Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[O:11]([CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCNCC1
Reactant: ClCCOc1ccccc1
Product: O=C1CCN(CCOc2ccccc2)CC1

Procedure:
1-(2-Phenoxyethyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-2-phenoxyethane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH2:7].C(N([CH2:26][CH3:27])CC)C.[C:28](=[S:30])=[O:29].C(I)C>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH:7][C:28](=[S:30])[O:29][CH2:26][CH3:27]
Reactant: O=C=S
Reactant: NCCOc1ccc(Oc2cc(F)cc(F)c2)cc1Cl
Reactant: CCN(CC)CC
Solvent: CCI
Solvent: C1CCOC1
Product: CCOC(=S)NCCOc1ccc(Oc2cc(F)cc(F)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Into a mixture of 1.20 g of 2-[2-chloro-4-(3,5difluorophenoxy)phenoxy]ethylamine, 0.81 g of triethylamine and 20 ml of tetrahydrofuran, excesss of carbonyl sulfide gas was introduced with stirring at room temperature for 30 minutes. To the above mixture, there was added dropwise 0.75 g of ethyl iodide, and the resultant mixture was stirred at the same temperature for 24 hours. The reaction mixture was concentrated, and the residue was poured into 100 ml of water and extracted twice with 100 ml of ethyl acetate. The extracts were combined together, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 0.95 g of ethyl 2-[2-chloro-4-(3,5-difluorophenoxy)phenoxy]ethylthiocarbamate. Yield: 61%. nD21 : 1.5707.
Reaction SMILES: C(O)(=O)C.[CH:5](N)=[NH:6].[NH2:8][N:9]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:23])[CH:17]=2)[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:10]1>C(O)CCC>[NH2:15][C:14]1[C:13]2=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:23])[CH:17]=3)[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:10][N:9]2[N:8]=[CH:5][N:6]=1
Reactant: CCOC(=O)c1cn(N)c(C#N)c1-c1ccc(N)c(F)c1
Reactant: N=CN
Solvent: CC(=O)O
Solvent: CCCCO
Product: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(N)c(F)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
Formamidine acetate (22.4 g, 215 mmol) was added to a suspension of ethyl 1-amino-4-(4-amino-3-fluorophenyl)-5-cyano-1H-pyrrole-3-carboxylate (6.2 g, 21.5 mmol) in n-butanol (100 mL). The reaction was heated (100° C.) for 16 h and then cooled to rt. The solvent was removed under reduced pressure and then ethanol (50 mL) and water (200 mL) were added. The mixture was stirred for 30 min and the resulting precipitate was collected by filtration. The solid was washed with water (2×50 mL) and dried to afford desired product (5.80 g, 85%); 1H NMR (300 MHz, DMSO-d6) δ 8.08 (s, 1H), 8.00-8.10 (br s, 1H), 7.90 (s, 1H), 7.03 (dd, J=12.3, 1.9 Hz, 1H), 6.77-6.88 (m, 2H), 5.36 (s, 2H), 5.21-5.31 (br s, 1H), 4.06 (q, J=7.1 Hz, 2H), 1.11 (t, J=7.1 Hz, 3H); ES-MS m/z 316.4 (MH)+; HPLC RT (Method B) 2.39 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:26]([C:29]1[CH:34]=[CH:33][C:32](OC(ON=C(C#N)C(OCC)=O)=O)=[CH:31][CH:30]=1)([O-:28])=[O:27]>C(OCC)(=O)C>[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([O:14][C:13](=[O:15])[C@@H:12]2[CH2:16][CH2:17][CH2:18][N:11]2[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)C(C#N)=NOC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 53.8 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-proline (1.25 g) and triethylamine (0.70 ml) in ethyl acetate (15 ml), ethyl 2-p-nitrophenyloxycarbonyloxyimino-2-cyanoacetate (1.55 g) in powder form is added at room temperature while stirring. The resulting mixture is stirred for 4 hours and then extracted with ethyl acetate. The extract is washed with water, dried and concentrated. The residue is recrystallized from an ethanol-petroleum ether mixture to give N-benzyloxycarbonyl-L-proline p-nitrophenyl ester (1.0 g). M.P. 94° - 96°C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C@H:9]2[C@@H:13]([CH2:14][OH:15])[O:12][C:11]([CH3:17])([CH3:16])[N:10]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:5]=[CH:4][N:3]=1.[CH3:25][O-:26].[Na+]>CO.O>[OH:15][CH2:14][C@H:13]1[O:12][C:11]([CH3:17])([CH3:16])[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:9]1[CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:26][CH3:25])[CH:7]=1
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccnc(Cl)c2)[C@@H](CO)OC1(C)C
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C[C@H]2[C@@H](CO)OC(C)(C)N2C(=O)OC(C)(C)C)ccn1

Procedure:
(4S,5S)-Tert-butyl 4-((2-chloropyridin-4-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate (0.200 g, 0.560 mmol) was dissolved in a 25% solution of SODIUM METHOXIDE (12.8 ml, 56.0 mmol) in methanol and refluxed for 12 hrs and cooled. The reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated to give (4S,5S)-tert-butyl 5-(hydroxymethyl)-4-((2-methoxypyridin-4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate, MS m/z: 353.3 (100%, M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:8][N:7]=1.[Se](=O)=[O:29]>C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:8][N:7]=1)=[O:29]
Reactant: O=[Se]=O
Reactant: CCOC(=O)c1cnc(Cc2cccc(O)c2)c2cc(OC)c(OC)cc12
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(C(=O)c2cccc(O)c2)c2cc(OC)c(OC)cc12
Yield: 97 %

Procedure:
To a solution of 1-(3-hydroxybenzyl)-6,7-dimethoxy-4-ethoxycarbonylisoquinoline (367 mg, 1.0 mmol) in 10 ml of ethyl acetate was added selenium dioxide (166 mg, 1.50 mmol) and the mixture was refluxed for 1.5 hr until all starting material was consumed. The mixture was filtered through a layer of silica gel and washed with ethyl acetate. After evaporation of solvents, a solid was obtained as 1-(3-hydroxybenzoyl)-6,7-dimethoxy-4-ethoxycarbonylisoquinoline (370 mg). This solid (325 mg, 0.85 mmol) was dissolved in 3 mL of DMF and the stirring solution was treated with potassium carbonate (300 mg, 2.17 mmol) followed by t-butyl-2-bromoisobutyrate (210 mg, 0.94 mmol). The resulting mixture was heated (50° C. in an oil-bath) and stirred for 25 hours. Mass spectrum and TLC indicated partial conversion to the desired product and additional potassium carbonate (330 mg, 2.17 mmol) and isobutyrate (210 mg, 0.94 mmol) were added. The mixture was heated with stirring for additional 25 hours. The reaction mixture was evaporated and the residue was partitioned with ethyl acetate (50 ml) and brine (25 ml). The organic layer was dried over sodium sulfate, filtered and evaporated to give an oil which was purified by silica gel chromatography, using gradient mixtures of ethyl acetate and hexanes, to produce 248 mg of the isobutyrate as a yellow oil.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]([C:15]2[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)[C:11]([NH2:14])=[N:12][CH:13]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH:29]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:26]2[CH:27]=[C:28]([C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[O:31])[CH:29]=[C:24]([Cl:23])[CH:25]=2)=[CH:9][C:10]=1[C:15]1[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Reactant: O=C(c1cc(Cl)cc(B(O)O)c1)N1CCOCC1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1cc(-c2cc(-c3cc(Cl)cc(C(=O)N4CCOCC4)c3)cnc2N)nn1
Temperature: 120 °C
Yield: 15.4 %

Procedure:
Cs2CO3 (682 mg, 2.10 mmol) was added to a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (200 mg, 0.70 mmol) and (3-chloro-5-(morpholine-4-carbonyl)phenyl)boronic acid (210 mg, 0.78 mmol) in dioxane: water (8 mL: 4 mL) degassed the reaction mixture for 10 min with nitrogen. Then added Pd(PPh3)4 (40 mg, 0.035 mmol), degassed the reaction mixture for additional 10 min with nitrogen, the reaction mixture was heated to 120° C. in microwave for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). Combined organic layers was dried over Na2SO4 and concentrated under reduced pressure. Crude product was purified by silica (100-200 mesh) column eluted with 80-90% ethyl acetate in pet-ether to afford 46 mg (Yield: 47.0%) of the title compound as a pale yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:31])[CH:3]=1.O.[NH2:33][NH2:34]>>[NH:33]([C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:31])[CH:3]=1)[NH2:34]
Reactant: CCc1nc2c(C)cc(Br)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: NN
Solvent: O
Product: CCc1nc2c(C)cc(NN)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A mixture of 5-Bromo-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine. (2.0 g), and hydrazine hydrate (15 mL) was heated to 120° C. for 24 hours. Concentration and purification (SiO2, 85/14/2 CH2Cl2 /MeOH/NH4OH) gave 1.80 g of 5-hydrazino-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine. Reduction in methanol (50 mL) under 1 atm. H2 with W-2 Raney nickle (1 mL, 50% dispersion/water) at RT for 48 hours gave the title compound (1.44 g) after purification (SiO2, 85/14/2 CH2Cl2 /MeOH/NH4OH). 1H NMR (300 MHz, CD3OD) δ7.60-7.50 (m, 2H), 7.49-7.42 (m, 2H), 7.10-7.00 (m, 4H), 6.38 (s, 1H), 5.39 (s, 2 H), 2.79 (q, 2H, J=7.5 Hz), 2.49 (s, 3H), 1.21 (t, 3H, J=7.5 Hz).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([NH2:28])=[O:27])=[C:24]([CH:29]([OH:32])[CH2:30][CH3:31])[N:23]=[C:22]2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl>O1CCOCC1>[CH2:33]([C:22]1[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:6]([OH:7])=[O:5])=[CH:19][CH:18]=2)[C:25]([C:26]([NH2:28])=[O:27])=[C:24]([CH:29]([OH:32])[CH2:30][CH3:31])[N:23]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCc1nc(C(O)CC)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nc(C(O)CC)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Following a procedure similar to that described in Example 45(d), but using 316 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxypropyl)imidazole-5-carboxamide [prepared as described in step (c) above] and 10 ml of a 4N solution of hydrogen chloride in dioxane, 148 mg of the hydrochloride of the title compound were obtained as an amorphous powder, melting at above 120° C. (with softening).
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].[F:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.C(I)C>O1CCCC1.O>[CH2:1]([C:14]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[F:8])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: Fc1cccnc1
Solvent: CCI
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccncc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
nButyllithium (1.6M in tetrahydrofuran, 62.4 ml, 100 mmol) was added dropwise to a solution of diisopropylamine (10 g, 100 mmol) in tetrahydrofuran (110 mL), cooled to −78° C. 3-Fluoropyridine (10 g, 100 mmol) was added dropwise and the reaction mixture was stirred for 1 hour with the temperature maintained below −60° C. Ethyl iodide (31.2 g, 200 mmol) was then added dropwise and the mixture was allowed to stir at room temperature for 30 minutes. The reaction mixture was slowly diluted with water, the solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to give a crude residue. The residue was distilled and title product was obtained during a temperature range of 152-156° C., in 35% yield, 4.46 g.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Cl)[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.O.[NH2:23][NH2:24]>C(O)C>[Br:1][C:2]1[N:3]=[C:4]([NH:23][NH2:24])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2Cl)CC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2NN)CC1
Yield: 36.5 %

Procedure:
A 500 mL 3-necked round bottom flask was charged with tert-butyl 4-(5-bromo-3-chloropyrazin-2-yl)piperazine-1-carboxylate (16.1 g, 42.6 mmol), hydrazine hydrate (4.2 mL, 85.2 mmol) and ethanol (200 mL). The resulting solution was refluxed overnight. TLC indicated an incomplete conversion. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 10% EtOAc in petroleum ether then 2% methanol in dichloromethane, to afford 5.8 g (47%) of the product as a yellow solid. MS m/z: 373 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([C:19]#[N:20])=[C:9]1[C:21](O)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:49][O:50][C:51](=[O:62])[C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([C:58](=[NH:61])[NH:59]O)[CH:53]=1>ClCCCl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([C:19]#[N:20])=[C:9]1[C:21]1[O:22][N:61]=[C:58]([C:54]2[CH:55]=[CH:56][CH:57]=[C:52]([C:51]([O:50][CH3:49])=[O:62])[CH:53]=2)[N:59]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1cccc(C(=N)NO)c1
Reactant: COc1ccc2c(C#N)c(C(=O)O)n(C(=O)OC(C)(C)C)c2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1cccc(-c2noc(-c3c(C#N)c4ccc(OC)cc4n3C(=O)OC(C)(C)C)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-cyano-6-methoxyindole-1,2-dicarboxylic acid 1-tert-butyl ester (474 mg, 1.5 mmol) prepared above, and HOBt (200 mg, 1.5 mmol) in DCE/DMF (10 mL/1 mL), was added DCC (310 mg, 1.5 mmol), followed by 3-(N-hydroxycarbamimidoyl)benzoic acid methyl ester (291 mg, 1.5 mmol). The mixture was stirred at room temperature for 2 h and filtered. The filtrate was collected and the solvent was replaced with chlorobenzene, followed by the heating at 150° C. for 48 h. After cooling to room temperature, the solvent was removed in vacuo and the residue was chromatographed (silica gel, CH2Cl2/EtOAc, 8/2) to furnish the intermediate, 3-cyano-6-methoxy-2-[3-(3-methoxycarbonylphenyl)-[1,2,4]oxadiazol-5-yl]-indole-1-carboxylic acid tert-butyl ester, which was treated with 50% TFA in DCM (10.0 mL) at room temperature for 1 h. After removal of the volatiles in vacuo, the residue was suspended in water and neutralized with K2CO3 to provide the desired product, methyl 3-[5-(3-cyano-6-methoxy-1H-indol-2-yl-)[1,2,4]oxadiazol-3-yl]benzoate, compound 226 (350 mg, 62%).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:29][O:30][CH2:31]Cl.O>C1COCC1.C1(C)C=CC=CC=1>[CH3:29][O:30][CH2:31][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: COCCl
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(COC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (2.57 g) in THF (26 ml) was added 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (24.0 ml) under at −70° C. After 15 minutes, chloromethyl methyl ether (1.2 ml) was added and it was stirred at 0° C. for 2 hours. Water was added and extracted with EtOAc. The organic phase was washed with water and brine, dried over MgSO4, evaporated under reduced pressure. The residue was purified by silica gel column to give 1-tert-butyl 4-ethyl 4-(methoxymethyl)piperidine-1,4-dicarboxylate (2.05 g) as oil.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[Cl:29][C:30]1[CH:31]=[C:32]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:33]=[CH:34][C:35]=1[Cl:36]>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:32]2[CH:33]=[CH:34][C:35]([Cl:36])=[C:30]([Cl:29])[CH:31]=2)[CH2:42][CH2:41]1)=[O:16]
Reactant: Nc1onc(-c2cccc(F)c2)c1C(=O)O
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 74.5 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(3-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3,4-dichlorophenyl)piperazine (425 mg, 1.84 mmol), a white solid required compound (596 mg, 1.37 mmol, 74%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH:10]=4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(-c3ccccc3)c2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(-c3ccccc3)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 95.9 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(3-phenylphenoxy)phenyl]-N-methylcarbamate (1.60 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.26 g), diethyl cyanophosphonate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (2.57 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[C:11]#[CH:12].C(N(CC)CC)C.C(OCC)(=[O:23])C>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH:13][CH2:10][C:11]#[CH:12])=[O:23])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: ClCc1ccc(Br)cc1
Reactant: C#CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCNC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To 4-bromobenzyl chloride (4.39 g, 20 mmol) in 40 mL dichloromethane at 0° C., propargylamine (1.10 g, 20 mmol) was added, followed by triethylamine (4.05 g, 40 mmol). The mixture was stirred at room temperature for 40 minutes. 150 mL ethyl acetate was added and filtered. The filtrate was washed with 2×40 mL water and 40 mL brine, dried and concentrated to give 4-Bromo-N-(2-propynyl) benzamide. 4-Bromo-N-(2-propynyl) benzamide was added into ice cooled 47 mL concentrated sulfuric acid. The reaction was stirred at 5°-10° C. for 3 hours and at room temperature overnight. The mixture was poured into 500 mL ice water, neutralized with sodium carbonate to pH 8 and extracted with 3×250 mL ethyl acetate. The combined organic extracts were washed with 200 mL water and 100 mL brine, dried and concentrated to afford compound A (4.5 g, 95%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:14])[CH2:10][CH2:11][CH2:12][Cl:13])[CH:5]=[CH:4][C:3]=1[O:15][CH3:16].Cl.[CH3:18]NC.C=O.C(O)(=O)C>O.CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:14])[C:10](=[CH2:18])[CH2:11][CH2:12][Cl:13])[CH:5]=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1ccc(C(=O)CCCCl)c(Cl)c1Cl
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: C=C(CCCl)C(=O)c1ccc(OC)c(Cl)c1Cl
Reaction time: 2 h

Procedure:
2,3-Dichloro-4-(4-chlorobutyryl)anisole (28.1 g, 0.1 mole), dimethylamine hydrochloride (36.7 g, 0.45 mole) and paraformaldehyde (7.65 g, 0.255 mole) were united and glacial acetic acid (2.6 ml) added. The mixture was stirred and heated on a steam bath under anhydrous conditions for 2 hours. Then the mixture was treated with N,N-dimethylformamide and heating and stirring on a steam bath continued for another 2 hours. The mixture was poured into a mixture of crushed ice and water (800 ml) and extracted with ether.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][N:3]=1.[CH2:16]([NH2:26])[C:17]1[CH:25]=[CH:24][C:23]2[O:22][CH2:21][O:20][C:19]=2[CH:18]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([NH:26][CH2:16][C:17]2[CH:25]=[CH:24][C:23]3[O:22][CH2:21][O:20][C:19]=3[CH:18]=2)=[N:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc2c(Cl)nnc(Cl)c2c1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc2c(Cl)nnc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 35 %

Procedure:
3.5 g of the 1,4-dichloro-6-nitrophthalazine prepared in the step (a) was dissolved in 100 ml of ethanol, followed by the addition thereto of 2.17 g of piperonylamine and 3 ml of triethylamine. The resultant mixture was heated under reflux for 12 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. Water was added to the residue thus obtained to give a solution. The obtained aqueous solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then subjected to vacuum concentration to remove the solvent. The residue was purified by silica gel column chromatography [n-hexane/ethyl acetate (2: 1 to 1: 1)]. Thus, 1.8 g of 1-chloro-4-(3,4-methylenedioxybenzyl)amino-6-nitrophthalazine was obtained from less polar fractions as a yellow solid and 1.2 g of 1-chloro-4-(3,4-methylene-dioxybenzyl)amino-7-nitrophthalazine was obtained from more polar fractions as a yellow solid.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[C:5](#N)C=C.[C:9](#N)C=C>>[CH3:5][C:3](=[CH2:4])[CH3:2].[CH2:1]=[CH:2][C:3](=[CH2:9])[CH3:4]
Reactant: C=CC#N
Reactant: C=CC=C
Product: C=C(C)C
Product: C=CC(=C)C

Procedure:
butadiene/acrylonitrile copolymers with acrylonitrile contents from 5 to 60, preferably 10 to 50 wt. % (NBR)