Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:12])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[OH:4].Br[CH2:14][CH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:18]([Cl:30])[CH:17]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:22][C:20]1[CH:21]=[C:16]([CH2:15][CH2:14][NH:1][C@@H:2]([CH3:12])[C@H:3]([OH:4])[C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)[CH:17]=[C:18]([Cl:30])[C:19]=1[NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CNc1c(Cl)cc(CCBr)cc1Cl
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1c(Cl)cc(CCN[C@@H](C)[C@H](O)c2ccc(O)cc2)cc1Cl
Temperature: 70 °C
Reaction time: 7 h
Yield: 58.6 %

Procedure:
To a solution of (1R,2S)-2-amino-1-(4-hydroxyphenyl)-propan-1-ol (495 mg) and ethyl N-[4-(2-bromoethyl)-2,6-dichloro-phenyl]aminoacetate (700 mg) in N,N-dimethylformamide (6 ml) was added N,N-diisopropylethylamine (343 μl), and the mixture was stirred for 7 hours at 70° C. The reaction mixture was concentrated in vacuo, and purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: dichloro-methane/ethanol=20/1) gave ethyl N-[2,6-dichloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]-ethyl]phenyl]aminoacetate (510 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[CH2:8](O)[CH2:9][OH:10]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[O:10][CH2:9][CH2:8][O:7]2)=[CH:2]1
Reactant: OCCO
Reactant: O=Cc1ccsc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1cc(C2OCCO2)cs1
Temperature: 0 °C
Yield: 95.9 %

Procedure:
To a solution of thiophene-3-carbaldehyde (25.00 g, 222.9 mmol) in toluene (250 ml) were added ethylene glycol (69.18 g, 1115 mmol) and p-toluenesulfonic acid (424.0 mg, 2.229 mmol). The mixture was heated under reflux for 4 hr while separating generated water using Dean-Stark trap. After cooling to 0° C., saturated aqueous sodium hydrogen carbonate solution (50 ml) was added, and the mixture was stirred, stood still and then partitioned. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure, filtered through silica gel pad (FUJI SILYSIA CHEMICAL LTD. BW-300SP 100 g), and washed with ethyl acetate/hexane mixed solvent (1:2, 1000 ml). The filtrate was concentrated under reduced pressure to give 2-(thiophen-3-yl)-1,3-dioxolane (33.40 g, 213.8 mmol, yield 95.9%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:33]=[CH:32][C:31]3[C:30]4[C:25](=[CH:26][C:27]([C:34]5[CH:60]=[CH:59][C:37]6[N:38]=[C:39]([CH:41]7[CH:46]8[CH2:47][CH:43]([CH2:44][CH2:45]8)[N:42]7[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])[NH:40][C:36]=6[CH:35]=5)=[CH:28][CH:29]=4)[C:24](F)(F)[C:23]=3[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[OH2:64]>CC#N.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3](=[O:63])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:33]=[CH:32][C:31]3[C:30]4[C:25](=[CH:26][C:27]([C:34]5[CH:60]=[CH:59][C:37]6[N:38]=[C:39]([CH:41]7[CH:46]8[CH2:47][CH:43]([CH2:44][CH2:45]8)[N:42]7[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])[NH:40][C:36]=6[CH:35]=5)=[CH:28][CH:29]=4)[C:24](=[O:64])[C:23]=3[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C
Reactant: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)C(=O)c2cc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C

Procedure:
(1-{2-[5-(9,9-Difluoro-7-{2-[2-(2-methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (10 mg) is dissolve in MeCN (1 mL) and water (1 mL). 1 drop of TFA was added. The mixture was treated with long wavelengh UV light at room temprature for 2 hours. The reaction crude was concentrated down and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H2O+0.1% TFA). Product was lyophilized to give (1-{2-[5-(7-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-9-oxo-9H-fluoren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DL) (3.7 mg).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](Cl)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].Cl.[CH3:19][CH:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>N1C=CC=CC=1>[CH3:19][CH:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:11](=[O:12])[CH:10]=[CH:9][C:8]2[CH:14]=[CH:15][C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([O:16][CH3:17])[CH:7]=2)[CH2:22][CH2:21]1
Reactant: CC1CCC(N)CC1
Reactant: COc1cc(C=CC(=O)Cl)ccc1OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(C=CC(=O)NC2CCC(C)CC2)ccc1OC(C)=O
Yield: 65.3 %

Procedure:
Using 5.09 g of 4-acetoxy-3-methoxycinnamoyl chloride, 2.98 g of 4-methylcyclohexylamine hydrochloride, and 100 ml of pyridine, a reaction similar to that conducted in Example 53 was carried out. As a result, 4.31 g of N-(4-methylcyclohexyl)-4-acetoxy-3-methoxycinnamamide was obtained as yellowish white crystal, which had the following physiochemical properties:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br-:20].[C:21]([C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][CH2:31]O)[CH:26]=[CH:27][CH:28]=1)#[N:22].C1C=CC=CC=1>C(#N)C>[Br:20][CH2:31][CH2:30][CH2:29][C:25]1[CH:24]=[C:23]([C:21]#[N:22])[CH:28]=[CH:27][CH:26]=1
Reactant: N#Cc1cccc(CCCO)c1
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CC#N
Product: N#Cc1cccc(CCCBr)c1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a mixture of 21.8 g (0.083 moles) of triphenyl phosphine stirred in 30 ml acetonitrile, 13.2 g (4.26 ml) bromide in 75 ml acetonitrile was added dropwise with stirring in an ice bath. After the addition was complete, the ice bath was removed and the mixture warmed to room temperature. Then a mixture of 12.1 g (0.075 mole) of 3-(3-cyanophenyl)-1-propanol (the product of step (b)) in 30 ml acetonitrile was added dropwise. The resulting mixture was allowed to warm to about 45°-50° C., was stirred overnight and then stripped. Benzene (50 ml) was added to the residue; the mixture was evaporated. Then, additional benzene (50 ml) was added. The mixture was stirred, and then filtered to remove the triphenyl phosphine. The filtrate was stripped to give an oil. The oil was chromatographed using a column containing 3.5 inches of 200 mesh silica gel (Merck) eluting with benzene, until TLC showed that no further product was eluted from the column. The eluates were pooled and stripped to give 17 g of an oil. The oil was distilled in a Kugelrohr apparatus, the fraction bpt. 102°-103° C. was collected to give 15.7 g of the above-identified product as an oil.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][C:20]1[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=1)[CH2:23][C:24]1[CH:25]=[C:26]([NH2:29])[NH:27][N:28]=1>O1CCCC1>[CH3:19][C:20]1[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=1)[CH2:23][C:24]1[CH:25]=[C:26]([NH:29][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[NH:27][N:28]=1
Reactant: Cc1cccc(Cc2cc(N)[nH]n2)c1
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: Cc1cccc(Cc2cc(NC=C3C(=O)Nc4ccccc43)[nH]n2)c1

Procedure:
The named compound is prepared by substituting 5-(3-methyl-benzyl)-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.240 gms. 5-(3-methyl-benzyl)-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.5 mL) overnight.
Reaction SMILES: [CH:1]([OH:14])([C:8]1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C1(C(C)C)C=CC=CC=1.[C:26]([O:34]C)(=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(C1C=CC=CC=1)(=O)C.S(=O)(=O)(O)O>>[C:1]([CH2:8][C:26](=[O:34])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)c1ccccc1
Solvent: CC(=O)c1ccccc1
Product: O=C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 95 %

Procedure:
Benzhydrol (189.77 g; 1.03 mol), potassium hydroxide (84.3%; 66.56 g; 1.0 mol) and cumene (375 mL) were placed into a four-necked, round bottom, one liter flask equipped with a stirrer, a thermometer, and an Oldershaw column with a Dean-Stark trap and a condenser. The mixture was heated to boiling with stirring under a blanket of nitrogen and the water was azeotroped out (temperature of reflux 148-150° C). When no more water was collected (27 mL, yield=95%, about 2 hours) the mixture was cooled down to and kept at 90° C. The fractionation column and trap were replaced with a reflux condenser, while maintaining the nitrogen stream. Methyl benzoate (181.5 g; 1.33 mol) was added at once, and slow addition (12 minutes) of acetophenone (80.10 g; 0.667 mol) by means of a syringe pump was begun. After 60 minutes from the beginning of the addition of the ketone, the mixture was allowed to cool to room temperature, whereupon it was acidified with 10% sulfuric acid. The cumene layer was washed with a saturated solution of sodium bicarbonate in water and then with water. The organic layer was then concentrated under vacuum in a rotary evaporator. The residue was crystallized from 90% isopropanol, affording DBM (112.13 g, 75% yield) having a purity of 98% (GC).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]1>>[O:30]=[S:27]1(=[O:31])[CH2:28][CH2:29][N:24]([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:25][CH2:26]1
Reactant: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)O)cn1
Reactant: O=S1(=O)CCNCC1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)cn1
Yield: 58 %

Procedure:
As described for example 147, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (93 mg, 0.3 mmol) was converted, using thiomorpholine-S,S-dioxide instead of cyclopropylmethylamine, to the title compound (75 mg, 58%) which was obtained as an off white solid. MS: m/e=429.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]2[CH2:10][CH2:9][O:8][C:6]=2[N:7]=1.[Cl:12][C:13]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[CH:14][Cl:15].ClCCCC>C(Cl)Cl>[Cl:12][C:13]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]([NH:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]2[CH2:10][CH2:9][O:8][C:6]=2[N:7]=1)=[O:28])(=[O:24])=[O:25])=[CH:14][Cl:15]
Reactant: O=C=NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Reactant: Cc1nc(N)nc2c1CCO2
Solvent: ClCCl
Solvent: CCCCCl
Product: Cc1nc(NC(=O)NS(=O)(=O)c2ccccc2OC(Cl)=CCl)nc2c1CCO2
Reaction time: 8 h

Procedure:
To 300 mg of 2-amino-5,6-dihydro-4-methylfuro[2,3-d]pyrimidine in 25 ml of methylene chloride was added 20 ml of 2-(1,2-dichloroethen-1-yloxy)benzenesulfonyl isocyanate in methylene chloride from the previous example. After heating to reflux, the mixture was stirred overnight at room temfperature. Removal of the solvent in vacuo yielded an amber oil. Trituration of this oil with 1-chlorobutane gave a tan solid. After filtration and washing with ethyl ether, a yield of 0.8 g of a tan solid melting at 208°-210° was obtained.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[OH-].[Na+].[F:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1>CO.COCCOC>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][S:1][C:2]3[NH:3][C:4](=[O:11])[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)=[CH:23][CH:22]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: O=c1[nH]c(S)nc2[nH]ccc12
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COCCOC
Product: O=C(c1ccc(F)cc1)c1ccc(CSc2nc3[nH]ccc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
In methanol (65.7 ml) was suspended 2-mercapto-7H-pyrrolo [2,3-d]pyrimidin-4(3H)-one (2.51 g) followed by addition of 1N-sodium hydroxide (15.75 ml) for dissolution. Then, a solution of 4-(4-fluorobenzoyl)benzyl bromide (5.06 g) in DME (15 ml) was added dropwise with ice-cooling. Then, the mixture was stirred at room temperature overnight. The solvent was then distilled off under reduced pressure and the residue was purified by flash column chromatography (silica gel; ethyl acetate: hexane=1:4-1:1-ethyl acetate) to provide the title compound (2.43 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[CH3:15][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]1[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=[C:2]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:3]=1
Reactant: C1CNCCN1
Reactant: CSc1ncnc2c(N(C)c3ccccc3)nc(Cl)nc12
Solvent: CS(C)=O
Product: CSc1ncnc2c(N(C)c3ccccc3)nc(N3CCNCC3)nc12

Procedure:
Prepared analogously to Example 2 from 2-chloro-4-(N-methyl-phenylamino)-8-methylthio-pyrimido[5,4-d]pyrimidine and piperazine in dimethylsulphoxide.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][N:14]2[CH:18]3[N:19]=[C:20]4[C:25]([N:17]3[N:16]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:15]2=[O:36])=[C:24]([C:26]2[O:27][CH:28]=[CH:29][CH:30]=2)[N:23]=[CH:22][N:21]4[NH2:31])(=O)=O)=CC=1.[F:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:31][N:21]1[C:20]2[C:25]([N:17]3[N:16]([CH2:32][CH:33]4[CH2:34][CH2:35]4)[C:15](=[O:36])[N:14]([CH2:13][CH2:12][O:11][C:41]4[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=4)[CH:18]3[N:19]=2)=[C:24]([C:26]2[O:27][CH:28]=[CH:29][CH:30]=2)[N:23]=[CH:22]1
Reactant: Cc1ccc(S(=O)(=O)OCCN2C(=O)N(CC3CC3)N3C4=C(c5ccco5)N=CN(N)C4=NC23)cc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NN1C=NC(c2ccco2)=C2C1=NC1N(CCOc3ccc(F)cc3)C(=O)N(CC3CC3)N21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 2-[5-amino-1-(cyclopropylmethyl)-8-(2-furyl)-2-oxo-[1,2,4]triazolo[5,1-f]purin-3-yl]ethyl 4-methylbenzenesulfonate obtained in step 7 of C1 (0.045 g, 0.088 mmol), 4-fluorophenol (0.018 g, 0.176 mmol) and K2CO3 (0.036 g, 0.22 mmol) were taken in DMF (2 ml) and stirred at 80° C. for 16 hours. To the reaction mixture water (25 ml) was added and extracted with ethyl acetate (3×20 ml). The crude product was purified by column chromatography to 5-amino-1-(cyclopropylmethyl)-3-[2-(4-fluorophenoxy)ethyl]-8-(2-furyl)-[1,2,4]triazolo[5,1-f]purin-2-one (8 mg, 20%) as an off white solid
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=O)=[CH:18][CH:17]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:23]([CH2:22][C:19]4[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=4)=[N:13][N:12]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: NNC(=O)c1ccc2occc2c1
Product: COc1ccc(Cc2nnc(-c3ccc4occc4c3)o2)cc1
Yield: 58 %

Procedure:
In the same manner as in Example 14 and using 1-benzofuran-5-carbohydrazide instead of 1H-benzotriazole-5-carbohydrazide and (4-methoxyphenyl)acetic acid instead of 3-(3-cyanophenyl)propionic acid, the title compound (yield 58%) was obtained as colorless crystals.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N+:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19])([O-:16])=[O:15].C(N(CC)CC)C>CC(C)=O>[C:1]12([C:11]([NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N+:14]([O-:16])=[O:15])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1[N+](=O)[O-])C12CC3CC(CC(C3)C1)C2
Reaction time: 22 h
Yield: 76.5 %

Procedure:
A solution of 1-adamantanecarbonyl chloride (17.95 g) in acetone (60 ml) was dropped into a solution of 2-nitroaniline (10.4 g) and triethylamine (12.6 ml) in acetone (50 ml), at ° under a nitrogen atmosphere. The mixture was stirred at 23° for 22 h; then further acetone (50 ml) was added. The mixture was heated at 70° for 3 h. The mixture was allowed to cool to 23°, then filtered; the brown solid obtained was crystallized from acetone to give the title compound as a yellow solid (17.3 g). T.l.c. CH-EA (10:2), Rf 0.67. M.p. 111°-4°.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][N:27]([CH2:29][CH:30]=O)[CH:28]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][N:27]([CH2:29][CH2:30][N:37]6[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]6)[CH:28]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: CN1CCN(CCn2cnc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)c2)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 50 %

Procedure:
To a solution of 264 (300 mg, 0.66 mmol), N-methylpiperazine (74 μl, 0.66 mmol) and AcOH (76 μl, 1.33 mmol) in NMP (10 mL) was added sodium triacetoxyborohydride (422 mg, 1.99 mmol) and the reaction mixture was stirred for 2.5 days at RT. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic extract was successively washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 40 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 0/100 to 15/85 over 20 CV) and by Gilson (Phenomenex, Luna 15μ, C18(2) 100A, 250×50.0 mm, 15 μm; 0.05% of formic acid in both MeOH/water:20/80 to 95/5 over 60 min, flow; 30 mL/min) to afford the title compound 266 (180 mg, 0.33 mmol, 51% yield, di-formate salt) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C)C=O.[CH3:20][C:21]1[NH:22][C:23]2[C:28]([C:29]=1[CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:26]=[CH:25][CH:24]=2>O>[CH2:7]([O:33][C:31](=[O:32])[CH2:30][C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][C:21]=1[CH3:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: Cc1[nH]c2ccccc2c1CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1[nH]c2ccccc2c1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under argon gas, potassium carbonate (2.52 g) and benzyl bromide (1.2 mL) were added to dimethyl formamide (20 mL) solution containing 2-(2-methylindol-3-yl)acetic acid (1.73 g), which was stirred at room temperature for 2 hours. The reaction mixture was radiationally cooled and water was added, and then the mixture was extracted by ethyl acetate. The extract was sequentially washed with water and saturated brine and dried by sulfuric anhydride sodium, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give a title compound (2.63 g) having the following physical properties was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10]C2N=C(NC3CCCCCC3)N=C(N(C)C3CCN(C)CC3)N=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N:34]1[C:41]([Cl:42])=[N:40][C:38]([Cl:39])=[N:37][C:35]=1Cl.ClC1C=C(C=CC=1OC)N.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:35]2[N:34]=[C:41]([Cl:42])[N:40]=[C:38]([Cl:39])[N:37]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(Nc2nc(NC3CCCCCC3)nc(N(C)C3CCN(C)CC3)n2)cc1Cl
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: COc1ccc(N)cc1Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1Cl

Procedure:
This reaction scheme illustrates synthesis of compound 137 by reaction of cyanuric chloride with 3-chloro-4-methoxyaniline using sodium hydroxide (NaOH) as base at 0-5° C. to yield (3-chloro-4-methoxy phenyl)-(4,6-dichloro-[1,3,5]triazine-2-yl)amine (compound 101), which on reaction with cycloheptylamine in presence of NaOH under reflux gave 6-chloro-N-(3-Chloro-4-methoxyphenyl)-N′-cycloheptyl-[1,3,5]triazine-2,4-diamine (compound 133). Compound 133 on reaction with 1-methyl-(4-methylamino)piperidine yields, the final compound 137.
Reaction SMILES: FC1C=CC([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2CCC2C(F)=CC=C(F)C=2F)=CC=1.FC1C=CC(N2C(C(OCC)=O)=CN=C2C#C[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:54]([F:57])([F:56])[F:55])=CC=1>[Pd].C(OCC)(=O)C.C(O)C>[F:55][C:54]([F:57])([F:56])[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[CH2:17][CH2:16][O:15][C:13]([C:12]1[NH:8][CH:9]=[N:10][CH:11]=1)=[O:14]
Reactant: CCOC(=O)c1cnc(C#Cc2ccccc2C(F)(F)F)n1-c1ccc(F)cc1
Reactant: CCOC(=O)c1cnc(CCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(OCCc1ccccc1C(F)(F)F)c1cnc[nH]1

Procedure:
Ethyl 1-(4-fluorophenyl)-2-((2-(trifluoromethyl)phenethyl)-1H-imidazole-5-carboxylate (47) was prepared in a similar manner as that described for the synthesis of compound 18 using ethyl 1-(4-fluorophenyl)-2-((2-(trifluoromethyl)phenyl)ethynyl)-1H-imidazole-5-carboxylate (46) (651 mg, 1.62 mmol), Pd/C (10% Degussa type, 65 mg), and ethyl acetate/ethanol (1:2) (61 mL).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH3:16]>C(OC(C)C)(C)C>[C:1]([O:5][C:6]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:21]([NH:20][C:18]([O:17][CH2:15][CH3:16])=[O:19])=[S:22])=[CH:11][CH:12]=1)=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)N=C=S
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Solvent: CC(C)OC(C)C
Product: CCOC(=O)NC(=S)Nc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
In 150 ml of isopropyl ether was dissolved 13.51 g of 4-amino-benzoic acid t-butyl ester. To the solution was added, while stirring at room temperature, 9.83 g of ethoxycarbonyl isothiocyanate. The mixture was stirred for two hours, then the resulting crystalline precipitate was collected by filtration, followed by recrystallization from isopropyl ether to give 21.83 g of the title compound as colorless needles.