Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:8](=O)[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[CH2:5][C:4]=2[N:3]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[NH:24]([N:25]=[C:8]1[CH2:7][CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:5][C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]([CH3:12])[C:9]1=2)[C:21]([NH2:23])=[NH:22]
Reactant: Cc1cc(C)c2c(n1)CC(c1ccccc1C)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2c(n1)CC(c1ccccc1C)CC2=NNC(=N)N
Yield: 89.6 %

Procedure:
A mixture of 2,4-dimethyl-7-(2-methylphenyl)-5,6,7,8-tetrahydroquinolin-5-one (0.48 g), aminoguanidine hydrochloride (0.21 g), concentrated hydrochloric acid (0.19 ml), water (0.19 ml) and ethanol (50 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether, and to the solution was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated. The residue was dissolved in ethanol, and to the solution was added 1N hydrochloric acid. Under reduced pressure, the solvent was evaporated to give 5-guanidinoimino-2,4-dimethyl-7-(2-methylphenyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 84) (0.58 g) as amorphous.
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]1[C:6]([C:13]([NH2:15])=[O:14])=[N:7][CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:12][O:11][C:9]1[CH:8]=[N:7][C:6]2[C:13](=[O:14])[NH:15][CH:3]=[CH:4][C:5]=2[CH:10]=1
Reactant: COc1cnc(C(N)=O)c(CC(OC)OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cnc2c(=O)[nH]ccc2c1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To a mixture of 3-(2,2-dimethoxyethyl)-5-methoxypicolinamide (6.74 g, 28.1 mmol) in toluene (112 ml) was added 4-methylbenzene sulfonic acid (monohydrate; 0.534 g, 2.81 mmol). The reaction mixture was heated to reflux for 20 h. The reaction mixture was cooled to rt and concentrated in vacuo to a volume of ca. 15 mL. The residue was triturated with heptanes and filtered to afford 3-methoxy-1,7-naphthyridin-8(7H)-one (4.53 g, 25.7 mmol, 92% yield) as a crude, tan solid that was advanced without further purification. MS m/z=177.1 [M+H]+
Reaction SMILES: CN([CH:4]=[C:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)C.O.C(=O)([O-])[OH:24].[Na+]>Cl.CS(C)=O>[OH:24][CH:4]=[C:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2
Reactant: O=C([O-])O
Reactant: CN(C)C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1[nH]c2c3ccccc3c(=CO)c2n2ccnc12

Procedure:
A solution of 1.4 g of 10-dimethylaminomethylene-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 35 ml of 5N hydrochloric acid is stirred for 30 minutes at a temperature in the region of 25° C. After addition of 60 ml of distilled water and neutralization with 120 ml of saturated aqueous sodium hydrogen carbonate solution, the solid formed is separated out by filtration, washed twice with 60 ml in total of distilled water and air-dried. The product obtained (1.1 g) is dissolved in 120 ml of dimethyl sulphoxide and, after addition of 120 ml of distilled water, the solid formed is separated out by filtration, washed twice with 10 ml in total of distilled water and twice with 10 ml in total of acetone and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 1 g of 10-hydroxymethylene-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one is thus obtained as a 60/40 mixture of the Z and E forms, decomposing without melting at 290° C. [N.M.R. spectrum: (200 MHz; DMSO d6 ; δ in ppm): a 60/40 mixture of isomers is observed: from 7.20 to 7.40 (mt, 2H: --H7 and --H8); 7.56 and 7.64-8.29 and 8.79 (4s broad, twice 1H: --H of the imidazole); from 7.80 to 8.15 (mt, 2H: --H6 and --H9); 8.21 and 8.24 (2s, 1H in total: =CH--O--); 12.43 (cplx, 1H: --NH--)].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21]>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:26]1[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=1)[C:20]#[N:21])=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3cccc(C#N)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-cyano phenylboronic acid to give 3-[6-methoxy-3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-benzonitrile. LC-MS m/e 342(MH+).
Reaction SMILES: Cl[CH:2]([C:14](=[O:16])[CH3:15])[CH2:3][S:4][CH2:5][CH2:6][NH:7][C:8]([NH:11][C:12]#[N:13])=[N:9][CH3:10].[C:17]([O-:20])(=[O:19])[CH3:18].[Na+]>CO>[C:17]([O:20][CH:2]([C:14](=[O:16])[CH3:15])[CH2:3][S:4][CH2:5][CH2:6][NH:7][C:8]([NH:11][C:12]#[N:13])=[N:9][CH3:10])(=[O:19])[CH3:18]
Reactant: CC(=O)[O-]
Reactant: CN=C(NC#N)NCCSCC(Cl)C(C)=O
Agent: [Na+]
Solvent: CO
Product: CN=C(NC#N)NCCSCC(OC(C)=O)C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
A 50 ml two-necked flask was charged with 0.64 g of the same N-{2-(2-chloro-3-oxobutylthio)ethyl}-N'-cyano-N"-methylguanidine as used in Example 1, 10 ml of methanol, and 0.31 g of anhydrous sodium acetate, and the mixture was stirred at room temperature for 8 hours. Methanol was evaporated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate and then dried over anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure to give 0.57 g (yield 82%) of the desired product as a brown liquid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:32])[CH2:15][CH:16]([C:22]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=1[O:30][CH3:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2].[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:7][C:6]=1[NH:13][C:14](=[O:32])[CH2:15][CH:16]([C:22]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=1[O:30][CH3:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCC(CC(=O)Nc1cc(CN)ccc1C(C)(C)C)c1c(OC)cccc1OC
Product: CCCCCC(CC(=O)Nc1cc(CNC(=O)c2ccccc2)ccc1C(C)(C)C)c1c(OC)cccc1OC

Procedure:
Following a similar procedure to that described in Example 144, but using N-(2-t-butyl-5-aminomethylphenyl)-3-(2,6-dimethoxyphenyl)octanamide (prepared as described in Preparation 72E) and benzoyl chloride, the title compound was obtained as a colorless foam-like substance.
Reaction SMILES: O.[C:2]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:9]([OH:13])[CH2:10][CH2:11][CH3:12]>C1(C)C=CC=CC=1>[CH2:7]([O:8][C:2]1([O:13][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCCCC1
Reactant: CCCCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC1(OCCCC)CCCCC1
Temperature: 125 °C
Yield: 187.7 %

Procedure:
In a 300-ml three-necked flask equipped with a water separator, 98 g (1 mole) of cyclohexanone, 148 g (2 moles) of n-butanol, 2.4 mg of stannous chloride dihydrate and 40 g of toluene were charged. The resulting mixture was heated at 125° C. under atmospheric pressure for 6 hours in a nitrogen atmosphere while removing the water formed from the reaction mixture by azeotropic distillation. When water was no longer distilled, the solvent (toluene) and unreacted starting materials were distilled off under reduced pressure. Distillation of the residue under reduced pressure gave 214.3 g of cyclohexanone dibutyl acetal [R1, R2 =a pentamethylene group and R3 =a n-butyl group] (boiling point: 102° C./3 mmHg) (yield: 94.0%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([N:20]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:4][CH:3]=1.[Li+].[Cl-].C([Sn](CCCC)(CCCC)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1)CCC>CN(C=O)C.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>[CH2:21]([N:20]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[CH:3][CH:4]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccc(Br)cc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@H](Cc1ccc(-c2ccccn2)cc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 80 °C
Yield: 72.3 %

Procedure:
A solution containing the product from Example 23K (11.0 g, 20.5 mmol) in DMF (90 mL) was treated with LiCl (8 g, 188.7 mmol), tetrakis(triphenylphosphine)palladium(0) (5 g, 4.3 mmol), and 2-tri-n-butylstannylpyridine (22 g, 59.8 mmol), heated at 80° C. for 16 hours, cooled, filtered and concentrated. The residue was partitioned between ethyl acetate and water, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with a gradient 0-25% ethyl acetate/hexanes to give the title compound (7.6 g, 72% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([O:10]CC)[C:7]=1[C:8]#[N:9].CO>O>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([OH:10])[C:7]=1[C:8]#[N:9]
Reactant: CCOc1csc(N)c1C#N
Agent: Cl
Solvent: CO
Solvent: O
Product: N#Cc1c(O)csc1N

Procedure:
A solution of 20 parts by volume of concentrated hydrochloric acid in 100 parts by volume of water is added dropwise to a boiling mixture of 168 parts of 2-amino-3-cyano-4-ethoxythiophene and 500 parts by volume of methanol. The mixture is refluxed for a further 2 hours and diluted with 400 parts by volume of water, and the product is filtered off under suction, washed with water and dried to give 136 parts of 2-amino-3-cyano-4-hydroxythiophene. The sample recrystallized from acetic acid does not melt below 300° C. and has the following analytical values:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[O:11])[O:9][C:8](=[O:12])[C:5]2=[N:6][CH:7]=1.[CH:13]([OH:16])([CH3:15])[CH3:14]>C1COCC1>[CH:13]([O:16][C:8]([C:5]1[C:4]([C:10]([OH:9])=[O:11])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:12])([CH3:15])[CH3:14]
Reactant: O=C1OC(=O)c2ncc(Br)cc21
Reactant: CC(C)O
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1ncc(Br)cc1C(=O)O
Reaction time: 0.08 h
Yield: 83.1 %

Procedure:
To a solution of 3-bromo-furo[3,4-b]pyridine-5,7-dione (200 mg, 0.877 mmol) in THF (3 ml) at −10° C. was added Mg(ClO4)2 (235 mg, 1.053 mmol, 1.2 equiv.) and the reaction mixture was stirred for 5 min at that temperature. Then isopropanol (6 ml) was added and the reaction mixture was stirred at 25° C. for 16 hours. The volatilities were removed in vacuo and the resultant residue was dissolved in EtOAc (30 ml). The organic layer was washed with water (15 ml) and brine (15 ml), dried over anhydrous Na2SO4, filtered and evaporated off in vacuo. The crude material thus obtained was purified by column chromatography over normal silica gel (30-50% EtOAc/hexane) to afford 5-bromo-pyridine-2,3-dicarboxylic acid 2-isopropyl ester (210 mg, 83.1%) as light brown solid, MS: m/e=286.0 (M−H+).
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:14]=[CH:15][C:16]2[C:17]([CH:28]=1)=[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[O:19][N:20]=2.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([C:18]2[O:19][N:20]=[C:16]3[CH:15]=[CH:14][C:13]([CH:34]([C:33]4[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=4)[OH:35])=[CH:28][C:17]=23)[CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Clc1cccc(-c2onc3ccc(Br)cc23)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 26.8 %

Procedure:
nBuLi 1.6M in hexane (0.112 mol) was added dropwise at −70° C. under N2 flow to a mixture of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (0.097 mol) in THF (300 ml). The mixture was stirred at −70° C. for 15 min. A mixture of 4-fluorobenzaldehyde (0.112 mol) in THF (100 ml) was added dropwise. The mixture was stirred at −70° C. for 30 min, then hydrolized and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue was taken up in diethyl ether and DIPE. The precipitate was filtered off, washed and dried, yielding 9.2 g (26.8%) of 3-(3-chlorophenyl)-α-(4-fluorophenyl)-2,1-benzisoxazole-5-methanol (intermediate 1), mp. 171° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].[Na].[CH2:17]([CH:20]([CH2:23]Br)[CH2:21]Br)[CH2:18][CH3:19]>C(O)C>[CH2:10]([O:9][C:1]([C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:23][CH:20]([CH2:17][CH2:18][CH3:19])[CH2:21]1)=[O:8])[CH3:11]
Reactant: CCCC(CBr)CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCC1CC(C(=O)OCC)(C(=O)OCC)C1
Reaction time: 1 h
Yield: 84 %

Procedure:
Diethyl malonate (96.0 g., 0.608 mol) was added to sodium ethoxide solution [prepared by the addition of 13.8 g. (0.6 gram atom) of sodium to 300 ml. of absolute ethanol] and the mixture was refluxed with stirring. Over a period of one hour, sodium ethoxide solution [prepared by the addition of 12.2 g. (0.5 gram atom) of sodiumto 200 ml. of absolute ethanol] and 2-n-propyl-1,3-dibromopropane (12.2 g., 0.5 mol, prepared as described in Reference Example 1) were added concurrently to the boiling reaction mixture. After the addition was completed, the mixture was refluxed with stirring for 2 hours, and then 400 ml. of ethanol was distilled from the reaction mixture. The residue was mixed with water and extracted with benzene (5×300 ml.). After concentration of the extracts under reduced pressure, a crude product was obtained, which was distilled in vacuo to give the title compound in 84% yield. This compound had the following physical characteristics:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH:11]([NH:13][C:14](=[O:29])[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)([CH3:17])[CH3:16])[CH3:12])[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:49][CH2:50][F:51])(=O)=O>CN(C)C=O.CCOCC>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:49][CH2:50][F:51])=[CH:33][CH:32]=2)[CH:11]([NH:13][C:14](=[O:29])[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)([CH3:17])[CH3:16])[CH3:12])[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2]
Reactant: CS(=O)(=O)OCCF
Reactant: CC(NC(=O)C(C)(C)Oc1ccc(C(F)(F)F)cn1)C(Cc1ccc(O)cc1)c1cc(F)cc(C#N)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(NC(=O)C(C)(C)Oc1ccc(C(F)(F)F)cn1)C(Cc1ccc(OCCF)cc1)c1cc(F)cc(C#N)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-[2-(3-cyano-5-fluorophenyl)-3-(4-hydroxyphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide from Example 7, Step B (15 mg, 0.039 mmol) in 2 mL of dimethylformamide was added cesium carbonate (15 mg, 0.046 mmol) and 2-fluoroethyl methanesulfonate (20 uL, 0.16 mmol), and the reaction was stirred at 70° C. for 0.5 h. The resulting mixture was diluted with ether (20 mL), washed with water and brine and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 10 to 40% ethyl acetate in hexane to give N-{2-(3-cyano-5-fluorophenyl)-3-[4-(2-fluoroethoxy)phenyl]-1-methylpropyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide. 1H NMR (500 MHz, CD3OD): PL 87 δ 8.27 (br s, 1H), 7.94 (dd, 1H), 7.48 (d, 1H), 7.73-7.32 (m, 3H), 7.04 (s, 1H), 6.64 (s, 4H) 4.68 (m, 1H), 4.59 (m, 1H), 4.25 (m, 1H), 4.11 (m, 1H), 4.04 (m, 1H), 3.02 (dd, 1H), 2.84 (m, 1H), 2.57 (dd, 1H), 1.75 (s, 3H), 1.73 (s, 3H), 0.80 (d, 3H). LC-MS: m/e 544 (M+H)+ (3.8 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:6]=2[CH:19]=1.[Cl:20][CH2:21][C:22]([N:24]=[C:25]=[O:26])=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:25]([NH:24][C:22](=[O:23])[CH2:21][Cl:20])=[O:26])[CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:6]=2[CH:19]=1
Reactant: O=C=NC(=O)CCl
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCCN2
Solvent: ClCCl
Product: O=C(CCl)NC(=O)N1CCN=C(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of 8 parts of 7-chloro-5-(o-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine, 4.9 parts of chloroacetylisocyanate, and 200 parts by volume of methylene chloride is stirred under nitrogen atmosphere at ambient temperature for about one hour. The mixture is then filtered through a layer of activated magnesium silicate and the filtrate evaporated to dryness. The resultant yellow oil is dissolved in ether and the solvent removed by evaporation to give gummy residue which upon crystallization from ether affords 7-chloro-N-chloracetyl-5-(o-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-1-carboxamide, as a yellow solid melting at about 152°-156° C. This compound is represented by the following formula ##STR21##
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]1=[O:13].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH3:18].O>CN(C)C=O>[CH2:14]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]1=[O:13])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCBr
Reactant: O=C1Nc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCN1C(=O)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
A stirred solution of 270 mg of sodium hydride was added to 1.00 g of 2,3-dihydro-1H-indol-2,3-dione in dimethylformamide at room temperature. After the reaction mixture was stirred at room temperature for 10 minutes, 5 ml of a dimethylformamide solution of 2.10 g of pentyl bromide was added dropwise thereto. After the reaction mixture was stirred at room temperature for 20 minutes, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was removed by evaporation. The residue was purified by silica gel column chromatography [ethyl acetate-hexane (1:5)] to afford 1.31 g of 2,3-dihydro-1-pentyl-1H-indol-2,3-dione as orange crystals. Melting point: 50° to 51° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][C@H:4]([NH:8][S:9]([C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:5](=[O:7])[CH3:6].[C:20]([O:24][CH2:25][Li])([CH3:23])([CH3:22])[CH3:21].O>C1COCC1>[C:20]([O:24][CH2:25][C:5]([CH3:6])([OH:7])[CH:4]([NH:8][S:9]([C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:3][CH:2]([CH3:19])[CH3:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(=O)[C@H](CC(C)C)NS(=O)(=O)c1ccccc1C
Reactant: [Li]COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1S(=O)(=O)NC(CC(C)C)C(C)(O)COC(C)(C)C
Temperature: 25 °C

Procedure:
To a -78° C. solution of the resultant compound of Example 57 (1.0 g, 3.5 mmol) in dry THF (7 ml) was added 3 equivalent, of t-butoxymethyl lithium [E. J. Corey and T. M. Eckridge, Tetrahedron Letters, 3165 (1983)]. The mixture was warmed to room temperature for 4 hours and then poured into water. Acidification with 0.1 M H3PO4, extraction into ether, washing with brine, drying, and evaporating gave 1.1 (85%) of the desired compound. Mass spectrum: M+ =371.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]([OH:9])=O.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:25]([NH2:33])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:25]([NH:33][C:7]([C:6]1[S:5][N:4]=[N:3][C:2]=1[CH3:1])=[O:9])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1nnsc1C(=O)O
Reactant: NCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1nnsc1C(=O)NCCc1ccccc1
Temperature: 5 °C
Yield: 94.6 %

Procedure:
A suspension of 9.65 g of 4-methyl-[1,2,3]thiadiazol-5-carboxylic acid in 70 ml of dichlormethane was cooled to 5° C. while stirring, treated with 0.15 g of 4-dimethylamino-pyridine and subsequently with 13.8 g of N,N'-dicyclohexyl-carbodiimide at such a rate that the internal temperature <10° C. could be maintained. After completion of the addition, the mixture was cooled to 5° C. and 8.92 g of phenethylamine were added at such a rate that the internal temperature of <37° C. could be maintained. After completion of the addition, the mixture was stirred for a further 1 h., then the precipitate was filtered off under suction, rinsed well with dichloromethane and the filtrate was evaporated. The residual yellow oil was subjected to chromatography on silica gel with hexane/ethyl acetate 50:50. There were obtained 15.66 g (92%) of 4-methyl-[1,2,3]thiadiazole-5-carboxylic acid phenethylamide as a colorless crystallizate of m.p. 64°-68° C. Recrystallization of a sample from tert.-butyl methyl ether gave colorless crystals of m.p. 64.5°-66° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][C@H:20]([CH3:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[C@H:20]([CH3:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])cn1

Procedure:
A mixture of 2-chloro-5-nitropyridine (1.0 g, 6.3 mmol), (R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.26 g, 6.31 mmol), and potassium carbonate (2.18 g, 15.77 mmol) was stirred in DMSO (5 mL) at 120° C. overnight. The reaction mixture was concentrated under rotary evaporation and mixed with water (50 mL). The resulting precipitate was filtered, washed with water (3×10 mL) and air-dried to provide the title intermediate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=O.C(=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[CH3:7][C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=1[CH3:11]
Reactant: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(Br)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Yield: 99 %

Procedure:
To stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid, prepared analogously to above, (287 g, 1103 mmol) in DMF (150 mL), sodium carbonate (468 g, 4415 mmol) and methyl iodide (626.6 g, 4415 mmol) were added. Resulting mixture was heated at 60° C. for 8 h. On completion, solid was remove by filtration, and the residue washed with diethyl ether (5 times). The combined organic layers were dried, concentrated under reduced pressure to give methyl 5-bromo-2-methyl-3-nitrobenzene (302 g, 99%).