Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@H:5]1[OH:27])[CH:2]=C.I([O-])(=O)(=O)=[O:37].[Na+].C(O)(C)(C)C>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH2:29]([O:28][C@:4]1([CH2:1][CH2:2][OH:37])[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@H:5]1[OH:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC[C@]1(OCc2ccccc2)[C@H](O)[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1COCc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: Cc1cn([C@@H]2O[C@H](COCc3ccccc3)[C@@](CCO)(OCc3ccccc3)[C@@H]2O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of nucleoside 4 (2.26 g, 4.68 mmol) in THF (12 cm3) and water (12 cm3) was added sodium periodate (3.04 g, 14.2 mmol) and a 2.5% solution of osmium tetraoxide in tert-butanol (w/w, 0.603 cm3, 40 μmol). The solution was stirred at room temperature for 45 min. Water (25 cm3) was added and the solution was extracted with dichloromethane (2×50 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×30 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was redissolved in THF (12 cm3) and water (12 cm3). The mixture was stirred at room temperature and sodium boronhydride (182 mg, 4.71 mmol) was added. After stirring for 1.5 h, water (25 cm3) was added and the solution was extracted with dichloromethane (2×50 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×30 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (98:2, v/v) as eluent to give 5 as a white solid material (1.13 g, 49%). δH (CDCl3) 9.29 (1 H, br s, NH), 7.47 (1 H, d, J 1.1, 6-H), 7.38-7.25 (10 H, m, Bn), 6.22 (1 H, d, J 3.4, 1′-H), 4.62 (2 H, s, Bn), 4.60 (1 H, m, 4′-H), 4.46 (2 H, s, Bn), 4.35 (1H, dd, J 3.4, 7.5, 2′-H), 3.83-3.73 (4 H, m, 2×5′-H, 2×2″-H), 2.67 (1 H, br s, OH), 2.07-2.01 (2 H, m, 2×1″-H), 1.77 (3 H, d, J 0.5, CH3). δC (CDCl3) 164.3 (C-4), 150.3 (C-2), 137.6, 137.4 (Bn, C-6), 136.7 (Bn), 128.6, 128.4, 128.2, 127.8, 127.6, 127.3, 127.1 (Bn), 108.4 (C-5), 88.0, 87.7, 81.6, 74.7 (C-1′, C-2′, C-3′, C-4′), 73.7, 69.6 (Bn), 64.6 (C-5′), 57.7 (C-2″), 28.6 (C-1″), 12.4 (CH3). FAB-MS m/z 483 (M+H)+, 505 [M+Na]+ (Found: C, 63.6; H, 6.2; N, 5.4. C26H30N2O7,0.5H2O requires C, 63.5; H 6.4; N, 5.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([C:21]#[C:22]C(C)(O)C)=[N:11][N:10]=1.[H-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([C:21]#[CH:22])=[N:11][N:10]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(C#CC(C)(C)O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C#Cc1nnc(Cc2c(Cl)cncc2Cl)c2ccc(OC)cc12
Reaction time: 8 h
Yield: 61 %

Procedure:
In a Claisen flask, a suspension under N2 of 4-[4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-phthalazin-1-yl]-2-methyl-but-3-yn-2-ol (0.4 g, 1 mmole), prepared as described in example 107, in dry toluene (50 ml) was added with a catalytic amount of NaH, the mixture was refluxed, then distilled up to half volume. The mixture was left to stand overnight, then poured into water, extracted three times with CH2Cl2, discoloured with charcoal, filtered over celite and dried to give a solid which was triturated in ethyl ether to give 0.21 g of the title compound. m.p.: 210.3-211.3° C. (dec.).
Reaction SMILES: [CH:1]1[CH:2]=C[C:4]2[N:9](O)N=[N:7][C:5]=2[CH:6]=1.[OH:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]([CH:20]=1)[C:17]([OH:19])=O.N1C=CC=C(N)C=1.C(Cl)CCl>CN(C=O)C.O>[OH:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]([CH:20]=1)[C:17]([NH:7][C:5]1[CH:4]=[N:9][CH:2]=[CH:1][CH:6]=1)=[O:19]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(O)ccc1OCc1ccccc1
Agent: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Solid HOBT (552 mg, 3.60 mmol) was added in one charge to a stirred solution of 5-hydroxy-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 38; 800 mg, 3.28 mmol), 3-pyridinamine (339 mg, 3.60 mmol) and EDC (691 mg, 3.60 mmol) in DMF (30 mL) at room temp. The reaction mixture was stirred at room temperature for 4 h. After 4 h, water was added to the reaction mixture. The reaction mixture was filtered and the residue was washed with ethyl acetate to yield the title compound as a white solid. 500 mg.
Reaction SMILES: [N:1]1([CH2:6][C:7]2([CH2:10][NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[N:26]=[C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:24]=[C:23]([NH:33][C:34]5([C:37]6[CH:47]=[CH:46][C:40]([O:41][CH2:42][C:43](O)=[O:44])=[CH:39][CH:38]=6)[CH2:36][CH2:35]5)[N:22]=4)=[CH:16][CH:15]=3)=[O:13])[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:48][CH:49]([S:51]([NH2:54])(=[O:53])=[O:52])[CH3:50].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:48][CH:49]([S:51]([NH:54][C:43](=[O:44])[CH2:42][O:41][C:40]1[CH:39]=[CH:38][C:37]([C:34]2([NH:33][C:23]3[N:24]=[C:25]([O:27][CH2:28][C:29]([F:32])([F:30])[F:31])[N:26]=[C:21]([NH:20][C:17]4[CH:16]=[CH:15][C:14]([C:12]([NH:11][CH2:10][C:7]5([CH2:6][N:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)[CH2:9][CH2:8]5)=[O:13])=[CH:19][CH:18]=4)[N:22]=3)[CH2:35][CH2:36]2)=[CH:47][CH:46]=1)(=[O:53])=[O:52])[CH3:50]
Reactant: CC(C)S(N)(=O)=O
Reactant: O=C(O)COc1ccc(C2(Nc3nc(Nc4ccc(C(=O)NCC5(CN6CCCC6)CC5)cc4)nc(OCC(F)(F)F)n3)CC2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC(=O)COc1ccc(C2(Nc3nc(Nc4ccc(C(=O)NCC5(CN6CCCC6)CC5)cc4)nc(OCC(F)(F)F)n3)CC2)cc1
Yield: 21.2 %

Procedure:
2-(4-(1-(4-(4-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methylcarbamoyl)phenylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)cyclopropyl)phenoxy)acetic acid (20 mg, 0.031 mmol), propane-2-sulfonamide (4.88 mg, 0.040 mmol), PyBOP (23.81 mg, 0.046 mmol), and Hunig's Base (0.027 mL, 0.153 mmol) were stirred in DCM (Volume: 3 mL) for 3 days. The solvent was removed and the crude material was purified by Prep-HPLC (Column: Sunfire prep C18 OBO 5 uM, 30×100 mm by Waters Corp) using a gradient of 10-60% ACN/water w/0.1% TFA modifier to give 4-(4-(1-(4-(2-(1-methylethylsulfonamido)-2-oxoethoxy)phenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl)benzamide (5 mg). 1H NMR (500 MHz, MeOD) δ ppm 0.75 (s, 2H), 0.83 (s, 2H), 1.14-1.42 (m, 10H), 2.12-2.26 (m, 4H), 3.06-3.43 (m, 7H), 3.77-3.88 (m, 2H), 4.64 (s, 2H), 4.81-4.92 (m, 2H), 6.86-7.00 (m, 2H), 7.21-7.32 (m, 2H), 7.64-7.76 (m, 3H), 7.89 (s, 1H); LC-MS (Condition A), MS m/z (M++H) 761.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=3)([F:13])[F:12])=[N:9][N:10]=2)[CH:7]=1.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[CH2:31][NH2:32].C([O-])(O)=O.[Na+]>CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:13])([F:12])[C:14]3[N:15]=[N:16][C:17]([NH:32][CH2:31][C:24]4[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:23]=4[O:22][CH3:21])=[CH:18][CH:19]=3)=[N:9][N:10]=2)[CH:7]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: FC(F)(c1ccc(Cl)nn1)c1nnc2ccc(Br)cn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc(CNc2ccc(C(F)(F)c3nnc4ccc(Br)cn34)nn2)c(OC)c1
Temperature: 140 °C
Yield: 88 %

Procedure:
A reaction mixture of 6-bromo-3-((6-chloropyridazin-3-yl)difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (0.5 g, 1.387 mmol), (2,4-dimethoxyphenyl)methanamine (0.696 g, 4.16 mmol) and NaHCO3 (0.58 g, 7.0 mmol) in IPA (10 mL) was heated at 140° C. in a microwave for 1 hr. The solvent was removed via rotary evaporation and the resulting residue was reconstituted in EtOAc. The organic solution was washed with water, separated and passed through a short silica plug to provide the title compound, 6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-N-(2,4-dimethoxybenzyl)pyridazin-3-amine 45G (0.6 g, 1.22 mmol, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.71-3.76 (s, 3 H) 3.79 (s, 3 H) 3.85-3.89 (m, 2 H) 6.46 (dd, J=8.34, 2.53 Hz, 1 H) 6.57 (d, J=2.27 Hz, 1 H) 6.61-6.66 (m, 1 H) 7.08 (d, J=9.35 Hz, 1 H) 7.14 (d, J=8.34 Hz, 1 H) 7.81 (d, J=9.35 Hz, 1 H) 7.99 (dd, J=9.60, 1.01 Hz, 1 H) 8.70 (s, 1 H). ESI-MS:m/z 491.1 (M+H)+.
Reaction SMILES: Cl.[CH3:2][CH:3]1[C:8]([CH3:14])([CH2:9][CH:10]=C(C)C)[CH:7]([CH3:15])[CH2:6][CH2:5][N:4]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O:23]=[O+][O-].[BH4-].[Na+]>C(O)C>[CH3:2][CH:3]1[C:8]([CH3:14])([CH2:9][CH2:10][OH:23])[CH:7]([CH3:15])[CH2:6][CH2:5][N:4]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[O+][O-]
Reactant: CC(C)=CCC1(C)C(C)CCN(Cc2ccccc2)C1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1CCN(Cc2ccccc2)C(C)C1(C)CCO
Temperature: -78 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
2,3,4-trimethyl-3-(3-methyl-2-buten-1-yl)-1-(phenylmethyl)piperidine hydrochloride (24.7 g, 76.7 mmol) was dissolved in ethanol (500 mL) and cooled to -78° C. ozone was bubbled into the reaction mixture until the solution turned blue and the mixture was purged with oxygen, then nitrogen until the solution turned colorless. Sodium borohydride (14.5 g, 383 mmol) was added to the reaction mixture while maintaining the temperature at -78° C. and the solution was stirred at -78° C. for 1 hour. The mixture was slowly warmed to room temperature over a period of 2 hours, 6 H HCl was added to acidify the solution and the solvent was removed in vacuo. The white residue was taken up in water, washed with ether (3×100 mL), basified with aqueous NAOH and extracted with methylene chloride (3×200 mL) The organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The residue was taken up in ether (500 mL), dried over anhydrous MgSO4 and the solvent was removed in vacuo to afford 19.1 g (95%) of 2,3,4-trimethyl-1-(phenylmethyl)-3-piperidineethanol.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([F:12])[CH:6]=1)C.[O:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19]OS(C)(=O)=O>>[F:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[O:11][CH2:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][O:14]1)[C:4]([OH:3])=[O:13]
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Reactant: CCOC(=O)c1ccc(O)c(F)c1
Product: O=C(O)c1ccc(OC[C@@H]2CCCO2)c(F)c1

Procedure:
According to method F, 3-fluoro-4-hydroxybenzoic acid ethyl ester was alkylated with methanesulfonic acid (S)-1-(tetrahydrofuran-2-yl)methyl ester, and the reaction product was hydrolyzed by method E. The product was thus obtained with the molecular weight of 240.23 (C12H13FO4); MS (ESI): 241 (M+H+).
Reaction SMILES: Cl.C[C:3]1[C:4](=[CH:9][C:10]2[NH:11][C:12](C)=[CH:13][C:14]=2C)[N:5]=[C:6](C)[CH:7]=1.C(N(CC)CC)C.[B:24](F)([F:26])[F:25].CCOCC>ClCCl>[B-:24]1([F:26])([F:25])[N+:5]2=[CH:6][CH:7]=[CH:3][C:4]2=[CH:9][C:10]2[N:11]1[CH:12]=[CH:13][CH:14]=2
Reactant: FB(F)F
Reactant: CC1=CC(C)=NC1=Cc1[nH]c(C)cc1C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: F[B-]1(F)n2cccc2C=C2C=CC=[N+]21
Reaction time: 0.25 h
Yield: 106.1 %

Procedure:
2-[(3,5-Dimethyl-2H-pyrrol-2-ylidene)methyl]-3,5-dimethyl-1H-pyrrole monohydrochloride (4 g, 16.89 mmol) was dissolved into 125 ml of dry dichloromethane to which triethylamine (17.09 g, 168.9 mmol) was added and allowed to stir for 15 minutes. The solution was then cooled with an ice bath to control the temperature during the slow addition of boron trifluoride etherate (2185 g, 168.9 mmol). Once the addition was complete, the ice bath was removed and the reaction was allowed to stir at room temperature for 2 hours. The reaction was then quenched with water and extracted three times with dichloromethane. The organic layer was then washed with saturated sodium carbonate. The organic layer was impregnated onto silica gel and then purified via column chromatography (10% dichloromethane in hexanes) to yield 3.44 g of Bodipy (82% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:5]2[N:6]=[C:7]([CH3:21])[CH:8]=[C:9]([NH:10][CH:11]=[C:12]([C:18]([O-:20])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:4]2[N:3]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[OH:20][C:18]1[C:8]2[C:7]([CH3:21])=[N:6][C:5]3[N:4]([N:3]=[C:2]([CH3:1])[CH:22]=3)[C:9]=2[N:10]=[CH:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(=CNc1cc(C)nc2cc(C)nn12)C(=O)[O-]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: CCOC(=O)c1cnc2c(c(C)nc3cc(C)nn32)c1O

Procedure:
33.2 g. of [[(2,5-dimethylpyrazolo[1,5-a]pyrimidin7-yl)amino]methylene]propanedioic acid, ethyl ester (0.1 mol.) are heated in 100 ml. of diphenyl ether at 240° for 7 minutes. The mixture is cooled rapidly and 100 ml. of diethyl ether are added. The product, 6-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester, precipitates and is filtered off, yield 20.1 g. (75%), m.p. 207°-208° (methanol).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([C:9]1[CH:10]=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[CH:17]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].C1COCC1.[Li+].[OH-]>CO>[CH:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:13]1[CH:14]=[C:9]([CH:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:3]([OH:35])=[O:2])[CH:10]=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=2)[CH:12]=1)([CH3:23])[CH3:24]
Reactant: COC(=O)C(CC(C)C)c1cc(Oc2cccc(C(C)C)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CC(C(=O)O)c1cc(Oc2cccc(C(C)C)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 30 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
A mixture of 2-[5-(3-isopropyl-phenoxy)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester (33 mg, 0.07 mmol), THF (0.6 mL), 10% aq. LiOH (0.2 mL) and MeOH (0.6 mL) was stirred at 30° C. for 3 h. The solution was concentrated and the residue was diluted with H2O (1 mL) and then acidified with conc HCl. The aqueous solution was extracted with DCM (3×1 mL) and the organic layers were filtered through PTFE filter. The solution was concentrated in vacuo to give a solid residue. The solid was purified using reverse phase preparative HPLC (MeCN, H2O) to afford the title compound (21.6 mg, 67%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:38]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:37][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[C:26]([C:29]6[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=6)[CH:25]=[CH:24]5)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>Cl.O1CCOCC1>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:38]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:37][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[C:26]([C:29]6[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=6)[C:35]#[N:36])[CH:25]=[CH:24]5)=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cc(-c6cccc(C#N)c6)ccc5nn4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3nn4cc(-c5ccccc5)c(-c5ccc(C6(N)CCC6)cc5)nc4c3c2)c1
Yield: 40.7 %

Procedure:
126.9 mg (0.21 mmol) (1-{4-[9-(3-Cyanophenyl)-3-phenylpyrimido[1,2-b]indazol-2-yl]phenyl}cyclobutyl)carbamic acid tert-butyl ester in 7 mL 4M hydrogen chloride in dioxane were stirred over night at room temperature. The solvent was evaporated and the residue was treated with saturated sodium bicarbonate solution. After extraction with dichloromethane (three times) the combined organic extracts were washed with brine, dried (sodium sulfate) and filtrated. The solvent was removed and the residue (102 mg) was purified by HPLC yielding 42 mg (37.9%) of the title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([CH:18]([O:25][C:26]([C:28]2[N:33]3[C:34](=[O:46])[C@@H:35]([NH:36][C:37](=[O:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@H:32]3[S:31][CH2:30][C:29]=2[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[S:27])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C(OC([C@@H]2N3C(=O)[C@@H](NC(=O)CC4C=CC=CC=4)[C@H]3SC=C2C2C=CC=CC=2)=S)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C>[C:12]1([CH:18]([O:25][C:26]([C:28]2[N:33]3[C:34](=[O:46])[C@@H:35]([NH:36][C:37](=[O:45])[CH2:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C@H:32]3[S:31](=[O:9])[CH2:30][C:29]=2[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[S:27])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3ccccc3)CS[C@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2[C@@H](C(=S)OC(c3ccccc3)c3ccccc3)C(c3ccccc3)=CS[C@H]12
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3ccccc3)CS(=O)[C@H]12
Reaction time: 0.5 h

Procedure:
A solution of 410 mg (2.03 mmols) of m-chloroperbenzoic acid in 10 ml of methylene chloride is added to a solution of 1.10 g (1.85 mmols) of a mixture of isomers consisting of 7β-phenylacetylamino-3-phenylthio-3-cephem-4-carboxylic acid diphenylmethyl ester and 7β-phenylacetylamino-3-phenylthio-2-cephem-4α-carboxylic acid diphenylmethyl ester in 11 ml of methylene chloride at 0° C. and the mixture is stirred in an ice bath for 30 minutes. The reaction mixture is diluted with ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and the organic phase is dried over sodium sulphate and evaporated in vacuo. The residue is chromatographed on silica gel thick layer plates with toluene/ethyl acetate, 1:1. 7β-Phenylacetylamino-3-phenylthio-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide of Rf value ~0.38 (silica gel; toluene/ethyl acetate, 1:1) is obtained and after recrystallisation from methylene chloride/diethyl ether melts at 180° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.OS(O)(=O)=O.[CH3:31]O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([C:16]([O:18][CH3:31])=[O:17])=[CH:11][C:10]=1[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Temperature: 25 °C

Procedure:
In a round bottom flask fitted with a condenser, a suspension of the product from Step D (2.89 g; 7.60 mmol) in methanol (60 mL) was treated with concentrated H2SO4 (0.5 mL; cat.) and heated to reflux overnight. The reaction mixture was allowed to cool to room temperature, and the volatiles were removed in vacuo. The reaction was quenched with saturated aq. NaHCO3 solution and extracted with methylene chloride (5×). The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Trituration with methanol gave the desired product: m/e=392 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[CH:5]=[CH:4][N:3]=1.[CH:19]1([C:22]([NH2:24])=[O:23])[CH2:21][CH2:20]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[N:9]1[CH:8]=[C:7]2[C:2]([NH:24][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])=[N:3][CH:4]=[CH:5][C:6]2=[N:10]1
Reactant: Fc1cccc(Cl)c1-n1cc2c(Cl)nccc2n1
Reactant: NC(=O)C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1nccc2nn(-c3c(F)cccc3Cl)cc12)C1CC1
Yield: 42.6 %

Procedure:
A mixture of 4-chloro-2-(2-chloro-6-fluorophenyl)-2H-pyrazolo[4,3-c]pyridine (76 mg, 0.27 mmol), cyclopropylcarboxamide (26 mg, 0.31 mmol), Pd2(dba)3 (7 mg, 0.007 mmol), Xantphos (16 mg, 0.027 mmol) and cesium carbonate (176 mg, 0.54 mmol) in dioxane (2 mL) was sealed in a microwave vial, purged with nitrogen, and irradiated at 150° C. for 20 minutes in the microwave. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (50% ethyl acetate in cyclohexane) to afford the title compound as a yellow solid (38 mg, 43% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.15 (br s, 1H), 8.94 (s, 1H), 8.00 (d, J=6.3 Hz, 1H), 7.73 (td, J=8.3, 5.8 Hz, 1H), 7.67-7.66 (m, 1H), 7.64-7.52 (m, 2H), 7.36 (d, J=6.3 Hz, 1H), 2.18-2.12 (m, 1H), 0.93-0.86 (m, 4H). LCMS (Method B): RT=2.77 min, m/z: 331 [M+H+].
Reaction SMILES: [CH3:1][CH:2]1[N:7]2[C:8]3[O:20][NH:19][C:18](=[O:21])[C:9]=3[C:10](=[O:17])[C:11]3=[CH:12][C:13]([F:16])=[C:14](F)[C:5](=[C:6]23)[O:4][CH2:3]1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>N1C=CC=CC=1>[CH3:1][CH:2]1[N:7]2[C:8]3[O:20][NH:19][C:18](=[O:21])[C:9]=3[C:10](=[O:17])[C:11]3=[CH:12][C:13]([F:16])=[C:14]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)[C:5](=[C:6]23)[O:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CC1COc2c(F)c(F)cc3c(=O)c4c(=O)[nH]oc4n1c23
Solvent: c1ccncc1
Product: CC1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c4c(=O)[nH]oc4n1c23
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1.45 g of the preceding isoxazolo-pyrido-benzoxazine derivative (9) (R8 =CH3) in 30 ml pyridine is added in 2.5 ml N-methylpiperazine. It is then heated under nitrogen atmosphere at 50° C. for 24 hours. The mixture is evaporated to dryness and is then boiled in ethanol for 5 minutes and the mixture is filtered and washed with water yielding the 1-methyl-4-(4-methyl-1-piperazinyl)-5-fluoro-1,2,8,9-tetrahydro-7H-isoxazolo[4',5':5,6]pyrido[1,2,3-de][1,4]benzoxazine-7,8-dione (I) ##STR15## R=CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH2:4]1.C(=O)([O-])O.[Na+].COC>O1CCCC1>[CH3:1][O:2][C:3]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:12][CH2:11][C:6](=[O:7])[CH2:5][CH2:4]1
Reactant: COC1(c2ccccc2)CCC2(CC1)OCCO2
Agent: COC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccccc2)CCC(=O)CC1
Yield: 73.4 %

Procedure:
A solution of 8-methoxy-8-phenyl-1,4-dioxaspiro[4.5]decane (5.96 g) and 3N-hydrrochloric acid (24 ml) in tetrahydrofuran was stirred at room temperature for 24 hours. The reaction mixture was added to a mixture of sodium hydrogen carbonate solution and dimethyl ether. The organic layer was washed with sodium hydrogen carbonate solution and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (1:0-150:1 dichloromethane-methanol elution) to give 4-methoxy-4-phenylcyclohexanone (3.6 g).