Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:34]([F:39])([F:38])C([O-])=O.[Na+].[F-:41].[K+]>COCCOCCOC.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:34]([F:39])([F:41])[F:38])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Reactant: [F-]
Agent: [K+]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOCCOC
Solvent: O
Product: FC(F)(F)C(c1ccc(Br)cc1)C(F)(F)F
Temperature: 150 °C
Reaction time: 1 h

Procedure:
1-(4-Bromo-phenyl)-2,2,2-trifluoro-ethanone (500 mg, 2 mmol) and triphenylphosphine (1.05 g, 4 mmol) were dissolved in diglyme (25 ml) and heated to 150° C. in a three-neck flask fitted with both an addition funnel and a reflux condenser under nitrogen. A solution of sodium chlorodifluoroacetate, dissolved in diglyme (13 ml), was slowly added via the addition funnel. The addition took about one hour. After it was complete, the reaction mixture was allowed to stir for an additional hour. It was then cooled to below 100° C., and potassium fluoride (476 mg, 8.2 mmol) and water (0.3 ml) were added. The mixture was allowed to stir for 18 h at 95° C. The reaction mixture was heated to 130° C., water was added and the title product was steam distilled into a collection flask (with a large amount of diglyme, complicating yield calculations). 1H NMR (CDCl3) δ=7.61 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 4.06 (septet, JH,F=8.2 Hz, 1H).
Reaction SMILES: [N:1]([CH2:4][C:5]1([OH:14])[CH2:10][CH2:9][CH2:8][N:7]2[CH:11]=[N:12][CH:13]=[C:6]12)=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][CH2:4][C:5]1([OH:14])[CH2:10][CH2:9][CH2:8][N:7]2[CH:11]=[N:12][CH:13]=[C:6]12
Reactant: [N-]=[N+]=NCC1(O)CCCn2cncc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NCC1(O)CCCn2cncc21

Procedure:
3 mmol of 8-azidomethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol are taken up in 10 ml of methanol and the solution is admixed with 0.30 mmol of 10% Pd/C. The reaction mixture is hydrogenated with a hydrogen pressure of 1 bar at 22° C. for 1-10 hours. The catalyst is filtered off over Hyflo and the filtrate is evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: Cl[C:2]1[C:3](=[O:13])[N:4]([CH2:9][CH2:10][S:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Br:15][C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[C:20]2[C:24]=1[NH:23][CH2:22][CH2:21]2>>[Br:15][C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[C:20]2[C:24]=1[N:23]([C:2]1[C:3](=[O:13])[N:4]([CH2:9][CH2:10][S:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:22][CH2:21]2
Reactant: COc1cc(Br)c2c(c1)CCN2
Reactant: CSCCn1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: COc1cc(Br)c2c(c1)CCN2c1nc(Cl)cn(CCSC)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[2-(methylthio)ethyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. 1H NMR (300 MHz, CDCl3): δ 6.93 (d, J=2.5 Hz, 1 H), 6.88 (s, 1 H), 6.79 (d, J=2.5 Hz, 1 H), 4.36 (t, J=7.7 Hz, 2 H), 4.05 (t, J=7.0 Hz, 2 H), 3.78 (s, 3 H), 3.10 (t, J=7.5 Hz, 2 H), 2.90 (t, J=7.0 Hz, 2 H), 2.17 (s, 3 H); HRMS (CI) calcd for C16H17N3O2SBrCl (M+): 428.9913; found m/z 428.9899.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.S(C1C=CC(C)=CC=1)(O)(=O)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH2:36][CH2:37][C:38]1[N:42]([C:43]2[S:44][C:45]([CH2:57][CH3:58])=[CH:46][C:47]=2[C:48](=[O:56])[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:55])[C:41]([CH3:59])=[N:40][N:39]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[C:48]([C:47]1[CH:46]=[C:45]([CH2:57][CH3:58])[S:44][C:43]=1[N:42]1[C:41]([CH3:59])=[N:40][N:39]=[C:38]1[CH2:37][NH:36][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)=[O:13])=[O:56]
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2cc3cc(F)ccc3[nH]2)s1
Reaction time: 4 h
Yield: 15.8 %

Procedure:
5-Fluoroindole-2-carboxylic acid (0.50 g) and 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole ditosylate (2.07 g) were dissolved in dimethylformamide (40 ml). Triethylamine (1.6 ml) and 1-benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (Bop reagent, 1.29 g) were added under ice-cooling, and the mixture was stirred for 4 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with an aqueous citric acid solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the obtained residue was crystallized from ethyl acetate to give 0.23 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-5-fluoroindole-2-carboxamide.
Reaction SMILES: [C:1]1(=[O:29])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:24])[C:3]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]12.C(N1C=CN=C1)([N:32]1C=CN=C1)=O>>[C:1]1(=[O:29])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:13]([O:22][CH3:23])[CH:12]=2)[CH2:7][C:8]([NH2:32])=[O:9])[C:4](=[O:24])[C:3]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCOc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC
Product: CCCCOc1ccc(C(CC(N)=O)N2C(=O)c3ccccc3C2=O)cc1OC

Procedure:
By following the procedure of Example 65 utilizing 3-phthalimido-3-(4-butoxy-3-methoxyphenyl)propionic acid and carbonyldiimidazole, there is obtained 0.742 g (74%) of crude product as a pale yellow powder. The crude product was recrystallized from ethyl acetate (16 mL) to afford 0.517 (52%) of 3-phthalimido-3-(4-butoxy-3-methoxyphenyl)propionamide as fine fluffy white needles: HPLC 99.1%; 1H NMR (DMSO-d6) δ7.95-7.75 (m, 4H, Ar), 7.54 (br s, 1H, CONH), 7.04 (s, 1H, Ar), 7.0-6.75 (m, 2H), 6.86 (br s, 1H, CONH), 5.67 (t, 1H, J=8 Hz), 3.90 (t, 2 H, J=6 Hz), 3.73 (s, 3H), 3.20 (d, 1H, J=8 Hz, CH2CO), 1.8-1.55 (m, 2H) 1.5-1.3 (m, 2H), 0.91 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6) δ171.2, 167.6, 148.8, 147.7, 134.5, 131.6, 131.2, 123.0, 119.4, 112.8, 111.4, 67.8, 55.5, 50.3, 36.9, 30.7, 18.6, 13.6.
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]1([P:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:20]C)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>ClC1C=CC=CC=1Cl>[C:13]1([P:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:2]2[C:11]([P:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:30]3[CH:29]=[CH:28][CH:33]=[CH:32][CH:31]=3)=[O:20])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: CCCCCC
Reactant: COP(c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1Cl
Product: O=P(c1ccccc1)(c1ccccc1)c1nc2ccccc2nc1P(=O)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a stirred, refluxing mixture of 5.00 g of 2,3-dichloroquinoxaline in 100 ml of o-dichlorobenzene under nitrogen was added dropwise 14.00 g of methyl diphenylphosphinite. The mixture was refluxed for 6 hours after the addition was completed and then allowed to stand overnight at room temperature. The next day the mixture was admixed with 500 ml of n-hexane, and the resulting solid was separated by filtration, washed with hexane, recrystallized from 100 ml of chlorobenzene, and dried at 100° C./0.1 mm (13 Pa) to give 9.87 g of 2,3-bis(diphenylphosphinyl)-quinoxaline (shown by formula in Claim 6) as a very slightly yellowish-white solid, mp 258°-272° C. with decomposition. Anal. Calcd for C32H24N2O2P2 : C, 72.45; H, 4.56; N, 5.28; P, 11.68. Found: C, 72.38; H, 4.23; N, 5.18; P, 11.39.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[O:9])[CH:7]=1.Br[CH2:23][C:24]#[N:25].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:23][C:24]#[N:25])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[O:9])[CH:7]=1
Reactant: O=C(c1cnn(-c2ccccc2)c1)c1cc(Br)ccc1O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCOc1ccc(Br)cc1C(=O)c1cnn(-c2ccccc2)c1
Reaction time: 24 h
Yield: 100.6 %

Procedure:
(5-Bromo-2-hydroxy-phenyl)-(1-phenyl-1H-pyrazol-4-yl)ketone (342 mg) was added bromoacetonitrile (122 mg), acetone (2 mL) and K2CO3 (140 mg), and the reaction was stirred for 24 h. The reaction mixture was concentrated and the residue was partitioned between water and EtOAc. The organic phase was washed with brine, dried (MgSO4) and concentrated to give 383 mg (100%) yellow solid, that was used directly in the next step: LC/MS (an10p8): Rt 4.39 min, m/z 381.5 [M+1]+; 1H NMR (CDCl3): δ 4.80 (s, 2H), 7.07 (d, J=8.7 Hz, 1H), 7.35-7.42 (m, 1H), 7.45-7.54 (m, 2H), 7.60-7.69 (m, 2H), 7.69-7.75 (m, 2H), 8.03 (s, 1H), 8.31 (s, 1H); 13C NMR (CDCl3): δ 55.2, 114.7, 116.6, 116.7, 120.1, 125.1, 128.2, 129.9, 131.0, 132.6, 133.2, 135.0, 139.3, 142.7, 153.0, 186.0.
Reaction SMILES: [OH:1][C:2]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C:7]2[C:3]=1[C:4]([CH3:18])([CH3:17])[C:5](=[O:16])[N:6]=2.[C:19]([O-])([O-])=O.[K+].[K+].CI.[CH3:27][C:28]([CH3:30])=[O:29]>>[CH3:19][O:1][C:2]1([CH2:27][C:28](=[O:29])[CH3:30])[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C:7]2[NH:6][C:5](=[O:16])[C:4]([CH3:18])([CH3:17])[C:3]1=2
Reactant: O=C([O-])[O-]
Reactant: CC(C)=O
Reactant: CC1(C)C(=O)N=C2C1=C(O)C(=O)c1ccccc12
Agent: [K+]
Solvent: CI
Product: COC1(CC(C)=O)C(=O)c2ccccc2C2=C1C(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-hydroxy-3,3-dimethyl-2H-benzo[g]indole-2,5(3H)-dione (compound 1) (0.1 g, 0.415 mmol) in acetone (5 mL) was added K2CO3 (0.132 g, 0.96 mmol) while stirring at RT. After 10 minutes, MeI (0.058 g, 0,41 mmol) was added via a syringe and the mixture was allowed to stir for 1 h followed by addition of more MeI (0.058 g, 0,41 mmol) and the reaction was stirred over night. The solvent was removed in vacuum and the solid was dissolved in CHCl3, filtered and purified by preparative HPLC. Yield: 64 mg (50%). 1H NMR (400 MHz, CDCl3) δ 1.46 (d, 6 H), 2.12 (s, 3 H), 2.90 (s, 2 H), 3.65 (s, 3 H), 7.42 (t, 1 H), 7.55 (t, 1 H), 7.78 (d, 1 H), 7.94 (d, 1 H): MS (CI) m/z 314.36 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C([Li])CCC.[C:12]1([CH2:18][CH2:19]C(Cl)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(CCC(O)=O)C=CC=CC=1>O1CCCC1.S(Cl)(Cl)=O>[O:6]=[C:4]([CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:1]#[N:2]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: N#CCC(=O)O
Agent: O=C(O)CCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: N#CCC(=O)CCc1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of cyanoacetic acid (1.0 g, 11.8 mmol) in tetrahydrofuran (20 mL) was cooled to −78° C. and treated with 1.6 M n-butyl lithium in hexanes (14.7 mL, 23.5 mmol). The mixture was warmed to −20° C. over 2 hours, cooled to −78° C. and treated with 3-phenylpropionyl chloride (prepared by refluxing a solution of 3-phenylpropionic acid (1.0 g, 6.7 mmol) in thionyl chloride (4 mL) for 3 hours, evaporating and drying). The mixture was stirred at −78° C. for 1 hour and 20% hydrochloric acid added until the pH=3. The mixture was diluted with diethyl ether, washed with saturated sodium bicarbonate, and the organic layer separated and concentrated. The crude product was purified by flash chromatography on silica gel using 0-50% ethyl acetate/hexanes to provide the title compound. MS (ESI) m/e 191 (M+H+NH3).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C:10]1([CH3:22])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]1[C:19]([OH:21])=[O:20].[C:23]([S:26][CH2:27][CH2:28][C:29](Cl)=[O:30])(=[O:25])[CH3:24].Cl>C(Cl)Cl>[C:23]([S:26][CH2:27][CH2:28][C:29]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH3:22])([CH3:9])[CH:11]1[C:19]([OH:21])=[O:20])=[O:30])(=[O:25])[CH3:24]
Reactant: CC(=O)SCCC(=O)Cl
Reactant: CC1(C)c2ccccc2NC1C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)SCCC(=O)N1c2ccccc2C(C)(C)C1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.93 g of triethylamine are added to the suspension of 0.7 g of 3,3-dimethylindoline-2-carboxylic acid hydrochloride in 20 ml of methylene chloride and the resulting solution is cooled to -10°. The solution of 0.51 g of 3-acetylthiopropanoyl chloride in 5 ml of methylene chloride is added dropwise and the mixture stirred at -5° to -10° for 1 hour and at room temperature for 3 hours. It is cooled to 0° and treated with 10 ml of 3N hydrochloric acid. The organic layer is separated and the aqueous solution further extracted with methylene chloride. The combined methylene chloride solutions are dried and evaporated, to give the 1-(3-acetylthiopropanoyl)-3,3-dimethylindoline-2-carboxylic acid as a foam.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9]([OH:17])=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][C:7]2=[O:18].C[O:21][C:22]([CH:24]=[CH2:25])=[CH2:23]>C1C=CC=CC=1>[Cl:1][C:2]1[C:15]2[C:10]([C:9]([OH:17])=[C:8]3[C:3]=1[C:4](=[O:19])[CH:5]1[CH:6]([CH2:25][CH2:24][C:22](=[O:21])[CH2:23]1)[C:7]3=[O:18])=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2
Reactant: O=C1C=CC(=O)c2c1c(Cl)c1cccc(O)c1c2O
Reactant: C=CC(=C)OC
Solvent: c1ccccc1
Product: O=C1CCC2C(=O)c3c(c(Cl)c4cccc(O)c4c3O)C(=O)C2C1

Procedure:
10-Chloro-8,9-dihydroxy-1,4-anthracenedione (compound 3) (100 mg), 2-methoxy-1,3-butadiene (564 mg) and dry benzene (10 ml) were heated in a sealed tube for 4 h at 130°. After cooling the crude solution was preparatively chromatographed on silica gel layers containing oxalic acid (2%) with chloroform as eluant. The major yellow band was recovered to give the product (compound 9) as a yellow crystalline solid (85 mg, 68%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24].[C:25]([O:29][C:30]([NH:32][C@H:33]([CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH3:47])[CH:39]=1)[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH3:47][N:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([CH2:37][C@@H:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])[C:34](=[O:35])[NH:1][CH:2]2[CH2:11][C:10]3[C:5](=[C:6]([N:12]4[CH2:16][CH2:15][CH2:14][C:13]4=[O:17])[CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[C:3]2=[O:24])=[CH:39]1
Reactant: Cn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Reactant: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Product: Cn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC2Cc3cccc(N4CCCC4=O)c3N(Cc3ccsc3)C2=O)c2ccccc21
Yield: 110.8 %

Procedure:
The procedure of Example 14(a) was repeated, except that (−)-3-amino-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-3,4-dihydroquinolin-2(1H)-one (268 mg) and (R)-2-(tert-butoxycarbonylamino)-3-(1-methyl-1H-indol-3-yl)propanoic acid (284 mg) synthesized in Referential Example 1(a) were used, whereby the title compound (558 mg) was yielded.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[N:24]([CH3:25])[N:23]=[N:22][N:21]=1.COC(C1C([Cl:36])=C(Cl)C(C(OC)=O)=C(Cl)C=1Cl)=O>C(#N)C>[ClH:36].[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: Cn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: COC(=O)c1c(Cl)c(Cl)c(C(=O)OC)c(Cl)c1Cl
Solvent: CC#N
Product: Cl
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 15 °C
Yield: 103.4 %

Procedure:
A 11 ml portion of acetonitrile was added to 2.72 g of 7-ACA and 1.28 g of 5-mercapto-1-methyl-1H-tetrazole, and 14.9 g of DCPA was added through a dropping funnel to the mixture with stirring and under cooling at -25° to -20° C., followed by rinsing the funnel with 1 ml of acetonitrile. The reaction mixture was warmed to 15° C., stirred at 14° to 16° C. for 40 minutes and cooled to -30° C., followed by adding dropwise 40 ml of ethanol at -30° to -20° C. The resultant solution was warmed to room temperature, and stirred under ice-cooling for 3.0 hours after the addition of 300 ml of methylene chloride, 100 ml of ether and 70 ml of ether saturated with water. The crystals separated out were recovered by filtration, washed with ether and dried, thereby affording 3.77 g (86.0% of purity as determined by high performance liquid chromatography, 88.9% of yield) of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride.
Reaction SMILES: Cl[C:2]1N=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[C:12](=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]([F:23])([F:22])[CH2:20][OH:21].O>CN(C=O)C>[F:18][C:19]([F:23])([F:22])[CH2:20][O:21][C:2]1[CH:12]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: O=C([O-])[O-]
Reactant: OCC(F)(F)F
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.1 %

Procedure:
To a solution of methyl 5-chloropyrazine-2-carboxylate (25 g, 144.87 mmol) in DMF (250 mL) under nitrogen atmosphere is added cesium carbonate (47.2 g, 144.8 mmol) and 2,2,2-trifluoro-ethanol (15.7 mL, 217.3 mmol). The reaction mixture is stirred 72 hours at room temperature. The mixture is poured over water (1 L) and a pale brown solid is collected by filtration. The solid is washed with water and dried under vacuum to a constant weight. The dry crude material is recrystallized twice from a mixture of water (200 mL) and isopropyl alcohol (40 ml) to yield the intermediate methyl 5-(2,2,2-trifluoroethoxyl)pyridine-2-carboxylate (15 g, 93%) as a pale cream solid and is used without further purification. A solution of intermediate methyl 5-(2,2,2-trifluoroethoxyl)pyridine-2-carboxylate (5 g, 21.17 mmol) in methanol (50 mL) and 1 M sodium hydroxide aqueous solution (42.3 mL, 42.3 mmol) is stirred at room temperature for 2 hours. Hydrochloric acid 35% w/w is added to adjust the ph to 2. Methanol is evaporated and a pale cream solid is isolated by filtration. The solid is washed with water and dried under vacuum to give the title compound (3 g, 51%). ES/MS (m/z): 223.1 (M+1).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])/[C:9]1=[O:24])=O)(C)(C)C.[Cl:25][C:26]1[C:27]([F:39])=[C:28](/[CH:32]=[N:33]/[CH2:34][Si](C)(C)C)[CH:29]=[CH:30][CH:31]=1.C(O)(=O)C.O>CN(C)P(N(C)C)(N(C)C)=O>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:24])[C:10]3([CH:18]([CH2:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:34][NH:33][CH:32]3[C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[C:27]=3[F:39])[C:11]2=[CH:12][CH:13]=1
Reactant: CC(C)(C)C/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Reactant: C[Si](C)(C)C/N=C/c1cccc(Cl)c1F
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of E/Z-6-chloro-3-(3,3-dimethyl-butylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 4 (2.5 g, 7.1 mmol) in hexamethylphosphoramide (30 mL) was added [1-(3-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-trimethylsilanylmethyl-amine prepared in Example 5 (2.4 g, 9.9 mmol), acetic acid (0.6 g, 10 mmol) and H2O (0.2 g, 11 mmol) sequentially. The reaction mixture was stirred at room temperature for 24 h. Water was added. The mixture was extracted with ethyl acetate. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water twice, dried over MgSO4, then concentrated. The residue was dissolved into dichloromethane (20 mL), and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and aqueous saturated NaHCO3 solution. The organic layer was separated, dried over MgSO4, then concentrated. The residue was purified by chromatography (50-100% EtOAc in hexanes) to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one as a white solid (Yield, 0.6 g, 20%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]=1.N1CCCC[CH2:16]1.C(O)(=O)C.C=O>CO>[CH2:16]=[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:14]
Reactant: CCCCCCC(=O)c1cccnc1
Reactant: C1CCNCC1
Agent: C=O
Solvent: CC(=O)O
Solvent: CO
Product: C=C(CCCCC)C(=O)c1cccnc1
Yield: 95 %

Procedure:
To 1 g (5.2 mmol) of compound 3, dissolved in 10 ml of MeOH, was added 0.1 ml of piperidine, 0.1 ml of acetic acid and 3 ml of an aqueous formaldehyde solution (37% formaldehyde in water). The mixture was heated to reflux for 48 hour. The mixture was cooled and concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with a 5% NaHCO3 solution, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (diethyl ether/PE 1/1) to give compound 4 as an oil (1.05 g, 95%). 1H-NMR (200 MHz, CDCl3): δ 8.94 (d, J=2 Hz, 1H), 8.76 (d, J=5 Hz, 2 Hz, 1H), 8.05 (dt, J=8 Hz, 2 Hz, 1H), 7.46-7.35 (m, 1H), 5.94 (s, 1H), 5.64 (s, 1H), 2.48 (bt, J=7 Hz, 2H), 1.60-1.25 (m, 6H), 0.99-0.82 (m, 3H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH2:10].[F:11][C:12]1[CH:13]=[C:14]([B:21]([OH:23])[OH:22])[CH:15]=[C:16]([F:20])[C:17]=1[CH:18]=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][CH2:18][C:17]1[C:16]([F:20])=[CH:15][C:14]([B:21]([OH:23])[OH:22])=[CH:13][C:12]=1[F:11]
Reactant: O=Cc1c(F)cc(B(O)O)cc1F
Reactant: NC1Cc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OB(O)c1cc(F)c(CNC2Cc3ccccc3C2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,3-dihydro-1H-inden-2-amine (0.780 mL, 5.99 mmol), (3,5-difluoro-4-formylphenyl)boronic acid (1.0 g, 5.99 mmol) and acetic acid (0.710 mL, 12.0 mmol) in THF (12 mL) was stirred at room temperature for 1 hr. To the solution was added NaBH(OAc)3 (3.81 g, 18.0 mmol) and the mixture stirred at room temperature for 16 hr. The mixture was diluted with EtOAc then washed with satd Na2CO3. The combined layers were filtered and the filter cake washed with H2O and EtOAc to give {4-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3,5-difluorophenyl}boronic acid as a beige glass. LC/MS (method A) tR 0.48 min; m/z 304 (M+H).