Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[OH:4][C@H:5]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@:11]3([OH:28])[CH2:12][CH2:13][C@@H:14]2/[CH:15]=[CH:16]/[CH:17]=O)[CH2:6]1>[OH-].[Na+].O1CCOCC1.O>[OH:3]/[N:2]=[CH:17]/[CH:16]=[CH:15]/[C@H:14]1[CH2:13][CH2:12][C@:11]2([OH:28])[C@H:10]3[C@H:22]([CH2:21][CH2:20][C@:19]12[CH3:27])[C@:23]1([CH3:26])[C@@H:7]([CH2:6][C@@H:5]([OH:4])[CH2:25][CH2:24]1)[CH2:8][CH2:9]3
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=O)CC[C@]12O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=N/O)CC[C@]12O
Yield: 63.9 %

Procedure:
To a solution of 0.65 g of hydroxylamine hydrochloride in 41 ml of 1N NaOH and 30 ml of dioxane a solution of 2.70 g of (E)-3β,14β-dihydroxy-5β-pregn-20-ene-21-carboxaldehyde (Fullerton D. S. et al., J. Med. Chem., 1976, 19,1330) in 40 ml of dioxane was added dropwise at room temperature. After 20 hrs the solution was diluted with water and extracted with methylene chloride. The crude product was purified by flash chromatography (SiO2) using hexane/ethyl acetate 1/1 as the eluant. The fractions containing the title compound were collected and evaporated to dryness. The residue was ground with di-iso-propyl ether to give 1.80 g of the title compound (I-am), as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:4][C:3]=1[C:22]#[N:23].[ClH:24]>O1CCOCC1>[ClH:24].[NH2:1][C:2]1[C:3]([C:22]#[N:23])=[CH:4][CH:5]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2ccc(C#N)c(N)n2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(NC2CCCNC2)nc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.00 g (6.3 mmol) of tert-butyl 3-[(6-amino-5-cyanopyridin-2-yl)amino]piperidine-1-carboxylate (Example 9A) were dissolved in 40 ml of a hydrochloric acid solution in dioxane (4 M) and stirred at RT for 2 h. On completion of reaction, the solvent was concentrated by half, and 20 ml of diethyl ether were added. The precipitate was filtered off and dried. 1.80 g (100% of theory) of the product were obtained in solid form.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[C:18]([Br:19])=[C:17]([N+:20]([O-:22])=[O:21])[C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]=1[C:23](Cl)=[O:24]>CC(CC)C(=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:23]([C:10]2[C:11]3[O:16][CH2:15][CH2:14][O:13][C:12]=3[C:17]([N+:20]([O-:22])=[O:21])=[C:18]([Br:19])[C:9]=2[Br:8])=[O:24])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1c(Br)c(Br)c([N+](=O)[O-])c2c1OCCO2
Agent: CCC(C)C(C)=O
Product: CN1CCN(C(=O)c2c(Br)c(Br)c([N+](=O)[O-])c3c2OCCO3)CC1
Temperature: 10 °C
Yield: 69.5 %

Procedure:
400 ml of methylethylacetone and 11 g of methylpiperazine were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was cooled to 10° C. and then 41 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carbonyl chloride were added in portions with the temperature being maintained below 20° C. After agitation of the mixture, the crystals were dried off, washed with methylethylcetone and dried and then dissolved in water and reprecipitated by addition of 50 ml of 20% ammonia. The crystals were dried off, washed with water and dried. 33 g of 5-[(4-methyl-1-piperazinyl)-carbonyl]-6,7-dibromo-8-nitro-1,4-benzodioxane were obtained (M.P: 164° C.; yield: 69.6%).
Reaction SMILES: Cl[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[OH:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.N1C=CN=C1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:6][C:5]([Si:2]([CH3:4])([CH3:3])[O:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:15]1)([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 40 °C

Procedure:
Chloro(1,1-dimethylethyl)dimethylsilane (115 g; 0.76 mol) was added in portions over 1 hour to a solution of commercially available ethyl 4-hydroxycyclohexanecarboxylate (118 g; 0.68 mol), imidazole (103 g; 1.52 mol) and dimethylformamide (400 mL) stirred under an atmosphere of argon. A small exotherm was observed resulting in the reaction mixture temperature increasing to ˜40° C. The mixture was stirred at room temperature overnight then poured into 10% citric acid solution (2 L) and extracted with diethyl ether (2×800 mL). The ether extracts were washed with water, brine and then dried (Na2SO4) and the solvent was removed to give the title compound as an oil (198.4 g)
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([CH2:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)[C:9](=[N:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:10][CH:11]=2)=[CH:3][CH:2]=1.Cl.O>O1CCOCC1>[NH2:22][CH2:21][CH2:20][CH2:19][N:8]1[C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:2][CH:3]=2)=[CH:11][S:10][C:9]1=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCCn1c(-c2ccc(-c3ccccc3)cc2)csc1=Nc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: NCCCn1c(-c2ccc(-c3ccccc3)cc2)csc1=Nc1ccccc1
Yield: 100 %

Procedure:
A mixture of t-butyl 3-[4-(1,1′-biphenyl-4-yl)-2-(phenylimino)-thiazol-3(2H)-yl]propylcarbamate (233 mg) and a 4N solution of hydrogen chloride in dioxane (2 ml) was stirred at room temperature for one hour. To the reaction mixture was added water, and the mixture was washed with diethyl ether. The aqueous layer was basified with a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with a saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (185 mg)
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@H:16]3[CH2:20][C@@H:19]([OH:21])[CH2:18][NH:17]3)=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N:24]1([CH2:29][C:30](O)=[O:31])[CH:28]=[N:27][CH:26]=[N:25]1>>[N:24]1([CH2:29][C:30]([N:17]2[CH2:18][C@H:19]([OH:21])[CH2:20][C@@H:16]2[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:12][CH:11]=2)=[O:15])=[O:31])[CH:28]=[N:27][CH:26]=[N:25]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@H]1C[C@@H](O)CN1
Reactant: O=C(O)Cn1cncn1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@H]1C[C@@H](O)CN1C(=O)Cn1cncn1
Yield: 70 %

Procedure:
Proceeding as in Reference 11, but substituting (2R,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-hydroxypyrrolidine-2-carboxamide and 2-(1H-1,2,4-triazol-1-yl)acetic acid gave (2R,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-hydroxypyrrolidine-2-carboxamide (1.37 g, 3.25 mmol, 70% yield) as an off-white solid.
Reaction SMILES: O=[C:2]([CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3](OCC)=[O:4].C(=O)(O)O.[NH2:21][C:22]([NH2:24])=[NH:23]>C(O)C>[NH2:24][C:22]1[N:23]=[C:3]([OH:4])[CH:2]=[C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:21]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(=O)CCOc1ccccc1
Agent: O=C(O)O
Solvent: CCO
Product: Nc1nc(O)cc(COc2ccccc2)n1
Yield: 58.8 %

Procedure:
A mixture of 7.8 g (36 mmol) of ethyl 2-oxo-4-phenoxybutanoate and 3.4 g (38 mmol) guanidine carbonate was heated to reflux in 100 ml abs. ethanol for 48 hours. Filtration of the cooled suspension afforded 4.6 g of 2-amino-4-hydroxy-6-phenoxymethylpyrimidine in two crops, m.p. 253°-254° (dec). This intermediate (4.3 g, 20 mmol) was heated to reflux in 50 ml phosphorous oxychloride for 2 hours then evaporated. The residue was treated with ice-water and neutralized with 10% sodium hydroxide solution then extracted with chloroform. Evaporation of the extracts left a residue which was purified by dissolution in 15% ethyl acetate/methylene chloride and filtration through silica gel. The filtrate was concentrated and crystallized from ether/1-chlorobutane/hexanes to yield 0.65 g of 2-amino-4-chloro-6-phenoxymethylpyrimidine, m.p. 123°-124°. An additional 0.8 g was deposited from the original aqueous phase, m.p. 118°-121°, for a total of 1.4 g of product. A 1.0 g (4.2 mmol) portion of this material was reacted with 20 mmol sodium methoxide in 30 ml methanol at reflux for 2 hours, then concentrated in vacuo. The residue was triturated with water, collected, water rinsed and dried to 0.9 g of the title compound, m.p. 94°-96°. NMR (90 MHz, CDCl3): δ 3.83 (s, 3H); 4.90 (s, 2H); 6.31 (s, 1H); 6.9-7.1 (m, 3H); 7.22-7.45 (m, 2H) ppm.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](=[O:6])[CH:4]=[CH2:5].Br[C:9]1[CH:10]=[CH:11][C:12]([O:29][CH2:30][CH3:31])=[C:13]([C:15]2[NH:16][C:17](=[O:28])[C:18]3[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=3[N:20]=2)[CH:14]=1>>[CH3:1][N:2]([CH3:7])[C:3](=[O:6])/[CH:4]=[CH:5]/[C:9]1[CH:10]=[CH:11][C:12]([O:29][CH2:30][CH3:31])=[C:13]([C:15]2[NH:16][C:17](=[O:28])[C:18]3[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=3[N:20]=2)[CH:14]=1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(Br)ccc3OCC)nc12
Reactant: C=CC(=O)N(C)C
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(/C=C/C(=O)N(C)C)ccc3OCC)nc12

Procedure:
The title compound was prepared from N,N-dimethylacrylamide and 5-(5-bromo-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one following the procedure of Example 69 and was obtained, following crystallisation from ethyl acetate-hexane, as colourless crystals (38%), m.p. 219-221° C. Found: C,64.15; H,6.46; N,16.96. C22H27N5O3 requires C,64.53; H,6.65; N,17.10%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18]([CH3:28])=[C:17]([C:29]([OH:31])=O)[C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2].[NH2:32][CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:18]([CH3:28])=[C:17]([C:29]([NH:32][CH:33]3[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]3)=[O:31])[C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2]
Reactant: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)c(C)n(COCC[Si](C)(C)C)c12

Procedure:
Starting from 4-(2-ethoxy-5-fluorophenyl)-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c4) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7]3[CH2:14][NH:13][CH2:12][CH2:11][N:8]3[C:9]=2[CH:10]=1.C([BH3-])#N.[Na+].O.[OH-].[NH4+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH:7]3[CH2:14][NH:13][CH2:12][CH2:11][N:8]3[C:9]=2[CH:10]=1
Reactant: Clc1ccc2cc3n(c2c1)CCNC3
Agent: [BH3-]C#N
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc2c(c1)N1CCNCC1C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.2 %

Procedure:
To a stirred solution of 7-chloro-1,2,3,4-tetrahydropyrazino[1,2-a]indole (1.185 g, 5.73 mmol) in acetic acid (40 mL) under Ar at 10° C. was added portion-wise over 5 min sodium cyanoborohydride (1.19 g, 18.94 mmol). The resultant mixture was allowed to warm to ambient temperature, and was stirred for 24 h. The mixture was poured into water (200 mL) and was basified (pH 8-9) by the careful addition, with cooling, of ammonium hydroxide (60 mL) over 5 min. The basified mixture was extracted with chloroform (3×200 mL), the combined organic extracts washed with brine (200 mL), dried (magnesium sulfate), and concentrated in vacuo. The residue was purified by flash chromatography [SiO2; ethyl acetate-methanol-ammonium hydroxide (90:8:2)] to afford the title compound (768 mg, 64%) as a colourless oil: NMR δH (400 MHz, CDCl3) 1.60 (1H, br s), 2.50 (1H, ddd, J 15.1, 9.0, 1.0 Hz), 2.74 (1H, dd, J 11.5, 10.5 Hz), 2.79-2.99 (4H, m), 3.04 (1H, dd, J 11.5, 3.5 Hz), 3.42-3.52 (2H, m), 6.37 (1H, d, J 2.0 Hz), 6.57 (1H, dd, J 7.5, 2.0 Hz) and 6.92-6.96 (1H, m).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[CH3:13][C:14]([CH3:18])([CH3:17])[C:15]#[CH:16]>CCN(CC)CC.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:12][C:4]1[CH:3]=[C:2]([C:16]#[C:15][C:14]([CH3:18])([CH3:17])[CH3:13])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: C#CC(C)(C)C
Reactant: COC(=O)c1ccc(Br)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CC(C)(C)C)cc1Cl
Temperature: 100 °C
Yield: 82.3 %

Procedure:
A mixture of methyl 4-bromo-2-chlorobenzoate (400 mg, 0.0016 mol), copper(I) iodide (30 mg, 0.00016 mol), 3,3-dimethyl-1-butyne (0.29 mL, 0.0024 mol) and bis(triphenylphosphine)palladium(II) chloride (110 mg, 0.00016 mol) in Et3N (5 mL) and DMF (2 mL) was heated at 100° C. in a 50 mL sealed reaction vessel for 32 hours. After cooling, the mixture was filtered through Celite® and the filter cake was washed repeatedly with ethyl acetate. The organic phase was washed with brine, dried (Na2SO4), and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the product (330 mg, 82%) as a light yellow oil.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:22])[C:8](=O)[CH:9]([C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:10][CH3:11])[CH3:5]>C(O)C>[CH2:4]([O:6][C:7]([C:8]1[C:9]([CH2:10][CH3:11])=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[NH:3][N:2]=1)=[O:22])[CH3:5]
Reactant: CCOC(=O)C(=O)C(CC)C(=O)c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1n[nH]c(-c2ccc(Cl)cc2)c1CC
Reaction time: 8 h
Yield: 42.3 %

Procedure:
Hydrazine monohydrate (0.13 ml, 3 mmol) was added at ambient temperature to a solution of 3-(4-chloro-benzoyl)-2-oxo-pentanoic acid ethyl ester (740 mg, 3 mmol) in ethanol (4 ml) under an argon atmosphere. The solution was stirred for 8 h at reflux temperature, the solvent was removed under reduced pressure and the residue partitioned between 1 M HCl/ice water and ethyl acetate. The aqueous layer was extracted two times with ethyl acetate, the combined extracts were washed with brine (3 times) and dried over sodium sulfate. Removal of the solvent under reduced pressure left an orange oil which was purified by column chromatography (silica gel, heptane/AcOEt) to give 355 mg (1.27 mmol, 49%) of the title compound as yellow crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=O)=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10].O1CCCC1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[CH2:7]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH2:17])=[CH:18][CH:19]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1ccc(C(N)=O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a suspension of 15 g of lithium aluminum hydride in 200 ml of anhydrous ethyl ether under argon was added, at room temperature, a solution of 32.0 g of 4-butylbenzamide in 200 ml of freshly distilled tetrahydrofuran. The resulting mixture was stirred at room temperature for one hour and then heated at reflux for 20 hours. The mixture was cooled and sodium sulfate decahydrate was cautiously added portionwise to the mixture until it was colorless. The mixture was stirred for 30 minutes. The mixture was filtered and the filter was washed with ether. The filtrate was evaporated in vacuo to yield 29 g (99% yield) of a liquid. The liquid was distilled by Kugelrohr distillation, bp 85° C./0.070 mm of mercury, to give the desired product as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]=[C:19]([Cl:21])[Cl:20])[CH:13]=[C:12]([Cl:22])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.[CH2:23]([NH:26][CH2:27][C:28]#[CH:29])[C:24]#[CH:25].CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[Cl:22][C:12]1[CH:13]=[C:14]([O:16][CH2:17][CH:18]=[C:19]([Cl:21])[Cl:20])[CH:15]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[O:11])[N:26]([CH2:27][C:28]#[CH:29])[CH2:23][C:24]#[CH:25]
Reactant: O=C(O)CCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: C#CCNCC#C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: C#CCN(CC#C)C(=O)CCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of 0.20 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)-phenoxy)valeric acid and 0.05 g of dipropargylamine dissolved in 10 ml of chloroform was added 0.11 g of WSC hydrochloride, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.21 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(N,N-dipropargylcarbamoyl)butyloxy)benzene (92% yield), nD25.0 1.5481.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH4+].[Cl-].[C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1)#[N:8]>CN(C=O)C>[NH:1]1[C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:11][CH2:10]2)=[N:8][N:3]=[N:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(c2nnn[nH]2)CC1
Reaction time: 24 h
Yield: 19.3 %

Procedure:
NaN3 (1.7 g, 26.14 mmol) and NH4Cl (1.75 g, 32.7 mmol) were added to the solution of benzyl 4-cyanopiperidine-1-carboxylate (1.6 g, 26.14 mmol) in DMF (16 mL) and stirring was continued at 90° C. for 24 h. The reaction mixture was quenched with 10% aqueous citric acid solution, extracted with EtOAc, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 1.45 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:17])(=[N:12][C:13](=[O:16])[NH:14][CH3:15])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:17])(=[N:12][C:13](=[O:16])[NH:14][CH3:15])=[O:11])=[CH:6][CH:5]=1
Reactant: CNC(=O)N=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)N=S(C)(=O)c1ccc(N)cc1

Procedure:
302 mg (1.17 mmol) (RS)—S-(4-nitrophenyl)-N-(methylcarbamoyl)-S-methylsulfoximide in 20 ml methanol is hydrogenated over 60 mg palladium (10% on carbon, 50% water wet) for 4 hours at 26° C. and 30 bar. The catalyst is filtered and the solvent evaporated to give 271 mg (corresponding to 100% of theor.) of the product.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]([C:13]1[N:14]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23]C)=[O:22])[CH:15]=[CH:16][CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O1CCOCC1.Cl>O.C(OCC)(=O)C>[CH2:3]([O:10][C:11]([C:13]1[N:14]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([OH:23])=[O:22])[CH:15]=[CH:16][CH:17]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccc(-n2cccc2C(=O)OCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(-n2cccc2C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.1 %

Procedure:
1N-Sodium hydroxide solution (1.5 ml) was added to a mixture of methyl 3-(2-benzyloxycarbonylpyrrol-1-yl)benzoate (0.5 g) and dioxane (20 ml), and the mixture was stirred for 3 days at ambient temperature. The reaction mixture was poured into the mixture of ethyl acetate and water and the separated aqueous layer was adjusted to pH 1 with 6N-hydrochloric acid. The mixture was extracted with ethyl acetate and extract was washed with brine and dried over magnesium sulfate. The solvent was removed by concentration and the residue was triturated with n-hexane to give 3-(2-benzyloxycarbonylpyrrol-1-yl)benzoic acid (0.24 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH2:25]([N:27]([CH2:35][CH3:36])[C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1)[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([N:27]([CH2:35][CH3:36])[CH2:25][CH3:26])[CH:29]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CCN(CC)c1cccc(O)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CCN(CC)c1cccc(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 39.3 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-diethylamino phenol (44 mg, 0.26 mmol) to give the title compound (26 mg, 39%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: C[N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=O.N[C:15]1[C:19]([C:20]#[N:21])=C[NH:17][N:16]=1>C(O)(=O)C>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:17]3[N:16]=[CH:15][C:19]([C:20]#[N:21])=[C:13]3[N:2]=[CH:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1ccncc1
Solvent: CC(=O)O
Product: N#Cc1cnn2c(-c3ccncc3)ccnc12

Procedure:
A mixture of 1.12 g. of 3-dimethylamino-1-(4-pyridyl)-2-propen-1-one and 0.69 g. of 3-aminopyrazole-4-carbonitrile in 25 ml. of glacial acetic acid is refluxed 6 hours. The solvent is removed under reduced pressure and the product worked up as for Example 53 to give 0.60 g. of crystals, m.p. 137°-138° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[C:9]([C:10]1[CH:11]=[CH:2][CH:3]=[CH:4][C:5]=1[C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1)#[N:8]
Reactant: CCCC(CCC)N1CCc2c(C(=O)OC)cc(Br)cc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(CCC)N1CCc2c(C(=O)OC)cc(-c3ccccc3C#N)cc2C1=O
Temperature: 150 °C

Procedure:
Added to a solution of 0.4 g of methyl 7-bromo-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate in 12.5 cm3 of dioxane and 2.5 cm3 of water, at a temperature close to 20° C., are 196 mg of sodium bicarbonate. The reaction medium is then degassed under an argon atmosphere, then 147.5 mg of 2-cyanophenylboronic acid and 96 mg of tetrakis(triphenylphosphine)palladium are added. The mixture is heated at 150° C. in a microwave oven for 4 minutes, cooled to a temperature close to 20° C. and filtered. The filtrate is taken up by 20 cm3 of dichloromethane and 20 cm3 of water. The organic phase is extracted, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa). The residual solution (around 3 cm3) is purified by flash chromatography over silica (column: 50 g; spherical silica of BP-SUP type, partical size: 20-40 μm; eluent: 80% heptane/20% ethyl acetate then 60% heptane/40% ethyl acetate then 50% heptane/50% ethyl acetate). After concentrating the fractions under reduced pressure, 178 mg of methyl 7-(2-cyanophenyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate are obtained in the form of a colorless oil.