Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1)[NH2:5].C(N(CC)CC)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:23](=[O:24])[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(F)cc(-c2cccnc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cc(F)cc(-c2cccnc2)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
3-Fluoro-5-(pyrid-3-yl)aniline (1.05 g, 0.0050 mole) in dry dichloromethane was treated under argon with triethylamine (1.12 ml, 0.0080 mole) followed dropwise by phenyl chloroformate (0.97 ml, 0.0077 mole) and stirred at ambient temperature for 18 hours. The reaction mixture was washed (x2) with deionised water, dried (Na2SO4) and evaporated in vacuo to afford the title compound (1.1 g, 71%) as an off white solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29]O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:50]C(Cl)(Cl)C(C(Cl)(Cl)Cl)=O>C(Cl)Cl>[Cl:50][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCCOCCOCCOCCO)(c1ccccc1)c1ccccc1
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCOCCOCCOCCCl)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 98.4 %

Procedure:
Compound 10 (813 mg, 1.88 mmol) and triphenylphosphine (995 mg, 3.76 mmol) were dissolved in CH2Cl2, and then at −78° C., hexachloroacetone (0.57 mL, 3.76 mmol) was added dropwise to the solution. The reaction temperature was raised to 0° C., and the progress of the reaction was monitored by TLC which indicated that it was over in 40 min Solvent was removed at room temperature and the crude product was chromatographed (SiO2, gradient, hexane/EtOAc 10:1 to 8:1) to give 834 mg (1.85 mmol, 98%) of 36 as a clear colorless oil. Rf 0.89 (hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCl3) 7.68 (m, 4H, H-2 of phenyl), 7.45-7.35 (m, 6H, H-3 and H-4 of phenyl), 3.81 (t, 2H, J=5.4 Hz, CH2CH2OSi), 3.74 (t, 2H, J=6.0 Hz, CH2CH2Cl), 3.67-3.59 (m, 12H, ClCH2CH2(OCH2CH2)2OCH2CH2OSi), 1.05 (s, 9H, C(CH3)3); MS (ESI) Calcd for C24H35ClO4SiNa (M+Na+): 473.2. Found: 473.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[O:20]1[C:25]2[CH:26]=[CH:27][C:28]([NH2:30])=[CH:29][C:24]=2[O:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCO>[O:20]1[C:25]2[CH:26]=[CH:27][C:28]([NH:30][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:18]#[N:19])=[CH:29][C:24]=2[O:23][CH2:22][CH2:21]1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: Nc1ccc2c(c1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4c(c3)OCCO4)c2cc1OCC
Temperature: 100 °C
Yield: 93 %

Procedure:
A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 232 mg (1.54 mM) of 1,4-Benzodioxane-6-amine in 15 ml of 2-methoxyethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80° C. to yield 526 mg of 4-(2,3-Dihydro-benzo[1,4]dioxin-6-ylamino)-6,7-diethoxy-quinoline-3-carbonitrile as a yellow solid: mass spectrum (electrospray, m/e): M+H 402.9, mp=225-227° C.
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:11][C:10]2=O.[CH2:29]([NH:31][CH3:32])[CH3:30]>>[CH2:29]([N:31]([CH3:32])[C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:28])[CH:8]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:11]=1)[CH3:30]
Reactant: CCNC
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(-c4ccccc4C)cc3c(=O)[nH]2)c1
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2ccc(-c3ccccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(o-tolyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-ethyl-N-methylamine in step E. MS (ESI/CI): predicted mass C22H21N5O2, 387.2.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[C:33]([O:36][CH2:37][C:38](Cl)=[O:39])(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:33]([O:36][CH2:37][C:38]([NH:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1)=[O:39])(=[O:35])[CH3:34]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 mmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, acetoxyacetyl chloride (37 mg, 262 mmol, 4 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (19.6 mg, 57% of theory).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[C:5]([C:7]2[C:8]([F:29])=[C:9]([N:14]([CH2:26][O:27][CH3:28])[S:15]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])(=[O:17])=[O:16])[CH:10]=[CH:11][C:12]=2[F:13])[N:6]=1.[CH:36]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>CC(N(C)C)=O>[CH:36]1([NH:42][C:2]2[S:3][C:4]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[C:5]([C:7]3[C:8]([F:29])=[C:9]([N:14]([CH2:26][O:27][CH3:28])[S:15]([C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=4[F:25])(=[O:17])=[O:16])[CH:10]=[CH:11][C:12]=3[F:13])[N:6]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COCN(c1ccc(F)c(-c2nc(Br)sc2-c2ccncc2)c1F)S(=O)(=O)c1cc(F)ccc1F
Reactant: NC1CCCCC1
Solvent: CC(=O)N(C)C
Product: COCN(c1ccc(F)c(-c2nc(NC3CCCCC3)sc2-c2ccncc2)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 110 °C
Reaction time: 16 h

Procedure:
N-{3-[2-bromo-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide (prepared as described in Example 3, 50 mg, 0.09 mmol) was dissolved in 3 mL of dimethylacetamide and 74 μL (0.85 mmol) of cyclohexylamine were added. The mixture was stirred at 110° C. for 16 h. The solvent was evaporated under reduced pressure and the residue was taken up with DCM and washed with brine. The organic layer was dried over Na2SO4 and evaporated, giving N-{3-[2-(cyclohexylamino)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide. The latter, without any further purification, was treated with 4 mL of TFA and 1 mL of water and stirred at 75° C. for 8 h. The solvent was then removed, the residue taken up with DCM and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated. The crude was purified by flash chromatography eluted with cyclohexane-ethanol 9/1, affording 20 mg (42%) of the title compound.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH:23]2[CH2:25][CH2:24]2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[C:31]([F:33])[CH:32]=1>>[CH:23]1([C:9]2[N:8]([CH2:7][C:5]3[O:6][C:2]([C:29]4[CH:28]=[C:27]([F:26])[CH:32]=[C:31]([F:33])[CH:30]=4)=[CH:3][CH:4]=3)[C:16]3[C:11]([CH:10]=2)=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:25][CH2:24]1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: N#Cc1ccc2c(cc(C3CC3)n2Cc2ccc(Br)o2)c1C(F)(F)F
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2ccc(-c3cc(F)cc(F)c3)o2)c1C(F)(F)F

Procedure:
Synthesizes as described in Example 310D using (1-[(5-bromo-2-furanyl)methyl]-2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 310C) and (3,5-difluorophenyl)boronic acid: MS (ES) m/z 443 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C(O)C>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[CH:12][NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:18]
Reactant: Nc1ccc(I)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(I)cc1)C(=O)OCC
Temperature: 90 °C
Reaction time: 10 h
Yield: 90490 %

Procedure:
A mixture of 4-iodoaniline (50 g, 0.23 mol) and diethyl ethoxymethylenemalonate (50.3 g, 0.23 mmol) was stirred at 90° C. for 10 hours. 150 mL of ethanol was added and the mixture was refluxed for 3 h. After cooling, the solid was collected, washed with hexane and dried over the oven to obtain 2-[(4-iodo-phenylamino)-methylene]-malonic acid diethyl ester (81 g, 91%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]1([CH3:21])[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1>>[CH3:21][C:12]1[CH:13]=[C:14]([C:2]2[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: COC(=O)c1cccc(Br)c1
Product: COC(=O)c1cccc(-c2cccc(C)c2)c1

Procedure:
Analogously to Example 1, by reaction of methyl 3-bromobenzoate with 3-tolylboronic acid, methyl 3′-methylbiphenyl-3-carboxylate is obtained. By bromination with NBS and reaction with methyl 3-hydroxybenzoate, methyl 3′-(3-methoxycarbonylphenoxymethyl)biphenyl-3-carboxylate is obtained therefrom. By reaction with guanidine hydrochloride in methanolic sodium methoxide solution, N-[3′-(3-guanidinocarbonylphenoxymethyl)biphenyl-3-carbonyl]-guanidine
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:27]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+].Cl.[CH3:31]O>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([OH:25])=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:27]=2)=[N:7][C:6]([CH3:31])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CO
Reactant: COC(=O)Cc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2cn3c(n2)-c2ccc(CC(=O)O)cc2OCC3)n(C(C)C)n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 98 mg (0.257 mmol) of methyl 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetate and 2.0 ml of 1.0 M of aqueous lithium hydroxide in 6 ml of methanol/tetrahydrofuram (1:1) mixture was stirred at 50° C. for 3 hours. The mixture was concentarted and acidified to pH 3 by careful addition of 1 N aqueous hydrogen chloride. The precipitate was collected and dried in high vacuum for 18 hours to give 2-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetic acid. Yield 58 mg. M/z 368.2, calc 367.16
Reaction SMILES: [OH-].[NH4+:2].[Cl:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](Cl)=[O:6]>>[Cl:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([NH2:2])=[O:6]
Reactant: [NH4+]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Agent: [OH-]
Product: NC(=O)C(Cl)c1ccccc1

Procedure:
To 150 ml. of concentrated ammonium hydroxide and 75 g. of ice was added 20 g. of 2-chloro-2-phenylacetylchloride. The amide formed immediately. The reaction mixture was stirred for 30 minutes and the white solid precipitate which was collected weighed 16.9 g. This precipitate was dissolved in 100 ml. of hot ethyl acetate and then diluted with petroleum ether, after which there was collected 14.3 g. of white cottony needles having an m.p. of 120°-121° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][C:5]2([CH3:15])[CH3:14].[CH2:16]([O:18][C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:20])[CH3:17]>N1C=CC=CC=1.O1CCCC1>[CH3:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:25]([C:24]3[CH:28]=[CH:29][C:21]([C:19]([O:18][CH2:16][CH3:17])=[O:20])=[CH:22][CH:23]=3)=[O:26])=[CH:11][CH:10]=2)[C:5]([CH3:15])([CH3:14])[CH2:6][C:7]1=[O:13]
Reactant: CCOC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CN1C(=O)CC(C)(C)c2cc(N)ccc21
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(=O)Nc2ccc3c(c2)C(C)(C)CC(=O)N3C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.7 %

Procedure:
37.2 g of 6-amino-3,4-dihydro-1,4,4-trimethyl-2(1H)-quinolinone were dissolved in 600 ml of pyridine and treated dropwise at room temperature with a solution of 43 g of 4-ethoxycarbonylbenzoyl chloride in 80 ml of tetrahydrofuran. After stirring at room temperature for 20 hours, the reaction mixture was poured on to ice-water, extracted several times with ethyl acetate, the organic phase was washed with cold 2N hydrochloric acid and water, dried and evaporated. Chromatography of the crude product (silica gel, eluent hexane/ethyl acetate 2:1, then ethyl acetate) and recrystallization from ethyl acetate/hexane, yielded 45.5 g of ethyl p-[(1,2,3,4-tetrahydro-1,4,4-trimethyl-2-oxo-6-quinolinyl)carbamoyl]-benzoate, m.p. 197°-199° C.
Reaction SMILES: [Si](O[CH2:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH:19]([O:22]C)OC)[C:13]1=[O:24])(C(C)(C)C)(C)C.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([O:32][C:33](=[O:47])[NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(#N)C>[OH:22][CH2:19][CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][N:12]([CH2:11][CH2:10][CH2:9][N:26]2[CH2:27][CH2:28][CH:29]([O:32][C:33](=[O:47])[NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:30][CH2:31]2)[C:13]1=[O:24]
Reactant: COC(CCN1CCN(CCCO[Si](C)(C)C(C)(C)C)C1=O)OC
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(CCCN2CCN(CCCO)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To crude 1-[3-(tert-butyldimethylsilanyloxy)propyl]-3-(3,3-dimethoxypropyl)imidazolidin-2-one (11.4 g, 32 mmol; prepared as described in Preparation 2) was added to a 1:1 mixture of 1N aqueous HCl (32 mL, 32 mmol, 1.0 eq) in ACN (32 mL). The reaction was allowed to stir at room temperature for 2 hours. To the reaction mixture was added biphenyl-2-ylcarbamic acid piperidin-4-yl ester (9.4 g, 32 mmol; prepared as described in Preparation 3) and was allowed to stir for 30 minutes, followed by the addition of NaBH(OAc)3 (20.3 g, 96 mmol). The reaction mixture was allowed to stir overnight. After overnight, the solution was concentrated in vacuo. The crude mixture was taken up in DCM (400 mL) and washed with 1N NaOH (200 mL), water (200 mL) and brine (200 mL). The organic phase was dried over MgSO4, filtered and concentrated then purified via silica gel chromatography (10% MeOH in DCM with 1% NH3(aq)) to afford the title compound (7.98 g, 16.6 mmol) in 52% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:6]=[CH:7][CH:8]=1)#[N:2].NN>[Pd].C(O)C>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([C:23]#[N:24])=[C:10]2[NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: N#Cc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: N#Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Yield: 98.1 %

Procedure:
Added 100 mg of 10% palladium on carbon to a round bottom flask under N2 and covered with 50 ml ethanol. Added 1.00 g (3.17 mmol) 4-[(3-cyanophenyl)amino]-6-nitro-3-quinolinecarbonitrile and 250 μl (7.39 mmol) anhydrous hydrazine and heated to reflux. Removed heat at 2 hours and filtered hot through celite. Stripped solvent and dried in vacuo, giving 887 mg of yellow solid: mass spectrum (electrospray m/e): M+H=286.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)[NH2:19])([CH3:15])[CH3:14]>>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([NH:19][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[N:4][C:5]=2[OH:11])[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)([CH3:12])[CH3:14]
Reactant: O=C(O)c1cc(Cl)cnc1O
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Product: CC(C)(C)c1cc(NC(=O)c2cc(Cl)cnc2O)cc(C(C)(C)C)c1
Yield: 59.1 %

Procedure:
Using 5-chloro-2-hydroxynicotinic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 24 gave the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH3:15][C:16]([O:19][C:20](=[O:23])[CH2:21]Br)([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:16]([O:19][C:20](=[O:23])[CH2:21][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)([CH3:18])([CH3:17])[CH3:15]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 g, 0.0077 mol) in DMF (25 mL) was added 2-bromoacetic acid 1,1-dimethylethyl ester (1.2 mL, 0.0085 mol) and cesium carbonate (3.8 g, 0.012 mol). The suspension was stirred at 90° C. overnight. The reaction mixture was cooled to RT and partitioned with ethyl acetate and water. The organic layer was washed with water, brine, and dried over MgSO4. The solution was concentrated to afford the desired compound (2.0 g, 84%). Analytical LC/MS: (M+H)+=309.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH2:27]([N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])[C:28]#[CH:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:29]#[C:28][CH2:27][N:30]3[C:34](=[O:35])[C:33]4[C:32](=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:31]3=[O:40])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: Fc1ccccc1C1=NCc2nnc(C(F)(F)F)n2-c2ccc(I)cc21
Reactant: C#CCN1C(=O)c2ccccc2C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CC#Cc1ccc2c(c1)C(c1ccccc1F)=NCc1nnc(C(F)(F)F)n1-2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 0.94 g (2 mmol) of 6-(2-fluorophenyl) 8-iodo-1-(trifluoromethyl)-4H-[1,2,4]triazolo [4,3-a][1,4]-benzodiazepine, 0.55 g (3 mmol) of N-propargylphthalimide 80 mg of triphenylphosphine, 20 mg of cuprous iodide, 0.6 ml of triethylamine and 50 ml of dimethylformamide was degassed with argon for 10 minutes. Palladium acetate, 25 mg. was then added and the mixture was stirred for 3 days at room temperature. The product was precipitated by dilution with sodium bicarbonate solution and was collected by filtration. It was dissolved in methylene chloride and the solution was washed with bicarbonate solution, dried and evaporated. The residue was chromatographed over 40 g of silica gel using 5% (v/v) of ethanol in methylene chloride. The combined good fractions were evaporated and the residue was crystallized from ethyl acetate to give colorless crystals of 2-{3-[6-(2-fluorophenyl)-1-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepin-8-yl]-2-ProPynyl}-1H-isoindole-1,3(2H)-dione with m.p. 204°-206° .
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]4)[C:12]=3[F:14])[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.[NH3:28]>CN(C)C=O>[NH2:28][C:9]1[C:10]([F:22])=[C:11]([N:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[C:12]([F:14])=[C:13]2[C:8]=1[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1
Reactant: N
Reactant: CN1CCN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1
Solvent: CN(C)C=O
Product: CN1CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1

Procedure:
In the same manner as described in Example 13, 1-cyclopropyl-5,6,8-trifluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was allowed to react with ammonia in dimethylformamide in a sealed tube to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 254°-255° C.
Reaction SMILES: [CH3:1][S-:2].[Na+].O1CCCC1.[CH:9]([O:12][N:13]=[C:14]([N:26]1[CH:30]=[N:29][CH:28]=[N:27]1)[C:15](=[N:21][O:22][CH:23]([CH3:25])[CH3:24])N1C=NC=N1)([CH3:11])[CH3:10]>O>[CH3:1][S:2][C:15](=[N:21][O:22][CH:23]([CH3:25])[CH3:24])[C:14]([N:26]1[CH:30]=[N:29][CH:28]=[N:27]1)=[N:13][O:12][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)ON=C(C(=NOC(C)C)n1cncn1)n1cncn1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSC(=NOC(C)C)C(=NOC(C)C)n1cncn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52 %

Procedure:
Sodium thiomethoxide was added to 5 ml of a tetrahydrofuran solution (which was under heating and refluxing) containing 0.35 g (1.14 mmol) of the 1,2-diisopropoxyimino-1,2-bis(1H-1,2,4-triazol-1-yl)ethane produced in Example 6, with confirming a reaction by thin-layer chromatography. Then, stirring was conducted for 5 hours. The reaction mixture was cooled to room temperature and poured into water, followed by extraction with ethyl acetate. The extract solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elutant:ethyl acetate/hexane=1/2) to obtain 0.17 g (yield: 52%) of a title compound.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:15][C:16]1[C:21]([I:22])=[C:20]([OH:23])[CH:19]=[CH:18][C:17]=1[C:24](=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[CH2:1]([O:15][C:16]1[C:21]([I:22])=[C:20]([O:23][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:19]=[CH:18][C:17]=1[C:24](=[O:29])[CH2:25][CH:26]([CH3:27])[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)CC(=O)c1ccc(O)c(I)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CC(=O)c1ccc(OCc2ccccc2)c(I)c1OCc1ccccc1
Yield: 95.9 %

Procedure:
Add benzyl bromide (17.63 g, 103.1 mmol, 12.3 mL) and cesium carbonate (30.53 g, 93.7 mmol) to a solution of 1-(2,4-dihydroxy-3-iodo-phenyl)-3-methyl-butan-1-one (15.00 g, 46.9 mmol) in anhydrous dimethylformamide (120 mL) at room temperature under Argon gas. Stir the reaction at room temperature overnight. Filter the mixture and concentrate the filtrate under reduced pressure to an oil. Partition the oil between ether and water. Separate the organic layer and extract the aqueous layer with ether (2×). Combine the organic layers, wash with brine, dry over sodium sulfate, filter and concentrate to provide a redish oil (22.5 g, 45 mmol, 96% yield). MS (m/z): 501 (M+1).