Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:14][C:15]1[N:16]=[C:17]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][Cl:35])=[CH:27][CH:26]=2)[O:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(OCC)C>C(#N)C>[Cl:35][CH2:34][CH2:33][CH2:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:17]2[O:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:15]([CH2:14][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:16]=2)=[CH:26][CH:27]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A suspension of piperidine (90 μl, 0.86 mmol, 1.1 eq) and potassium carbonate (0.43 g, 3 mmol, 4 eq) in acetonitrile (5 ml) is treated dropwise with a solution of ethyl 4-(bromomethyl)-2-[4-(3-chloropropoxy)phenyl]-1,3-oxazole-5-carboxylate i93 (0.30 g, 0.77 mmol, 1 eq) in acetonitrile (2 ml) and is stirred at room temperature overnight. Diethyl ether is then added and the solution is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 210 mg of crude ethyl 2-[4-(3-chloropropoxy)phenyl]-4-(piperidin-1-ylmethyl)-1,3-oxazole-5-carboxylate i95, used as such in the next step.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH:32]1([NH:36][CH2:27][C:23]2[CH:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]3)[CH:26]=[CH:25][CH:24]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: NC1CCC1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC5CCC5)c4)cc23)CC1
Yield: 34.5 %

Procedure:
Following the general procedure of example 31, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.113 mmol), cyclobutanamine (24.1 mg, 0.339 mmol) and NaBH(OAc)3 (75 mg, 0.545 mmol) were reacted to give the title compound (19.3 mg, 35%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14](O)[CH2:15][S:16][C@H:11]12)=[O:8].CN(C=O)C.C(Cl)(=O)C([Cl:41])=O.Cl>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14]([Cl:41])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Reaction time: 4 h

Procedure:
To a solution of 439 mg. (0.93 mmole) of p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate in 4.4 ml. of DMF cooled in an ice bath was added dropwise 118 mg. (0.07 ml., 0.93 mmole) of oxalyl chloride. The reaction mixture was allowed to stand for 4 hours at room temperature and was then poured into a mixture of aqueous 5% hydrochloric acid and ethyl acetate. The organic layer was separated and was washed sequentially with 5% hydrochloric acid, water and a saturated solution of sodium chloride. The washed layer was dried and evaporated to dryness to yield the reaction product, p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem-4-carboxylate as an amorphous solid. The product was obtained crystalline by triturating the amorphous residue with ether. Yield 360 mg. The infrared spectrum and NMR spectrum of the crystalline product were consistent with the spectra of authentic material.
Reaction SMILES: [CH:1]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][S:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][S:24][CH2:25][C:26]([NH:13][CH:1]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: NC1CCCCCCCCCCC1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CSCC(=O)O
Product: O=C(CSCC(=O)NC1CCCCCCCCCCC1)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 1-(ii), cyclododecylamine was reacted with the [(2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethyl)sulfanyl]acetic acid obtained in Example 12-(i) to give 5-chloro-2-[(([2-(cyclododecylamino)-2-oxoethyl]sulfanyl)acetyl)amino]benzoic acid.methyl ester (yield: 95%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.C(=O)([O-])[O-:26].[K+].[K+].Cl>O1CCOCC1.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10](/[CH:9]=[CH:8]/[C:6]2[N:5]=[CH:4][NH:3][C:2](=[O:26])[CH:7]=2)=[CH:11][CH:12]=1
Reactant: Clc1ccc(/C=C/c2cc(Cl)ncn2)cc1
Reactant: O=C([O-])[O-]
Agent: C1CN2CCN1CC2
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1cc(/C=C/c2ccc(Cl)cc2)nc[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of (E)-4-chloro-6-(4-chlorostyryl)pyrimidine Part A (120 mg, 0.48 mmol), DABCO (107 mg, 0.96 mmol), and potassium carbonate (660 mg, 4.78 mmol) in Dioxane (0.4 mL) and Water (4 mL) was stirred at 60° C. overnight. The reaction was cooled to RT, acidified with 10% HCl, extracted with EtOAC, dried (Na2SO4), and concentrated. The product was triturated with DCM to afford the desired product (E)-6-(4-chlorostyryl)pyrimidin-4(3H)-one 20B (108 mg, 0.46 mmol, 97% yield) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][CH2:9][C:10]2([CH2:23][CH:24]3[CH2:26][CH2:25]3)[CH2:15][CH2:14][CH:13]([S:16]([CH2:19][CH:20]3[CH2:22][CH2:21]3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[O:7])=[C:4]([C:29]([F:32])([F:31])[F:30])[N:3]=1.[CH3:33][N:34](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:33]([C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][CH2:9][C:10]2([CH2:23][CH:24]3[CH2:26][CH2:25]3)[CH2:15][CH2:14][CH:13]([S:16]([CH2:19][CH:20]3[CH2:22][CH2:21]3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[O:7])=[C:4]([C:29]([F:32])([F:31])[F:30])[N:3]=1)#[N:34]
Reactant: CN(C)C=O
Reactant: O=C(NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1)c1ccc(Cl)nc1C(F)(F)F
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(C(=O)NCC2(CC3CC3)CCC(S(=O)(=O)CC3CC3)CC2)c(C(F)(F)F)n1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
A mixture of 6-chloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-2-(trifluoromethyl)nicotinamide (37 mg, 0.076 mmol), zinc cyanide (44 mg, 0.38 mmol) and tetrakis triphenylphosphine palladium (0) (8.7 mg, 0.008 mmol) in N,N-dimethylformamide (1.5 mL) was heated at 150° C. for 600 s under microwave irradiation. The mixture was allowed to cool to ambient temperature, the supernatent layer removed and evaporated. The residue was partitioned between dichloromethane (5 ml) and water (5 ml) and stirred vigerously for 5 min. The mixture separated using a 5 micron PTFE frit and the filtrate was evaporated. The yellow oil was purified by preparative plate chromatography eluting with 10% ethyl acetate in dichloromethane. Collecting the appropriate band followed by trituation with ethyl acetate, filtration of the solid and evaporation of the filtrate gave a white solid. The solid was recrystallised from ethyl acetate/isohexane which gave 6-cyano-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-2-(trifluoromethyl)-nicotinamide a white solid (21 mg, 57%): 1H NMR (400MHz, CDCl3) δ 8.11 (1H, d, J=7.9 Hz), 7.95 (1H, d, J=7.9 Hz), 5.98 (1H, s), 3.61 (2H, d, J=6.3 Hz), 2.98-2.88 (3H, m), 2.04-2.01 (2H, m), 1.96-1.84 (4H, m), 1.43-1.37 (2H, m), 1.24 (2H, d, J=6.7 Hz), 1.18-1.12 (1H, m), 0.76 (2H, q, J=6.4 Hz), 0.68-0.64 (1H, m), 0.53-0.49 (2H, m), 0.41 (2H, q, J=5.3 Hz), 0.06-0.05 (2H, m); m/z=484 (M+H+).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:30]=[N:29][C:17]4[NH:18][C:19]5[CH:24]=[N:23][C:22]([C:25]([NH:27][NH2:28])=[O:26])=[CH:21][C:20]=5[C:16]=4[CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31]OC(OC)OC.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(O)(=O)C>[O:26]1[CH:31]=[N:28][N:27]=[C:25]1[C:22]1[N:23]=[CH:24][C:19]2[NH:18][C:17]3[N:29]=[CH:30][C:14]([C:11]4[CH:12]=[CH:13][C:8]([CH2:7][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:9][CH:10]=4)=[CH:15][C:16]=3[C:20]=2[CH:21]=1
Reactant: NNC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Reactant: COC(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: c1nnc(-c2cc3c(cn2)[nH]c2ncc(-c4ccc(CN5CCCCC5)cc4)cc23)o1
Yield: 10.9 %

Procedure:
A solution of 3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbohydrazide (53.8 mg, 0.134 mmol) and trimethoxymethane (1.21 mL, 11.0 mmol) in DMF (0.81 mL) was heated at 120° C. for 24 h. The mixture was cooled, treated with trimethoxymethane (1.0 mL) and a few drops of acetic acid and heated under reflux for 48 h. The mixture was allowed to cool, treated with saturated aqueous sodium bicarbonate solution, and the resultant white precipitate collected by filtration and washed with water. The filtrate was extracted with DCM, 20% methanol in DCM, and the combined organic phases dried over sodium sulfate, combined with the isolated solid and concentrated in vacuo. The resultant residue was purified by preparative HPLC [2-60% MeCN/water modified with 0.1% ammonium hydroxide] to afford a light-yellow flaky solid (6.0 mg, 27%). 1H NMR (DMSO-D6, 400 MHz): 12.77-12.69 (s, 1H), 9.41 (s, 1H), 9.26 (d, J=2.2 Hz, 1H), 9.18 (s, 1H), 9.08 (s, 1H), 9.00 (d, J=2.2 Hz, 1H), 8.31 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 3.50 (s, 2H), 2.37 (m, 4H), 1.52 (m, 4H), 1.41 (m, 2H). LCMS (Method D): RT=7.69 min, M+H+=411.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[C:20]1([C:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>C(O)(=O)C>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH:5][C:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 13.3 g of Z-Asn-OH (50 mmol), 26 g of triphenylmethanol (100 mmol), 150 ml of acetic acid and 9.5 ml (100 mmol) of acetic anhydride is stirred at 50° for 15 minutes. Addition of 0.25 ml of conc. sulfuric acid produces, after 5 minutes, a clear yellow solution. After 11/2 hours, it is cooled and poured into 1.5 liters of ice-water. The precipitate is filtered off, thoroughly washed with water and dissolved in about 500 ml of ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to 250 g. Z-Asn(Trt)-OH is induced to crystallize by addition of 125 ml of hexane, m.p. 195°-196°.
Reaction SMILES: Br.Br[CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([F:19])[CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)=O.[NH2:20][C:21]([NH2:23])=[S:22].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[F:19][C:15]1[CH:14]=[C:13]([C:3]2[S:22][C:21]([NH2:23])=[N:20][C:4]=2[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=2)[CH:18]=[CH:17][N:16]=1
Reactant: NC(N)=S
Reactant: Cc1cccc(C(=O)C(Br)c2ccnc(F)c2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccc(-c2nc(N)sc2-c2ccnc(F)c2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a mixture of 2-bromo-2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone hydrobromide [synthesized according to Reference Example 19 using 2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanbne (8.46 g, 36.9 mmol) instead of 2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3methylphenyl)ethanone] and thiourea (3.03 g, 39.8 mmol) in acetonitrile (50 mL) was added triethylamine (5.2 mL, 37.3 mmol), and the mixture was stirred at 80° C. for 2 hrs. Aqueous sodium hydrogen carbonate solution was poured into the reaction mixture and the precipitated solids were collected by filtration. The obtained solid was washed with water and dried. Crude crystals were recrystallized from ethanol to give the title compound (3.67 g, yield 35%).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]([NH:11][C:12](=[O:29])[NH:13][C:14]2[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][CH:15]=2)=[O:10])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:36]>C(N(CC)CC)C>[C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]([NH:11][C:12](=[O:29])[NH:13][C:14]2[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:16][CH:15]=2)=[O:10])=[CH:5][CH:4]=1)(=[S:36])[NH2:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C#N)nc2)cc1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C(N)=S)nc2)cc1

Procedure:
In a similar manner to Example 1, starting material step (b), the product of step (a) (2.29 g), pyridine (105 ml), triethylamine (15 ml) and H2S gas were reacted to give t-butyl 4-[3-(6-thiocarbamoylpyrid-3-ylcarbonyl)ureido]phenoxyacetate (2.76 g) as a yellow solid: m.p. 248°-249° C. (decomposes); NMR Spectrum (DMSO-d6) 1.44 (9H, s), 4.62 (2H, s), 6.90 (2H, d), 7.49 (2H, d), 8.48 (1H, dd), 8.58 (1H, d), 9.10 (1H, d), 10.02 (1H, bs), 10.30 (1H, br s), 10.49 (1H, s), 11.30 (1H, s); Mass Spectrum m/Z 431 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:20][OH:21])[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCc1ccc(C(=O)c2ccc(Cl)cc2)c(O)c1
Agent: Cl
Product: CCc1ccc(C(=NO)c2ccc(Cl)cc2)c(O)c1

Procedure:
4'-Chloro-4-ethyl-2-hydroxybenzophenone (130.4g) was treated with hydroxylamine hydrochloride (140g) similarly to Example 12, to give the title compound, one isomer only (81.2g), m.p. 159°-161°C,
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=O.[O:16]=[C:17]1[CH2:21][CH2:20][S:19][CH2:18]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=[C:18]1[C:17](=[O:16])[CH2:21][CH2:20][S:19]1
Reactant: COC(=O)C(C)c1ccc(C=O)c(F)c1
Reactant: O=C1CCSC1
Product: COC(=O)C(C)c1ccc(C=C2SCCC2=O)c(F)c1
Yield: 52.4 %

Procedure:
By using methyl 2-(3-fluoro-4-formylphenyl)propionate (1.05 g) obtained in Example 58 and 3-oxothiolane (1.02 g), the title compound (770 mg, 52%) was obtained in the same manner as that of Example 1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CN1CCOCC1.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>O1CCCC1>[CH2:34]([O:33][C:31]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:32])[CH3:35]
Reactant: CCCCCCCCCCCCCCCC(=O)NCCCO
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCCCCCCCCCCCCC(=O)NCCCOC(=O)OCC

Procedure:
3.14 g of N-(3-hydroxypropyl) hexadecanamide (10 mmoles) was suspended in 75 ml of tetrahydrofuran (THF) at 45° C. with stirring. 1.11 g of N-methylmorpholine (11 mmoles) and 1.19 g of ethyl chloroformate (11 mmoles) were added and the resulting mixture was stirred for a further 3 hours at ambient temperature. The mixture was then evaporated to dryness under vacuum. The residue was taken up with 50 ml of water and extracted 3 times with 30 ml of ethyl acetate; the organic phases were washed twice with 20 ml of water, recombined and evaporated to dryness. The residue was crystallized from 30 ml of tert-butylmethyl ether. The crystallizate was separated by filtration, washed twice with 5 ml of cold tert-butylmethyl ether and finally dried in a high degree of vacuum. The yield of the reaction was 92%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=2)(Cl)Cl)[CH:5]=[CH:6][CH:7]=1.[F:18][C:19]1[CH:24]=[C:23]([OH:25])[C:22]([OH:26])=[CH:21][C:20]=1[C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=3)[O:25][C:23]3[CH:24]=[C:19]([F:18])[C:20]([C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:28])=[CH:21][C:22]=3[O:26]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cc(O)c(O)cc1F)N1CCOCC1
Reactant: ClC(Cl)(c1cccc(Br)c1)c1cccc(Br)c1
Product: O=C(c1cc2c(cc1F)OC(c1cccc(Br)c1)(c1cccc(Br)c1)O2)N1CCOCC1

Procedure:
79 mg bis-(3-bromophenyl)-dichloromethane and 48 mg (2-fluoro-4,5-dihydroxy-phenyl)-morpholin-4-yl-methanone were heated to 180° C. for one hour. Chromatography of the dark residue gave 30 mg of an off-white waxy solid, MS: m/e=564 ([M+H])+.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.C([N-]C(C)C)(C)C.[Li+]>C1COCC1.C(O)(=O)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][N:3]=[C:2]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14])[CH3:13]
Reactant: CCn1c(=O)ccc2cnc(F)cc21
Reactant: COc1ccc(N)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCn1c(=O)ccc2cnc(Nc3ccc(OC)cc3)cc21
Reaction time: 8 h
Yield: 57 %

Procedure:
A stirred solution of (XV, where R2 is ethyl) (100 mg, 0.52 mmol) and p-anisidine (160 mg, 1.3 mmol) in THF (5.0 mL) under nitrogen at -78° C. was treated with a solution (1.2 mL, 1.8 mmol) of lithium diisopropylamide (1.5 M in cyclohexane), then the temperature was allowed to rise slowly to 20° C. overnight. The resulting solution was treated with 3 drops of glacial acetic acid and concentrated to a brown residue that was purified by silica gel chromatography eluting with 1:1 EtOAc hexanes then EtOAc. The product fractions were pooled and concentrated to a solid that was crystallized to give 1-ethyl-7-(4-methoxyphenylamino)-1H -[1,6]naphthyridin-2-one (87 mg, 57%): mp (2-propanol) 165-166° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24](O)=[O:25])([CH3:20])[CH3:19]>C(#N)C.C(OCC)C>[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24]([N:15]1[CH2:14][CH2:13][N:12]([C:9]2[CH:10]=[CH:11][C:5]3[S:4][C:3]([CH3:2])=[N:7][C:6]=3[CH:8]=2)[CH2:17][CH2:16]1)=[O:25])([CH3:20])[CH3:19]
Reactant: Cc1nc2cc(N3CCNCC3)ccc2s1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: Cc1nc2cc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OC(C)C)CC3)ccc2s1

Procedure:
Prepared in analogy to example 1.1(b) from 2-methyl-5-piperazin-1-yl-benzothiazole hydrochloride and 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Trituration in diethyl ether yields the title compound as a yellowish solid.
Reaction SMILES: [CH2:1]([CH2:11][C:12](=O)[CH3:13])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.O>C1(C)C=CC=CC=1>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][CH:12]([CH3:13])[CH2:11][CH2:1][C:2]2[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=2)=[CH:19][CH:18]=1
Reactant: COc1cc(CCC(C)=O)ccc1O
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(CCC(C)NCc2ccc(C(F)(F)F)cc2)ccc1O
Temperature: 0 °C
Yield: 74 %

Procedure:
Vanillylacetone (5.00 g, 25.7 mmol) was dissolved in toluene (250 mL) and 4-trifluoromethylbenzylamine (4.73 g, 27.0 mmol) was added. The mixture was maintained under an atmosphere of nitrogen and heated at reflux with removal of water by Dean-Stark distillation for 16 hours. At this time the Dean-Stark trap was removed and the reaction mixture was cooled to 0° C. on an ice bath. A solution of sodium borohydride (5 g) in methanol (100 mL) was added portion-wise over 30 minutes with vigorous stirring. When the addition was complete the mixture was heated at reflux for 16 hours. At this time the reaction mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate solution (300 mL). The resulting mixture was concentrated by rotary evaporation and the aqueous residue was partitioned between water and chloroform. The chloroform layer was dried over anhydrous sodium sulfate and then filtered and concentrated. The product was then purified using silica gel column chromatography employing a mobile phase of 5% ammonia-methanol in chloroform. Product-containing fractions were combined and concentrated then dried under high vacuum overnight to provide a light brown oil (6.72 g, 74%). 1H NMR, 13C NMR, and Mass Spectrum of the product were substantially the same as those in Example 2, A (made by the Conditioned Extraction method).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[CH:6][N+:7]=1[O-].P(Cl)(Cl)([Cl:24])=O.O>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[C:6]([Cl:24])[N:7]=1
Reactant: CC(C)n1cc(-c2c[n+]([O-])c(N)c(C(N)=O)n2)ccc1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cc(-c2nc(C(N)=O)c(N)nc2Cl)ccc1=O
Temperature: -30 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
3-Amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide 4-oxide (8 g) was dissolved in DMF (80 ml). The solution was cooled to −30° C. To the cooled solution was added phosphoryl chloride (12.7 g) dropwise at −30˜−40° C. After addition of phosphoryl chloride, the temperature of the reaction mixture was raised to −10˜−5° C. The mixture was stirred at −10˜−5° C. for 1 hour. To the reaction mixture was added water (400 ml). The suspension was stirred at 30-35° C. for 15 hours. The pH of the suspension was adjusted to 4.5. The suspension was cooled to 0-5° C. and stirred at the same temperature for 2 hours. The precipitate was collected by filtration and washed with water, and dried in vacuo at 40-50° C., to give 3-amino-5-chloro-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide (7.1 g).