Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1([CH:7]2[CH2:10][NH:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.C1([O:24][C:25](=O)[N:26]([C:36]2[CH:41]=[C:40]([O:42][C:43]3[CH:48]=[CH:47][C:46]([NH:49][C:50]([C:52]4([C:55](=[O:64])[NH:56][C:57]5[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=5)[CH2:54][CH2:53]4)=[O:51])=[C:45]([F:65])[CH:44]=3)[CH:39]=[CH:38][N:37]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[N:3]1([CH:7]2[CH2:10][N:9]([C:25]([NH:26][C:36]3[CH:41]=[C:40]([O:42][C:43]4[CH:48]=[CH:47][C:46]([NH:49][C:50]([C:52]5([C:55]([NH:56][C:57]6[CH:58]=[CH:59][C:60]([F:63])=[CH:61][CH:62]=6)=[O:64])[CH2:54][CH2:53]5)=[O:51])=[C:45]([F:65])[CH:44]=4)[CH:39]=[CH:38][N:37]=3)=[O:24])[CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: C1CN(C2CNC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CC(N2CCC2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 5.9 %

Procedure:
To a suspension of 3-(azetidin-1-yl)azetidine dihydrochloride (111 mg) in N,N-dimethylformamide (1.5 ml) was added triethylamine (0.167 ml), followed by stirring at room temperature for 15 min. A crude product of [4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (100 mg) was added thereto, followed by stirring at room temperature for 25 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. This was concentrated and the residue was purified by LC-MS. Fractions containing the target compound were concentrated, and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and to the resultant solid (31.5 mg) was added diethyl ether (2 ml) to suspend. This was collected by filtration and washed with diethyl ether. This was dried under aeration to provide the titled compound as colorless powder (5.0 mg).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[CH3:28][O:29][CH:30]([O:33][CH3:34])[CH2:31][NH2:32]>>[CH3:28][O:29][CH:30]([O:33][CH3:34])[CH2:31][NH:32][C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[N:20][CH:21]=1)=[O:24]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: COC(CN)OC
Product: COC(CNC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1)OC
Yield: 78 %

Procedure:
By the same procedure as described in the example 24, the synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using 2,2-dimethoxyethylamine. And then, the product was crystallized with ethanol and hexane to give a desired compound.
Reaction SMILES: Cl[C:2]([N:4]=[C:5]=[O:6])=[O:3].[Cl:7][C:8]1[CH:28]=[CH:27][C:11]2[N:12]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH3:26])=[O:24])=[CH:18][CH:17]=3)[S:14][C:10]=2[CH:9]=1>O1CCOCC1>[Cl:7][C:8]1[CH:28]=[CH:27][C:11]2[N:12]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[C:2](=[O:3])[NH:4][C:5](=[O:6])[N:25]([CH3:26])[C:23]4=[O:24])=[CH:18][CH:17]=3)[S:14][C:10]=2[CH:9]=1
Reactant: O=C=NC(=O)Cl
Reactant: CNC(=O)Nc1ccc(Oc2nc3ccc(Cl)cc3s2)cc1
Solvent: C1COCCO1
Product: Cn1c(=O)[nH]c(=O)n(-c2ccc(Oc3nc4ccc(Cl)cc4s3)cc2)c1=O
Yield: 72.5 %

Procedure:
Chlorocarbonyl isocyanate (0.8 g) was added to a suspension of N-[4-(6-chlorobenzothiazol-2-yloxy)phenyl]-N'-methylurea (2.4 g) in 1,4-dioxane (50 ml), and the mixture was heated at the boiling point for 5 hours. The mixture was evaporated under reduced pressure and the residue was dissolved in a minimal volume of boiling 1,4-dioxane. After addition of ethanol (50 ml), the clear solution was cooled in a refrigerator. The resulting solid substance was collected by filtration, washed with cold ethanol and dried to give 2.1 g of 1-[4-(6-chlorobenzothiazol-2-yloxy)phenyl]-3-methyl-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione of melting point 270°-271° C. Preparation of N-[4-(6-chlorobenzothiazol-2-yloxy)phenyl]-N'-methylurea: ##STR15##
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].Br[CH2:13][CH2:14][OH:15].C[O-].[Na+]>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:13][CH2:14][OH:15]
Reactant: OCCBr
Reactant: Oc1ccc2ccccc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: OCCOc1ccc2ccccc2c1
Reaction time: 48 h

Procedure:
A solution of 14.4 g of 2-naphthol, 12.1 g of 2-bromoethanol and 5.9 g of sodium methoxide in 100 ml of ethanol is allowed to stand two days at room temperature. The solvent is removed under vacuum and the residue extracted with ether. The ether extract is washed with water dried (magnesium sulfate) and the solvent removed under vacuum to give crystals, mp 65°-70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=O)[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=4[CH3:25])[N:13]=[C:12]([OH:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1.FC(F)(F)C(O)=O.[BH4-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=4[CH3:25])[N:13]=[C:12]([OH:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(-n2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(O)c3c(c2=O)Cc2ccc(Cl)cc2N3)c(C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.4 %

Procedure:
7-Chloro-4-hydroxy-2-(4-methoxy-2-methylphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (5.0 mL, 13.1 mmol) was suspended in tetrahydrofuran (170 mL) under nitrogen cooled to 0° C. and treated with trifluoroacetic acid (18 mL, 235 mmol). Over a 10 minute period, the reaction mixture was then treated with NaBH4 (1.973 g, 52.2 mmol). The reaction mixture was stirred at 0° C. for 6 hours and then was stored in a freezer overnight. The reaction mixture was then treated with additional NaBH4 (approximately 1.0 g) and stirred at 0° C. for 2 hours. The reaction mixture was poured onto water (500 mL) and extracted with ethyl acetate (2×200 mL). The ethyl acetate extracts were combined and then concentrated in vacuo. The residue was poured onto ether (400 mL) and the solid which formed was collected by filtration to afford crude product. The crude was recrystallized from methanol to afford 1.91 g of the title compound as an off-white solid, mp 264-266° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:14]/[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[CH:19][CH:18]=2)/[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[S:37]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38]1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.C(O)C>[CH3:30][C:29]1[O:28][C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:26][C:25]=1[CH2:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:15]/[N:14]=[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([C:39]3[CH:40]=[CH:41][S:37][CH:38]=3)=[CH:3][CH:4]=2)\[C:9]([OH:11])=[O:10])=[CH:18][CH:19]=1
Reactant: OB(O)c1ccsc1
Reactant: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\C(=O)O)c2ccc(-c3ccsc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
A mixture of ethyl Z-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate (800 mg), 3-thienylboronic acid (224 mg), potassium carbonate (604 mg), toluene (20 ml), ethanol (2 ml) and water (2 ml) was stirred under an argon atmosphere for 30 minutes at room temperature. Tetrakis (triphenylphosphine)palladium (0) (101 mg) was added and the mixture was heated under reflux for 14 hours. The reaction mixture was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v). This oil was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueous solution of sodium hydroxide (5 ml) was added and the mixture was stirred for 2 hours at 40° C. 1N HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain Z-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-[4(3-thienyl)phenyl]acetic acid (442 mg, yield 58%) as pale-yellow crystals. m.p. 205-206° C. (decomposition)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:12][N:11]3[C:23]=2[CH:24]2[CH:29]=[CH:28][N:27](C(OCC)=O)[CH:26]=[CH:25]2)=[CH:4][CH:3]=1.C1(Cl)C(Cl)=C(Cl)C(=O)C(=O)C=1Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]4)=[N:12][N:11]3[C:23]=2[C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1C=CC(c2c(-c3ccc(F)cc3)nc3ccc(N4CCN(C)CC4)nn23)C=C1
Agent: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccncc4)n3n2)CC1
Yield: 56 %

Procedure:
To a suspension of 1.00 g (2.16 mmol) of ethyl 4-[2-(4-fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl]-4H-pyridine-1-carboxylate in 35 mL of toluene is added a solution of 0.65 g (2.6 mmol) of ortho-chloranil in 6 mL of toluene. After reaction for 6 hours, 60 mL of 1N sodium hydroxide are added and the product is extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solvent is evaporated off under reduced pressure. 1.2 g of solid are thus recovered, and are purified on a column of silica gel, eluting with a stepwise gradient of 3% to 15% methanol in dichloromethane. The product obtained is washed with diisopropyl ether and recrystallized from isopropyl alcohol to give 0.47 g of crystals after filtering off and drying under reduced pressure.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:26]3=[C:27]4[N:22]([CH:23]([CH3:28])[CH2:24][CH2:25]3)[CH:21]=[C:20]([C:29]([OH:31])=[O:30])[C:19](=[O:32])[C:18]4=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>C(O)=O>[OH2:3].[CH:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:26]3=[C:27]4[N:22]([CH:23]([CH3:28])[CH2:24][CH2:25]3)[CH:21]=[C:20]([C:29]([OH:31])=[O:30])[C:19](=[O:32])[C:18]4=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:3]
Reactant: CC1CCc2c(-c3ccc(N)cc3)ccc3c(=O)c(C(=O)O)cn1c23
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC1CCc2c(-c3ccc(NC=O)cc3)ccc3c(=O)c(C(=O)O)cn1c23
Product: O

Procedure:
To a hot mixture of 20 ml of 97% formic acid and 10 ml of acetic anhydride was added 1.5 g of 8-(4-aminophenyl)-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo-[ij]quinolizine-2-carboxylic acid. The mixture was heated on a steam bath for 15 minutes and then evaporated. The residue was triturated with water to provide a solid. The solid was recrystallized from glacial acetic acid to provide 6,7-dihydro-8-(4-formamidophenyl)-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrate, m.p. >300° C. Analysis: Calculated for C21H18N2O4.1/3H2O: %C, 68.5; %H, 5.1; %N, 7.6; Found: %C, 68.8; %H, 5.2; %N, 7.6. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([C:11]1[N:12](S(C)(=O)=O)[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([C:20]#[N:21])=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:14]=2)([OH:10])[CH3:9])(C)(C)C.[OH-].[Na+].Cl>CO.O>[OH:10][C:8]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([C:20]#[N:21])=[C:15]([C:22]([F:25])([F:23])[F:24])[CH:14]=2)([CH3:9])[CH2:7][OH:6]
Reactant: CC(O)(CO[Si](C)(C)C(C)(C)C)c1cc2cc(C#N)c(C(F)(F)F)cc2n1S(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(O)(CO)c1cc2cc(C#N)c(C(F)(F)F)cc2[nH]1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-[2-(tert-butyl-dimethyl-silanyloxy)-1-hydroxy-1-methyl-ethyl]-1-methanesulfonyl-6-trifluoromethyl-1H-indole-5-carbonitrile (9.22 g, 0.01935 mole) in methanol (150 mL), a solution of NaOH (4.64 g 0.1161 mole) in water (25 mL) was added. The resulting mixture was heated in an oil-bath at 50° C. for 4 hr and then stirred at room temperature overnight. To the reaction mixture was then added 1 N HCl until the pH was 3. The aqueous mixture was extracted with EtOAc, the organic layer was washed with water, brine, then dried over MgSO4. The solvent was stripped off, the residue was triturated with DCM, and the resulting solid collected by filtration to yield the title compound as a light grey solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[CH:10][C:9]2[C:5](=[CH:6][C:7](=[O:12])[N:8]=2)[CH:4]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[C:15]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:11][CH:10]=2)[CH2:6][C:7]1=[O:12])(=[O:17])[CH3:16]
Reactant: O=C1C=c2cc(C(F)(F)F)ccc2=N1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CC(=O)N1C(=O)Cc2cc(C(F)(F)F)ccc21
Temperature: 25 °C

Procedure:
2.0 g of 5-trifluoromethyloxoindole were dissolved in 25 ml of xylene, 2.41 ml of acetic anhydride were added and the mixture was heated to boiling under reflux for 5 hours. The reaction solution was cooled to room temperature and diluted with 150 ml of ethyl acetate, and washed with 80 ml each of water, saturated sodium bicarbonate solution and saturated NaCl solution. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified on silica gel with the eluent n-heptane=>n-heptane/ethyl acetate=3:1. This gave 1.74 g of 1-acetyl-5-trifluoromethyl-1,3-dihydroindol-2-one as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][C:44]([OH:46])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][C:44](=[O:46])[NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: Nc1ccccc1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCC(=O)Nc4ccccc4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 0.10 g of (2R,4R,5R)-2-(2-carboxy-ethyl)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (from example 19b) and aniline are reacted to afford the title compound as a colourless oil. Rf=0.50 (dichlormethane-methanol 10:1); Rt=5.40.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1/[C:14](/[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[CH3:27])=[CH:15]\[CH2:16][C:17]([OH:19])=[O:18].[CH3:28][C:29]([NH2:32])([CH3:31])[CH3:30]>C1COCC1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1/[C:14](/[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[CH3:27])=[CH:15]\[CH2:16][C:17]([O-:19])=[O:18].[CH3:28][C:29]([NH3+:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)N
Reactant: Cc1cc(Cl)ccc1/C(=C/CC(=O)O)c1c(-c2ccccn2)nn(C)c1Cl
Solvent: C1CCOC1
Product: CC(C)(C)[NH3+]
Product: Cc1cc(Cl)ccc1/C(=C/CC(=O)[O-])c1c(-c2ccccn2)nn(C)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of (Z)-methyl 4-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(4-chloro-2-methylphenyl)but-3-enoate (13.34 g, 32.0 mmol) in dioxane (150 mL) was added 2 N aqueous NaOH (32 mL, 64 mmol). The mixture was stirred at rt for about 16 h then partitioned between EtOAc (300 mL) and 10% citric acid (200 mL). The layers were separated and the aqueous layer was extracted with EtOAc (300 mL). The combined organic layers were washed with water (300 mL) followed by brine (300 mL) then concentrated in vacuo. The residue was triturated in Et2O to give (Z)-4-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(4-chloro-2-methylphenyl)but-3-enoic acid (12.31 g, 95%) as an off-white solid: LC-MS (Table 1, Method g) Rt=2.20 min, m/z 402/404 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 12.18 (s, 1H), 8.42-8.39 (m, 1H), 7.80-7.68 (m, 2H), 7.26-7.19 (m, 1H), 7.16 (d, J=2.2 Hz, 1H), 7.08-7.04 (m, 1H), 7.01-6.97 (m, 1H), 5.91 (t, J=7.2 Hz, 1H), 3.92 (s, 3H), 2.95 (s, 2H), 2.34 (s, 3H). To a suspension of (Z)-4-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(4-chloro-2-methylphenyl)but-3-enoic acid (12.31 g, 30.6 mmol) in THF (50 mL) was added 2-methylpropan-2-amine (6.46 mL, 61.2 mmol). The mixture was stirred at rt for about 10 min then concentrated in vacuo to give 2-methylpropan-2-aminium (Z)-4-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(4-chloro-2-methylphenyl)but-3-enoate (14.40 g, 95%): LC-MS (Table 1, Method g) Rt=2.20 min, m/z 402/404 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 8.41-8.38 (m, 1H), 7.78-7.67 (m, 2H), 7.24-7.17 (m, 1H), 7.13 (d, J=2.1 Hz, 1H), 7.05-7.01 (m, 1H), 6.99-6.96 (m, 1H), 6.01 (t, J=7.1 Hz, 1H), 3.91 (s, 3H), 2.81-2.59 (m, 2H), 2.32 (s, 3H), 1.16 (s, 9H).
Reaction SMILES: [C:1]([O:4][CH:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:8]=2[N:7]2[N:23]=[C:24]([C:26]([NH2:28])=[O:27])[N:25]=[C:6]12)(=O)C>S(=O)(=O)(O)O.CO>[Cl:22][C:19]1[CH:20]=[CH:21][C:8]2[N:7]3[N:23]=[C:24]([C:26]([NH2:28])=[O:27])[N:25]=[C:6]3[CH:5]([O:4][CH3:1])[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:9]=2[CH:18]=1
Reactant: CC(=O)OC1N=C(c2ccccc2)c2cc(Cl)ccc2-n2nc(C(N)=O)nc21
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC1N=C(c2ccccc2)c2cc(Cl)ccc2-n2nc(C(N)=O)nc21

Procedure:
To a solution of 0.396 g. of 4-acetoxy-8-chloro-6-phenyl-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide in 10 ml. of methanol are added two drops of concentrated sulfuric acid, and the mixture was refluxed for 5 minutes, followed by evaporation of methanol. The residue is neutralized with saturated aqueous sodium bicarbonate solution and the precipitated crystals are collected by filtration, washed with water and dried to obtain 8-chloro-4-methoxy-6-phenyl-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide as crystals. Recrystallization from a mixture of chloroform and methanol yields colorless prisms (1/3 hydrate) melting at 264° to 267° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#N.[CH2:11]([Mg]Br)[CH3:12].Cl.C([O:18]CC)C>>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:18])[CH2:11][CH3:12])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: CC[Mg]Br
Reactant: N#Cc1cc(F)cc(F)c1
Reactant: CCOCC
Agent: Cl
Product: CCC(=O)c1cc(F)cc(F)c1
Yield: 91 %

Procedure:
To a solution of 3,5-difluorobenzonitrile (Aldrich Chemical Co . Milwaukee. WI 53233)(50.0 g. 0.36 mole) in 500 mL of diethyl ether at 0° C. was added dropwise a solution of ethylmagnesium bromide (135 mL of a 3.OM solution 0.41 mole) in diethyl ether. The reaction mixture was refluxed for 3 hr. then chilled in an ice bath and hydrolyzed with 100 mL of 6N aqueous hydrogen chloride. The mixture was heated on a steam bath for 0.5 hr. The pH was adjusted to acid (litmus) and two phases were separated by extraction of the aqueous phase with diethyl ether. The combined extracts were dried (sodium sulfate) and concentrated in vacuo to give 61.3 g (91% of theory) of crude 3',5'-difluoropropiophenone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:24]=4[O:23][CH3:22])[CH2:29]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1OC)CCNC2
Reactant: Cc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3ccc(C)cc3)nc3ccccc13)C2
Yield: 17 %

Procedure:
Reaction of 2-(4-methylphenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 14 (17% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.41 (s, 3H), 2.73 and 2.98 (2t, 2H), 3.48 and 4.03 (2t, 2H), 3.69 and 3.75 (2s, 3H), 3.76 and 3.82 (2s, 3H), 4.41 and 4.93 (2s, 2H), 6.62 and 7.01 (2d, 1H), 6.80 and 7.08 (2d, 1H), 7.37-7.41 (m, 2H), 7.67-7.77 (m, 1H), 7.86-7.98 (2d, 1H), 8.04-8.16 (m, 2H), 8.40-8.43 (m, 2H); MS (ESI) m/z 440 ([M+H]+).
Reaction SMILES: [CH2:1]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([O-])=[O:16])[N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNc1nc(C(=O)[O-])cs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCNc1nc(CO)cs1

Procedure:
The reaction described in preparabion 15 was repeated, but using 1.5 g of 2-octylaminothiazol-4-carboxylate, 0.2 g of lithium aluminum hydride and 30 ml of tetrahydrofuran, giving the title compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])[C:9]2[C:8]3[CH:24]=[CH:25][CH:26]=[CH:27][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.O.[NH2:29][NH2:30]>ClCCl>[CH3:23][O:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[CH2:13][N:10]1[C:9]2[C:8]3[CH:24]=[CH:25][CH:26]=[CH:27][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=[C:2]([NH:29][NH2:30])[C:11]1=[O:12]
Reactant: NN
Reactant: COc1ccc(Cn2c(=O)c(Cl)nc3ccc4ccccc4c32)c(OC)c1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cn2c(=O)c(NN)nc3ccc4ccccc4c32)c(OC)c1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A mixture of 3-chloro-1-(2,4-dimethoxybenzyl)benzo[f]quinoxalin-2(1H)-one (900 mg, 2.4 mmol) and hydrazine hydrate (250 μl, 5.1 mmol) in dichloromethane (70 ml) was stirred at room temperature. After 48 h the mixture was evaporated to dryness. The residue was triturated with ice/water, filtered and dried in vacuo to give 800 mg (85%) of the title compound. M.p. 182°-183° C., 1H-NMR (CDCl3): δ 3.80 (s, 3H), 3.85 (s, 3H), 4,15 (br. s, 2H), 5.58 (s, 2H), 6.45 (dd, 1H), 6.58 (d, 1H), 7.05 (d, 1H), 7.40 (m, 3H), 7.70 (s, 2H), 7.85 (dd, 1H), 8.10 (d, 1H).