Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C:24]1[C:29]([N+:30]([O-])=O)=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:33])[N:17]=[CH:16]2>CO.C(OCC)(=O)C.[Pd]>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C:24]1[C:29]([NH2:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:33])[N:17]=[CH:16]2
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(Nc4c(C)cccc4[N+](=O)[O-])ncc3c2)c1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(Nc4c(C)cccc4N)ncc3c2)c1Cl
Reaction time: 8 h

Procedure:
6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(2-methyl-6-nitrophenyl)quinazolin-2-amine (5.5 g, 11.33 mmol) was taken up in methanol (200 ml) and Ethyl Acetate (100 ml), 10% Pd/C (650 mg) was added. The mixture was stirred under H2 balloon overnight. The reaction mixture was filtered through celite and the solvent was removed to give N1-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)-6-methylbenzene-1,2-diamine in quantitative yield. It was carried on to the next step without further purification. MS (ES+) C23H20Cl2N4O2, 455 [M+H]+
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:19]=[C:18]3[C:12]([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)=[N:11]2)=[CH:6][CH:5]=1.[CH3:22][CH:23]([CH3:26])[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:19]=[C:18]3[C:12]([CH2:13][CH2:14][N:15]([CH2:22][CH:23]([CH3:26])[CH3:24])[CH2:16][CH2:17]3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)C=O
Reactant: CN(C)C(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)CN1CCc2cn(-c3ccc(C(=O)N(C)C)cc3)nc2CC1
Temperature: 25 °C

Procedure:
A solution of N,N-dimethyl-4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)benzamide (24.0 mg, 0.085 mmol) (may be prepared as described in Description 42) in dichloromethane (2 ml) was treated with 2-methylpropanal (16.0 μl, 0.17 mmol) and acetic acid (1 drop) and stirred at room temperature. Sodium triacetoxyborohydride (36.0 mg, 0.17 mmol) was added and the mixture was stirred at room temperature for approximately 50 hours. The mixture was diluted with methanol and passed down a SCX cartridge eluting with methanol and then a 2M solution of ammonia in methanol. The basic fractions were combined and evaporated to afford the title compound (E1); MS (ES+) m/e 357 [M+NH3]+.
Reaction SMILES: [Br-].[OH:2][C:3]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([O:6][CH:7]1[CH2:12][CH2:11][N+:10]([CH2:14][C:15](=[O:22])[NH:16][C:17]2[CH:21]=CO[N:18]=2)([CH3:13])[CH2:9][CH2:8]1)=[O:5].[Br:35][CH2:36][C:37]([NH:39]C1C=CON=1)=O.BrCC(NC1C=NC=CN=1)=O>>[Br-:35].[OH:2][C:3]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:4]([O:6][CH:7]1[CH2:12][CH2:11][N+:10]([CH3:13])([CH2:14][C:15](=[O:22])[NH:16][C:17]2[CH:21]=[N:39][CH:37]=[CH:36][N:18]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: C[N+]1(CC(=O)Nc2ccon2)CCC(OC(=O)C(O)(c2ccccc2)c2ccccc2)CC1
Reactant: O=C(CBr)Nc1ccon1
Agent: O=C(CBr)Nc1cnccn1
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2cnccn2)CCC(OC(=O)C(O)(c2ccccc2)c2ccccc2)CC1

Procedure:
This compound is prepared by an analogous method to 4-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-methyl-piperidinium bromide (Example 13) by replacing 2-bromo-N-isoxazol-3-yl-acetamide (Intermediate A) with 2-bromo-N-pyrazin-2-yl-acetamide (Intermediate G).
Reaction SMILES: [CH2:1]([CH:3]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH2:22])[C:9]([NH2:21])=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH3:18])[CH3:2].[C:27]1(=O)[C:31]2=[CH:32][S:33][CH:34]=[C:30]2[C:29](=O)[O:28]1>C(O)(=O)C.C(O)C>[CH2:19]([CH:14]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][O:12][C:11]1[C:6]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:7][C:8]2[N:22]3[C:29](=[O:28])[C:30]4[C:31](=[CH:32][S:33][CH:34]=4)[C:27]3=[N:21][C:9]=2[CH:10]=1)[CH3:20]
Reactant: CCCCC(CC)COc1cc(N)c(N)cc1OCC(CC)CCCC
Reactant: O=C1OC(=O)c2cscc21
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCC(CC)COc1cc2nc3n(c2cc1OCC(CC)CCCC)C(=O)c1cscc1-3

Procedure:
A mixture of 4,5-bis((2-ethylhexyl)oxy)benzene-1,2-diamine (5.8 g, 0.016 mol) and thieno[3,4-c]furan-1,3-dione (2.5 g, 0.016 mol) is refluxed in a 100 mL acetic acid:ethanol (1:1) solvent blend for 24 hours. The solvent is distilled off and the crude product is purified by column chromatography (CHCl3) to yield the final product.
Reaction SMILES: C1C(C(N[C@H](C(O)=O)CCC(O)=O)=[O:8])=CC=C(NCC2N=C3C(N=C(N)NC3=NC=2)=O)C=1.[CH2:33]1[CH2:38][CH2:37][CH:36]([N:39]=[C:40]=[N:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH2:35][CH2:34]1>CS(C)=O>[C:40]([NH:39][CH:36]1[CH2:35][CH2:34][CH2:33][CH2:38][CH2:37]1)([NH:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=[O:8]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Nc1nc(=O)c2nc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2[nH]1
Solvent: CS(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
The carboxylic acid group of folic add (1.0 g, 2 mmol) dissolved in 20 mL of DMSO was pre-activated with DCC (0.495 g, 2.4 mmol) and NHS (0.463 g 4 mmol) at room temperature (Scheme 2). In the reaction, dicyclohexylurea was formed and removed by filtration. The vacuum-dried precursor polymer was added to the reaction solution. The reaction was kept at room temperature for 48 hours. The resulting solution was placed in a dialysis membrane with a molecular weight cut-off of 2000 and dialyzed against DI water for one week. The final product was harvested by freeze-drying.
Reaction SMILES: [H-].[Na+].[C:3](=[N:6][OH:7])([NH2:5])[CH3:4].[CH3:8][C:9]1[C:10]([C:28](OC)=O)=[C:11]([NH:14][C:15](=[O:27])[CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[S:12][CH:13]=1>C1COCC1>[CH3:8][C:9]1[C:10]([C:28]2[O:7][N:6]=[C:3]([CH3:4])[N:5]=2)=[C:11]([NH:14][C:15](=[O:27])[CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[S:12][CH:13]=1
Reactant: CC(N)=NO
Reactant: COC(=O)c1c(C)csc1NC(=O)Cc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(-c2c(C)csc2NC(=O)Cc2cccc3ccccc23)n1
Reaction time: 72 h
Yield: 10.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 106 mg, 2.65 mmol) was added to a solution of acetamide oxime (218 mg, 2.94 mmol) in dry THF (5 mL) at rt. Methyl 4-methyl-2-(2-(naphthalen-1-yl)acetamido)thiophene-3-carboxylate (Aldrich, 500 mg, 1.47 mmol) was added, and the reaction mixture was allowed to stir over 3 days. The mixture was concentrated under reduced pressure, then partitioned between ethyl acetate and water. The organic layer was separated, and washed with saturated NaCl solution. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (EtOAc/hexanes elution), and then triturated from acetonitrile to afford the desired product (58 mg) as a white solid. Method [7]: rt=9.42 min; 1H NMR (CDCl3) δ 11.3 (s, 1H), 8.02-7.89 (m, 3H), 7.63-7.50 (m, 4H), 6.48 (s, 1H), 4.35 (s, 2H), 2.42 (s, 3H), 2.08 (s, 3H); 13C NMR (CDCl3) δ 172.1, 168.9, 165.2, 146.4, 134.0, 133.4, 132.4, 129.4, 129.1, 129.0, 128.8, 127.2, 126.4, 125.7, 123.7, 114.0, 106.9, 42.1, 16.9, 11.4; MH+ 364.1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([NH:20][C:21]([C:23]3([NH:29]C(=O)OC(C)(C)C)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])[C:18]#[N:19])=[CH:12][CH:11]=2)=[CH:6][C:5]=1[F:37])(=[O:3])[NH2:2].O>C(#N)C>[NH2:29][C:23]1([C:21]([NH:20][C@H:17]([C:18]#[N:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:1](=[O:3])[NH2:2])=[C:5]([F:37])[CH:6]=3)=[CH:15][CH:14]=2)=[O:22])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc(C(N)=O)c(F)c3)cc2)CCOCC1
Solvent: O
Solvent: CC#N
Product: N#C[C@H](Cc1ccc(-c2ccc(C(N)=O)c(F)c2)cc1)NC(=O)C1(N)CCOCC1
Yield: 120.3 %

Procedure:
(S)-4-Amino-N-(2-(4′-carbamoyl-3′-fluorobiphenyl-4-yl)-1-cyanoethyl)tetrahydro-2H-pyran-4-carboxamide (Example 25, 212 mg) was suspended in acetonitrile (353 μL) and water (6.7 mL) and stirred under nitrogen at room temperature for 17.5 h. The solid was collected by filtration and dried under vacuum to give the titled compound as a solid (205 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)=[O:5].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([Cl:25])=[O:24]>>[ClH:25].[NH:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccccc1C(=O)NCCc1ncc[nH]1
Product: Cl
Product: O=C(Nc1ccccc1C(=O)NCCc1ncc[nH]1)c1cccc(C(F)(F)F)c1
Yield: 85.5 %

Procedure:
The titled compound was prepared substantially in accordance with the method detailed in Example 11 using 14.1 g (0.0612 mol) of 2-amino-N-[2-(1H-imidazol-2-yl)-ethyl]benzamide, prepared as in Example 6A, and 25.5 g (0.1224 mol) of m-trifluoromethylbenzoyl chloride with the exception that after removing ethyl acetate the resulting solid was suspended in methanol. To this suspension was added a diethyl ether/hydrochloric acid solution. The resulting solution was reduced to dryness under reduced pressure and the final product was recrystallized from an ethanol/diethyl ether solution to provide 22.97 g of the desired titled compound (m.p. 199°-201.5° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[NH:5][C@@H:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[NH:13][CH3:14].[OH-].[Na+].Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23].C(=O)(O)[O-].[Na+]>C(OCC)C.C(N(CC)CC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[NH:5][C@@H:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[N:13]([CH3:14])[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]
Reactant: CN[C@@H]1CCCCC[C@H]1Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CN(C(=O)OCC(Cl)(Cl)Cl)[C@@H]1CCCCC[C@H]1Nc1ccc(Cl)c(Cl)c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of equimolar quantities of triethylamine and the free diamine, trans-3,4-dichloro-N-[2-(N-methylamino)cycloheptyl]-aniline, released from its hydrochloride salt with sodium hydroxide, in ethyl ether, there is added an equimolar amount of 2,2,2-trichloroethyl chloroformate in ethyl ether. The mixture is stirred at room temperature for 2 hours. Then saturated sodium bicarbonate solution is added. The organic layer is dried over magnesium sulfate and concentrated to an oil. This oil is converted to its hydrochloride salt by treatment with excess ethereal hydrochloric acid. This sub-titled salt is recrystallized from a mixture of methanol and ethyl ether.
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:2].Cl.N.[CH2:21]1CCCCC1>O.C(Cl)Cl>[C:1]([NH:3][C:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:2])[CH3:21]
Reactant: C1CCCCC1
Reactant: O=CNc1c(-c2ccccc2)sc2ccccc12
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1c(-c2ccccc2)sc2ccccc12
Reaction time: 8 h

Procedure:
67.0 g (0.265 mol) of 3-formamido-2-phenyl-benzo(b)thiophene and 700 milliliters of HCl at 25% are refluxed with stirring for 8 hours. After cooling, it is diluted with water, neutralised by ammonia and the product is dissolved in CH2Cl2. By evaporating the organic phase dried over K2CO3, 58.7 g (98% of theory) of 2-phenyl-3-amino-benzo-(b)thiophene are obtained; yellow plates melting between 110° and 112° C. (cyclohexane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]\[C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[N:30]=[C:29](Cl)[C:28]([Cl:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:25]1[N:30]=[C:29]([NH:1][C:2]2[CH:3]=[C:4](/[CH:8]=[CH:9]\[C:10]3[CH:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:13]=[CH:12][N:11]=3)[CH:5]=[CH:6][CH:7]=2)[C:28]([Cl:32])=[CH:27][N:26]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(/C=C\c2cccc(N)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccnc(/C=C\c2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Yield: 90 %

Procedure:
To a solution of tert-butyl {2-[(Z)-2-(3-aminophenyl)vinyl]pyridin-4-yl}carbamate (50.0 mg, 0.16 mmol) and 2,4,5-trichloropyrimidine (0.019 mL, 0.17 mmol) in N,N-dimethylformamide (0.50 mL) was added potassium carbonate (66.6 mg, 0.48 mmol). The resultant mixture was stirred for 16 hours at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine then dried (Na2SO4), filtered and concentrated to give the desired product as a light brown gum (66 mg, 90%). LCMS for C22H22Cl2N5O2 (M+H)+: m/z=458.0, 460.0.
Reaction SMILES: [NH2:1][CH:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]12.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.S1C2C=CC=CC=2N=C1S[C:41](=[O:50])[C:42]([C:44]1[N:45]=[C:46]([NH2:49])[S:47][CH:48]=1)=[O:43]>ClCCl>[NH2:49][C:46]1[S:47][CH:48]=[C:44]([C:42](=[O:43])[C:41]([NH:1][CH:2]2[C:17](=[O:18])[N:4]3[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]23)=[O:50])[N:45]=1
Reactant: Nc1nc(C(=O)C(=O)Sc2nc3ccccc3s2)cs1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.44 g of 7-amino-3-acetoxymethylceph-3-em-4-carboxylic acid are suspended under a nitrogen atmosphere in 50 ml of dry di-chloromethane, and mixed with 5.4 ml of N,O-bis(trimethylsilyl)acetamide. The preparation is stirred at room temperature until a clear solution is present, and then cooled to -15°. 8.4 g of 2-(2-amino-4-thiazolyl)-2-oxothioacetic-acid-S-benzothiazol-2-ylester are added, and stirred for two hours at -15° and then for two hours at 0°. The solvent is carefully drawn off in a rotary evaporator, and the oily residue is rubbed with 50 ml of ethanol, whereby the title compound precipitates. 6.3 g are obtained in the form of a yellow powder.
Reaction SMILES: Br[CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:23]([O:24][CH3:25])=[C:22]([CH3:26])[C:21]([CH3:27])=[C:20]([O:28][CH3:29])[C:19]=2[CH3:30])=[CH:13][CH:12]=1)[C:3](OCCCC)=[O:4].[NH2:31][C:32](N)=[S:33].S1(CCCC1)(=O)=[O:36].Cl>O.COCCO>[CH3:30][C:19]1[C:20]([O:28][CH3:29])=[C:21]([CH3:27])[C:22]([CH3:26])=[C:23]([O:24][CH3:25])[C:18]=1[O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH:2]2[S:33][C:32](=[O:36])[NH:31][C:3]2=[O:4])=[CH:12][CH:13]=1
Reactant: NC(N)=S
Reactant: CCCCOC(=O)C(Br)Cc1ccc(Oc2c(C)c(OC)c(C)c(C)c2OC)cc1
Reactant: O=S1(=O)CCCC1
Agent: Cl
Solvent: COCCO
Solvent: O
Product: COc1c(C)c(C)c(OC)c(Oc2ccc(CC3SC(=O)NC3=O)cc2)c1C
Temperature: 120 °C

Procedure:
A mixture of 5.7 g of butyl 2-bromo-3-[4-(2,4,5-trimethyl-3,6-dimethoxyphenoxy)phenyl]propionate (prepared as described in Preparation 1), 1.2 g of thiourea and 10 ml of sulfolane was heated at 120° C. for 5 hours under an atmosphere of nitrogen, and then 20 ml of ethylene glycol monomethyl ether and 10 ml of 2N aqueous hydrochloric acid were added to the resulting mixture. The mixture was then heated at 100° C. for 5 hours, after which the reaction mixture was poured into water and then extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed from the extract by distillation under reduced pressure, and the residue thus obtained was purified by column chromatography through silica gel, using a 9:1 by volume mixture of benzene and ethyl acetate as the eluent, to give 4.7 g of the title compound as a white glassy powder softening at 47°-50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[N:15]([CH3:16])[C:14]([C:17]([CH3:29])([O:19][C:20]2[C:25]([F:26])=[CH:24][C:23]([F:27])=[CH:22][C:21]=2[F:28])[CH3:18])=[N:13][N:12]=1)[C:5]([OH:7])=O.C1C=CC2N(O)N=[N:36][C:34]=2C=1.CN(C=O)C.CN.C1COCC1>O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[N:15]([CH3:16])[C:14]([C:17]([CH3:18])([O:19][C:20]2[C:21]([F:28])=[CH:22][C:23]([F:27])=[CH:24][C:25]=2[F:26])[CH3:29])=[N:13][N:12]=1)[C:5]([NH:36][CH3:34])=[O:7]
Reactant: Cn1c(-c2ccc(C(=O)O)cc2Cl)nnc1C(C)(C)Oc1c(F)cc(F)cc1F
Reactant: On1nnc2ccccc21
Agent: CN
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(-c2nnc(C(C)(C)Oc3c(F)cc(F)cc3F)n2C)c(Cl)c1
Product: Cl
Reaction time: 0.5 h
Yield: 110.7 %

Procedure:
3-chloro-4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}benzoic acid (204 mg), WSC•monohydrochloride (138 mg), HOBt (98 mg) and DMF (4 ml) were mixed and stirred for 30 minutes. A 2M methylamine-THF solution (0.72 ml) was added thereto, followed by stirring for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water, a 1M aqueous sodium hydroxide solution and then saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1 to 30:1). The residue was dissolved in ethyl acetate, 4M hydrogen chloride-ethyl acetate (1 ml) was added thereto, and the solvent was evaporated under reduced pressure. The resulting solid was washed with hexane to obtain 3-chloro-N-methyl-4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}benzamide monohydrochloride (126 mg), as a white solid.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16][NH2:17]>>[CH3:14][C:15]([CH3:19])([CH3:18])[CH2:16][NH:17][CH2:3][C:2]([CH3:1])([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)[CH3:5]
Reactant: CC(C)(C=O)n1cnc([N+](=O)[O-])c1
Reactant: CC(C)(C)CN
Product: CC(C)(C)CNCC(C)(C)n1cnc([N+](=O)[O-])c1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted with 2,2-dimethyl-propyl amine to provide the title compound: H1 NMR (400 MHz, CDCl3) 0.74 (s,9H), 1.52 (s, 6H), 2.2 (s, 2H), 2.8 (s, 2H), 7.6 (s, 1H), 7.9 (s, 1H); MS m/z 255.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].[CH:26](OCC)(OCC)[O:27][CH2:28][CH3:29]>CC1C=CC=CC=1>[C:19]([C:4]1[C:3]([S:21][C:22]([F:25])([F:24])[F:23])=[C:2]([N:1]=[CH:26][O:27][CH2:28][CH3:29])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Reactant: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOC=Nc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
5-Amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (4.0 g) was added to triethyl orthoformate (19.0 ml) and p-toluene/-sulphonic acid (0.019 g) added. The mixture was heated under reflux for 21 hours cooled, and the triethyl orthoformate evaporated in vacuo to give a brown oil as residue. This was purified by chromatography eluting with a mixture of dichloromethane and hexane (1:1). Evaporation of the eluates in vacuo gave 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethyleneamino-4-trifluoromethylthiopyrazole as a colourless solid, m.p. 70-71.5° C.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:17](=[O:18])[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]([C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[CH:21][CH:20]=2)[CH:26]=1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: COC(=O)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of the (4-adamantan-1-yl-phenoxy)-acetic acid (140 mg, 0.5 mmol) and 3-aminobenzoic acid methyl ester (110 mg, 0.75 mmol) in DMF (5.0 mL) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (144.0 mg, 0.75 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (101 mg, 0.75 mmol), and N,N-diisopropylethylamine (DIPEA) (0.13 mL, 0.75 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. Purification by silica gel column chromatography (n-Hexane:Ethyl acetate:MeOH=15:3:1) gave 3-[2-(4-Adamant-1-yl-phenoxy)-acetylamino]-benzoic acid methyl ester as a white solid (160 mg, 76% yield).
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.C(OC(C1N=CC2C(C=1O)=CC=C(OC1C=CC(OC)=CC=1)C=2)=O)CCC.P(Br)(Br)([Br:56])=O>C(#N)C>[Br:56][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([OH:5])=[O:7])[N:9]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1nc(O)c2cc(Sc3ccccc3)ccc2c1O
Agent: CCCCOC(=O)c1ncc2cc(Oc3ccc(OC)cc3)ccc2c1O
Solvent: CC#N
Product: O=C(O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Reaction time: 8 h

Procedure:
1,4-Dihydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (Example A-63 d) Compound A) (29.0 g) and phosphorous oxybromide (67.5 g) in 600 ml anhydrous acetonitrile was stirred at reflux for 4 hours. After cooling the reaction mixture was concentrated and saturated sodium bicarbonate solution and ethyl acetate were added to the residue and stirred overnight. Precipitate that formed between layers was collected and washed with water to give the title compound (10.2 g). MS-(+)-ion M+1=376.0, 378.1.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:21](I)[CH3:22]>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([CH2:21][CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCI
Reactant: COc1ccc(Nc2nc(Cl)nc3ccccc23)cc1
Product: CCN(c1ccc(OC)cc1)c1nc(Cl)nc2ccccc12

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-amine and ethyl iodide by a procedure similar to example 7 (58% yield). 1H NMR (CDCl3): 7.69-7.72 (m, 1H), 7.53 (ddd, J=8.1, 6.9 and 1.5 Hz, 1H), 7.09-7.14 (m, 2H), 6.94-6.70 (m, 3H), 6.83-6.87 (m, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.87 (s, 1H), 1.30 (t, J=6.9 Hz, 3H).