Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH3:27][N:28]([CH3:35])[C@H:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1>>[CH3:27][N:28]([CH3:35])[C@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[CH2:30]1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN(C)[C@H]1CCCNC1
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCC[C@H](N(C)C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)—N,N-dimethylpiperidin-3-amine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (d, J=13.39 Hz, 1H) 1.83 (br. s., 2H) 2.06-2.23 (m, 1H) 2.43 (s, 3H) 2.81 (br. s., 7H) 3.04-3.25 (m, 1H) 3.35-3.42 (m, 1H) 3.54 (br. s., 1H) 4.02 (br. s., 1H) 4.44 (br. s., 1H) 7.67 (d, J=8.22 Hz, 1H) 7.74 (s, 1H) 7.78 (d, J=7.83 Hz, 1H) 8.11 (dd, J=8.59, 1.77 Hz, 1H) 8.17 (br. s., 1H) 8.42 (br. s., 1H) 8.58 (d, J=1.52 Hz, 1H); ESI-MS m/z [M+H]+ 431.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=O)=[CH:5][CH:4]=1.C[O-].[Na+].Cl.[C:17](#[N:19])[CH3:18]>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH2:18][C:17]#[N:19])=[O:9])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(OC)cc1
Reactant: CC#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C(=O)CC#N)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-methoxybenzoate (7.2 kg) in dimethyl sulfoxide (21.6 L) were added sodium methoxide (3.046 kg) and acetonitrile (2.135 kg) and the mixture was stirred at 110° C. for 2 hours. Then, water (10.83 L) was added dropwise thereto at 15° C. or lower and further acetonitrile (14.4 L) was added to the mixture. Then, 6 N HCl was added thereto to adjust to pH 7.9 and the mixture was extracted with ethyl acetate (72 L). The aqueous layer was further extracted with ethyl acetate (36.32 L). The organic layers were combined and concentrated until the content became 17.39 kg. Methanol (17.84 L) was added thereto and water (17.84 L) was added dropwise. Then, the mixture was stirred at 5° C. for 1 hours and crystals deposited were filtered off and washed with methanol-water (1:1) to obtain the titled compound '6.40 kg, 82.7 g). 1H-NMR (CDCl3)δ: 3.90 (3H, s), 4.03 (2H, s), 6.98 (2H, d, J=11.25 Hz), 7.50 (2H, d, J=11.25 Hz).
Reaction SMILES: O=C1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:26])[NH:17][CH2:18][CH2:19][O:20][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH:10]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[C:4](=[O:31])O1.Cl.[C:33]([C:35]1[CH:43]=[CH:42][C:38]([CH2:39][O:40][NH2:41])=[CH:37][CH:36]=1)#[N:34]>>[C:33]([C:35]1[CH:43]=[CH:42][C:38]([CH2:39][O:40][NH:41][C:4]([C:5]2[CH:30]=[CH:29][CH:28]=[CH:27][C:6]=2[NH:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:26])[NH:17][CH2:18][CH2:19][O:20][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH:10]=2)=[O:31])=[CH:37][CH:36]=1)#[N:34]
Reactant: C=C(C)C(=O)OCCNC(=O)Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Reactant: N#Cc1ccc(CON)cc1
Agent: Cl
Product: C=C(C)C(=O)OCCNC(=O)Nc1cc(CNc2ccccc2C(=O)NOCc2ccc(C#N)cc2)ccn1

Procedure:
To a stirred solution of 1-(2-amino-pyridin-4-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (1.2 g, see preparation 7b) in pyridine was added isocyanatoethyl methacrylate (0.76 ml). The reaction mixture was heated to 40° C. and stirred for 2 hours. More isocyanatoethyl methacrylate (0.1 ml) was added and stirring was continued for 2 hours. The solvent was evaporated under reduced pressure and EtOAc (10 ml) was added to the residue. On scraping a solid material formed, that was isolated by filtration and dried in vacuo, affording 2-methyl-acrylic acid 2-{3-[4-(2,4-dioxo-4H-benzo[d][1,3]oxazin-1-ylmethyl)-pyridin-2-yl]-ureido}-ethyl ester (1.78 g). Step 2: This anhydride intermediate was converted into the title compound by reaction with O-(4-cyanobenzyl)hydroxylamine hydrochloride (see preparation 10), using general procedure 1A. 13C-NMR (DMSO-d6) δ 167.5, 166.5, 154.8, 153.7, 151.4, 148.6, 146.6, 141.9, 135.8, 132.8, 132.3, 129.2, 128.1, 125.9, 118.8, 115.4, 114.9, 113.0, 111.6, 110.9, 109.4, 76.1, 63.7, 45.4, 38.0, 18.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]([Cl:16])[N:8]=1)[CH3:2].C(N(CC)CC)C.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>O1CCCC1.[Pt](=O)=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([Cl:25])=[CH:27][CH:28]=2)=[CH:11][CH:10]=[C:9]([Cl:16])[N:8]=1)[CH3:2]
Reactant: CCOC(=O)CNc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1nc(Cl)ccc1NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 31 %

Procedure:
A solution of N-(6-chloro-3-nitro-2-pyridinyl) glycine ethyl ester (5.0 g, 0.0193 mole) in tetrahydrofuran (100 ml) was hydrogenated over platinum dioxide (0.5 g) at room temperature. After 2/3 of the theoretical amount of hydrogen had been absorbed, the mixture was filtered and a fresh portion of platinum dioxide (0.5 g) was added. The hydrogenation was continued until the theoretical amount of hydrogen was absorbed. The reaction mixture was cooled in ice, dried over magnesium sulfate and filtered. Triethylamine (2.05 g, 0.0203 mole) and 4-chlorobenzoyl chloride (3.55 g, 0.0203 mole) were added simultaneously, dropwise, to the cooled and stirred solution. After stirring at room temperature for 1.75 hours, the mixture was evaporated under reduced pressure and partitioned between water (100 ml) and ethyl acetate (100 ml). The layers were separated and the aqueous layer was re-extracted with ethyl acetate. The combined ethyl acetate layers were washed three times with saturated sodium chloride solution, dried over magnesium sulfate, charcoaled, filtered, and evaporated under reduced pressure. The resulting solid was dissolved in hot isopropyl alcohol, filtered hot and cooled to room temperature to give a solid which was collected by filtration and rinsed with isopropyl ether to give 2.2 g of title compound (31% yield). A 0.5% g portion was dissolved in hot isopropyl alcohol, filtered hot, isopropyl ether was added, and the mixture was cooled. The resulting suspension was filtered, the filtrate was evaporated under reduced pressure, and the residue was recrystallized from isopropyl alcohol/water and dried under high vacuum at 60° C. to give 0.37 g of the title compound, mp 157°-158.5° C.
Reaction SMILES: [OH-].[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][P:10]([OH:19])([O:12][CH:13]([N+:15]([CH3:18])([CH3:17])[CH3:16])[CH3:14])=[O:11].C(N(CC)CC)C.C1C(=O)N(O[C:35]([CH2:37][CH2:38][S:39][S:40][C:41]2[N:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:36])C(=O)C1>CS(C)=O>[OH-:9].[N:46]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:40][S:39][CH2:38][CH2:37][C:35]([C:13]([O:12][P:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH2:2])([OH:19])=[O:11])([N+:15]([CH3:17])([CH3:18])[CH3:16])[CH3:14])=[O:36]
Reactant: CC(OP(=O)(O)OCCCCCCN)[N+](C)(C)C
Reactant: O=C(CCSSc1ccccn1)ON1C(=O)CCC1=O
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(OP(=O)(O)OCCCCCCN)(C(=O)CCSSc1ccccn1)[N+](C)(C)C
Temperature: 25 °C

Procedure:
2-[(6-Aminohexoxyhydroxyphosphinyl)oxy-N,N,N-trimethylethanaminium hydroxide, inner salt (90 mg, 0.28 mmol) was dissolved in dry dimethyl sulphoxide (2 ml). Triethylamine (197 μl, 1.41 mmol) was added, followed by N-succinimidyl 3-(2-pyridyldithio)propionate (88 mg, 0.28 mmol). The mixture was stirred at ambient temperature for eighteen hours. The solvent was evaporated under vacuum at a temperature of 60° C. and re-evaporated from methanol. The residue was chromatographed on silica gel eluting with methanol. The relevant fractions were combined and evaporated to dryness to give 2[N(3-(2 pyridyldithio)propionyl)(6-aminohexoxyhydroxy
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:11][N:12]([CH3:14])[CH:13]=[CH:2][C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: CC(=O)c1cccs1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1cccs1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A mixture of 2-acetylthiophene (198 mmol) and N,N-dimethylformamide dimethyl acetal (297 mmol) was refluxed overnight and then allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure and dried in vacuo to afford 36 g (100% yield) of 3-(dimethylamino)-1-(2-thienyl)prop-2-en-1-one which was used in the next step without further purification.
Reaction SMILES: [I:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1>CN(C=O)C>[I:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[CH:3]=1
Reactant: O=c1c(I)c[nH]c2ccccc12
Reactant: Cc1cccc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2cc(I)c(=O)c3ccccc32)n1
Reaction time: 3 h

Procedure:
3-iodo-1H-quinolin-4-one (1.36 g, 5 mmol, 1 equiv) in 5 mL of DMF was treated with 0.22 g of NaH (1.1 equiv) for 10 min. 2-Bromomethyl-6-methyl-pyridine (1.11 g, 1.2 equiv) was then added and stirring continued for 3 h. The reaction was quenched by slow addition of saturated aqueous solution of NH4Cl. Standard workup followed by flash chromatography gave 3-iodo-1-(6-methyl-pyridin-2-ylmethyl)-1H-quinolin-4-one as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.O>C1(C)C(C)=CC=CC=1>[CH3:14][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[N:9]=[CH:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([C:16]([F:15])([F:25])[F:26])[CH:18]=1
Reactant: CN(C)CCCOc1ccccc1N
Reactant: O=Cc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: Cc1ccccc1C
Product: CN(C)CCCOc1ccccc1N=Cc1cccc(C(F)(F)F)c1
Yield: 52.6 %

Procedure:
A solution of 19.4g of 2-(3-dimethylaminopropoxy)aniline and 17.4g of m-trifluoromethylbenzaldehyde in 100ml of xylene is refluxed for about 6 hours. The water formed in the reaction is collected in a Dean-Stark tube. The solvent is removed under reduced pressure and the residue fractionated to yield 18.4g of the title compound as an oil, boiling point 155°-160° C. at 0.2-0.3 mm. of Hg.
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)C.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:20][CH2:1][C:3]1[N:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCc1ncc2ccccc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: BrCc1ncc2ccccc2n1
Yield: 12.2 %

Procedure:
To a solution of the title compound from Step B (1.39 g 8.79 mmol) in chloroform (50 ml) was added NBS (1.56 g, 8.79 mmol) and benzoyl peroxide (213 mg, 0.88 mmol) and the resulting mixture heated at reflux for 5 h. The mixture cooled and evaporated, the residue purified by MPLC (Biotage Horizon: FLASH 25+M) eluent: 100% Hexanes (90 ml), gradient rising from 100% Hexanes to 10% EtOAc in Hexanes (1200 ml) to afford the title compound 240 mg (11.5%) as a red oil. 1H NMR (CDCl3): 2.25 (d, J 6.9 Hz, 3H), 5.51 (q, J 6.9 Hz, 1H), 7.64 (m, 1H), 7.71 (m, 1H), 7.97 (m, 1H), 8.08 (d, J 8.6 Hz, 1H), 9.49 (s, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].C(OCC)(=[O:13])C>ClCCl>[CH3:1][S:2]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6])=[O:13]
Reactant: CSc1ccccc1C=O
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)c1ccccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 2-(methylthio)benzaldehyde (500 mg, 3.28 mmol) in 6.6 mL of dichloromethane was added m-chlorobenzoic peracid (0.85 g, 4.9 mmol) at 0° C. After being stirred at room temperature for 1 h, the reaction mixture was diluted with ethyl acetate. The solution was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50 to 15/85) to obtain the title compound as a white crystal (493 mg, 89%).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH:24]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:25](=[O:27])[NH2:26])=[CH:17][CH:16]=1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO.ClCCl>[C:32]([O:31][C:29](=[O:30])[NH:28][CH:24]([C:25](=[O:27])[NH2:26])[CH2:23][CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:20][CH:19]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC(CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)C(N)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CCOc1ccc(CCCCN)cc1)C(N)=O
Reaction time: 18 h

Procedure:
A mixture of N-Cbz amide 110 (436 mg, 0.873 mmol) and Pearlman's catalyst (100 mg) in methanol (10 mL) and dichloromethane (10 mL) was stirred under atmospheric hydrogen for 18 h. Catalyst was removed by suction filtration over Celite and the filtrate was concentrated to give a colorless oil (318 mg, 100% crude yield). Crude product 120 was used for next step without further purification. m/z (ESI) 366 [C19H31N3O4+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[Cl:25]C1C=CC(C2N=C3C=CC=CN3C=2C=O)=CC=1.CN1C=CN=C1>>[Cl:25][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][N:6]3[C:8]=2[CH2:18][C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)=[CH:12][CH:13]=1
Reactant: Cn1ccnc1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Reactant: O=Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cn1ccnc1
Product: Cn1ccnc1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Yield: 19 %

Procedure:
The title compound was prepared according to Method C and the experimentals described for compound 199 from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and 1-methyl-1H-imidazole. (21.6 mg, 19% yield). M/e+ 323.1 for C18H15ClN4 (M+H)+; 1H-NMR (300 MHz, DMSO, δ) 8.25 (d, J=6.9 Hz, 1H), 7.75 (dd, J=8.7, 2.1 Hz, 2H), 7.61 (d, J=9.0 Hz, 1H), 7.51 (dd, J=8.4, 1.8 Hz, 2H), 7.28 (t, J=2.1 Hz, 1H), 7.08 (d, J=0.9 Hz, 1H), 6.91 (t, J=6.9 Hz, 1H), 6.68 (d, J=0.9 Hz, 1H), 4.53 (s, 2H), 3.58 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([NH:16][NH2:17])=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26]([C:28](=O)[CH3:29])[CH:27]=1>CO.C(O)(=O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26](/[C:28](=[N:17]/[NH:16][C:14](=[O:15])[C:13]2[CH:18]=[CH:19][CH:20]=[C:11]([S:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)(=[O:10])=[O:9])[CH:12]=2)/[CH3:29])[CH:27]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: CN1CCN(S(=O)(=O)c2cccc(C(=O)NN)c2)CC1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCN(C)CC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 53.3 %

Procedure:
3-((4-methylpiperazin-1-yl)sulfonyl)benzohydrazide (85 mg, 0.285 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (48.6 mg, 0.285 mmol) was dissolved in methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the product (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-3-((4-methylpiperazin-1-yl)sulfonyl)benzohydrazide (70 mg, 0.152 mmol, 53.4% yield) as a solid. 1H NMR (CD3OD, 400 MHz): δ 8.29 (s, 1H), 8.21 (d, 1H, J=7.2 Hz), 7.99 (d, 1H, J=8.0 Hz), 7.78 (t, 1H, J=7.6 Hz), 7.59 (d, 1H, J=2.4 Hz), 7.27 (dd, 1H, J=2.4 & 9.2 Hz), 6.92 (d, 1H, J=8.8 Hz), 3.09 (m, 4H), 2.54 (m, 4H), 2.48 (s, 3H), 2.28 (s, 3H). Mass [M+H]+: 450.9
Reaction SMILES: [CH3:1][C@:2]1([C:18]([O-])=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1.[Li+].Cl.[NH2:23][C:24]1([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)C[CH2:25]1>>[CH3:1][C@:2]1([C:18]([NH:23][C@H:24]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH3:25])=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: C[C@]1(C(=O)[O-])CCCN1Cc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@@]2(C)CCCN2Cc2cccc(C(F)(F)F)c2)cc1
Yield: 53 %

Procedure:
The title compound (D37) (30.9 mg) was prepared according to the general procedure for amides preparation starting from lithium (R)-2-methyl-1-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D17) (37 mg, 0.13 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (27.2 mg, 0.13 mmol).
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]=[O:22]>>[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20][C@@H:21]([OH:22])[C@@H:2]([CH3:3])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: COCCOCC=O
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Product: COCCOC[C@@H](O)[C@@H](C)C(=O)n1c(=O)oc2ccccc21

Procedure:
Prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolinone with (2-methoxyethoxy)acetaldehyde. 13C-NMR (CDCl3, 100 MHz): δ 175.01, 151.02, 142.18, 127.91, 125.30, 124.77, 116.15, 109.76, 73.23, 71.86, 70.73, 70.64, 58.88, 41.63, 11.88.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][O:17]C(=O)C2C=CC=CC=2)[C:8]([O:10]CC)=[O:9])[N:6]=1.CO.O1CCCC1>[OH-].[Na+]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][OH:17])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOCCO)C(=O)O)cs1
Temperature: 40 °C
Reaction time: 9 h
Yield: 61 %

Procedure:
A solution of ethyl 2-(2-aminothiazol-4-yl)-2-(2-benzoyloxyethoxyimino)acetate (syn isomer, 8.5 g.) in a mixture of 1N aqueous sodium hydroxide (35 ml.), methanol (40 ml.) and tetrahydrofuran (40 ml.) was stirred at 40° C. for 9 hrs. and at room temperature for 12 hrs. The reaction mixture was treated in a conventional manner to give 2-(2-aminothiazol-4-yl)-2-(2-hydroxyethoxyimino)acetic acid (syn isomer, 3.3 g.).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]([CH2:7][C:8](=[O:12])SCC)[C:4](=[O:13])[O:3]1.C([SiH](CC)CC)C>[Pd].C(Cl)Cl>[CH3:1][C:2]1([CH3:14])[O:6][C@H:5]([CH2:7][CH:8]=[O:12])[C:4](=[O:13])[O:3]1
Reactant: CCSC(=O)C[C@H]1OC(C)(C)OC1=O
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: CC1(C)OC(=O)[C@@H](CC=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a stirred suspension of (R)—S-ethyl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)ethanethioate (1.9 g, 8.7 mmol), 10% palladium on carbon (470 mg), and CH2Cl2 (20 mL) under N2, at 25° C., was added triethylsilane (2.08 mL, 13.0 mmol) dropwise over 10 minutes. The mixture was stirred at 25° C. for 1 hour. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to give the desired aldehyde as a clear oil (1.2 g, 87%). 1H-NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 4.72 (q, J=3.5 Hz, 1H), 3.10-3.01 (m, 1H), 2.93-2.84 (m, 1H), 1.56 (s, 3H), 1.51 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[C:6]([NH2:10])([CH3:9])([CH3:8])[CH3:7]>>[Cl:5][CH2:4][CH2:3][CH2:2][NH:10][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)N
Reactant: ClCCCBr
Product: CC(C)(C)NCCCCl
Reaction time: 8 h

Procedure:
A round-bottom, 250 milliliter, three-necked flask was equipped with a magnetic stir bar, a Claisen adapter, equipped with a thermocouple and a dry-ice condenser with a gas inlet, and a pressure-equalizing dropping funnel. This apparatus was baked in an oven overnight at 125° C., assembled hot, and purged with argon until cool. The reaction flask was charged with 1-bromo-3-chloropropane 15.74 grams, (0.10 moles, 1 equivalent). t-Butylamine 29.26 grams, (0.40 moles, 4 equivalents) was added dropwise via the addition funnel over a period of one hour. After addition was complete, samples of the reaction mixture were removed periodically, washed with saturated sodium bicarbonate solution, and assayed for unreacted 1-bromo-3-chloropropane by gas chromatography (GLC). The reaction was allowed to stir until 1-bromo-3-chloropropane was consumed. Next, 75 milliliters of saturated sodium bicarbonate solution and 25 milliliters of distilled water were added to the reaction flask. The reaction mixture was then transferred to a separatory funnel and extracted 2×75 milliliters with ethyl ether. The organic layer was then dried with magnesium sulfate, filtered, and concentrated on a rotary evaporator, to afford a colorless, slightly hazy solution with a yield=10.47 g (70%); (GC assay=93%).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][N:8]3[C:12](=[O:18])[CH2:13][NH:14][C:15](=[O:17])[CH2:16][CH:7]3[C:6]=2[N:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([Sn](CCCC)(CCCC)CCCC)=[CH:22][N:21]=1.O1CCOCC1>>[F:19][C:20]1[N:21]=[CH:22][C:23]([C:2]2[C:11]3[CH2:10][CH2:9][N:8]4[C:12](=[O:18])[CH2:13][NH:14][C:15](=[O:17])[CH2:16][CH:7]4[C:6]=3[N:5]=[CH:4][CH:3]=2)=[CH:24][CH:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(F)nc1
Reactant: O=C1CC2c3nccc(Cl)c3CCN2C(=O)CN1
Solvent: C1COCCO1
Product: O=C1CC2c3nccc(-c4ccc(F)nc4)c3CCN2C(=O)CN1
Temperature: 150 °C
Yield: 39.2 %

Procedure:
94-10. To a degassed solution of 4-chloro-5,6,9,10,12,12a-hexahydro-[1,4]diazepino[1,7-h][1,7]naphthyridine-8,11-dione (66 mg, 0.25 mmol) and 2-fluoro-5-(tributylstannyl)pyridine (120 mg, 0.31 mmol) in dioxane (2 mL) Pd(PPh3)4 (15 mg, 0.012 mmol) was added and the mixture was heated in the microwave at 150° C. for 5 h. The solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: from 2% MeOH in AcOEt to 20% MeOH in AcOEt in 21 min) to yield the title compound as a beige solid (32 mg). UPLC-MS: MS 327.2 (M+H+); UPLC rt 0.58 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:8][NH:7][C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([NH:19][C:20]([N:7]2[C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3][C:2]([CH3:12])([CH3:1])[CH2:8]2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC1(C)CNC(=O)CC(C)(C)N1
Product: CC1(C)CC(=O)N(C(=O)Nc2ccccc2)CC(C)(C)N1

Procedure:
Using the same conditions as Example 1, 34 parts of 2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one and 26 parts of phenylisocyanate afforded 49 parts of 4-phenylcarbamoyl-2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one as an almost colourless solid. Crystallisation from petrol ether (40°-60°) yielded crystalline material of melting point 68.5° - 70°C which gave the following elemental analysis by weight: