Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]=[N:3]C1CC(C)(C)CC(C)(CN=C=O)C1.C([C:21]1C=C(C)C=C(C(C)(C)C)[C:22]=1[OH:32])(C)(C)C.C1OC1.C1OC1C.OCC[O:43][C:44](=[O:47])[CH:45]=[CH2:46]>>[C:44]([OH:47])(=[O:43])[CH:45]=[CH2:46].[NH2:3][C:2]([O:32][CH2:22][CH3:21])=[O:1]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: C=CC(=O)OCCO
Agent: CC1CO1
Solvent: C1CO1
Product: C=CC(=O)O
Product: CCOC(N)=O
Reaction time: 5 h

Procedure:
To a reaction vessel equipped with a stirrer, 100 gm of ARONIX M113 manufactured by Toagousei Chemicals, 124.7 gm of isophorone diisocyanate, 1 gm of dibutyltindilaurate, and 0.3 gm of 2,6-di-t-butyl-4-methylphenol were added. To this, 842.7 gm of a copolymerization diol of ethylene oxide and 1,2-propylene oxide [ethylene oxide: 1,2 propylene oxide=2:8 (by weight)] of a number average molecular weight of 2,000 was added while maintaining the temperature in the 40° to 50° C. range, and the mixture was reacted for 2 hours. Then 32.6 gm of hydroxyethylacrylate was added, after which the mixture was continuously stirred for 5 hours at 50° to 60° C. to complete the reaction. A urethane acrylate [C-1] of a number average molecular weight of about 7,120 was obtained.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[NH:8][C:9]1[C:10]2[N:11]([CH:18]=[C:19]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=3)[CH:20]=2)[N:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16])[CH3:2].Cl[C:35]1[S:36][C:37]([C:40]#[N:41])=[CH:38][N:39]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[C:40]([C:37]1[S:36][C:35]([N:6]2[CH2:7][C@H:3]([CH2:1][CH3:2])[C@H:4]([NH:8][C:9]3[C:10]4[N:11]([CH:18]=[C:19]([C:21]5[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=5)[CH:20]=4)[N:12]=[CH:13][C:14]=3[C:15]([NH2:17])=[O:16])[CH2:5]2)=[N:39][CH:38]=1)#[N:41]
Reactant: N#Cc1cnc(Cl)s1
Reactant: CC[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H]1CN(c2ncc(C#N)s2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 22 %

Procedure:
A mixture of 4-(((3S,4S)-4-ethylpyrrolidin-3-yl)amino)-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide, 2hydroiodide from Step 5 of Example 266 (30 mg, 0.042 mmol), 2-chlorothiazole-5-carbonitrile (7.36 mg, 0.051 mmol) and diisopropylethylamine (0.052 mL, 0.297 mmol) in DMA (0.25 mL) was heated to 100° C. for 2 hr. The reaction mixture was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×150 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (5.3 mg, 0.024 mmol, 22% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.80 (d, J=2.0 Hz, 1H), 8.14 (s, 1H), 8.02 (dd, J=8.2, 2.2 Hz, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.69 (s, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.14 (d, J=1.5 Hz, 1H), 5.07 (t, J=4.5 Hz, 1H), 4.58 (s, 2H), 4.01 (dd, J=10.9, 4.0 Hz, 1H), 3.97 (s, 2H), 3.83 (d, J=7.9 Hz, 2H), 3.46 (s, 4H), 2.79-2.66 (m, 1H), 1.77 (tq, J=14.6, 7.1 Hz, 2H), 1.04 (t, J=7.4 Hz, 3H). MS (ES+) m/z: 560.1 (M+H); LC retention time: 1.31 min (analytical LCMS Method H).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]1[C:9](=[O:20])[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)[C:4]([OH:6])=[O:5].[OH-].[Na+].[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.Cl>O>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:2][CH:3]([CH2:7][C:8]2[C:9](=[O:20])[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=3)[C:4]([OH:6])=[O:5])=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1ccc2[nH]c(=O)c(CC(N)C(=O)O)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2[nH]c(=O)c(CC(NC(=O)c3ccc(Cl)cc3)C(=O)O)cc2c1

Procedure:
1.5 Grams of 2-amino-3-(6-methoxy-2-quinolon-3-yl)propionic acid hydrochloride was dissolved in a solution containing 0.8 g of sodium hydroxide in 25 ml of water, then under ice-cooled condition, 1 g of p-chlorobenzoyl chloride was added dropwise with stirring. The reaction was carried out by adding 1N-sodium hydroxide aqueous solution and p-chlorobenzoyl chloride properly, until the starting material os disappeared from the reaction mixture by checking a sample of the reaction mixture through a thin-layer-chromatograph. After completion of the reaction, the reaction mixture was acidified with hydrochloric acid, the crystals precipitated were collected by filtration. The crystals were washed with ether, then recrystallized from methanol-water to obtain 0.7 g of 2-(4-chlorobenzoylamino)-3-(6-methoxy-2-quinolon-3-yl)propionic acid in the from of yellowish powdery product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].C1C[O:13][CH2:12]C1.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl>O>[Cl:1][C:2]1[C:3]2[NH:9][C:12](=[O:13])[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: Nc1cccc(Cl)c1N
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O
Product: O=c1[nH]c2cccc(Cl)c2[nH]1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
To a solution of 3-chloro-benzene-1,2-diamine (0.820 g, 5.75 mmol) and THF (25 mL), was added carbonyl diimidazole (1.12 g, 6.90 mmol) at 0° C. The mixture was stirred for 16 h and allowed to warm to 23° C. A solution of 1M aqueous HCl (25 mL) was added to the reaction mixture at 0° C., followed by water (100 mL) and the mixture was stirred for 1 h. The precipitated solid was filtered and dried under high vacuum for 18 h to yield the titled compound, which was used in the next step without further purification (0.800 g, 83%). MS (ESI/CI): mass calcd. for C7H5ClN2O, 168.0; m/z found, 169.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 11.13 (s, 1H), 10.88 (s, 1H), 7.00-6.86 (m, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH2:12]O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:5][C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH2:12][Cl:3]
Reactant: Cc1csc(CO)c1Cl
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1csc(CCl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (2.1 ml) was added dropwise to a chloroform (30 ml) solution of (3-chloro-4-methyl-2-thienyl)methanol (2.34 g), followed by stirring at room temperature for 30 minutes. The reaction solution and chloroform were added to a saturated aqueous sodium hydrogen carbonate solution and then the organic layer was separated. Furthermore, the organic layer washed with brine and, after drying over anhydrous sodium sulfate and filtration, the solvent was removed by evaporation under reduced pressure to obtain 3-chloro-2-(chloromethyl)-4-methylthiophene. Sodium cyamide (1.06 g) and water (15 ml) were added to an acetone (9 ml) solution of 3-chloro-2-(chloromethyl)-4-methylthiophene, followed by stirring at 60° C. for 1 hour. After water and ether were added to the reaction solution, the organic layer was separated. Furthermore, the organic layer washed with brine and, after drying over anhydrous sodium sulfate and filtration, the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by column chromatography (hexane:ethyl acetate=9:1) to obtain 1.33 g of (3-chloro-4-methyl-2-thienyl)acetonitrile (yellow oil).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][N:17]=2)[CH2:12][CH2:11]1)C(=O)OC(C)(C)C.C([Cl:25])(=O)C>C(O)C.C(OCC)C>[ClH:25].[ClH:25].[CH3:1][NH:2][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][N:17]=2)[CH2:12][CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccncn2)CC1
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: CCO
Product: CNC1CCN(c2ccncn2)CC1
Product: Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
tert-Butyl methyl(1-(pyrimidin-4-yl)piperidin-4-yl)carbamate (3.63 mmol, 1 eq) was dissolved in ethanol (13 ml), and acetyl chloride (18.13 mmol, 5.0 eq) was added while cooling with ice. The reaction mixture was then stirred for 2 hours at 40° C. The reaction mixture was concentrated under reduced pressure. A white precipitate formed from the concentrated solution. The suspension was diluted with diethyl ether and stirred for 1 hour at RT. Then the precipitate was filtered off with suction, washed with diethyl ether and dried. Yield: 96%
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=3Br)[C@H:14]2[CH3:30])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1(C)C=CC=CC=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]([CH3:49])[CH3:48])=[CH:43][C:42]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=3[C:42]3[CH:43]=[C:44]([CH:47]([CH3:49])[CH3:48])[CH:45]=[CH:46][C:41]=3[Cl:40])[C@H:14]2[CH3:30])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)c1ccc(Cl)c(B(O)O)c1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc([N+](=O)[O-])ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)c1ccc(Cl)c(-c2ccc([N+](=O)[O-])cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 80 °C

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-nitrobenzyl)-4-methyl-1,3-oxazolidin-2-one (950 mg, 1.80 mmol) in a toluene (5.2 mL): ethanol (2.6 mL): water (1.3 mL) mixture was added (2-chloro-5-isopropylphenyl) boronic acid (325 mg, 1.64 mmol), tetrakis(triphenylphosphine)palladium(0) (188 mg, 10 mol %) and sodium carbonate (346 mg, 3.26 mmol). The resulting mixture was heated in an 80° C. oil bath for 12 h. The reaction crude was evaporated into dryness. The resulting residue was taken up by a mixture of water and EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by SiO2 (Biotage 40+S cartridge, EtOAc/hexane, gradient) to afford the titled compound. LC-MS: 601.19 (M+1)+. 1H NMR (CDCl3, 500 MHz) a 1:1 mixture of rotamers δ 8.31-8.30 (m, 1H), 8.24-8.28 (m, 1H), 7.85-7.89 (m, 1H), 7.68-7.76 (m, 2H), 7.42-7.48 (m, 2H), 7.26-7.30 (m, 1H), 7.04-7.11 (m, 1H), 5.74 (d, J=7.8 Hz, 0.5H), 5.58 (d, J=8.0 Hz, 0.5H), 4.92 (d, J=15.8 Hz, 0.5H), 4.76 (d, J=16.2 Hz, 0.5H), 3.97-4.04 (m, 1.5H), 3.82 (dt, J=8.0, 6.6 Hz, 0.5H), 2.89-2.99 (m, 1H) 1.22-1.29 (m, 6H), 0.60 (d, J=6.4 Hz, 1.5H), 0.52 (d, J=6.6 Hz, 1.5H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH3:31])[CH:26]=[C:25]2[C:32]#[N:33]>O1CCCC1.O>[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH3:31])[CH:26]=[C:25]2[C:32]1[NH:33][C:19]2=[N:18][CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=1
Reactant: COc1ccc2c(c1)c(C#N)cn2C
Reactant: Cc1cnccn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)c(-c1cc3nccnc3[nH]1)cn2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.5 %

Procedure:
A stirred solution of diisopropylamine (59.9 mL) in tetrahydrofuran (1400 mL), at −15° C. and under nitrogen, was treated with a solution of n-butyllithium in hexanes (131 mL, 1.6M) over 25 minutes, whilst maintaining the temperature below −10° C. After stirring for 30 minutes the mixture was treated with methylpyrazine (26.8 g) over 15 minutes, then stirred for 1 hour and then treated with a solution of 5-methoxy-1-methyl-1H-indole-3-carbonitrile [53 g, Reference Example 1(a)] in tetrahydrofuran (600 mL) over 1 hour, keeping the temperature below −10° C. The reaction mixture was allowed to warm to room temperature over 2 hours, then stood overnight, then treated with water (100 mL). The tetrahydrofuran was removed in vacuo and the resultant mixture was partitioned between ethyl acetate (500 mL) and water (20 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (200 mL). The combined organics were washed with water (500 mL) then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (19:1, v/v) to give the title compound (19.4 g) as a grey solid, m.p. 270-272° C. MS: 279 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH:23]=[CH:22][C:21](NCC)=[N:20][C:19]2=[O:27])=[CH:4][CH:3]=1.ClC1C=CN(CC2N3C=CC=CC3=NC=2C2C=CC(Cl)=CC=2)C(=O)N=1.[CH3:53][CH2:54][O-:55].[Na+]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH:23]=[CH:22][C:21]([O:55][CH2:54][CH3:53])=[N:20][C:19]2=[O:27])=[CH:6][CH:7]=1
Reactant: CC[O-]
Reactant: CCNc1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)n1
Agent: O=c1nc(Cl)ccn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)n1

Procedure:
The title compound was prepared according to the experimental for compound 132 from 4-chloro-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-one and NaOEt in EtOH. M/e+ 381 for C20H18ClN4O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.36 (d, J=7.0 Hz, 1H), 8.17 (s, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.30 (m, 1H), 6.92 (m, 1H), 6.89 (d, J=6.9 Hz, 1H), 5.71 (d, J=6.9 Hz, 1H), 5.60 (s, 2H), 4.40 (q, J=6.9 Hz, 2H), 1.32 (t, J=6.9 Hz, 3H) ppm.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH:16]3[CH2:25][CH2:24][C:19]4([CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:18][CH2:17]3)[CH:11]=2)[CH:6]=1)=O.O1CCCC1>[AlH4-].[Li+]>[CH2:20]1[C:19]2([CH2:24][CH2:25][CH:16]([O:15][C:10]3[CH:11]=[C:12]4[C:7](=[CH:8][CH:9]=3)[CH:6]=[C:5]([CH2:3][OH:2])[CH:14]=[CH:13]4)[CH2:17][CH2:18]2)[CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1ccc2cc(OC3CCC4(CCCC4)CC3)ccc2c1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2cc(OC3CCC4(CCCC4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
6-(Spiro[4.5]dec-8-yloxy)-naphthalene-2-carboxylic acid methyl ester (0.312 g, 0.000922 mol) in tetrahydrofuran (9 mL, 0.1 mol) and 1.0 M of lithium tetrahydroaluminate in tetrahydrofuran (2.76 mL, 0.00276 mol) was added at 0° C. After stirring at rt for 2 h, quench with EtOAc, then Rochele's salt was added and stirred at rt for 1 h. Extraction with EtOAc, c/c give the product as a white solid (257.2 mg, 90%). LCMS Rt=2.21 min m/z=293.30 ([M-17], 100%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][OH:9])[CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][CH2:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)(=[O:20])=[O:19]
Reactant: OCCC1CCCOC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1CCCOC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 2-(tetrahydro-2H-pyran-3-yl)ethanol (1.54 gm) and triethylamine (3.3 ml) in dichloromethane (25 ml) was cooled (ice bath) and methanesulphonyl chloride (1.19 ml) added dropwise with stirring over 5 min. The reaction slowly warmed to ambient temperature as the ice bath melted. After 16 h the mixture was washed with saturated aq. sodium hydrogen carbonate, the aqueous layer extracted twice with dichloromethane and the combined extracts washed with dilute brine, dried by passing through a hydrophobic frit and evaporated to give the title compound as a brown oil, yield 2.38 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][CH2:20][CH3:21])=[C:6]([C:8]2[N:16]=[C:15]3[C:11](=[N:12][N:13]=[N:14]3)[C:10](=[O:17])[N:9]=2)[CH:7]=1.C(O[CH:25]=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])C>S1(CCCC1)(=O)=O>[CH4:2].[CH2:35]([O:34][C:32]([C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][CH2:20][CH3:21])=[C:6]([C:8]2[N:16]=[C:15]3[C:11](=[N:12][N:13]=[N:14]3)[C:10](=[O:17])[N:9]=2)[CH:7]=1)=[O:33])[CH3:36]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCCOc1ccc(N)cc1C1=NC(=O)C2=NN=NC2=N1
Solvent: O=S1(=O)CCCC1
Product: C
Product: CCCOc1ccc(NC=C(C(=O)OCC)C(=O)OCC)cc1C1=NC(=O)C2=NN=NC2=N1
Temperature: 140 °C
Reaction time: 1 h
Yield: 113.7 %

Procedure:
A suspension of 2-(5-amino-2-propoxyphenyl)-8-azapurin-6-one (1.43 g) in dry sulpholane (15 ml) was treated with diethyl ethoxymethylenemalonate (1.25 g). The mixture was then stirred at 140° C. for one hour, under a slight vacuum in order to remove ethanol. After cooling, the mixture was poured with stirring into dilute hydrochloric acid (150 ml; 2 N), to give a buff-coloured gum which, on scratching, crystallised. Recrystallisation twice from a mixture of dimethylformamide and water, with the aid of charcoal, gave 2-[5-{2,2-bis(ethoxycarbonyl)-vinylamino}-2-propoxyphenyl]-8-azapurin-6-one (1.3 g), m.p. 226°-227° C.
Reaction SMILES: [ClH:1].[CH:2]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1>>[ClH:1].[CH:2]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][C:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)([OH:15])[CH:11]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:10]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cccc(Br)c1
Reactant: CN(C)CC1CC(CCC2CCCC2)CCC1=O
Agent: Cl
Product: COc1cccc(C2(O)CCC(CCC3CCCC3)CC2CN(C)C)c1
Yield: 54 %

Procedure:
The base of compound (56) was reacted with 1-bromo-3-methoxy-benzene corresponding to the conditions described in Example 1. The base obtained was purified with diisopropyl ether via a silica gel column and was taken up in ether. After adding trimethylchlorosilane/water, compound (52) was obtained in a yield of 54% theoretical.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2].[CH2:13]([NH:20][C:21](=[O:42])[CH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[O:29][C:28]([CH3:34])([CH3:33])[CH:27]([OH:35])[CH:26]2[NH:36][CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.O>ClCCl>[CH2:13]([NH:20][C:21](=[O:42])[CH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[O:29][C:28]([CH3:34])([CH3:33])[CH:27]([OH:35])[CH:26]2[N:36]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)CNC1c2cc(CC(=O)NCc3ccccc3)ccc2OC(C)(C)C1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCc1ccc(S(=O)(=O)N(CC(C)(C)C)C2c3cc(CC(=O)NCc4ccccc4)ccc3OC(C)(C)C2O)cc1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
4.1 ml 4-ethyl benzenesulfonyl chloride was added dropwise to a solution of 10.8 g of the N-benzyl-2-[3-hydroxy-2,2-dimethyl-4-(neopentylamino)-3,4-dihydro-2H-chromen-6-yl]acetamide obtained above in Example 3 and 5 ml triethylamine in 100 ml dichloromethane. Dichloromethane was immediately substantially completely evaporated at reduced pressure, and the resulting reaction mixture was stirred for 90 minutes at 65° C. and 180 bar. The entire batch was poured into 150 ml water, and the aqueous phase was extracted once with 200 ml ethyl acetate. The solvent was largely evaporated at reduced pressure, the remaining residue was dried over sodium sulfate, and the remaining residue was chromatographed on silica gel (mobile phase: petroleum ether/ethyl acetate 3:1 v/v). Drying the product fractions in an oil pump vacuum yielded 3.6 g of the title compound (2 conformers) as colorless oil.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][C:18]([CH3:23])=[C:19]([CH:21]=[CH2:22])[N:20]=2)=[CH:12][CH:11]=1.CCOC(C)=O.[OH2:30]>CS(C)=O>[Br:8][CH2:22][CH:21]([C:19]1[N:20]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([Br:9])=[CH:15][CH:14]=2)[O:17][C:18]=1[CH3:23])[OH:30]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=Cc1nc(-c2ccc(Br)cc2)oc1C
Reactant: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1oc(-c2ccc(Br)cc2)nc1C(O)CBr
Yield: 74 %

Procedure:
Add NBS (1.44 g, 8.08 mmol) to a solution of 2-(4-bromo-phenyl)-5-methyl-4-vinyl-oxazole (1.01 g, 4.02 mmol) in water (0.180 mL) and DMSO (30 mL). After 10 min add water and EtOAc. Separate the layers, extract aqueous material with EtOAc, and wash the crude organic extracts with water. Dry over MgSO4, filter and concentrate. Purify on silica gel eluting with 20% EtOAc/Hexanes to give the title compound (1.08 g, 74%): MS (m/e): 362 (M+1).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:33])[C@@H:24]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:21]2[S:20][CH2:19][C:18]=1[CH:34]=[CH:35][S:36][C:37]1[S:38][C:39]2[CH:47]=[C:46]([CH2:48]O)[CH:45]=[CH:44][C:40]=2[C:41](=[O:43])[CH:42]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:52])=O>C1C=CC=CC=1>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:33])[C@@H:24]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:21]2[S:20][CH2:19][C:18]=1[CH:34]=[CH:35][S:36][C:37]1[S:38][C:39]2[CH:47]=[C:46]([CH2:48][Cl:52])[CH:45]=[CH:44][C:40]=2[C:41](=[O:43])[CH:42]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3cc(=O)c4ccc(CO)cc4s3)CS[C@H]12
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3cc(=O)c4ccc(CCl)cc4s3)CS[C@H]12
Temperature: 25 °C
Yield: 88.9 %

Procedure:
7β-Tert-butoxycarbonylamino-3-[2-(7-hydroxymethyl-4-oxo-4H-1-benzothiopyran-2-yl)thiovinyl]-3-cephem-4-carboxylic acid benzhydryl ester (330 mg, 0.46 mmol) was suspended in anhydrous benzene (10 ml), added dropwise with thionyl chloride (0.55 ml, 7.59 mmol) while stirred at room temperature. Then, the reaction mixture was stirred at 50 minutes, added with ice water and extracted with ethyl acetate (50 ml). Ethyl acetate layer was washed with saturated saline solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was crystallized from isopropyl ether to obtain 300 mg (yield: 89%) of 7β-tert-butoxycarbonylamino-3-[2(7-chloromethyl-4-oxo-4H-1-benzothiopyran-2-yl)thiovinyl]-3-cephem-4-carboxylic acid benzhydryl ester. Further, the process similar to that shown in (2) of the Example 1 was conducted to obtain 160 mg (yield: 62%) of the titled compound.