Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[N:19]1([C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:2]3[C:11]4[C:6](=[CH:7][C:8]5[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=5[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:26][CH:27]=2)[CH2:20][CH2:21][CH2:16][CH2:17][CH2:18]1
Reactant: Nc1ccc(N2CCCCC2)cc1
Reactant: Brc1ccnc2cc3ccccc3cc12
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1ccc2cc3c(Nc4ccc(N5CCCCC5)cc4)ccnc3cc2c1
Yield: 77.5 %

Procedure:
4-Bromobenzo[g]quinoline (7a) (140 mg, 0.54 mmol), 4-(I-piperidino)aniline (115 mg, 1.2 equivalents), tris(dibenzylideneacetone)dipalladium (Pd2(dbba)3, (10 mg, 0.02 equivalents), 1,1′-bis(diphenylphosphino)ferrocene (DPPF, 12 mg, 0.04 equivalents) and sodium t-butoxide (73 mg, 1.4 equiv) in 5 mL of dry toluene were refluxed under a nitrogen atmosphere until observed complete by TLC (approximately 1 h). The mixture was concentrated in vacuo and purification by flash chromatography (gradient: 5 50:50:2 to 60:40:2 hexane:EtOAc:Et3N) provided 148 mg of clean N-[4-(1-piperidinyl)phenyl]benzo[g]quinolin-4-amine (8) (77% yield).
Reaction SMILES: [C:1](=[O:8])([O:3][CH2:4][CH:5]([OH:7])[CH3:6])[NH2:2].[C:9]([O:14]C(=O)C(C)=C)(=[O:13])[C:10]([CH3:12])=[CH2:11]>COC1C=C(O)C=CC=1O.N1C=CC=CC=1>[C:9]([OH:14])(=[O:13])[C:10]([CH3:12])=[CH2:11].[C:1](=[O:8])([O:3][CH2:4][CH:5]([OH:7])[CH3:6])[NH2:2]
Reactant: C=C(C)C(=O)OC(=O)C(=C)C
Agent: CC(O)COC(N)=O
Agent: COc1cc(O)ccc1O
Solvent: c1ccncc1
Product: C=C(C)C(=O)O
Temperature: 65 °C

Procedure:
A four-necked, five-liter round-bottomed reaction flask equipped with a thermometer, condenser, mechanical stirrer, and air sparger is charged with 1,920 g (16.1 moles) of 2-hydroxypropyl carbamate, 2,236 g (14.5 moles) of distilled methacrylic anhydride, 83 g of anhydrous pyridine, and 4.2 g (1,000 parts per million) methoxyhydroquinone. The reaction mass is stirred and slowly heated to 65° C. with a hot-water bath. During this heating period and during the course of the reaction, the reaction mass is sparged with air. The reaction mass is held at 65° C. until the concentration of methacrylic anhydride decreased to less than 1.5 percent by weight. The resulting product is then washed with a saturated solution of sodium carbonate, and the aqueous layer removed from the solids by decantation. This washing procedure is repeated two more times to neutralize all of the methacrylic acid. The resulting solid product is then washed twice with a total of two gallons of distilled water. For each wash, the solids are melted by heating the wash water to 50° C. During the washing procedure, the melted solids are well stirred and the aqueous material is allowed to separate from the molten organic material and decanted before the desired product resolidifies. The wet product is dried overnight in a hood to yield 2,000 g of anhydrous 2-hydroxypropyl carbamate methacrylate that analysis indicates has a 97% purity.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[C:8]([O:16][CH2:17][CH2:18][O:19][C:20](ON1C(=O)CCC1=O)=[O:21])(=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[C:8]([O:16][CH2:17][CH2:18][O:19][C:20]([NH:1][C@H:2]([CH2:3][OH:4])[C:5]([OH:7])=[O:6])=[O:21])(=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCC(=O)OCCOC(=O)ON1C(=O)CCC1=O
Reactant: N[C@H](CO)C(=O)O
Product: CCCCCCC(=O)OCCOC(=O)N[C@H](CO)C(=O)O
Yield: 55.5 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (0.509 g, 4.8 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl heptanoate (1 g, 4.03 mmol) were reacted to provide 0.683 g (70% yield) of the title compound (36) as a colorless liquid after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.81 (q, 1H), 5.9 (t, 1H), 4.4 (br s, 1H), 4.14-3.98 (m, 2H), 2.36 (t, 2H), 1.63 (t, 2H), 1.5 (d, 3H), 1.3 (m, 6H), 0.85 (t, 3H). MS (ESI) m/z 327.97 (M+Na)+; 304.00 (M−H)−.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:9]Br)=[C:4]([CH2:7][Br:8])[CH2:5]Br.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:12]1([CH3:11])[CH:13]=[CH:14][C:15]([S:18]([N:21]2[CH2:9][C:3]([CH2:2][Br:1])=[C:4]([CH2:7][Br:8])[CH2:5]2)(=[O:19])=[O:20])=[CH:16][CH:17]=1
Reactant: BrCC(CBr)=C(CBr)CBr
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CC(CBr)=C(CBr)C2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.7 %

Procedure:
19 g of tetrakis (bromomethyl)ethylene and 9 g of p-toluene sulfonamide were dissolved in 220 ml of dimethylformamide. 30 g of anhydrous potassium carbonate was added and then stirred at room temperature for 20 hours. Thereafter solvent was removed by vacuum distillation. 50 ml of ethylacetate was added to obtain solid product, and solid product was purified by silica gel column chromatography. 12 g of the title compound was obtained (yield 60%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[C:14](=O)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1C=CC=CC=1>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:22])[C:14]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:23][CH:24]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: Nc1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)C=C(Nc1ccccc1)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Using the procedure of Reynolds and Hauser, Org. Syn. Coll. Vol 3, a mixture of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-oxopentanoate (1.51 g), benzene (15 ml) and aniline (0.5 g) is azeotropically distilled. The reaction product is purified using a florisil column and eluting with hexane/ethylacetate (9:1) to yield (fractions 2, 3 and 4) ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-phenylamino-2-pentenoate.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[S-:10][C:11]#[N:12].[K+].C(O)C>CCCCC>[S:10]([CH2:2][C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4])[C:11]#[N:12]
Reactant: O=C(CCl)N1CCCC1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Solvent: CCCCC
Product: N#CSCC(=O)N1CCCC1
Reaction time: 4 h

Procedure:
1-(α-Chloroacetyl pyrrolidine (14.7 grams; 0.1 mol), potassium thiocyanate (18 grams; 0.2 mol) and ethanol (50 ml) were charged into a glass reaction flask equipped with a mechanical stirrer and reflux condenser. The reaction mixture was heated at reflux, with stirring, for a period of about 4 hours. The mixture was then cooled and filtered. The filtrate was stripped of solvent to yield a solid product. The solid was extracted with three 200 ml portions of boiling benzene, and the benzene extracts were combined and evaporated under reduced pressure to yield an oil. The oil was poured into pentane wherein it solidified. The solid was recrystallized from a benzene-pentane mixture to yield 1-(α-thiocyanoacetyl) pyrrolidine having a melting point of 95° to 96° C. and having the following elemental analysis; calculated for C7H10N2OS.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5]([CH:8]([CH2:13][C:14]([O:16]C)=[O:15])[C:9](OC)=[O:10])(=O)[CH3:6].[Na]>CO>[OH:10][C:9]1[C:8]([CH2:13][C:14]([OH:16])=[O:15])=[C:5]([CH3:6])[N:4]=[C:2]([SH:3])[N:1]=1
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Reactant: NC(N)=S
Agent: [Na]
Solvent: CO
Product: Cc1nc(S)nc(O)c1CC(=O)O
Yield: 94.9 %

Procedure:
Thiourea (80 g, 1.05 mol) and dimethyl acetylsuccinate (188 g, 1.0 mol) are added at room temperature to a solution of sodium (46 g, 2.0 mol) in methanol (800 ml). The reaction mixture is refluxed for 14 hours. The crystalline precipitate is filtered and added with stirring to a concentrated aqueous solution of hydrochloric acid (250 ml). The resulting colorless crystalline precipitate is filtered, washed with methanol and dried at high vacuum to give 4-hydroxy-2-mercapto-6-methyl-5-pyrimidinyl acetic acid (190 g, 95%). 1H-NMR (DMSO):12.4 (s, 1H); 12.3 (s, 1H); 3.4 (s, 2H); 2.1 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:15]1([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>>[CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][N:11]([CH2:24][CH2:23][C:22]([NH:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:25])[CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: CC1=C2CCNCC2c2ccccc21
Reactant: C=CC(=O)Nc1ccccc1
Agent: Cl
Product: CC1=C2CCN(CCC(=O)Nc3ccccc3)CC2c2ccccc21

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and N-phenyl acrylamide are reacted in accordance with the process described in Example 6. Reaction period 4 hours. M.P. of the hydrochloride of the title compound 207°-209° from 95% ethanol.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]([OH:18])=O)=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:4])=[O:3].C1C=C2N=NN(O)C2=CC=1.O.CN1CCOCC1.CCN=C=NCCCN(C)C.[C:54]1([C@@H:60]([NH2:63])[CH2:61][CH3:62])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>O1CCCC1>[CH3:1][S:2]([NH:5][C:6]1[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]([NH:63][C@H:60]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:61][CH3:62])=[O:18])=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Nc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Reactant: CC[C@H](N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H](NC(=O)c1c(NS(C)(=O)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.2 %

Procedure:
A solution of 3-[(methylsulfonyl)amino]-2-phenylquinoline-4-carboxylic acid (1c) (342 mg, 1.0 mmol), HOBT hydrate (231 mg, 1.5 mmol), 4-methylmorpholine (276 μL, 1.5 mmol) in tetrahydrofuran (50 ml) was added EDCI (289 mg, 1.5 mmol) at RT under N2. (S)-1-Phenyl propylamine (135 mg, 1.0 mmol) was then added and the reaction mixture stirred at RT for 12 h. All solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 10% aqueous sodium bicarbonate solution, dried over sodium sulfate and then concentrated in vacuo. The residue was purified by chromatography eluting with 15-25% ethyl acetate/hexane to give the title compound (70 mg, 15%) as a solid. 1H NMR (300 MHz, CDCl3) δ 0.94 (t, 3H), 1.97 (m, 2H), 3.44 (s, 3H), 5.17 (q, 1H), 5.47 (m, 2H), 7.32 (d, 2H), 7.34 (d, 2H), 7.39 (m, 1H), 7.78 (m, 2H), 7.84 (m, 2H), 8.08 (m, 1H), 8.30 (m, 2H), 8.42 (m, 2H). MS APCI, m/z=460 (M+1). LCMS: 2.51 min.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33]Cl.Cl>C(#N)C.C(OCC)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:33][CH2:32][N:31]([CH3:35])[CH3:30])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: CN(C)CCCl
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(O)ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CN(C)CCOc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 32.7 %

Procedure:
To a solution of 2-chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)benzamide from Example 51 (0.05 g) in acetonitrile (5 ml) was added potassium carbonate (0.065 g) and 2-dimethylaminoethyl chloride hydrochloride (0.037 g). The reaction mixture was stirred and heated at reflux temperature for 48 hours. The reaction mixture was evaporated under reduced pressure and residue dissolved in ethyl acetate and washed with brine. Drying over sodium sulphate (Na2SO4), followed by concentration under reduced pressure gave a residue which was subsequently purified by supercritical chromatography, eluting with CO2/methanol/0.1% diethylamine. Fractions containing product were concentrated under reduced pressure and the residue obtained was dissolved in diethyl ether. Hydrogen chloride (1 ml of a 1M solution in diethyl ether) was added dropwise and the resulting solid was triturated under diethyl ether and then dried in vacuo to leave the title compound as a white solid (0.020 g).
Reaction SMILES: [O:1]1[CH2:10][CH:2]1[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N-:11]=[N+:12]=[N-:13].[Na+].C(OC)=O.CO>O>[C:4]1([CH2:3][CH:2]([OH:1])[CH2:10][N:11]=[N+:12]=[N-:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: c1ccc(CC2CO2)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: COC=O
Product: [N-]=[N+]=NCC(O)Cc1ccccc1
Yield: 91.3 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 5 g of (±)-(2,3-epoxypropyl)benzene, 12.1 g of sodium azide, 60 ml of methyl formate and 270 ml of an 8:1 by volume mixture of methanol and water were used, to give 6.03 g of the title compound as a colorless oil having an Rf value of 0.3 (on silica gel thin layer chromatography, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][F:11].[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>C1COCC1.[Cl-].[Na+].O.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[C:9](=[N:19]\[S@@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])/[CH2:10][F:11]
Reactant: O=C(CF)c1cccc(F)c1F
Reactant: CC(C)(C)[S@](N)=O
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[S@@](=O)/N=C(/CF)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.7 %

Procedure:
To a solution of 1-(2,3-difluorophenyl)-2-fluoroethanone (18.9 g, 109 mmol) in THF (400 mL) was added (R)-(+)-2-methyl-2-propanesulfinamide (26.3 g, 217 mmol) followed by tetraisopropoxytitanium (93 g, 326 mmol). The reaction was heated to reflux for 2 h. The mixture was allowed to cool to room temperature and then treated with brine (400 ml). The resulted suspension was stirred for 15 min and filtered through a pad of celite. The filter cake was washed with EtOAc. The filtrate was extracted with EtOAc (2×). The organic extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (0-20% EtOAc/hexane) to afford (R,E)-N-(1-(2,3-difluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (12.3 g, 44.4 mmol, 40.9% yield) as yellow oil, MS m/z=278.0 [M+H]+. calculated for C12H14F3NOS: 277.3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]([F:36])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]([F:36])([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1)=[O:23]
Reactant: Cc1ccc(Cl)c(Nc2c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc12
Yield: 21.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-chloro-5-methylphenylamino)-6-(4-fluoro-4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (71 mg, 0.14 mmol) obtained in step 2 and ethanesulfonamide (74 mg, 0.7 mmol), the title compound (18 mg, 22%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(O[CH:14](OCC)[N:15]([CH3:17])[CH3:16])C>CCO>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])/[CH:9]=[CH:14]\[N:15]([CH3:17])[CH3:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: CCOC(OCC)N(C)C
Solvent: CCO
Product: CN(C)/C=C\C(=O)c1cccc(Br)c1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a stirred solution of 1-(3-bromophenyl)ethanone (4 g, 20 mmol) in EtOH (60 ml), was added at room temperature N,N-Dimethylformamide diethylacetal (7.15 g, 60 mmol) and the mixture was stirred at reflux temperature for 2 hours. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was purified using normal phase chromatography, eluting with petroleum ether containing 50% ethyl acetate to give (Z)-1-(3-bromophenyl)-3-(dimethylamino)prop-2-en-1-one (3.0 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:13]=[O:14]>[OH-].[Na+]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[C:7]([CH2:13][OH:14])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: Oc1ccnc2cc(Br)ccc12
Agent: [Na+]
Agent: [OH-]
Product: OCc1cnc2cc(Br)ccc2c1O

Procedure:
7-Bromo-4-hydroxyquinoline was reacted with formaldehyde in aqueous sodium hydroxide to give the novel compound 7-bromo-4-hydroxy-3-hydroxymethylquinoline, m.p. >300°
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=3)[C:28](O)=[O:29])[CH2:20][CH2:19]2)=[C:14]([CH3:34])[N:13]([CH2:35][C:36]2[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:39]=[CH:38][C:37]=2[F:46])[C:12]1=[O:47])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[CH2:55]([O:57][C:58](=[O:63])[CH2:59][CH2:60][CH2:61][NH2:62])[CH3:56].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:55]([O:57][C:58](=[O:63])[CH2:59][CH2:60][CH2:61][NH:62][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([CH2:24][N:21]2[CH2:22][CH2:23][N:18]([C:15]3[C:16](=[O:17])[N:11]([CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:12](=[O:47])[N:13]([CH2:35][C:36]4[C:41]([C:42]([F:44])([F:45])[F:43])=[CH:40][CH:39]=[CH:38][C:37]=4[F:46])[C:14]=3[CH3:34])[CH2:19][CH2:20]2)[CH:26]=1)[CH3:56]
Reactant: Cc1c(N2CCN(Cc3cccc(C(=O)O)c3)CC2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reactant: CCOC(=O)CCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCNC(=O)c1cccc(CN2CCN(c3c(C)n(Cc4c(F)cccc4C(F)(F)F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c4ccccc4)c3=O)CC2)c1
Yield: 99.7 %

Procedure:
To a solution of 3-{4-[3-((R)-2-tert-butoxycarbonylamino-2-phenyl-ethyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-piperazin-1-ylmethyl}-benzoic acid (40 mg, 0.0541 mmol) and 4-amino-butyric acid ethyl ester chloride (19 mg, 0.108 mmol) in DMF (0.5 mL) was added N,N-diisopropylethylamine(38 μl, 0.216 mmol), after which HBTU (51 mg, 0.162 mmol) was added to the solution, with stirring. The solution was concentrated at room temperature for 6 hrs, with stirring. The residue was diluted in EtOAc and washed with an aqueous saturated sodium bicarbonate solution, an aqueous saturated ammonium chloride solution, and an aqueous saturated sodium chloride solution in that order. After being separated, the organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified using silica gel chromatography (eluent: dichloromethane/methanol, 30/1) and dried in a vacuum to afford 46 mg of the compound as a yellowish solid (yield 99%). 1H NMR (300 MHz, CDCl3) δ 1.24 (3H, t), 1.34 (9H, s), 1.98 (2H, pentet), 2.31 (2H, m), 2.34 (3H, s), 2.44 (2H, t), 2.53 (2H, m), 2.82 (2H, m), 3.53 (2H, q), 3.64 (4H, m), 4.06 (1H, m), 4.12 (2H, q), 4.24 (1H, t), 5.00 (1H, m), 5.45 (2H, dd), 5.78 (1H, m), 6.30 (0.2H, t), 6.77 (0.8H, t), 7.20-7.41 (8H, m), 7.53 (2H, t), 7.83 (1H, d), 7.71 (1H, d), 7.75 (1H, s)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[CH3:16][S:17]([NH2:20])(=[O:19])=[O:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2/[CH:14]=[N:20]/[S:17]([CH3:16])(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: CS(N)(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1/C=N/S(C)(=O)=O

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (2 g, 7.5 mmol) was mixed with methanesulfonamide (0.714 g, 7.5 mmol) and p-toluenesulfonic acid monohydrate (0.010 g, 0.053 mmol) in toluene. The reaction was heated to reflux for 24 hours with Dean-Stark apparatus in place. Upon cooling the product precipitated from the reaction mixture and was isolated by filtration to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.Br[CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15]>>[CH3:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][N:6]1[CH:5]=[C:4]([CH3:7])[S:3][C:2]1=[NH:1]
Reactant: Cc1cnc(N)s1
Reactant: COCCOCCBr
Product: COCCOCCn1cc(C)sc1=N
Yield: 83.8 %

Procedure:
A mixture of 2-amino-5-methylthiazole (1.5 g, 13.0 mmol) and 1-bromo-2-(2-methoxyethoxy)ethane (Aldrich, 2.0 mL, 14.5 mmol) was processed as in Example 157A to afford the title compound (2.2 g, 10.9 mmol, 78% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.29 (d, J=1.36 Hz, 3H) 3.34 (s, 3H) 3.49-3.54 (m, 2H) 3.60-3.66 (m, 2H) 3.80 (t, J=5.10 Hz, 2H) 4.13 (t, J=4.80 Hz, 2H) 6.99-7.04 (m, 1H); MS (DCI/NH3) m/z 217 (M+H)+.
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:30](=[O:31])[N:6]2[C:7]([C:14]([O:16][CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:8]([C:12]#[CH:13])[CH2:9][S:10](=O)[C@H:5]12)=[O:2].P(Cl)(Cl)Cl.O.C(OCC)(=O)C>CN(C)C=O>[CH:1]([NH:3][CH:4]1[C:30](=[O:31])[N:6]2[C:7]([C:14]([O:16][CH:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:15])=[C:8]([C:12]#[CH:13])[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: C#CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC=O)[C@H]2S(=O)C1
Solvent: O
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: C#CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC=O)[C@H]2SC1
Yield: 9.9 %

Procedure:
To a solution of benzhydryl 7-formamido-3-ethynyl-3-cephem-4-carboxylate-1-oxide (12 g) in N,N-dimethylformamide (96 ml) was added phosphorus trichloride (0.48 ml) at -20° C. and the resultant mixture was stirred at -20° C. to -10° C. for 10 minutes. After water and ethyl acetate were added to the reaction mixture, the separated organic layer was washed with water and brine, dried over magnesium sulfate. The solution was evaporated in vacuo to give benzhydryl 7-formamido-3-ethynyl-3-cephem-4-carboxylate (1.15 g).