I
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Nc1cnc(Cl)cc1-c1cc(Br)cnc1F
Temperature: 80 °C
Yield: 48.6 %

Procedure:
A mixture of 6-chloro-4-iodo-pyridin-3-ylamine (2.37 g, 9.31 mmol), 2-fluoro-5-bromopyridine-3-boronic acid (2.64 g, 12.0 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.76 g, 0.93 mmol) in acetonitrile (35 mL) and 1N aqueous potassium fluoride solution (35 mL) was degassed with nitrogen for 20 minutes. The reaction mixture was heated at 80° C. for 3 h, allowed to cool to ambient temperature then partitioned between ethyl acetate (100 mL) and water (75 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resultant solid residue was triturated using 1:1 DCM/methanol, collected by filtration, washed with diethyl ether and ethyl acetate to afford the title compound as a tan solid (1.37 g, 49%). The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (silica, 80 g column, ISCO, 0-40% ethyl acetate in pentane) to afford further title compound as a brown solid (0.73 g, 26%). 1H NMR (DMSO-Do, 300 MHz): 8.46 (dd, J=2.5, 1.3 Hz, 1H), 8.24 (dd, J=8.3, 2.5 Hz, 1H), 7.88 (s, 1H), 7.19 (s, 1H), 5.57 (s, 2H). LCMS (Method B): RT=3.21 min, M+H+=304.
Reaction SMILES: CO[CH:3]=[C:4]([CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13])[CH:5]=O.Cl.[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[NH:25])=[CH:22][CH:21]=1)([CH3:18])[CH3:17].C[O-].[Na+]>CO>[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]2[N:26]=[CH:3][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13])=[CH:5][N:25]=2)=[CH:22][CH:21]=1)([CH3:18])[CH3:17]
Reactant: CC[C@H](C)CCCCC(C=O)=COC
Reactant: CC(C)Oc1ccc(C(=N)N)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC[C@H](C)CCCCc1cnc(-c2ccc(OC(C)C)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A mixture of 23 g of (S)-2-(methoxymethylidene)-7-methylnonanal, 26.2 g of 4-isopropoxybenzamidine hydrochloride and 250 ml of absolute methanol was treated dropwise at 10° C. with 80 ml of a 5% solution of sodium methylate in methanol. The reaction mixture was stirred at room temperature overnight and subsequently made acid (pH 4-5) with concentrated hydrochloric acid, filtered and the filtrate was concentrated. The residue was taken up in 500 ml of dichloromethane, washed several times with water, dried over sodium sulphate and concentrated. Chromatography of the residue on silica gel with hexanethyl acetate (vol. 19:1) and recrystallization from methanol gave 22.2 g of (S)-2-(4-isopropoxyphenyl)-5-(5-methylheptyl)pyrimidine; m.p. 47.2°-47.7° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([C:13]([Cl:16])([Cl:15])[Cl:14])[C:10](F)=[S:11].[CH3:17][N:18]1[CH:22]=[C:21]([OH:23])[CH:20]=[N:19]1>C1(C)C=CC=CC=1>[CH3:17][N:18]1[CH:22]=[C:21]([O:23][C:10](=[S:11])[N:9]([CH3:8])[C:13]([Cl:16])([Cl:15])[Cl:14])[CH:20]=[N:19]1
Reactant: Cn1cc(O)cn1
Reactant: CN(C(F)=S)C(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C(=S)Oc1cnn(C)c1)C(Cl)(Cl)Cl
Reaction time: 4 h
Yield: 86.6 %

Procedure:
5.1 g (0.05 mol) of triethylamine were added dropwise to a mixture of 11.3 g (0.05 mol) of N-methyl-N-trichloromethylthio-carbamoyl fluoride, 4.9 g (0.05 mol) of 1-methyl-4-hydroxypyrazole and 150 ml of toluene. After 4 hours, the mixture was extracted twice with 25 ml of water each time. The organic phase was dried over sodium sulphate and evaporated in vacuo. The residue was subjected to incipient distillation under a high vacuum. 12.5 g (82% of theory) of N-methyl-N-trichloromethylthiocarbamic acid O-(1-methyl-pyrazol-4-yl) ester were thus obtained in the form of a yellow oil with a refractive index nD23 of 1.5492.
Reaction SMILES: C([O:5][C:6](=[O:125])[CH2:7][N:8]([CH2:117][C:118](=[O:124])[O:119]C(C)(C)C)[C:9](=[O:116])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:16][N:17]([CH2:59][C:60]1[CH:65]=[CH:64][C:63]([O:66][CH2:67][C:68]2[N:69]=[N:70][N:71]([CH2:73][CH2:74][CH2:75][NH:76][C:77](=[O:115])[CH2:78][N:79]3[CH2:90][CH2:89][N:88]([CH2:91][C:92](=[O:98])[O:93]C(C)(C)C)[CH2:87][CH2:86][N:85]([CH2:99][C:100](=[O:106])[O:101]C(C)(C)C)[CH2:84][CH2:83][N:82]([CH2:107][C:108]([O:110]C(C)(C)C)=[O:109])[CH2:81][CH2:80]3)[CH:72]=2)=[CH:62][CH:61]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:58])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C@@H:29]([C:51]([O:53]C(C)(C)C)=[O:52])[NH:30][C:31](=[O:50])[NH:32][C@H:33]([C:43]([O:45]C(C)(C)C)=[O:44])[CH2:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:118]([CH2:117][N:8]([CH2:7][C:6]([OH:125])=[O:5])[C:9](=[O:116])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:16][N:17]([CH2:59][C:60]1[CH:61]=[CH:62][C:63]([O:66][CH2:67][C:68]2[N:69]=[N:70][N:71]([CH2:73][CH2:74][CH2:75][NH:76][C:77](=[O:115])[CH2:78][N:79]3[CH2:90][CH2:89][N:88]([CH2:91][C:92]([OH:98])=[O:93])[CH2:87][CH2:86][N:85]([CH2:99][C:100]([OH:106])=[O:101])[CH2:84][CH2:83][N:82]([CH2:107][C:108]([OH:110])=[O:109])[CH2:81][CH2:80]3)[CH:72]=2)=[CH:64][CH:65]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:58])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C@@H:29]([C:51]([OH:53])=[O:52])[NH:30][C:31](=[O:50])[NH:32][C@H:33]([C:43]([OH:45])=[O:44])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])([OH:124])=[O:119]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCN(Cc1ccc(OCc2cn(CCCNC(=O)CN3CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC3)nn2)cc1)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCN(Cc1ccc(OCc2cn(CCCNC(=O)CN3CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC3)nn2)cc1)Cc1nccn1CC(=O)N(CC(=O)O)CC(=O)O)C(=O)O)C(=O)O

Procedure:
A solution of ((14S,18S)-tri-tert-butyl 1-(1-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-((1-(3-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)propyl)-1H-1,2,3-triazol-4-yl)methoxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (21 mg, 0.012 mmol) in TFA (2.0 mL) and DCM (2.0 mL) was stirred at rt overnight. The solvent was removed under a stream of nitrogen to give a crude ((14S,18S)-1-(1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-((1-(3-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)propyl)-1H-1,2,3-triazol-4-yl)methoxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylic acid, (MIP-1459), which was dissolved in ammonium acetate (0.30 mL, 0.50 N) solution in water (0.50 mL) with InCl3 (10 mg). The reaction mixture was heated at 95° C. for 1 h and was purified by HPLC to give the product (MIP-1445, (1 mg)). MS (ESI), 714.9 (M/2+H)+.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:12]([CH:26]([F:37])[C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[C:11]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[C:10]1=2)(C(C)(C)C)(C)C.CO.O1CCCC1.C(=O)([O-])O.[Na+]>Cl.C(OCC)(=O)C>[CH:21]1([C:13]2[C:12]([CH:26]([F:37])[C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=3)=[C:11]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[C:10]3[CH:9]([OH:8])[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]=3[N:14]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)cc3)c2C(O[Si](C)(C)C(C)(C)C)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)Cc2nc(C3CCCC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)cc3)c2C(O)C1

Procedure:
110 g of 5-(tert-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline were stirred at 40° C. for 2 hours in a mixture of 913 ml of 5 N hydrochloric acid, 1364 ml of methanol and 902 ml of tetrahydrofuran. Working up was carried out by pouring into saturated aqueous sodium hydrogencarbonate solution and extraction with ethyl acetate. The organic phases were dried after fresh washing with saturated aqueous sodium hydrogencarbonate solution. After distilling off the solvent in vacuo, the residue was recrystallized from cyclohexane. After drying in an oil-pump vacuum, a total of 71.1 g of colorless crystals having a purity of 99.4% according to HPLC (e.e. 99.5%) resulted. By chromatography on silica gel, it was possible from the mother liquor of the crystallization, using petroleum ether/ethyl acetate 7:1, to obtain a further 10.8 g of the same quality.
Reaction SMILES: [OH2:1].O.O.[N+]([O-])(O)=O.[C:8]([O:11][CH:12]1[CH2:20][CH2:19][CH:18]2[CH:13]1[CH2:14][CH2:15][C:16](=[O:21])[CH2:17]2)(=[O:10])[CH3:9]>C(O)(=O)C>[C:8]([O:11][CH:12]1[CH2:20][CH2:19][CH:18]2[CH:13]1[CH2:14][CH2:15][CH:17]2[C:16]([OH:21])=[O:1])(=[O:10])[CH3:9]
Reactant: O
Reactant: CC(=O)OC1CCC2CC(=O)CCC21
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)OC1CCC2C(C(=O)O)CCC12
Yield: 12.2 %

Procedure:
Thallic nitrate trihydrate (133 g) was added to a stirred solution of 7-acetoxybicyclo[4,3,0]nonan-3-one (57 g; prepared as described in Reference Example 4) in glacial acetic acid (290 ml). After 30 minutes the resulting solid was filtered off and the filtrate was heated at reflux for 30 minutes. The acetic acid was distilled off under reduced pressure and the residue was neutralised by treatment with aqueous sodium hydroxide solution to pH 5 and then with aqueous sodium bicarbonate solution to neutral. The resulting solution was washed with diethyl ether, and then it was acidified by treatment with concentrated hydrochloric acid and extracted with chloroform. The combined chloroform extracts were washed with saturated aqueous sodium chloride solution, then dried over magnesium sulphate, and concentrated under reduced pressure. The residue was purified by medium pressure, short column chromatography on silica gel, eluting with a mixture of ethyl acetate, hexane, and acetic acid (45:55:1 by volume), to give 6-acetoxy-2-carboxybicyclo[3,3,0]octane (7.55 g), predominantly in the 2β-configuration.
Reaction SMILES: C(Cl)Cl.[SH:4][C:5]1[N:9]([CH3:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]=1.Br[CH:16]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:17]([OH:19])=[O:18]>C(N(CC)CC)C>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH:16]([S:4][C:5]2[N:9]([CH3:10])[C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[N:6]=2)[C:17]([OH:19])=[O:18])=[CH:25][CH:24]=1
Reactant: O=C(O)C(Br)c1ccc(Cl)cc1
Reactant: Cn1c(S)nc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(SC(C(=O)O)c2ccc(Cl)cc2)nc2ccccc21
Yield: 41 %

Procedure:
A methylene chloride solution of 3.3 g (0.02M) of 2-mercapto-1-methyl-1H-benzimidazole, 5.0 g (0.02M) of α-bromo-(p-chlorophenyl)acetic acid and 4.0 g (0.04M) of triethylamine is heated to reflux overnight. The reaction mixture is neutralized with a diluted HCL solution. The layers are separated and the organic layer is dried over anhydrous magnesium sulfate. After removal of methylene chloride the residue is recrystallized from acetonitrile. The recrystallized material weighs 4.1 g (41% yield) and has a melting point of 161°-3° C. dec.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C@@H:4]([C:6]([S:9][CH3:10])([CH3:8])[CH3:7])[NH2:5].C(N(C(C)C)CC)(C)C.[O:21]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C@@H:4]([C:6]([S:9][CH3:10])([CH3:8])[CH3:7])[NH:5][S:34]([C:31]1[CH:30]=[CH:29][C:28]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:33][CH:32]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)[C@H](N)C(C)(C)SC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](NS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(C)(C)SC
Reaction time: 2.5 h
Yield: 87 %

Procedure:
To a solution of S-methyl-D-penicillamine methyl ester (0.160 g., 0.904 mmol) and diisopropylethylamine (0.172 mL, 0.99 mmol) in dichloromethane (3 mL) was added 4-phenoxybenzenesulfonyl chloride (0.304 g, 1.13 mmol) via solid addition funnel. After 2.5 hours at room temperature, the solution was concentrated and the residue was purified on silica, eluting with 20% ethyl acetate in hexane, to give S-methyl--N--[4-(phenoxy)benzenesulfonyl]-D-penicillamine methyl ester as a white solid in 87% yield: 1H NMR (CDCl3) δ 1.31 (s, 3H), 1.37 (s, 3H), 1.96 (s,3H), 3.48 (s, 3H), 3.79 (d, 1H, J=9 Hz), 5.34 (d, 1H, J=10 Hz), 6.99-7.79 (m, 9H); FAB HRMS: expected (M+Na)=432.0915, found (M+Na)=432.0907.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)=[CH:13][CH:12]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)O1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[NH:35]1[CH:34]=[C:33]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=4)=[CH:13][CH:12]=3)=[N:6][CH:7]=2)[CH:37]=[N:36]1
Reactant: Cc1cc(-c2ccc(CC(=O)Nc3ccc(I)cn3)cc2)ccn1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(-c4cn[nH]c4)cn3)cc2)ccn1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
N-(5-Iodopyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)phenyl)acetamide 65-2 (20 mg, 0.046 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (13.5 mg, 0.07 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol) was mixed in toluene (3 mL)/ethanol (1 mL)/Na2CO3 (2M, 1 mL). The reaction mixture was stirred at 90° C. for 10 hours. The solvent was removed by rotary evaporation and the residue was dissolved in DMSO. The inorganic salt was removed by filtration. The crude product in DMSO was purified by reverse phase HPLC to give N-(5-(1H-pyrazol-4-yl)pyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)phenyl)acetamide 65 as off-white solid. MS m/z 370.2 (M+1).
Reaction SMILES: N([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([CH3:18])([CH3:17])[O:15][C:14](=[C:19]([C:22]#[N:23])[C:20]#[N:21])[C:13]=2[C:24]#[N:25])=[CH:8][CH:7]=1.[N-:26]=[N+:27]=[N-].[Na+]>O.Cl>[N:5]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:16]([CH3:17])([CH3:18])[O:15][C:14](=[C:19]([C:22]#[N:23])[C:20]#[N:21])[C:13]=2[C:24]#[N:25])=[CH:10][CH:11]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(N=[N+]=[N-])cc1
Reaction time: 0.75 h

Procedure:
A solution of NaNO2 (0.69 g, 10.0 mmol) in 10 mL water was added dropwise to a solution of 2-[4-(4-aminophenyl)-3-cyano-5,5-dimethyl-5H-furan-2-ylidene]malononitrile (1.4 g, 5.0 mmol) in 30 mL 4M HCl at 0-5° C. After stirring the mixture at this temperature for 45 min, a solution of NaN3 (0.53 g, 8.0 mmol) in 10 mL water was added dropwise to the mixture at the same temperature. Stirring was continued for 1 h below 5° C. and then at room temperature overnight. The precipitate formed was filtered off, washed with water and air-dried. The yellow product was recrystallized from dichloromethane/1-propanol. Yield: 1.25 g (82%). Mp: 184° C. IR (neat) 3056, 2990, 2235, 2122, 2091, 1601, 1568 cm−1; 1H NMR (400 MHz, DMSO) δ 7.90 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 1.86 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 177.1, 176.6, 145.0, 130.61, 123.4, 120.30, 112.35, 111.4, 111.3, 101.60, 100.30, 55.20, 24.90; Anal. Calcd for C16H10N6O: C, 63.57; H, 3.33; N, 27.80. Found: C, 63.51H, 3.44; N, 27.20. UV-Vis (CH2Cl2): λmax=384 nm ε=2.9×104 L·mol−1 cm−1.
Reaction SMILES: C1(=O)[NH:5]C(=O)C2=CC=CC=C12.Br[CH2:13][CH:14]=[CH:15][C:16]#[C:17][C:18]([CH3:21])([CH3:20])[CH3:19]>CN(C)C=O>[CH3:19][C:18]([CH3:21])([CH3:20])[C:17]#[C:16]/[CH:15]=[CH:14]/[CH2:13][NH2:5]
Reactant: CC(C)(C)C#CC=CCBr
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)C#C/C=C/CN

Procedure:
As an alternative method of synthesizing the above compound, phthalimide and 1-bromo-6,6-dimethyl-2-hepten-4-yne (a mixture of E and Z forms in a ratio of about 3:1) are reacted in dimethylformamide. The resulting (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)phthalimide (by recrystallization from hexane, it is separated into an E form and a Z form, m.p. 106°-108° C.) is reacted with hydrazine to produce (E)-6,6-dimethyl-2-hepten-4-ynylamine. This compound is reductively alkylated by using equimolar proportions of 3-benzyloxybenzaldehyde and sodium borohydride in methanol to give the captioned compound.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16](=[O:32])[CH2:17][CH2:18][C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[CH3:34]I.[H-].[Na+]>>[CH3:34][N:15]([C:16](=[O:32])[CH2:17][CH2:18][C:19]#[C:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]([F:30])([F:29])[F:31])=[CH:25][CH:26]=1)[C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][N:6]2[CH2:5][C:4]([OH:3])=[O:33])=[CH:10][CH:11]=1
Reactant: CI
Reactant: CCOC(=O)Cn1ccc2ccc(NC(=O)CCC#Cc3ccc(OC(F)(F)F)cc3)cc21
Agent: [H-]
Agent: [Na+]
Product: CN(C(=O)CCC#Cc1ccc(OC(F)(F)F)cc1)c1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 8 d], {6-[5-(4-trifluoromethoxy-phenyl)-pent-4-ynoylamino]-indol-1-yl}-acetic acid ethyl ester was reacted with methyl iodide in the presence of sodium hydride to give the title compound as brown liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:16](=[O:20])[C:17]([O-:19])=[O:18])[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:16](=[O:20])[C:17]([OH:19])=[O:18])[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([O-:3])=[O:2]
Reactant: O=C([O-])C(=O)c1ccc(C2CCCCC2)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)C(=O)c1ccc(C2CCCCC2)c([N+](=O)[O-])c1

Procedure:
A mixture of 0.66 moles of 3-nitro-4-cyclohexylphenylglyoxylate is stirred in 1.5 l. of boiling 10% sodium carbonate solution for 16 hours. The mixture is slowly filtered through charcoal into 1.1 l. of ice-cold 3 N-hydrochloric acid. The precipitate of crude material is collected on a filter, the recrystallized from benzene to give 3-nitro-4-cyclohexylphenylglyoxylic acid.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]([O:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Si:18]([O:25][C@H:26]1[CH2:35][C@H:34]([OH:36])[C@H:33]2[C:28]([CH:29]=[CH:30][C@H:31]([CH3:54])[C@@H:32]2[CH2:37][CH2:38][C@H:39]2[O:44][C:43](=[O:45])[CH:42](O[SiH3])[C@H:41](C(C)(C)C)[C:40]2(C)C)=[CH:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>>[Si:18]([O:25][C@H:26]1[CH2:35][C@H:34]([O:36][C:11](=[O:13])[C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:17][CH:16]=2)([CH3:15])[CH3:14])[C@H:33]2[C:28]([CH:29]=[CH:30][C@H:31]([CH3:54])[C@@H:32]2[CH2:37][CH2:38][C@H:39]2[O:44][C:43](=[O:45])[CH2:42][C@H:41]([O:25][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:40]2)=[CH:27]1)([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:19])[CH3:20]
Reactant: CC(C)(Oc1ccc(C(C)(C)C)cc1)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@H]1OC(=O)C(O[SiH3])[C@H](C(C)(C)C)C1(C)C
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)Oc3ccc(C(C)(C)C)cc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Yield: 160.4 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 858 mg of 2-(4-t-butylphenoxy)-2-methylpropionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethyl silyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.12 g of the title compound as a colorless foam.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:3]1.[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][N:2]([O:1][C:15](=[O:16])[N:14]([CH3:13])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1
Reactant: On1ccc(-c2ccccn2)n1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)On1ccc(-c2ccccn2)n1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-3-(2-pyridyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (90%, oil).
Reaction SMILES: Br[CH2:2][C:3]([N:5]([CH2:8][CH3:9])[CH2:6][CH3:7])=[O:4].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[C:18]1(/[CH:24]=[CH:25]/[S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:6]([N:5]([CH2:8][CH3:9])[C:3](=[O:4])[CH2:2][N:10]([S:26](/[CH:25]=[CH:24]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:28])=[O:27])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH3:7]
Reactant: Cc1ccc(N)cc1
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Reactant: CCN(CC)C(=O)CBr
Product: CCN(CC)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)/C=C/c1ccccc1

Procedure:
prepared by reaction of 2-bromo-N,N-diethylacetamide with p-toluidine and (E)-2-phenyl-ethenesulfonyl chloride