Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([NH:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)=[O:21])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:9].N([O-])=[O:35].[Na+].Cl>O.C(#N)C.O1CCOCC1>[OH:35][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([NH:19][C:20]([C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:26][CH:27]=1)=[O:21])[C:8]([NH:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[O:9]
Reactant: NCCCCC(NC(=O)c1ccc(-c2ccccc2)cc1)C(=O)NCc1ccc(Cl)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: O=C(NC(CCCCO)C(=O)NCc1ccc(Cl)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
6-Amino-2-(4-phenylbenzenecarbonyl)amino-N-(4-chlorobenzyl)hexanamide hydrochloride (173) (1.29 g) was dissolved in water (50 ml) and acetonitrile (20 ml). To the solution were added sodium nitrite (4.02 g) and a solution of 4 N hydrochloric acid in 1,4-dioxane (3.31 ml) under cooling with ice, and the mixture was stirred for 1.0 hour under cooling with ice. After 1.5 hours, the reaction liquid was warmed to room temperature and stirred for 2.0 hours. The reaction liquid was concentrated and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (100 ml), dried over anhydrous sodium sulfate, and filtered. After that, the filtrate was concentrated and the residue was purified by silica gel flash column chromatography (developing solvent: chloroform:methanol=100:1 to chloroform:methanol=30:1) to give a compound (175) (561 mg, yield: 47%) as a white solid. 1H NMR data on the compound (175) is shown below.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[O:16][C:17]=2[CH3:18])=[N:9][CH:10]=1.[CH2:24]([O:26][C:27](=[O:40])[CH2:28][C:29]1[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:31][NH:32][CH:33]=1)[CH3:25].O>CN(C)C=O>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:15]1[O:16][C:17]([CH3:18])=[C:13]([CH2:12][O:11][C:8]2[N:9]=[CH:10][C:5]([CH2:4][N:32]3[CH:33]=[C:29]([CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:40])[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:31]3)=[CH:6][CH:7]=2)[N:14]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cn1
Reactant: CCOC(=O)Cc1c[nH]nc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 5-chloromethyl-2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]pyridine (533 mg) and ethyl(3-phenyl-1H-pyrazol-4-yl)acetate (403 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl [1-[6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (581 mg, yield: 67%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:10](=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14]>>[OH:12][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][C:10]([NH:16][CH:13]([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)N
Reactant: O=C1CCC(c2ccccc2)O1
Product: CC(C)NC(=O)CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 100.4 %

Procedure:
A mixture of γ-phenyl-γ-butyrolactone (10.0 g, 61.7 mmol) and isopropylamine (50 ml, 587 mmol) was stirred at room temperature for approximately 26 hours. The solvent was removed under reduced pressure to give 4-hydroxy-N-isopropyl-4-phenyl-butyramide (13.71 g, 100%) as a yellow solid, mp 131-135° C.
Reaction SMILES: C(=O)C.[C:4](O)(=O)[C:5]1C=CC=C[CH:6]=1.C1(P(=C[C:33]2[CH2:34][S:35][C@@H:36]3[C@H:56]([NH:57][C:58](=[O:65])[CH2:59][C:60]4[S:61][CH:62]=[CH:63][CH:64]=4)[C:55](=[O:66])[N:37]3[C:38]=2[C:39]([O:41][CH:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH:4]([C:33]1[CH2:34][S:35][C@@H:36]2[C@H:56]([NH:57][C:58](=[O:65])[CH2:59][C:60]3[S:61][CH:62]=[CH:63][CH:64]=3)[C:55](=[O:66])[N:37]2[C:38]=1[C:39]([O:41][CH:42]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])=[CH:5][CH3:6]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: O=C(O)c1ccccc1
Agent: CC=O
Solvent: ClCCl
Product: CC=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 4 h
Yield: 55.9 %

Procedure:
A solution of acetaldehyde (20 ml., 354 mmole) and benzoic acid (73 mg., 0.6 mmole) in dry methylene chloride (50 ml.) as stirred at 23° and treated, over 30 minutes, with diphenylmethyl 3-(triphenylphosphoranylidenemethyl)-7β-(2-thienylacetamido)ceph-3-em-4-carboxylate (1.528 g., 2 mmoles). After stirring for a further 4 hours, the solvent was removed in vacuo, the residue was extracted with ethyl acetate (50 ml.) and the insoluble material was filtered off; the filtrate was washed with saturated sodium bicarbonate (50 ml.), water (50 ml.) and brine (50 ml.), and dried and evaporated to a foam (1.58 g.). This material was purified by chromatography on 0.05-0.2mm. Kieselgel with benzene: ethyl acetate = 10:1 as eluent. Combination of similar fractions (as judged by t.l.c.) gave pale-yellow crystals of the title compound (178 mg., 17%), Rf 0.58, m.p. 144° to 148° (decomp.), [α]D -25.9° (CHCl3), λmax. 286.5 nm. (ε 7,900), with an inflexion at 237 nm. (ε 13,200); the p.m.r. spectrum indicated that the compound was mainly the cis-isomer (with 5-10% trans) with signals at τ 3.96 (--CH=CHCH3, d, J 12 Hz.), 4.51 (=CHCH3, dd, J 12 and 7 Hz.) and 8.61 (CH=CHCH3, methyl dd, J 7 and 0.5 Hz.) [Found: C, 65.2; H, 5.0; N, 5.2; S, 11.9; C29H26N2O4S2 (530.7) requires C, 65.6; H, 4.9; N, 5.3; S, 12.1%].
Reaction SMILES: C([Li:5])CCC.[CH3:6][Si:7]([CH3:20])([CH3:19])[CH:8]1[C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=2[CH2:11][CH2:10][CH2:9]1>CCCCCC.C1COCC1>[Li:5][C:8]1([Si:7]([CH3:19])([CH3:20])[CH3:6])[C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=2[CH2:11][CH2:10][CH2:9]1
Reactant: [Li]CCCC
Reactant: Cc1ccnc2c1CCCC2[Si](C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]C1([Si](C)(C)C)CCCc2c(C)ccnc21

Procedure:
A mixture of a 1.55 molar solution of n-butyl lithium in hexane (14.2 ml, 22mM) and THF (25 ml), maintained below 5° was treated with a solution of 5,6,7,8-tetrahydro-8-trimethylsilyl- 4-methylquinoline (4.4 g, 20 mM) in THF (10 ml) to give 5,6,7,8-tetrahydro-8-lithio-8-trimethylsilyl -4-methylquinoline. After 0.5 hour a solution of t-butyldimethylsilyl isothiocyanate (22 mM) in benzene (15 ml) was added; after a further 0.5 hour the mixture was quenched with 0.5 N hydrochloric acid (60 ml). After 1 hour toluene (50 ml) was added, the aqueous layer was separated, adjusted to pH10 and extracted with dichloromethane. The organic extract was evaporated and chromatographed on silica using ether as eluant. The title thioamide was obtained in 60% yield (identical to authentic material) together with the corresponding nitrile (20%) and 5,6,7,8-tetrahydro-4-methylquinoline (20%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([CH:16]=[CH2:17])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.Br[CH:19]([C:24]1[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=1)[C:20]([F:23])([F:22])[F:21].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[Cl:1][C:2]1[CH:15]=[C:14](/[CH:16]=[CH:17]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:22])([F:21])[F:23])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: C=Cc1ccc(CNc2ccccn2)c(Cl)c1
Reactant: FC(F)(F)C(Br)c1cc(Cl)c(Cl)c(Cl)c1
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: FC(F)(F)C(/C=C/c1ccc(CNc2ccccn2)c(Cl)c1)c1cc(Cl)c(Cl)c(Cl)c1
Temperature: 180 °C
Reaction time: 24 h
Yield: 32.4 %

Procedure:
To a stirred solution of N-(2-chloro-4-vinylbenzyl)pyridin-2-amine (0.3 g, 1.22 mmol) in 1,2-dichlorobenzene (5 mL) were added 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.83 g, 2.44 mmol), CuCl (24 mg, 0.24 mmol) and 2,2-bipyridyl (76 mg, 0.48 mmol). The resultant reaction mixture was degassed with argon for 30 min and then stirred at 180° C. for 24 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 15% EtOAc in n-hexane) afforded the title compound as an off-white solid (0.2 g, 35%): mp 140-142° C.; 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=4.0 Hz, 1H), 7.40 (m, 5H), 7.22 (m, 1H), 6.61 (m, 2H), 6.35 (m, 2H), 4.94 (br s, 1H), 4.61 (d, J=6.4 Hz, 2H), 4.11 (m, 1H); ESIMS m/z 505.39 ([M+H]+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][N:6]1[CH2:7][CH:2]([CH3:1])[CH2:3][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:5]1
Reactant: O=Cc1ccccc1F
Reactant: COC(=O)C1CNCC(C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C1CC(C)CN(Cc2ccccc2F)C1
Reaction time: 0.25 h

Procedure:
In a flask, dichloromethane (8 mL) and acetic acid (8 drops) was added to methyl 5-methylpiperidine-3-carboxylate (300 mg, 1.9 mmol) and 2-fluorobenzaldehyde (3.8 mmol). The reaction was stirred for 15 minutes. Sodium triacetoxyborohydride (1.6 g, 7.6 mmol) was added in one portion. The reaction was stirred overnight. The reaction was concentrated in vacuo and purified using prep LC/MS.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:24][CH2:23][C:18]5(OCC[O:19]5)[CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:25])[CH2:3][CH2:2]1.C1COCC1.Cl.C(=O)([O-])O.[Na+]>O.CO>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:24][CH2:23][CH:18]([OH:19])[CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:25])[CH2:2][CH2:3]1
Reactant: Fc1cc(-c2nc3c(o2)CCC2(C3)OCCO2)ccc1OCC1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: OC1CCc2oc(-c3ccc(OCC4CC4)c(F)c3)nc2C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To 2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-6,7-dihydro-4H-spiro[1,3-benzoxazole-5,2′-[1,3]dioxolane] (6.00 g) in a mixed solvent of THF (40 mL)-methanol (20 mL)-water (20 mL) was added 6 M hydrochloric acid (17.4 mL), and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. To the organic layer was added sodium tetrahydroborate (657 mg), and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.93 g).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1.Cl.[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[C:24]([F:30])[CH:23]=1.CCN(C(C)C)C(C)C>C(#N)C>[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:2]2[CH:3]=[C:4]([O:5][CH2:6][C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=3)[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])=[C:24]([F:30])[CH:23]=1
Reactant: Cc1ccc(COc2ccc([N+](=O)[O-])c(F)c2)nc1
Reactant: NCc1ccc(Br)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(COc2ccc([N+](=O)[O-])c(NCc3ccc(Br)cc3F)c2)nc1
Temperature: 75 °C

Procedure:
A mixture of 2-((3-fluoro-4-nitrophenoxy)methyl)-5-methylpyridine (1.50 g, 5.72 mmol), 4-bromo-2-fluorobenzylamine hydrochloride (1.51 g, 6.29 mmol), DIPEA (2.96 mL, 17.2 mmol) and acetonitrile (19.1 mL) was sealed in reaction vessel and heated to 75° Celsius for 18 h. The mixture was then cooled to RT, transferred to a round bottomed flask and concentrated to dryness. The resulting residue was then heated in a minimum amount of i-PrOH to 70° Celsius until homogeneous. The resulting solution was then cooled to RT where yellow solids precipitated, which were collected by filtration. (2.40 g, 94%). MS (ESI): mass calcd. for C20H17BrFN3O3, 445.04; m/z found, 446.0 [M+H]+.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[OH-].[Na+:5].[CH2:6]([P:8]([CH2:11]CC#N)(=[O:10])[OH:9])[CH3:7].S(=O)(=O)(O)[OH:16]>O>[Na+:5].[CH2:6]([P:8]([OH:9])([CH2:11][CH2:2][C:1]([O-:16])=[O:3])=[O:10])[CH3:7]
Reactant: O=S(=O)(O)O
Reactant: CCO
Reactant: CCP(=O)(O)CCC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCP(=O)(O)CCC(=O)[O-]
Yield: 197.5 %

Procedure:
A stirred apparatus is initially charged with 150 g of ethanol, 65 g of water, 150 g (3.75 mol) of sodium hydroxide and 183 g (1.25 mol) of ethyl(2-cyanoethyl)-phosphinic acid (produced as in Example 5). The mixture was heated under reflux and reacted at that temperature for about 10 hours. Then water and the butanol were removed from the reaction mixture by distillation. Following the addition of a further 500 ml of water, the mixture was neutralized by addition of about 61 g (0.63 mol) of concentrated sulfuric acid. The water is then distilled off in vacuo. The residue is taken up in ethanol and the insoluble salts are filtered off. The solvent of the filtrate is removed in vacuo to obtain 234 g (89% of theory) of 3-(ethylhydroxyphosphinyl)propionic acid sodium salt as a solid material.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]#[N:8])[N:6]=1.[C:9](OC)(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[SH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9](=[O:17])[N:8]=2)[N:6]=1
Reactant: COC(=O)c1ccccc1S
Reactant: Cc1nc(C#N)cs1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1nc(-c2nc(=O)c3ccccc3s2)cs1
Yield: 77.9 %

Procedure:
2-Methyl-1,3-thiazole-4-carbonitrile (0.46 g, 3.7 mmol) and methyl thiosalicylate (1.26 g, 7.4 mmol) were dissolved in toluene (6 ml), and triethylamine (3.0 ml, 21.5 mmol) was added thereto. The mixture was refluxed for 15 hrs. After cooling, the precipitates were collected by filtration and recrystallized from ethanol to give the titled compound (0.75 g, 78%) as white crystals.
Reaction SMILES: [NH:1]1[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>C(OCC)C>[C:11]([N:1]1[CH2:3][CH2:2]1)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: C1CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, distilled aziridine solution (500 mL, 0.1 mol) in a round-bottom flask cooling with an ice bath, three equivalents of potassium carbonate was added. After all of the solid dissolved, benzyl chloroformate (1.5 equivalents) in ethyl ether (150 mL) was added over 2 h. The solution was stirred overnight and warmed to room temperature, and the aqueous phase was extracted with methylene chloride (5×30 mL). The organic phases were combined and passed through a flash silica gel pad and concentrated to afford the Cbz-aziridine as colorless thick oil, yield: 7.2 g, 81%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[N:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:5]2=[N:6][CH:7]=1.[CH3:25][O:26][C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(#N)C.O>[CH3:25][O:26][C:27](=[O:28])[C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[O:17][CH3:18])=[N:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:5]3=[N:6][CH:7]=2)[CH:34]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: COCCOCn1nc(-c2ccccc2OC)c2cc(Br)cnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COCCOCn1nc(-c2ccccc2OC)c2cc(-c3cccc(C(=O)OC)c3)cnc21
Yield: 100 %

Procedure:
A mixture of 5-bromo-1-(2-methoxy-ethoxymethyl)-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine (535 mg, 1.36 mmol), 3-methoxycarbonylphenylboronic acid (258 mg, 1.43 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (50 mg, 68 μmol) in acetonitrile (7 mL) and 2 M aqueous solution of sodium carbonate (7 mL) was irradiated in a Personal Chemistry Optimizer at 90° C. for 10 minutes. The resulting mixture was distributed between ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by flash silica gel chromatography using a gradient of ethyl acetate and hexanes to afford 3-[1-(2-methoxy-ethoxymethyl)-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid methyl ester (612 mg, 1.36 mmol, 100% yield) as a yellow oil. 1H-NMR (500 MHz, d6-DMSO) δ 8.96 (d, 1H), 8.43 (d, 1H), 8.28 (t, 1H), 8.07 (td, 1H), 7.99 (td, 1H), 7.67-7.69 (m, 2H), 7.51 (ddd, 1H), 7.25 (d, 1H), 7.12 (dt, 1H), 5.92 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.73-3.75 (m, 2H), 3.43-3.45 (m, 2H), 3.21 (s, 3H). MS: m/z 372 [MH+].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][CH2:10][P:11](=[O:14])([OH:13])[OH:12])(=[O:8])=[O:7].[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH4+:9].[CH2:15]([O:14][P:11]([CH2:10][NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])(=[O:12])[O-:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=P(O)(O)CNS(=O)(=O)c1cccs1
Reactant: OCc1ccccc1
Product: O=P([O-])(CNS(=O)(=O)c1cccs1)OCc1ccccc1
Product: [NH4+]

Procedure:
According to the procedure described in Example 1, step 4, the phosphonic acid 43 was treated with benzyl alcohol. The ammonium salt was purified by flash chromatography (elution with chloroform:methanol:concentrated ammonium hydroxide; 8:2:0.25), followed by lyophilization, to afford the title compound: 1H NMR (300 MHz, D2O) δH 7.71 (m, 1H), 7.58 (m, 1H), 7.29 (s, 5H), 7.07 (t, J=7.0 Hz, 1H), 4.75 (d, J=7.8 Hz, 2H), 2.93 (d, J=12.9 Hz, 2H); 31P NMR: (121 MHz, D2O) δP 16.65; 13C NMR (75 MHz, D2O) δC 132.75; 131.10, 129.07, 128.72, 124.12, 123.70, 123.47, 123.13, 62.55, 34.40, (d, J=147.4 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4](Cl)[CH:3]=1.C([Li])CCC.CCCCCC.[B:22]([O:27]C)([O:25]C)[O:23]C.C1C[O:32][CH2:31]C1>>[CH3:31][O:32][C:4]1[CH:3]=[C:2]([O:27][B:22]([OH:23])[OH:25])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: C1CCOC1
Reactant: COB(OC)OC
Reactant: COc1ccc(Br)cc1Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: COc1ccc(OB(O)O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a THF solution of 4-bromo-2-chloroanisole was added an n-butyllithium/n-hexane solution at −78° C., followed by 30 minutes of stirring. Then, trimethyl borate was added and the whole was warmed to room temperature, followed by 30 minutes of stirring. Using the residue obtained by evaporation of the solvent instead of 3,4-dimethoxyphenylboric acid, an objective compound was obtained in a similar manner to Reference Example 1.
Reaction SMILES: C([NH:8][C:9]1[C:18]([F:19])=[C:17]([Cl:20])[C:16]([F:21])=[C:15]2[C:10]=1[C:11](=[O:30])[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][N:14]2[CH:22]1[CH2:24][CH2:23]1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.C(O)C.[Pd]>[NH2:8][C:9]1[C:18]([F:19])=[C:17]([Cl:20])[C:16]([F:21])=[C:15]2[C:10]=1[C:11](=[O:30])[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][N:14]2[CH:22]1[CH2:23][CH2:24]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(Cl)c(F)c(NCc3ccccc3)c2c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(Cl)c(F)c(N)c2c1=O
Reaction time: 3 h
Yield: 83.8 %

Procedure:
To a solution of 48.0 g of ethyl 5-benzylamino-1-cyclopropyl-7-chloro-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (0.111 mol) dissolved in a mixture of 200 ml of acetic acid and ethanol was added 0.5 g of 5% Pd/C catalyst. Hydrogen gas was introduced at room temperature. The reaction was monitored with TLC and carried out for around 3 hours. Precipitates collected by filtration were dissolved in chloroform and filtered to remove the catalyst. After removing the solvent by evaporation, the residue was recrystallized from a mixture of chloroform and ethanol to give 32.0 g of ethyl 5-amino-1-cyclopropyl-7-chloro-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (0.093 mol) in 83.9% yield.
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[C@H:21]([S:22][CH2:23][C:24]=1/[CH:25]=[C:26]1/[C:27](=[O:35])[N:28]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:29][CH2:30]/1)[C@H:20]([NH:36]C(OC(C)(C)C)=O)[C:19]2=[O:44])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl.C1(OC)C=CC=CC=1>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[NH2:36][C@@H:20]1[C:19](=[O:44])[N:18]2[C@@H:21]1[S:22][CH2:23][C:24](/[CH:25]=[C:26]1/[C:27](=[O:35])[N:28]([CH2:31][CH:32]([CH3:33])[CH3:34])[CH2:29][CH2:30]/1)=[C:17]2[C:15]([OH:16])=[O:14]
Reactant: CC(C)CN1CC/C(=C\C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]3SC2)C1=O
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN1CC/C(=C\C2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(E)-(6R,7R)-7-tert-Butoxycarbonylamino-3-(1-isobutyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (21.9 g, 35.0 mmol) was dissolved in 240 ml dichloromethane and 23 ml anisole. At 20° C. 120 ml trifluoroacetic acid were added dropwise while maintaining the temperature below 50° C. After complete addition the ice-bath was removed and the solution was stirred at ambient temperature for 2.5 hours The volatile material was then removed under reduced pressure and the remaining yellow oil was added slowly to 400 ml of diethyl ether, in which the product started to precipitate. After 1.5 hours the suspension was filtered under argon atmosphere and the remaining crystals were stirred in 150 ml of ethyl acetate for 2 hours. The suspension was filtered under argon giving the desired product as a yellow crystalline powder.