Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[O:3][C:4]([C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[C:17]([NH2:19])=[O:18])=[O:7])=[O:5].[OH-].[Na+]>O>[CH3:16][O:15][C:11]1[C:10]([C:17]([NH2:19])=[O:18])=[C:9]([NH:8][C:6]([C:4]([OH:5])=[O:3])=[O:7])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=O)Nc1cccc(OC)c1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(NC(=O)C(=O)O)c1C(N)=O
Yield: 59.6 %

Procedure:
2'-Carbamoyl-3'-methoxyoxanilic acid ethyl ester (1.33 g, 0.005 mole) is stirred in 50 ml water, and 5.0 ml of N NaOH is slowly added, giving a solution. After 1/2 hour the solution is filtered, and the filtrate is acidified to pH 2 with N HCl, giving 0.71 g of the title compound, m.p. 214°-215° C., after crystallization from ethanol.
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]=[CH:9][C:8]2[N:7]=[C:6]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=3)[C:5]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:4][C:3]1=2.[H-].[Na+].CI.[C:30](O)(=O)C>CN(C=O)C.C(OCC)(=O)C>[CH3:30][N:11]1[CH:10]=[CH:9][C:8]2[N:7]=[C:6]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=3)[C:5]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:4][C:3]=2[C:2]1=[O:1]
Reactant: O=Cc1ccc(-c2nc3cc[nH]c(=O)c3cc2-c2ccccc2)cc1
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ccc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzaldehyde (186 mg, 0.57 mmol) in dry DMF (2 mL) was added 60% sodium hydride in mineral oil (29 mg, 0.72 mmol). The reaction was stirred at room temperature for 15 minutes and then methyl iodide was added via syringe (40 μL, 0.70 mmol). After 30 minutes the reaction was diluted with ethyl acetate and some acetic acid was added to neutralize the base. The solution was washed with aqueous NaHCO3 and the organic layer was dried (anhydrous Na2SO4), filtered and the solvent evaporated. The residue was triturated with diethyl ether to give the title compound as a pale yellow solid. The mother liquors were chromatographed on silica gel eluting with a 30-70% ethyl acetate/hexane gradient to give additional product. 1H-NMR (500 MHz, CDCl3): δ 10.02 (1H, s), 8.74 (1H, s), 7.80 (2H, d, J=8 Hz), 7.60 (2H, d, J=8 Hz), 7.37 (1H, d, J=7.6 Hz), 7.28-7.31 (2H, m), 7.19-7.22 (2H, m), 6.85 (1H, d, J=7.6 Hz), 3.67 (3H, s). m/e (m+1): 341.1.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2([C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14])[CH2:11][O:10]2)=[CH:3][CH:2]=1.[Na].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>C(O)CC>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]([OH:10])([CH2:11][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[C:12]([CH3:15])([CH3:16])[CH:13]=[CH2:14])=[CH:3][CH:2]=1
Reactant: c1c[nH]cn1
Reactant: C=CC(C)(C)C1(COc2ccc(-c3ccccc3)cc2)CO1
Agent: [Na]
Solvent: CCCO
Product: C=CC(C)(C)C(O)(COc1ccc(-c2ccccc2)cc1)Cn1ccnc1
Yield: 62.5 %

Procedure:
35.3 g (0.120 mol) of 2-(biphenyl-4-yloxymethyl)-2-(3,3-dimethylprop-1-en-3-yl)-oxirane, dissolved in 80 ml of n-propanol, were added to a boiling solution of 1 g (0.012 mol) of sodium propylate and 9 g (0.132 mol) of imidazole in 50 ml of n-propanol, in the course of 5 minutes. After the solution had been boiled under reflux for two days, the solvent was distilled off under reduced pressure, the residue was taken up in a mixture of 150 ml of ethyl acetate and 100 ml of dichloromethane, and the solution was washed with three times 50 ml of water. After the organic phase had been dried over anhydrous sodium sulphate, the solution was concentrated to dryness under reduced pressure. 10 ml of ethyl acetate were added to the solid residue, and the product was filtered off. 27.2 g (62.5% of theory) of 4-(biphenyl-4-yloxymethyl)-3,3-dimethyl-4-hydroxy-5-(imidazol-1-yl)pent-1-ene were obtained in the form of colorless crystals of melting point 151° to 153° C. in this manner.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]=O.[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][CH2:20][NH2:21].[Na]>ClCCl>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][NH:21][CH2:20][CH2:19][CH:15]1[CH2:16][CH2:17][CH2:18][N:14]1[CH3:13]
Reactant: CN1CCCC1CCN
Reactant: Cn1c(C=O)nc2ccccc21
Agent: [Na]
Solvent: ClCCl
Product: CN1CCCC1CCNCc1nc2ccccc2n1C

Procedure:
Experimental condition analogous to Example 5, from 1-methyl-1H-benzoimidazol-2-carbaldehyde 0.2 g (1.25 mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethylamine 0.18 g (1.38 mmol), and sodium triacethoxyborohydride 0.39 g (1.87 mmol), in 10 mL dichloromethane. After work-up the material was used as a crude.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH2:29][N:30]3[C:34]4[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=4[N:32]([CH3:41])[C:31]3=[O:42])[CH2:25][CH2:24]2)=[O:22])[CH2:17][CH2:16]1)=O)(C)(C)C.O>C(Cl)Cl>[CH3:40][O:39][C:36]1[CH:37]=[CH:38][C:33]2[N:32]([CH3:41])[C:31](=[O:42])[N:30]([CH2:29][C@H:26]3[CH2:27][CH2:28][C@H:23]([C:21]([N:18]4[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]4)=[O:22])[CH2:24][CH2:25]3)[C:34]=2[CH:35]=1
Reactant: COc1ccc2c(c1)n(C[C@H]1CC[C@H](C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC1)c(=O)n2C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1)n(C[C@H]1CC[C@H](C(=O)N3CCNCC3)CC1)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoro acetic acid (8 ml) was added to a solution of trans-4-[4-(6-Methoxy-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-cyclohexanecarbonyl]-piperazine-1-carboxylic acid tert-butyl ester in DCM (19 ml). The solution was stirred at room temperature overnight and then 10 ml of water were added. The mixture was concentrated under reduced pressure and DCM (20 ml) were added. The organic solution was washed with a saturated solution of NaHCO3 (2×20 ml), dried over Na2SO4, filtered and the solvent evaporated to give the titled compound
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24](O)=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:7]=1[C:8]#[CH:9].C(N(CC)C(C)C)(C)C.Cl.[CH3:37][NH:38][O:39][CH3:40].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]([N:38]([O:39][CH3:40])[CH3:37])=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:7]=1[C:8]#[CH:9]
Reactant: C#Cc1c(Cl)cc(C(=O)O)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Reactant: CNOC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1c(Cl)cc(C(=O)N(C)OC)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 91.2 %

Procedure:
A solution of 4-chloro-6-[(1E)-3,3-diethyltriaz-l-en-l-yl]-5-ethynyl-3′-fluorobiphenyl-2-carboxylic acid (2.7 g, 7.1 mmol) in N,N-dimethylformamide (14 mL) was treated with N,N-diisopropylethylamine (4.3 mL, 25 mmol) followed by O-(benzotriazol-1-yl)-N,N,N,′N′-tetramethyluronium hexafluorophosphate (3.5 g, 9.3 mmol) and stirred at 20° C. for 5 minutes. The reaction mixture was treated with N,O-dimethylhydroxylamine hydrochloride (0.9 g, 9.3 mmol) and stirred at 20° C. for 1 hour. The reaction mixture was poured into 0.5 M hydrogen chloride in water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was washed with saturated sodium bicarbonate (50 mL), brine (25 mL), dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (0%-40%) gave the desired product (2.7 g, 92% for 2 steps). LCMS for C21H23ClFN4O2 (M+H)+: m/z=417.1; Found: 417.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([NH2:41])[CH2:40][CH2:39]1>>[CH:38]1([NH:41][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:40][CH2:39]1
Reactant: NC1CC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NC3CC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and cyclopropylamine according to conditions described in general procedure C. Mp: 118-120° C.; 1H NMR (400 MHz, CDCl3) δ 0.42-0.49(m, 2 H), 0.70(d, J=5.6 Hz, 2 H), 2.65(s, 1 H), 3.25(t, J=4.0 Hz, 4 H), 3.86(t, J=4.8 Hz, 4H), 5.25(s, 1 H), 6.15(d, J=4.8 Hz, 1 H), 6.78(d, J=11.6 Hz, 1 H), 7.06(d, J=8.4 Hz, 2 H), 7.26-7.31(m, 2 H), 7.49-7.57(m, 2 H), 7.89(d, J=8.0 Hz, 1H), 7.96(d, J=8.0 Hz, 1 H), 8.15(s, 1 H), 8.20(d, J=4.4 Hz, 1 H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=4[CH3:35])[CH2:24][CH2:23]3)[CH:17]=1)[CH2:10][C:9]2([CH3:37])[CH3:36])=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:35][C:29]1[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=1[N:25]1[CH2:26][CH2:27][N:22]([C:18]2[CH:17]=[C:16]([CH:11]3[CH2:10][C:9]([CH3:37])([CH3:36])[C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:21]=[CH:20][CH:19]=2)[CH2:23][CH2:24]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(N3CCN(c4ccc(C)cc4C)CC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(N2CCN(c3cccc(C4CC(C)(C)c5cc(C(=O)O)ccc5N4)c3)CC2)c(C)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 95.1 %

Procedure:
A mixture of 2-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.28 g, 0.56 mmol) in methanol (3 mL) and tetrahydrofuran (10 mL), 30% sodium hydroxide in water (1 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.25 g, 90%) as a white solid which was used for next step without further purification: MS (ESI) M+1=470.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH3:16]N(C(OC)OC)C.C(O)C.[C:27]1([NH:33][NH2:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:34]=[CH:16][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: NNc1ccccc1
Reactant: COC(OC)N(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnn(-c2ccccc2)c1-c1ccc(F)cc1
Yield: 85.8 %

Procedure:
A solution of ethyl 3-(4-fluorophenyl)-3-oxopropanoate (1.50 g, 7.14 mmol) and DMFDMA (1.15 mL, 8.56 mmol) in toluene (23 mL) was heated under reflux for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethanol (23 mL). To the ethanol solution was added phenylhydrazine (0.779 mL, 7.85 mmol) at room temperature, and the mixture was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent; 2% ethyl acetate/hexane) to give ethyl 5-(4-fluorophenyl)-1-phenyl-1H-pyrazole-4-carboxylate (1.90 g, 86%) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][C:23]([O:25]CC)=[O:24])[CH:19]=3)[CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][C:23]([OH:25])=[O:24])[CH:19]=3)[CH2:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 80 °C
Yield: 91.1 %

Procedure:
16.5 g of ethyl [2-[(4-chlorophenyl)sulfonylaminomethyl)indan-5-yl]acetate was suspended in 50 ml of 1N sodium hydroxide, and heated at 80° C. for 1 hour. After cooling, conc. HCl was added thereto to make the system acidic. The precipitates were collected by filtration, followed by recrystallization from 80% ethanol to obtain 14.0 g of colorless needles. Yield: 91%
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[CH3:20][N:21]([CH3:30])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.C([O-])(=O)C.[NH4+]>C(O)C>[CH3:20][N:21]([CH3:30])[C:22]1[CH:23]=[C:24]([C:25]2[NH:1][C:2]3=[N:3][CH:4]=[CH:5][C:6]([NH:9][C@@H:10]4[C@@H:15]5[CH2:16][C@@H:12]([CH:13]=[CH:14]5)[C@@H:11]4[C:17]([NH2:19])=[O:18])=[C:7]3[N:8]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CN(C)c1cccc(C=O)c1
Reactant: NC(=O)[C@@H]1[C@H](Nc2ccnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN(C)c1cccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)ccnc3[nH]2)c1
Yield: 37.3 %

Procedure:
(1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 3-dimethylamino-benzaldehyde (31.6 mg, 0.212 mmol) were combined with ammonium acetate (29.7 mg, 0.386 mmol) and heated in ethanol (2.5 mL) at 70° C. for 18 h. The reaction mixture was concentrated and chromatographed by reverse phase preparative HPLC. The desired fractions were neutralized with bicarb solution and extracted into EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. This residue was triturated in ethyl ether and filtered to yield 28 mg (37%) of the title compound. mp: 200-204° C., 1H NMR (300 MHz, DMSO-d6): 13.02 (s, 1H), 7.90 (d, 1H), 7.66 (s, 1H), 7.50 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.30 (t, J=8 Hz, 1H), 7.15 (s, 1H), 6.86 (m, 1H), 6.81 (d, J=8 Hz, 1H), 6.40 (d, J=5 Hz, 1H), 6.33 (s, 2H), 2.98 (s, 6H), 2.87 (s, 1H), 2.77 (s, 1H), 2.60 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.42 (d, J=8 Hz, 1H). HPLC: 1.63 min (G method), MS: 389 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH3:8])[N:6]=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:19]([C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH3:8])[N:6]=1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCc1csc(N)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1nc(CC)cs1)C(=O)OCC

Procedure:
2-Amino-4-ethylthiazole (20.5 g., 0.16 mole) and diethyl ethoxymethylenemalonate (35 g., 0.17 mole) were combined and heated on a steam bath for 2 hours. 2-(2,2-dicarbethoxyethenylamino)-4-ethylthiazole was obtained as an oil on cooling, and was used directly in the next step. (Rf 0.75 on silica gel thin layer chromatography with chloroform/1% ethanol as eluant.)
Reaction SMILES: [CH2:1]([CH:8]1[CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([CH:8]1[CH2:9][N:10]([C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CNC2)cc1
Reactant: O=C(Cl)CCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCc1ccccc1)N1CC(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.6 %

Procedure:
A solution of 3-benzylazetidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 4-phenylbutyryl chloride (456.6 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:5). The fractions containing 1-(3-benzylazetidin-1-yl)-4-phenylbutan-1-one are collected and the solvent is removed in vacuo to give 479 mg of colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:9]3[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=3)[NH2:12])[CH:7]=[N:8][C:4]=2[CH:3]=1.Cl[C:19](OC1C=CC([N+]([O-])=O)=CC=1)=[O:20].C(N(CC)CC)C.[F:38][C:39]([F:43])([F:42])[CH2:40][NH2:41]>O1CCCC1.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:9]3[CH:10]=[C:11]([NH:12][C:19]([NH:41][CH2:40][C:39]([F:43])([F:42])[F:38])=[O:20])[CH:13]=[CH:14][CH:15]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: NCC(F)(F)F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1cccc(-n2cnc3cc(Br)ccc32)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(Br)ccc32)c1
Temperature: 25 °C
Yield: 56 %

Procedure:
To a solution of 3-(5-bromo-1H-benzimidazol-1-yl)aniline (1.0 g, 3.5 mmol) in tetrahydrofuran (20 mL) was added p-nitrophenyl chloroformate (980 mg, 4.8 mmol, Aldrich, Cat. 160210), triethylamine (1.4 mL, 10. mmol) and 4-dimethylaminopyridine (80 mg, 0.7 mmol, Aldrich, Cat. 107700). The solution was stirred at r.t. 1 h., then 2,2,2-trifluoroethanamine (520 mg, 5.2 mmol, Alfa Aesar, Cat. No. B20789) was added. The reaction mixture was stirred at r.t. overnight and quenched with NaHCO3 aqueous solution, extracted with ethyl acetate. The combined organic phases were washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatograph on a silica gel column using 85% ethyl acetate in methylene chloride as eluent to afford the desired compound (0.81 g, 56%). LCMS (M+H)+: m/z=413.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([CH2:21][C:22]([O:24]CC)=O)[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32][NH2:33])[CH3:28]>>[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32][NH:33][C:22](=[O:24])[CH2:21][N:13]1[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:11]=[N:12]1)[CH3:28]
Reactant: CCN(CC)CCCN
Reactant: CCOC(=O)Cn1ncc(-c2ccc([N+](=O)[O-])cc2)c1-c1ccccc1
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc([N+](=O)[O-])cc2)c1-c1ccccc1

Procedure:
A solution of 3.51 g (0.01 mol) of ethyl 4-(4-nitrophenyl)-5-phenyl-1H-pyrazole-1-acetate of example 8 in 10 mL of 3(diethylamino)propanamine was reacted as in example 44. The product was recrystallized from methyl t-butyl ether to yield 5.4 g, mp 100°-101° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH2:15][O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOCc1ccc(Cl)cc1Cl)C(C)=O
Yield: 99.2 %

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 17.0 g.), 2,4-dichlorobenzyl chloride (25 g.), potassium carbonate (22.0 g.), N,N-dimethylformamide (25 ml.) and ethyl acetate (25 ml.) were treated in a similar manner to that of Example A - (1) to give ethyl 2-(2,4-dichlorobenzyloxyimino)-3-oxobutyrate (syn isomer, 33.7 g.)
Reaction SMILES: [Cl-].[CH:2]1([NH:5][C:6](=[O:39])[C@@H:7]([OH:38])[C@@H:8]([NH:12][C:13]([C@@H:15]2[CH2:19][C@@H:18]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=4)[N:24]=[C:23]([N:33]4[CH:37]=[CH:36][CH:35]=[N:34]4)[CH:22]=3)[CH2:17][NH2+:16]2)=[O:14])[CH2:9][CH2:10][CH3:11])[CH2:4][CH2:3]1.[C:40]([NH:44][C:45](=[O:55])[NH:46][C@H:47]([C:51]([CH3:54])([CH3:53])[CH3:52])[C:48](O)=[O:49])([CH3:43])([CH3:42])[CH3:41].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CS(C)=O.O>[C:40]([NH:44][C:45](=[O:55])[NH:46][C@@H:47]([C:51]([CH3:54])([CH3:53])[CH3:52])[C:48]([N:16]1[CH2:17][C@H:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=3)[N:24]=[C:23]([N:33]3[CH:37]=[CH:36][CH:35]=[N:34]3)[CH:22]=2)[CH2:19][C@H:15]1[C:13]([NH:12][C@@H:8]([CH2:9][CH2:10][CH3:11])[C@H:7]([OH:38])[C:6]([NH:5][CH:2]1[CH2:4][CH2:3]1)=[O:39])=[O:14])=[O:49])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)NC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)C[NH2+]1)[C@H](O)C(=O)NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)[C@H](O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of (2S,4R)-2-((2S,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidinium chloride (6.3 g, 11.2 mmol) in dimethylsulfoxide (20 mL) was added (R)-2-(3-tert-butylureido)-3,3-dimethylbutanoic acid (2.33 g, 10.2 mmol), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 4.74 g, 12.1 mmol) followed by diisopropylethylamine (4.95 g, 38.4 mmol), and the reaction mixture was stirred at room temperature for 3 hours under nitrogen atmosphere. Completion of the reaction was monitored by TLC analysis. The reaction mixture was diluted with water and the resulting solid was filtered and dried under reduced pressure to yield 6.3 g (71.6%) of (2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-N-((2S,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidine-2-carboxamide (HPLC purity: 99.2% by area; HPLC retention time: 15.06 minutes).