Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6]C)=[O:5].CN(C)C=O.[CH2:13]([NH:15][C:16]([N:18]1[C:26]2[C:21](=[CH:22][C:23]([O:27][C:28]3[CH:33]=[CH:32][N:31]=[C:30]([N:34](C(OC4C=CC=CC=4)=O)[C:35](=O)[O:36]C4C=CC=CC=4)[CH:29]=3)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1)=[O:17])[CH3:14]>C(N(CC)CC)C>[CH2:13]([NH:15][C:16]([N:18]1[C:26]2[C:21](=[CH:22][C:23]([O:27][C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]([NH:2][CH2:3][C:4]([OH:6])=[O:5])=[O:36])[CH:29]=3)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1)=[O:17])[CH3:14]
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)NCC(=O)O)c3)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.5 %

Procedure:
Methyl aminoacetate hydrochloride (292 mg, 2.33 mmol) was suspended in a solvent mixture of N,N-dimethylformamide (4 ml) and triethylamine (1 ml); phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (250 mg, 0.466 mmol, Production example 55-1) was added thereto; and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in a solvent mixture of tetrahydrofuran (2 ml) and methanol (1 ml); and 4N aqueous solution of sodium hydroxide was added thereto while stirred at room temperature; and the reaction mixture was stirred for 1.5 hour at room temperature. After 1N hydrochloric acid was added, extraction was performed with ethyl acetate-tetrahydrofuran, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crystals were suspended in diethyl ether, filtered off, washed with dimethyl ether, and dried under aeration to yield the title compound as colorless crystals (149 mg, 0.375 mmol, 80.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25])=[C:19]=[O:20]>>[C:24]([C:23]1[CH:22]=[C:21]([NH:18][C:19]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:20])[CH:28]=[CH:27][CH:26]=1)#[N:25]
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: N#Cc1cccc(N=C=O)c1
Product: N#Cc1cccc(NC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)c1
Yield: 67.5 %

Procedure:
Example 5 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 3-isocyanatobenzonitrile (0.0196 g) to give the title compound (0.0257 g). LC-MS (System A): Rt 2.29 mins, Mass Spectrum m/z 419 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8][CH2:9][C:10]=1[NH:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:4].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(#N)C>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1=C(NC(C)c2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1NC(C)c1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 62.1 %

Procedure:
A solution of 4-(1-phenyl-ethyl amino)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (4 g, 11.1 mmol) in acetic acid-acetonitrile (1:1, 80 mL) was treated with sodium triacetoxyborohydride (2.59 g, 12.2 mmol), and stirred for 5 h at 0° C. The reaction was cooled to 0° C. and neutralized with saturated aqueous sodium bicarbonate (5 mL). The organic layer was washed with brine (3×20 mL), then dried over MgSO4, filtered and concentrated to obtain a crude oil (3.6 g). The crude product was purified by Biotage Flash 40S chromatography, eluting with 1:1 ethyl acetate-hexanes, to provide 4-(1-phenyl-ethylamino)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as a white solid (2.5 g, 62.5%). MS: 363 (M+H)+
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[CH2:1]([N:8]1[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnn(Cc2ccccc2)c1
Agent: [Pd]
Product: Nc1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.6 %

Procedure:
A mixture of 1-benzyl-4-nitro-1H-pyrazole (33 mg, 0.162 mmol) and 10% Pd/C (10 mg) was stirred under an hydrogen atmosphere at rt for 12 h. The catalyst was filtered off, washed with methanol and the solvent was removed under reduced pressure to give the title compound as dark brown oil (27.4 mg, 97%). MS ISP (m/e): 174.2.3 (100) [(M+H)+].
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH:34]=O)=[C:29]([C:36]([F:39])([F:38])[F:37])[CH:28]=2)=[O:25])=[CH:19][CH:18]=1)(C)(C)C.C(O)(=O)C.[CH3:46][NH:47][CH3:48].C([BH3-])#N.[Na+]>C(O)C>[CH3:46][N:47]([CH3:48])[CH2:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([N:12]3[CH:11]=[N:10][C:9]4[C:13]3=[N:14][CH:15]=[N:16][C:8]=4[NH:7][CH3:6])=[CH:22][CH:21]=2)=[O:25])=[CH:28][C:29]=1[C:36]([F:38])([F:37])[F:39]
Reactant: CNC
Reactant: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(CC=O)c(C(F)(F)F)c2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CNc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(CCN(C)C)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
In 1 mL of ethanol, 25 mg (0.04 mmol) of methyl-[9-(4-{3-[4-(2-oxoethyl)-3-(trifluoromethyl)phenyl]ureido}-phenyl)-9H-purin-6-yl]-carbamic acid tert-butyl ester was dissolved, and 10 μL of acetic acid and 0.1 mL (0.20 mmol) of 2N dimethylamine were added thereto and the mixture solution was stirred at room temperature for 30 minutes. Furthermore, 7 mg (0.11 mmol) of sodium cyanoborohydride was added to the obtained solution and the mixture solution was stirred at room temperature for one hour. The reaction solution was concentrated and to the residue, 0.5 mL of trifluoroacetic acid was added and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated, and a target product was obtained by a reversed phase HPLC (a product of Wako Pure Chemical, Combi ODS, 28 mm×50 mm, 0.05% acetonitrile-water, 30 mL/min). The fraction containing the target product was concentrated, and then dissolved in methanol and neutralized by addition of amino silica gel R 66030 B (a product of Silicycle), and then a solid was removed by filtration and the filtrate was concentrated to obtain 15 mg (52%) of a title compound.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5](/[CH:9]=[CH:10]/[S:11]([NH2:14])(=[O:13])=[O:12])[CH:4]=1.[Cl:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].O>O1CCOCC1>[Cl:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18]([NH:14][S:11](/[CH:10]=[CH:9]/[C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)(=[O:12])=[O:13])=[O:19]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: NS(=O)(=O)/C=C/c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NS(=O)(=O)/C=C/c1cccnc1)c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (36 mg, 0.9 mmol) was added to a solution of (E)-2-Pyridin-3-yl-ethenesulfonic acid amide (56 mg, 0.3 mmol) in dioxane (1 mL) and the mixture was shaken for 30 minutes. A solution of 2,4-dichlorobenzoyl chloride (63 μL, 0.45 mmol) in dioxane (0.5 mL) was added to the mixture and the whole was shaken at room temperature for 18 hours. Water (0.1 mL) was added to the mixture and the whole was concentrated in vacuo. The resultant residue was purified by preparative HPLC to give (E)-2-pyridin-3-yl-ethenesulfonic acid 2,4-dichloro-benzoylamide (29.1 mg, 26%) as sodium salt.
Reaction SMILES: CC(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=[C:10]([S:33][CH3:34])[CH:9]=1)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:34][S:33][C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(NC(=O)OC(C)(C)C)cc(SC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(SC)c1
Yield: 87 %

Procedure:
A solution of 2.65 g (5.2 mmol) of 3-(methylthio)-5-(octadecyloxy)phenylcarbamic acid dimethylethyl ester and2.0 ml (26 mmol) of trifluoroacetic acid in 50 ml of methylene chloride waskept at room temperature for 24 hours. The mixture was concentrated at reduced pressure and the residue was treated with excess NaHCO3 solution. The product was extracted with methylene chloride and the dried extract was concentrated and recrystallized from methylene chloride-hexaneto give 1.85 g (87% yield), nap 75°-77° of 3-(methylthio)-5-(octadecyloxy)benzenamine. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[CH2:3][OH:4].[CH:6]1([C:9]2[N:14]=[C:13]([C:15]([NH:17][C:18]3[CH:26]=[N:25][CH:24]=[CH:23][C:19]=3[C:20](O)=[O:21])=[O:16])[C:12]([NH:27][C:28]3[CH:29]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1>>[OH:4][CH2:3][CH:2]([NH:1][C:20]([C:19]1[CH:23]=[CH:24][N:25]=[CH:26][C:18]=1[NH:17][C:15]([C:13]1[C:12]([NH:27][C:28]2[CH:29]=[N:30][CH:31]=[N:32][CH:33]=2)=[CH:11][CH:10]=[C:9]([CH:6]2[CH2:8][CH2:7]2)[N:14]=1)=[O:16])=[O:21])[CH3:5]
Reactant: CC(N)CO
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: CC(CO)NC(=O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 32 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 2-amino-propan-1-ol with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (32%) as amorphous yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:22][C:23]1[C:28](Cl)=[N:27][CH:26]=[CH:25][N:24]=1>CN(C=O)C>[Cl:22][C:23]1[C:28]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[O:9])=[CH:4][CH:3]=2)=[N:27][CH:26]=[CH:25][N:24]=1
Reactant: Clc1nccnc1Cl
Reactant: O=C(c1ccc(O)cc1)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1ccccn1
Temperature: 80 °C

Procedure:
To a stirred solution of (4-hydroxy-phenyl)-pyridin-2-yl-methanone (2.5 g, 0.0125 mol) in DMF (35 mL) was added cesium carbonate (6.14 g, 0.0188 mol). The resulting mixture was stirred for 15 minutes before addition of 2,3-dichloro pyrazine(1.87 g, 0.0125 mol) at 0° C. The reaction mixture was heated to 80° C. for 16 h. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (2×100 mL). The organic layer was dried over sodium sulphate and concentrated to afford the product. MS (ESI, pos. ion) m/z: 312 (M+1). IC50 (uM) 30.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]=[S:29]1(=[O:44])[CH2:34][CH2:33][N:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:39](=[O:40])[C:38]5[CH:42]=[CH:43][C:35]([N:32]6[CH2:31][CH2:30][S:29](=[O:44])(=[O:28])[CH2:34][CH2:33]6)=[CH:36][CH:37]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(N2CCS(=O)(=O)CC2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(N2CCS(=O)(=O)CC2)cc1

Procedure:
The title compound, white solid (129 mg, 91%), MS (ISP) m/z=568.4 [(M+H)+], mp 261.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-benzoic acid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[C:5]([C:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH:9]=2)[C:4]([CH3:15])=[N:3]1.[C:16](OC(=O)C)(=[O:18])C>C(O)=O>[CH3:1][N:2]1[C:6]([NH:7][CH:16]=[O:18])=[C:5]([C:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH:9]=2)[C:4]([CH3:15])=[N:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nn(C)c(N)c1C1=CCC(C)CC1
Solvent: O=CO
Product: Cc1nn(C)c(NC=O)c1C1=CCC(C)CC1
Reaction time: 2 h

Procedure:
To a suspension of 1,3-dimethyl-4-(4-methyl-1-cyclohexen-1-yl)-5-(1H)-pyrazolamine (24.5 g; 0.119 mole) in 99% formic acid (245 ml), acetic acid anhydride (64.14 g, 0.628 mole) is added at a temperature of about 20° C. Then the mixture is heated to 80°-90° C. and kept at this temperature for about 2 hours. After distillation of the solvent under vacuum, the residue is taken up with water and the pH is adjusted to about 8 with aqueous sodium carbonate. The solution is extracted with methylene chloride and the organic layer is washed with water and then dried over sodium sulfate. After distillation of the solvent, the crude product of the title is recovered and crystallized from the mixture t.butylmethyl-ether and hexane. M.p. 97°-99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][C:18](O)=[O:19])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[NH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][C:18]([NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:19])[C:9]2[C:10]([CH3:16])=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN
Reactant: Cc1cccc(C)c1N(CC(=O)O)C(=O)c1ccc(Cl)cc1
Product: CCOC(=O)CNC(=O)CN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-2-(2,6-dimethylanilino)acetic acid and ethyl glycinate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-2-(2,6-dimethylanilino)acetyl]glycinate (M.P. 127° to 129°), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-2-(2,6-dimethylanilino)acetyl]glycine (M.P. 200° to 201°).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8].[H-].[Na+].Br[CH2:15][CH3:16]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][O:11][CH2:15][CH3:16])[CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8]
Reactant: CCBr
Reactant: Cc1c(Br)cc(CO)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCc1cc(Br)c(C)c(Br)c1
Temperature: 70 °C
Yield: 49.7 %

Procedure:
A mixture of (3,5-dibromo-4-methyl-phenyl)-methanol (4 g, 14.288 mmol), 60% NaH (690 mg, 28.75 mmol) and THF (72 mL) was heated to 70° C. in a sealed tube for 15 minutes. The reaction was cooled, bromoethane (3.2 mL, 42.86 mmol) was added and the reaction continued heating at 70° C. for 6 h. The reaction was cooled, poured onto water, extracted with EtOAc (×3). The organics were washed with water, brine and dried (Na2SO4). Chromatography (Hexanes/EtOAc) afforded 1,3-dibromo-5-ethoxymethyl-2-methyl-benzene (2.187 g) as a colourless oil. 1H NMR (400 MHz, d6-DMSO) δ: 1.15 (t, 3H), 2.48 (s, 3H), 3.46 (q, 2H), 4.41 (s, 2H), 7.57 (s, 2H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[CH:4][CH:3]=1.C(COC)OC.Br[CH2:27][CH2:28][CH2:29][CH3:30]>C(O)C.[OH-].[K+]>[CH2:27]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:6][CH:7]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCBr
Reactant: COC(=O)CCCCCCCCc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: COCCOC
Product: CCCCOc1ccc(CCCCCCCCC(=O)O)cc1
Reaction time: 24 h
Yield: 43.5 %

Procedure:
A mixture of 7 gms 9(4-hydroxyphenyl)nonanoic acid, methyl ester, 1.45 gms KOH, 100 ml dry dimethoxyethane, and 3.6 gms 1-bromobutane was refluxed with stirring for 24 hrs. The reaction was cooled, filtered through diatomaceous earth, and the solvent was removed in vacuo. The residue was dissolved in CHCl3, washed twice with 5% Na2CO3, twice with water and once with NaCl solution, and dried over MgSO4. The drying agent was filtered off and the solvent removed in vacuo to give an oil. This oil was stirred overnight at room temperature in a mixture of 70 ml ethanol and 30 ml 10% KOH solution. The solvent was then evaporated in vacuo, the residue dissolved in hot water, cooled, acidified, and the precipitated solid filtered off. The solid was boiled with hexane, filtered, and the solid boiled with cyclohexane and filtered. The insoluble material was again dissolved in water, the aqueous phase acidified with HCl, and the resulting solid was boiled with hexane and filtered. All hexane and cyclohexane solutions were combined and evaporated in vacuo to give 3.5 gms of solid m.p. 45°-8°, which was used directly in the next step.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C(O)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Na].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>O1CCCC1>[CH:10]1([NH:6][C:5]2[CH:7]=[CH:8][C:2]([I:1])=[CH:3][C:4]=2[CH3:9])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C1CCCC1
Reactant: Cc1cc(I)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(I)ccc1NC1CCCC1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
A mixture of 2.5 g (10.7 mmol) of 4-iodo-2-methylaniline, 1.0 ml (11.8 mmol) of cyclo-pentanone, 0.9 ml (16.1 mmol) of glacial acetic acid and 0.1 g of p-toluenesulphonic acid are stirred in 50 ml tetrahydrofuran for 30 minutes. Then 3.1 g (13.9 mmol) of sodium-triacetoxyborohydride are added and the mixture is stirred for a further 26 hours at ambient temperature. The solvent is distilled off and the residue is chromatographed on silica gel, eluting with petroleum ether/ethyl acetate 0 to 10%.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1.C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[ClH:15].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]([Cl:1])=[O:10])[CH2:5][CH2:4]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN1CCC(C(=O)O)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCC(C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 111.1 %

Procedure:
To a suspension of 1-methyl-piperidine-4-carboxylic acid hydrochloride (11.36 mmol, 2.04 g) and N,N-dimethylformamide (0.129 mmol, 0.01 ml, 9.40 mg) in dichloromethane (10 ml) at 0° C. was added oxalyl chloride (14.76 mmol, 1.40 ml) drop wise. The cooling bath was removed and the reaction mixture stirred at room temperature for 20 hours. Then the reaction mixture was concentrated in vacuo to give 1-methylpiperidine-4-carbonyl chloride hydrochloride (2.5 g).
Reaction SMILES: [C:1](/[C:5]1[C:6]([C:12]([F:15])([F:14])[F:13])=[N+:7]([O-:11])[CH:8]=[CH:9][CH:10]=1)(=[N:3]\[NH2:4])\[NH2:2].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:29](=O)[CH:30]=O)[CH:21]=[C:22]([N+:26]([O-:28])=[O:27])[C:23]=1[O:24][CH3:25]>C(O)C>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:29]2[N:2]=[C:1]([C:5]3[C:6]([C:12]([F:13])([F:15])[F:14])=[N+:7]([O-:11])[CH:8]=[CH:9][CH:10]=3)[N:3]=[N:4][CH:30]=2)[CH:21]=[C:22]([N+:26]([O-:28])=[O:27])[C:23]=1[O:24][CH3:25]
Reactant: N/N=C(\N)c1ccc[n+]([O-])c1C(F)(F)F
Reactant: COc1cc(C(=O)C=O)cc([N+](=O)[O-])c1OC
Solvent: CCO
Product: COc1cc(-c2cnnc(-c3ccc[n+]([O-])c3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C

Procedure:
To a stirred solution of (Z)-3-carbamohydrazonoyl-2-(trifluoromethyl)pyridine 1-oxide (1.10 g, 5 mmol) in ethanol (30 mL) was added 2-(3,4-dimethoxy-5-nitrophenyl)-2-oxoacetaldehyde (1.19 g, 5 mmol). The reaction mixture was heated to reflux for 5 hours, and then cooled to room temperature and the solvent was removed by evaporation. The residue was dissolved in dichloromethane (30 mL) and the organic phase was washed with water and dried over anhydrous magnesium sulphate, filtered and evaporated. The crude product was recrystallized from isopropanol to give 3-(5-(3,4-dimethoxy-5-nitrophenyl)-1,2,4-triazin-3-yl)-2-(trifluoromethyl)pyridine 1-oxide, 1.69 g (80%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:12])[NH:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]([CH2:18][CH2:19][C:20](Cl)=[O:21])([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3](=[S:12])[NH:4][N:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:20](=[O:21])[CH2:19][CH2:18][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: CNC(=S)NNc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC(=O)N(NC(=S)NC)c1ccccc1
Temperature: 80 °C

Procedure:
With 100 ml of toluene was mixed 18.1 g of 4-methyl-1-phenylthiosemicarbazide as prepared in Synthesis Example 1, and 18.1 g of β-carboethoxypropionyl chloride was added thereto. The mixture was heated at 80° C. for 3 hours and then cooled to obtain crystals of 4-methyl-1-phenyl-1-(β-carboethoxypropionyl)thiosemicarbazide. Ten grams of the product was suspended in 70 ml of ethanol, followed by heat refluxing, and a small amount of sodium ethoxide was added to the reaction mixture. The reaction mixture once became uniform, and then crystals precipitated. After cooling, the thus formed crystals were removed by filtration and dried to obtain 16.0 g (55%) of Compound No. 64. Melting point: 162°-163° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[I-:32].[Li+].[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[C:37]([NH:43][CH:44]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:45][CH2:46]O)[CH:36]=1>O1CCCC1>[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[C:37]([NH:43][CH:44]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:45][CH2:46][I:32])[CH:36]=1
Reactant: [I-]
Reactant: N#Cc1ccc(Cl)cc1NC(CCO)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(Cl)cc1NC(CCI)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of triphenylphosphine (1.83 g, 6.98 mmol) in dry tetrahydrofuran (30 ml) at 0° C. and under an atmosphere of nitrogen was added diethyl azodicarboxylate (1.2 g, 6.9 mmol) dropwise. After 20 minutes, lithium iodide and 4-chloro-2-[(3-hydroxy-1-phenylpropyl)amino]-benzonitrile (0.8 g, 2.79 mmol) were added to the mixture and stirring was continued for 5 h. The mixture was then concentrated to dryness, and the residue purified on silica (ether/isohexane 1:4). The title compound was isolated as a colourless solid (0.35 g, 32%).