Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:6][C:5]=1C(=O)NCl.C(N(CC)CC)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C@@H:43]([NH2:45])[CH3:44])=[CH:39][CH:38]=1.CN1[C:51](=[O:52])CCC1>>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:12]2[CH:13]=[CH:14][C:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:16][CH:17]=2)[C:51]([NH:45][C@H:43]([C:40]2[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=2)[CH3:44])=[O:52])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CNc2ccc(C3CCCCC3)cc2)cc1C(=O)NCl
Reactant: C[C@H](N)c1ccc(Cl)cc1
Reactant: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CN(C(=O)N[C@@H](C)c2ccc(Cl)cc2)c2ccc(C3CCCCC3)cc2)cc1
Reaction time: 2 h

Procedure:
A 2 l reaction flask equipped with mechanical stirring was charged with N-chloro-carbamoyl-4-[(4-cyclohexylphenylamino)methyl]benzoic acid methyl ester (94 g, 0.244 mol), NMP (1.0 l) and triethylamine (68 ml, 0.487 mol). To the clear solution was added drop wise (S)-1-(4-chlorophenyl)ethylamine (38.0 g, 0.244 mol), keeping the internal reaction temperature below 30° C. Stirring was continued for 2 hours, then the reaction mixture was partitioned between water (1.0 l) and ethyl acetate (1.0 l). After extensive mixing, the organic layer was separated, and washed with a 5% aqueous solution of citric acid (500 ml), and saturated ammonium chloride (500 ml), before drying with anhydrous sodium sulfate. Solvent was removed, and the residual oil was evaporated once from acetonitrile. This product was sufficiently pure for further synthesis. Yield: 103 g (84%).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)C(C)C)(C)C.[C:14]([NH:18][C:19]([C:21]1[S:54][C:24]2[N:25]=[C:26]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36]([O:38]C4C=CC([N+]([O-])=O)=CC=4)=O)[CH:30]=3)[C:23]=2[C:22]=1[NH2:55])=[O:20])([CH3:17])([CH3:16])[CH3:15]>ClCCl>[C:14]([NH:18][C:19]([C:21]1[S:54][C:24]2[N:25]=[C:26]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36]([N:3]([CH3:4])[CH3:2])=[O:38])[CH:30]=3)[C:23]=2[C:22]=1[NH2:55])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CNC
Reactant: CC(C)(C)NC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(NC(=O)Oc4ccc([N+](=O)[O-])cc4)c3)c2c1N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)Nc1cccc(-c2nc(-c3ccccc3)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethyl amine hydrochloride (150 mg) was added to a solution of N,N-diisopropylethylamine (DIPEA, 0.50 ml) and tert-butyl 5-amino-2-phenyl-4-(3-(p-nitro-phenoxycarbonylamino)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 31(h), 250 mg) in dichloromethane (5 ml) and the reaction mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was diluted with CH2Cl2 and washed with H2O. The organic layer was concentrated under reduced pressure. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: H2O/CH3CN=80/20 to 0/100 (v/v) in 45 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH2:14][CH2:15][NH2:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH2:14][CH2:15][NH:16][C:25]3=[O:27])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: NCCNc1nc(-c2ccc(Br)cc2)cs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1NCCN1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 20.8 %

Procedure:
N-[4-(4-bromophenyl)-1,3-thiazol-2-yl]ethane-1,2-diamine (1.1 g, 3.7 mmol), prepared in the previous step, was dissolved in 30 mL methylene chloride and triethylamine (5.1 mL, 36.9 mmol) was added. The mixture was cooled to 0° C., triphosgene (2.7 g, 9.2 mmol) was added, and the mixture was stirred for 3 h. The mixture was diluted with ethyl acetate, washed with NaHCO3, water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (2% methanol/methylene chloride) afforded the title compound (250 mg, 21%) as a white solid; mp 230-233° C. HRMS: calcd for C12H10BrN3OS+H+, 323.98007; found (ESI, [M+H]+), 323.9808. Analytical HPLC: retention time 9.7 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40 C 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][C:9]1([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.Br[CH2:23][CH2:24][CH2:25][CH2:26][Cl:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:9]2([CH2:8][NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: Oc1ccc(C2(CNc3ccccn3)CCOCC2)cc1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCCOc1ccc(C2(CNc3ccccn3)CCOCC2)cc1
Yield: 63.3 %

Procedure:
4-{4-[(pyridin-2-ylamino)methyl]tetrahydro-2H-pyran-4-yl}phenol (220 mg, 0.775 mmol), 1-bromo-4-chlorobutane (146 mg, 0.852 mmol) and potassium carbonate (118 mg, 0.852 mmol) were stirred in DMF (1 ml) at 60° C. for 24 hours until complete. Reaction was partitioned between ethyl acetate (50 ml) and water (75 ml). The organic layer was separated and washed further with water (2×30 ml), then dried over sodium sulphate, filtered and concentrated in vacuo. The crude compound was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (100:0:0 to 98:2:0.2 by volume) to give the title compound (184 mg, 63%) as a yellow solid. LRMS APCI+ m/z 375 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.[C:10]([CH:12]1[CH2:14][NH:13]1)#[N:11].C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O>C(OCC)C.O1CCCC1>[CH3:1][C:2]1[S:3][C:4]([C:7]([N:13]2[CH2:14][CH:12]2[C:10]#[N:11])=[O:9])=[CH:5][N:6]=1
Reactant: Cc1ncc(C(=O)O)s1
Reactant: N#CC1CN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ncc(C(=O)N2CC2C#N)s1
Reaction time: 8 h

Procedure:
1.6 g. 2-Methylthiazole-5-carboxylic acid (m.p. 209° C.) and 0.76 g. 2-cyanoaziridine in 20 ml. tetrahydrofuran are mixed at 0° to 5° C. with 2.4 g. dicyclohexylcarbodiimide. The reaction mixture is stirred for 1 hour at 0° C. and for 3 hours at ambient temperature, whereafter the precipitated dicyclohexylurea is filtered off with suction and washed with the above-mentioned solvent and with diethyl ether. The filtrate is evaporated in a vacuum and the evaporation residue is taken up in ethyl acetate and shaken out with a saturated aqueous solution of sodium bicarbonate. The organic phase is dried and evaporated in a vacuum to give 2.38 g. of an oil. This oily residue is dissolved in 90 ml. diethyl ether, left to stand overnight, precipitated dicyclohexylurea is filtered off with suction, the ethereal solution is evaporated and the evaporation residue is triturated with a little diethyl ether, 1.4 g. 1-(2-methylthiazole-5-carbonyl)-2-cyanoaziridine being obtained; m.p. 90°- 92° C.
Reaction SMILES: [C:1]1([C@@H:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:26][CH2:27][C:28]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:30][N:29]=1>CCOC(C)=O.C(#N)C>[Cl-:26].[C:33]1([C:31]2[O:30][N:29]=[C:28]([CH2:27][N+:13]34[CH2:14][CH2:15][CH:16]([CH2:17][CH2:18]3)[C@@H:11]([O:10][C:8](=[O:9])[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:12]4)[N:32]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: ClCc1noc(-c2ccccc2)n1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(O[C@H]1C[N+]2(Cc3noc(-c4ccccc4)n3)CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.5 %

Procedure:
To a solution of (R)—((R)-quinuclidin-3-yl) 2-phenyl-2-(phenylamino)acetate (diastereomer 1 of I2) (100 mg, 0.30 mmol) in EtOAc (2 ml) and acetonitrile (0.99 ml) was added 3-(chloromethyl)-5-phenyl-1,2,4-oxadiazole (I45) (69.4 mg, 0.36 mmol). The pale yellow solution was stirred at room temperature for 24 hours. The suspension was filtered on a buckner funnel washing with EtOAc (5 ml). The white solid was recovered from the filter to obtain the title compound (98 mg, 62.1% yield).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[N:5]2[CH:4]=[C:3]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21]([O-])([O-])=O.[K+].[K+].CI>CN(C)C=O>[CH3:21][N:9]1[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[N:6]2[C:2](=[O:1])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][N:5]2[C:10]1=[O:11]
Reactant: CCOC(=O)c1cn2c(=O)[nH]c3ccccc3n2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(=O)n(C)c3ccccc3n2c1=O
Reaction time: 20 h

Procedure:
5.22 g 5,6-dihydro-1,5-dioxo-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester, made as in Example 1, 2.76 g K2CO3 and 50 mM CH3I are dissolved in 100 ml dimethylformamide and stirred for 20 hours. The crystalline 5,6-dihydro-6-methyl-1,5-dioxo-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester is isolated after filtration and recrystallized from dimethylformamide/ethanol. The yield is 4.7 g as white needles with a melting point of 243°-244° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.Cl.[CH3:7][CH:8]([NH2:21])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[CH:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[ClH:3].[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=[CH:14][C:9]([CH:8]([N:21]=[C:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:23][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:21]2)[CH3:7])=[CH:10][CH:11]=1
Reactant: CC(N)c1ccc(-c2ccccc2)cc1
Reactant: O=P(Cl)(Cl)Cl
Reactant: c1ccccc1
Agent: Cl
Product: CC(N=C1CCCCCCCCCCCN1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 5.0 g (25 m mole) of 2-azatridecanone in 100 ml of benzene is added dropwise 3.9 g (25 m mole) of phosphorous oxychloride and the mixture stirred at room temperature for a period of 4 hours. α-Methyl-p-phenylbenzylamine hydrochloride, 5.3 g (23 m mole), is added and stirred at room temperature for 1 hour and refluxed for an additional 4 hours. Hydrochloric acid, 2N, is added and the benzene layer separated, dried over sodium sulfate, and evaporated to dryness. The crude product is crystallized from acetone, M.P. 135°-142° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:26]2[NH:27][C:23](=[CH:24][CH:25]=2)[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[C:21]2[N:34]=[C:18]([CH:19]=[CH:20]2)[C:17]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[C:16]2[NH:41][C:13]([CH:14]=[CH:15]2)=[C:12]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[C:11]2=[N:48][C:8]=1[CH:9]=[CH:10]2.[C:49]12[CH:72]=C3N=C(C=C3)C=C3NC(C=C3)=CC3=NC(C=C3)=CC(N1)=C[CH:50]=2.CO.C(Cl)(Cl)Cl>C(Br)C=C>[CH2:7]([C:33]1[C:28]([C:22]2[C:23]3[NH:27][C:26](=[CH:25][CH:24]=3)[C:7]([C:2]3[C:3]([CH2:6][CH:5]=[CH2:4])=[CH:4][CH:5]=[CH:6][N:1]=3)=[C:8]3[N:48]=[C:11]([CH:10]=[CH:9]3)[C:12]([C:42]3[C:47]([CH2:72][CH:49]=[CH2:50])=[CH:46][CH:45]=[CH:44][N:43]=3)=[C:13]3[NH:41][C:16]([CH:15]=[CH:14]3)=[C:17]([C:35]3[C:40]([CH2:10][CH:9]=[CH2:8])=[CH:39][CH:38]=[CH:37][N:36]=3)[C:18]3=[N:34][C:21]=2[CH:20]=[CH:19]3)=[N:29][CH:30]=[CH:31][CH:32]=1)[CH:2]=[CH2:3]
Reactant: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3
Reactant: C1=Cc2nc1c(-c1ccccn1)c1ccc([nH]1)c(-c1ccccn1)c1nc(c(-c3ccccn3)c3ccc([nH]3)c2-c2ccccn2)C=C1
Solvent: ClC(Cl)Cl
Solvent: C=CCBr
Solvent: CO
Product: C=CCc1cccnc1-c1c2nc(c(-c3ncccc3CC=C)c3ccc([nH]3)c(-c3ncccc3CC=C)c3nc(c(-c4ncccc4CC=C)c4ccc1[nH]4)C=C3)C=C2
Temperature: 100 °C
Yield: 78 %

Procedure:
In an oven-dried flask under argon, 100 mg tetrakis(2-pyridyl)porphyrin (2-PyP) was dissolved in 5 mL allyl bromide, and reaction was heated at 100° C. for 16 hours. The reaction mixture was heated at 100° C. for 8 hours. Two methods were used to monitor the completion of the reaction. First, the shift of the porphyrin Soret band from λmax=412 nm (methanol) to λmax=418 nm (methanol) was monitored. A second method involved partition of an aliquot of the reaction mixture between H2O and CHCl3 whereby a complete reaction showed no color in the CHCl3 layer. Upon completion of the reaction, the allyl bromide was distilled off under high vacuum, and the residue was triturated with ethyl ether (Et2O). Chromatography was performed on Sephadex LH-20 (column dimensions were 2×20 cm) using methanol as the eluent and fractions that showed porphyrin with λmax=418 nm were retained. Compound VIII was produced as a shiny purple solid, in 78% yield. Absorbance data included the following: UV-vis: λmax (nm) (log10εo) 418(5.29) 512 (4.50) 587(4.32). Electrospray mass spectrometry (ES-MS) showed a molecular ion at 782 (M-4 Br).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[O:28])[CH:6]([NH:15][C:16]([CH3:27])=[CH:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Br:29][CH2:30][CH2:31]Br>C(O)C>[CH3:3][O:4][C:5](=[O:28])[CH:6]([NH:15][C:16]([CH3:27])=[CH:17][C:18](=[O:26])[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:31][CH2:30][Br:29])=[CH:12][CH:13]=1
Reactant: BrCCBr
Reactant: COC(=O)C(Cc1ccc(O)cc1)NC(C)=CC(=O)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C(Cc1ccc(OCCBr)cc1)NC(C)=CC(=O)c1ccc(F)cc1
Yield: 27 %

Procedure:
To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) is added 2-[1-methyl-3-oxo-3-(4-fluorophenyl)-propenylamino]-3-(4-hydroxyphenyl)-propionic acid methyl ester (1.05 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). Then the mixture is heated to reflux for 8 hours. After cooled, the reaction mixture is filtered to remove the solid formed, and then the filtrate is evaporated under a vacuum. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (0.37 g, 27%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[CH3:17])[NH2:13]>CO.O>[NH2:9][C:10]1[CH:11]=[C:12]([NH:13][C:2]2[N:7]=[C:6]([NH:13][C:12]3[CH:14]=[CH:15][C:16]([CH3:17])=[C:10]([NH2:9])[CH:11]=3)[CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:15][C:16]=1[CH3:17]
Reactant: Cc1ccc(N)cc1N
Reactant: Clc1ccnc(Cl)n1
Solvent: O
Solvent: CO
Product: Cc1ccc(Nc2ccnc(Nc3ccc(C)c(N)c3)n2)cc1N
Temperature: 70 °C

Procedure:
2,4-Dichloropyrimidine (45 mg, 0.30 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 3-amino-4-methylaniline (146 mg, 1.2 mmol) was added and the mixture was refluxed for 20 hours (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3—Acetone, 2:1) to give N2,N4-bis(3-amino-4-methylphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.13 (s, 1H), 6.95 (d, 2H, J=7.5 Hz), 6.82 (d, 2H, J=1.8 Hz), 6.60 (dd, 2H, J=1.8, 7.5 Hz), 6.17 (s, 1H), 2.12 (s, 6H); LCMS purity: 97.3%; MS (m/e): 321.09 (M+, 100).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[C:18]([F:26])[C:19]([F:25])=[C:20](F)[C:21]=3[F:23])[C:16](=[O:27])[C:15]([C:28]([OH:30])=[O:29])=[CH:14]2)[C:10]([F:31])=[CH:9][C:8]=1[F:32].Cl.Cl.[NH2:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:35][CH:36]1[CH2:39][N:38]([C:20]2[C:21]([F:23])=[C:22]3[C:17]([C:16](=[O:27])[C:15]([C:28]([OH:30])=[O:29])=[CH:14][N:13]3[C:11]3[C:10]([F:31])=[CH:9][C:8]([F:32])=[C:7]([NH2:6])[N:12]=3)=[C:18]([F:26])[C:19]=2[F:25])[CH2:37]1
Reactant: NC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(F)c(F)c(F)c(F)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(F)c(F)c(N4CC(N)C4)c(F)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To 300 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino-3,5-difluoropyridine-2-yl)-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 30 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 50 mg of the title compound as a pale yellow powder.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](O)=O)[CH:10]=2)[NH:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:54]([O:56][C:57](=[O:72])[C:58]1[CH:63]=[CH:62][C:61]([NH:64][CH:65]2[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]2)=[C:60]([NH2:71])[CH:59]=1)[CH3:55]>CN(C=O)C>[CH2:54]([O:56][C:57]([C:58]1[CH:63]=[CH:62][C:61]2[N:64]([CH:65]3[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70]3)[C:12]([C:9]3[CH:10]=[C:11]4[C:6](=[CH:7][CH:8]=3)[NH:5][C:4]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:3][C:2]4=[O:1])=[N:71][C:60]=2[CH:59]=1)=[O:72])[CH3:55]
Reactant: O=C(O)c1ccc2[nH]c(-c3ccccc3)cc(=O)c2c1
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3[nH]c(-c4ccccc4)cc(=O)c3c1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 800.1 %

Procedure:
4-Oxo-2-phenyl-1,4-dihydro-quinoline-6-carboxylic acid (2.78 g, 1.05 mmol) was dissolved in DMF (50 mL), and HATU (1.1 eq.) and diisopropyl ethylamine (2.2 eq, 402 μL) were added. After stirring at room temperature for 15 minutes, 3-amino-4-cyclohexylamino-benzoic acid ethyl ester (2.89 g, 1.1 eq.) dissolved in 20 mL DMF was added. After stirring overnight, the reaction was evaporated, dissolved in ethyl acetate and washed with water and brine, dried with sodium sulfate, evaporated and dried overnight. The product was then refluxed in acetic acid for 4 hr, evaporated to dryness, and coevaporated 2 more times with toluene. The product was recrystallized from methanol to give 4.13 g of product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:15]([NH2:18])(=[S:17])[CH3:16]>>[CH3:1][O:2][C:3]([C:4]1[N:18]=[C:15]([CH3:16])[S:17][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:14]
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccccc1

Procedure:
prepared by reaction of 3-Chloro-2-oxo-3-phenyl-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.89 min; [M+H]+=234.0.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]2[N:14]3[CH2:15][CH2:16][C@@H:11]([C@@H:12]([C:17](O)=[O:18])[CH2:13]3)[C:10]2=[O:20])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([N:29](CC)[CH2:30]C)C.ClC(OCC)=O.N>C1COCC1.O>[CH3:27][N:29]([CH3:30])[C:17]([C@@H:12]1[C@@H:11]2[CH2:16][CH2:15][N:14]([CH:9]([CH:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:10]2=[O:20])[CH2:13]1)=[O:18]
Reactant: O=C(O)[C@H]1CN2CC[C@@H]1C(=O)C2C(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)[C@H]1CN2CC[C@@H]1C(=O)C2C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A suspension of 46 (1.1 g, 3.3 mmol) in THF (10 ml) was treated with triethylamine (0.66 g, 6.6 mmol) at room temperature. To this suspension was added ethyl chloroformate (0.36 g, 3.3 mmol) at 0° C. After 30 minutes, NH3 aq (0.67 g, 6.7 mmol) was added at 0° C. The mixture was stirred at room temperature for 1 hour, poured into H2O and extracted with EtOAc three times. The combined extracts were dried over Na2SO4 and concentrated to give 48 (1.2 g, 3.0 mmol, 90%; 4:1 mixture of isomers at 3-position). This was used without further purification.
Reaction SMILES: ClC1N=C(Cl)C(C(C)C)=C(O[C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)N=1.[C:21]([O-:29])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na+].[CH3:31]N(C=O)C>>[CH3:20][C:15]1[CH:16]=[C:17]([CH:18]=[C:13]([CH3:31])[CH:14]=1)[CH2:19][O:28][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C([O-])c1ccccc1
Reactant: Cc1cc(C)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Reactant: CN(C)C=O
Agent: [Na+]
Product: Cc1cc(C)cc(COC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A mixture of 3,5-dimethylbenzyl bromide (2, 39.8, 0.2M) and sodium benzoate (34.56 g, 0.24M) in anhydrous DMF (400 ml) was stirred at room temperature for overnight. The mixture was then partitioned between ether and water. The organic layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a pale yellow oil. The crude product was purified by silica gel column chromatography (eluent, hexane) to afford 32 g (71%) of a colorless oil. 1H NMR (200 MHz, CDCl3) δ 2.33 (6H, s), 5.29 (2H, s), 6.98 (1H, s), 7.05 (2H, s), 7.38-7.59 (3H, m), 8.05-8.11 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1)=[O:6].[CH3:20][N:21]1[C:25]([CH:26]=O)=[CH:24][CH:23]([CH3:28])[NH:22]1.C([BH3-])#N.[Na+].C1COCC1>O.C(O)(=O)C>[CH3:20][N:21]1[C:25]([CH2:26][NH:1][C:2]2[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=2)[C:5]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)=[O:6])=[CH:24][C:23]([CH3:28])=[N:22]1
Reactant: CC1C=C(C=O)N(C)N1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(CNc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)n(C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A dry round bottom flask was charged with 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.300 g, 1.19 mmol), 1,3-Dimethyl-2H-pyrazole-5-carbaldehyde (0.191 g, 1.91 mmol) and acetic acid (0.3 mL). The mixture was allowed to stir for 4 h at room temperature. A 1M solution of sodium cyanoborohydride in THF (3.57 mL, 3.57 mmol) was then added and the mixture was allowed to stir for 45 minutes. The reaction mixture was poured into H2O (100 mL) and allowed to stir for 15 minutes. The resulting suspension was vacuum filtered and the filtrate was extracted with EtOAc (3×˜100 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford a yellow oil. The yellow oil was then chromatographed over silica which had been previously neutralized by flushing the column with the purification eluant (97/3, chloroform/methanol w/0.5% NEt3) several times. This chromatographic purification resulted in the isolation of pure 6-{3-[(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-amino]-benzoyl}-1,3-dihydro-indol-2-one in 30% yield (0.128 g, 0.357 mmol).