Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:10][CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:35]N(C=O)C.CI>>[CH3:35][O:12][CH2:11][CH2:10][CH:9]([N:13]1[CH:17]=[C:16]([C:18]2[C:19]3[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH:15]=[N:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CCO)c4ccccc4)c3)ncnc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COCCC(c1ccccc1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79.9 %

Procedure:
Sodium hydride (9.6 mg, 0.00040 mol) was added to a solution of 3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propan-1-ol (120 mg, 0.00027 mol) in DMF (3 mL, 0.04 mol) and the mixture was cooled to 0° C. The reaction was stirred for 20 min and methyl iodide (22 mL, 0.00035 mol) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give 4-[1-(3-methoxy-1-phenylpropyl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 88%) as a semisolid. m/z=464 (M+1).
Reaction SMILES: [C:1]1([C:7]2O[N:10]=[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:18]1[NH:22]C(=O)[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:30]>Cl[Ti](Cl)(Cl)Cl.O1CCOCC1>[C:1]1([C:7]2[C:8]3[C:9](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:18]([C:19]([NH:20][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:30])[N:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2onc3ccccc23)cc1
Reactant: COC1NC(=O)N(c2ccccc2)C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)c1nc(-c2ccccc2)c2ccccc2n1
Yield: 82 %

Procedure:
The reaction between 3-phenylbenzo[c]isoxazole and 5-methoxy-3-phenyl-2,4-imidazolidinedione in refluxing dioxane containing TiCl4 as catalyst to give 82% of 4,N-diphenyl-2-quinazolinecarboxamide [39];
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16](Cl)[N:15]=[C:14]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[NH2:34][CH2:35][CH2:36][OH:37]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:37][CH2:36][CH2:35][NH2:34])[N:15]=[C:14]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: NCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)c1ccc(C)cn1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCCN

Procedure:
According to the procedure described in Example 4b) 1.0 g 5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with 2-aminoethanol to give 950 mg 5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrmidinyl]-2-pyridine sulfonamide. LC-MS: tR=3.00 min, (M+1]+=509.53, [M−1]−=507.57.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[C:11]=1[N:20]=[C:21]=[O:22]>C1COCC1>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:21]([NH:20][C:11]1[C:12]([C:16]([F:17])([F:19])[F:18])=[CH:13][CH:14]=[CH:15][C:10]=1[Cl:9])=[O:22]
Reactant: O=C=Nc1c(Cl)cccc1C(F)(F)F
Reactant: N[C@@H]1CCCC[C@H]1N
Solvent: C1CCOC1
Product: N[C@@H]1CCCC[C@H]1NC(=O)Nc1c(Cl)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
A solution of 0.46 g of trans-1,2-diaminocyclohexane in 10 ml of THF was added to a solution of 1.6 g of 2-chloro-6-trifluoromethylphenyl isocyanate in 30 ml of THF, and the mixture was stirred at room temperature for about 3 hours. The mixture was allowed to stand overnight and the solvent was then distilled off, giving 0.57 g of the desired compound as a semi-solid yellow product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[CH:7]=1)[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=3)[C:14]=2[CH3:24])[CH:7]=1)[CH3:2]
Reactant: CCCn1cc(Br)cn1
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(CC(=O)OCC)c3)c3ccc(Cl)c(F)c32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: [3-(6-Chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid ethyl ester and 4-bromo-1-propyl-1H-pyrazole.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][O:12][C:5]2([CH2:11][CH2:10][C:8](=[O:9])[CH2:7][CH2:6]2)[O:4][CH2:3]1.[Cl-].[NH4+].[CH2:17]([Mg]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH2:17]([C:8]1([OH:9])[CH2:7][CH2:6][C:5]2([O:4][CH2:3][C:2]([CH3:14])([CH3:1])[CH2:13][O:12]2)[CH2:11][CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)COC2(CCC(=O)CC2)OC1
Reactant: Br[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1(C)COC2(CCC(O)(Cc3ccccc3)CC2)OC1
Reaction time: 2.5 h

Procedure:
To a solution of 1,4-cyclohexanedione mono-2,2-dimethyltrimethylene ketal (3.76 g) and zinc chloride (about 1.0 mol/L, solution in diethyl ether, 1.90 mL) in tetrahydrofuran (63.0 mL), benzylmagnesium bromide (about 1.0 mol/L, solution in tetrahydrofuran, 24.7 mL) was added at 0° C. and thereafter the mixture was stirred at that temperature for 2.5 hours. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added and three extractions were conducted with ethyl acetate. The combined organic layers were washed with saturated brine and thereafter dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-60:40) to give 9-benzyl-3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-ol as a colorless solid (1.28 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]([C@@H:14]1[C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([CH2:29][CH2:30]2)[C@:26]2([CH3:27])[C:21]([CH2:22][C@@H:23]([O:33][CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[CH2:24][CH2:25]2)=[CH:20][C:19]3=[O:40])[CH2:16][CH2:15]1)[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CCOC(C)=O.[Pt](=O)=O>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]([C@@H:14]1[C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([CH2:29][CH2:30]2)[C@:26]2([CH3:27])[C@H:21]([CH2:22][C@@H:23]([O:33][CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[CH2:24][CH2:25]2)[CH2:20][C:19]3=[O:40])[CH2:16][CH2:15]1)[CH3:13])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 2.5 h
Yield: 69.6 %

Procedure:
Compound 2004 (1.0 g, 1.75 mmol) was dissolved in EtOAc (75 ml) and platinum(IV) oxide (0.012 g, 0.049 mmol) was added. The mixture was placed on a hydrogenation apparatus (atmospheric). The set-up was evacuated to remove the dissolved oxygen and then hydrogen was introduced. The evacuation and introduction of hydrogen process was repeated 2 times. The reaction was stirred under hydrogen at atmospheric pressure for 2.5 hours. The reaction mixture was filtered through Celite and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, hexanes:EtOAc gradient starting with 20:1) giving compound 2005 as a white solid (0.70 g, 71%). 24-t-Butyldimethylsilyloxy-3β-tetrahydropyranyloxy-5α-cholan-7β-ol was obtained as a by-product (21%). (Note: This by-product could be converted to the desired ketone 2005 with Collin's reagent in 64% yield.) Compound 2005: 1H NMR (500 MHz, CDCl3) δ: 4.73-4.66 (m, 1H, THP methine H), 3.95-3.85 (m, 1H, THP CH2O), 3.66-3.52 (m, 3H, THP CH2O & C-24 H), 3.50-3.45 (M, 1H, C-3 H), 1.08 (s, 3H, C-19 H), 0.91 (d, J=6.6 Hz, C-21 H), 0.89 (s, 9H, t-Bu), 0.64 (s, 3H, C-18 H), 0.04 (s, 6H, TBDMS CH3); IR (CHCl3) 2900, 1685 cm−; MS (CI/isobutane) m/z 575 (M+1, 85%), 491 (M+1-THP, 100%); m.p. 166-170° C.; Anal. calcd. for C35H62O4Si: C=73.12; H=10.87. Found: C=72.88; H=10.78.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH:9]=O)[CH:2]=1.Cl.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1.C(O)(=O)C>C(O)C>[Br:12][C:13]1[CH:14]=[C:15]2[C:16](=[CH:17][CH:18]=1)[NH:19][CH:9]=[C:8]2[CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=CCCc1cccnc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: Brc1ccc2[nH]cc(Cc3cccnc3)c2c1

Procedure:
A mixture of 3-pyridin-propionaldehyde (1 g; 0.0074 mol) and of 4-bromophenylhydrazin hydrochloride (1.8 g; 0.0074 mol) with acetic acid (4.44 ml) in absolute ethanol (50 ml) was refluxed for 3 hours. The reaction was then quenched with a saturated solution of aqueous sodium carbonate and the product was extracted with ethyl acetate. The organic extract was dried (MGSO4) and evaporated under vacuum. After purification by Flash Chromatography on silica gel using as eluent methylene chloride/methanol (98/2), the desired compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([NH2:21])=[O:20])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:23]1C=C(C#CC2CC3(CCNC3)ON=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([NH2:21])=[O:20])[CH2:15][CH2:23]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Reactant: Clc1cccc(C#CC2=NOC3(CCNC3)C2)c1
Product: NC(=O)N1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2

Procedure:
The title compound was synthesized following the method herein described for the compound of Example 96 but replacing Compound 22c for Compound 27d. After the usual work-up procedure the crude was purified by means of automated flash chromatography (Isolera®TM-Biotage; gradient Petroleum Ether-EtOAc from 1:0 to 93:7) giving the title compound as a white solid. Yield: 76.9%.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[C:17]([O:18][CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[C:16]2[C:11]([CH:12]=[N:13][C:14]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([S:39](=[O:42])(=[O:41])[NH2:40])=[CH:35][CH:34]=3)=[N:15]2)=[CH:10][CH:9]=1.[CH3:43][N:44]1[CH:48]=[CH:47][C:46](B2OC(C)(C)C(C)(C)O2)=[CH:45]1>COCCOC.[Pd]>[CH3:43][N:44]1[CH:48]=[CH:47][C:46]([C:8]2[C:17]([O:18][CH:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)=[C:16]3[C:11]([CH:12]=[N:13][C:14]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([S:39]([NH2:40])(=[O:41])=[O:42])=[CH:37][CH:38]=4)=[N:15]3)=[CH:10][CH:9]=2)=[CH:45]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(Br)ccc3cnc(Nc4ccc(S(N)(=O)=O)cc4)nc23)CC1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cn1ccc(-c2ccc3cnc(Nc4ccc(S(N)(=O)=O)cc4)nc3c2OC2CCNCC2)c1
Temperature: 92.5 °C
Reaction time: 1.5 h
Yield: 22.9 %

Procedure:
A 2M solution of K2CO3 (180 μL) was added to a mixture of tert-butyl 4-(7-bromo-2-(4-sulfamoylphenylamino)quinazolin-8-yloxy)piperidine-1-carboxylate (18 mg, 0.031 mmole), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (20 mg, 0.093 mmole) and palladium (4 mg, 0.005 mmole) in DME (0.6 mL). The reaction was sparged with argon, sealed and heated at 90-95° C. with stirring. After 90 minutes, LCMS showed that the reaction had reached completion. The Boc group was removed by adding 4M HCl (1.5 mL) in dioxane to the cooled reaction mixture. After 2 hours, the reaction was complete by LCMS. The reaction was filtered, evaporated, dissolved in DMSO (1 mL) and purified by prep. HPLC to give 3.4 mg of the pure product as a TFA salt.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:11].CN1C2C(=CC=CC=2)C(C)=C1[CH:23]=[O:24]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:23]=[O:24])=[C:3]1[CH3:11]
Reactant: Cc1cc2ccccc2n1C
Reactant: Cc1c(C=O)n(C)c2ccccc12
Product: Cc1c(C=O)c2ccccc2n1C

Procedure:
1,2-Dimethylindole-3-carboxaldehyde (mp 129° C.) was prepared from 1,2-dimethylindole following essentially the same procedure as that used for the preparation of 1,3-dimethylindole-2-carboxaldehyde referred to in (g) above.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][OH:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:14][C:4]1[CH:3]=[C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:13])=[CH:9][CH:10]=2)[N:5]=1
Reactant: C1CCNC1
Reactant: Cc1cc(Cl)c2ccc(CO)cc2n1
Product: Cc1cc(N2CCCC2)c2ccc(C(=O)N3CCCC3)cc2n1
Yield: 54 %

Procedure:
(4-Chloro-2-methyl-quinolin-7-yl)-methanol (example 2, 200 mg, 0.80 mmol) was heated in pyrrolidine (2 mL) at 70° C. for 48 h. After cooling the reaction mixture was partitioned between sat. aq. ammonium chloride solution and dichloromethane. The organic layer was separated, dried (MgSO4), and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 19:1) afforded the title compound (134 mg, 54%). Light yellow solid, ISP-MS: m/e=310.3 ([M+H]+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[N:14]=[C:13](S(C)(=O)=O)[N:12]=[C:11]([NH:19][CH:20]([CH3:22])[CH3:21])[C:10]=1[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30]>CN(C=O)C>[Cl:8][C:9]1[N:14]=[C:13]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[N:12]=[C:11]([NH:19][CH:20]([CH3:22])[CH3:21])[C:10]=1[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30]
Reactant: CC(C)Nc1nc(S(C)(=O)=O)nc(Cl)c1-c1c(F)cccc1Cl
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Nc1nc(-n2cccn2)nc(Cl)c1-c1c(F)cccc1Cl
Reaction time: 1 h
Yield: 93.1 %

Procedure:
A solution of 180 mg (2.64 mmol) of pyrazole in 4 ml of anhydrous DMF was treated with 106 mg (2.64 mmol) of NaH (60% suspension in mineral oil), with ice-cooling. After the mixture had been stirred for one hour, 500 mg (1.32 mmol) of the product of step d were added and the mixture was stirred for approximately 14 hours at 20 to 25° C. The product was precipitated by adding water. Filtration, washing with water and drying gave 450 mg of the title compound as colorless crystals of m.p. 185–187° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:31]/[O:32][CH2:33][CH3:34])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH2:18]OC(=O)CC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[CH3:35][C:36]1[N:41]2[CH:42]=[N:43][CH:44]=[C:40]2[CH:39]=[CH:38][CH:37]=1>>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:31]/[O:32][CH2:33][CH3:34])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:43]4[CH:44]=[C:40]5[CH:39]=[CH:38][CH:37]=[C:36]([CH3:35])[N:41]5[CH:42]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: Cc1cccc2cncn12
Reactant: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1nsc(N)n1
Product: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cc4cccc(C)n4c3)CS[C@H]12)c1nsc(N)n1

Procedure:
By the procedure of Example 1, 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-ethoxyiminoacetamido]-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid is reacted with 5-methylimidazo[1,5-a]pyridine to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:16][CH2:15]1)[CH3:2]>CCOC(C)=O.[Pt]>[CH2:1]([C:3]1[C:4]([N:14]2[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:19]2)=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:8]=1)[NH2:9])[CH3:2]
Reactant: CCc1cc([N+](=O)[O-])c(OC)cc1N1CCC(CCS(C)(=O)=O)CC1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCc1cc(N)c(OC)cc1N1CCC(CCS(C)(=O)=O)CC1
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To 1-[2-ethyl-5-(methyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperidine (0.25 g, 0.68 mmol) in EtOAc (30 mL) was added platinum on carbon (sulfided) (0.13 g, 0.034 mmol). The mixture was stirred under H2 (1 atm.) overnight. Filtering the mixture through Celite® and concentrating provided the title compound of Step B (0.18 g, 0.54 mmol, 79%). 1H NMR (400 MHz, DMSO-d6) δ 6.55 (s, 1H), 6.42 (s, 1H), 4.30 (br. s., 2H), 3.67 (s, 3H), 3.04-3.16 (m, 2H), 2.92 (s, 3H), 2.77 (d, J=11.5 Hz, 2H), 2.52 (t, J=10.9 Hz, 2H), 2.38-2.44 (m, 2H), 1.56-1.75 (m, 4H), 1.39 (ddd, J=10.7, 7.1, 3.5 Hz, 1H), 1.24 (qd, J=11.7, 3.2 Hz, 2H), 1.04 (t, J=7.6 Hz, 3H).
Reaction SMILES: C1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[C@H:24]4[C@H:19]([CH2:20][CH:21]=[CH:22][CH2:23]4)[C:18](=[O:25])[N:17]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[N:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([C:15]2[C@H:24]3[C@H:19]([CH2:20][CH:21]=[CH:22][CH2:23]3)[C:18](=[O:25])[N:17]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:16]=2)=[CH:8][C:7]=1[OH:6]
Reactant: COc1ccc(C2=NN(C3CCCC3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C2=NN(C3CCCC3)C(=O)[C@H]3CC=CC[C@@H]23)cc1O
Temperature: 25 °C

Procedure:
A solution of 3.3 g of compound 21 and 2 g of p-toluenesulfonic acid in 15 ml of toluene was refluxed for 4 h. After cooling to room temperature, themixture was washed with aqueous sodium carbonate, the toluene solution was dried over magnesium sulfate and evaporated. Crystallization from diethyl ether/petroleum ether (60-80° C.). M.p. 142-144° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([C:13]#[N:14])=[CH:8][C:7]=1[Cl:15])=[O:4].CC(O)C.Cl.[H][H]>[Pd].CO>[NH2:14][CH2:13][C:9]1[CH:8]=[C:7]([Cl:15])[C:6]([NH:5][C:3](=[O:4])[CH2:2][Cl:1])=[C:11]([Cl:12])[CH:10]=1
Reactant: [H][H]
Reactant: N#Cc1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: NCc1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Yield: 100 %

Procedure:
A mixture of 10.5 parts of 2-chloro-N-(2,6dichloro-4-cyanophenyl) acetamide, 22 parts of 2-propanol, saturated with hydrogen chloride and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in water and treated with a sodium hydroxide solution 50%. The product was extracted twice with dichloromethane. The combined extracts were dried, filtered and evaporated, yielding 10.7 parts (100%) of N-[4-(aminomethyl)-2,6-dichlorophenyl]-2-chloroacetamide as a residue (int. 100).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16]1(=[O:21])[NH:20][CH2:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.C(OCC)(=O)C>C(OCC)(=O)C>[C:6]([C:5]1[CH:14]=[CH:15][C:2]([N:20]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:21])=[CH:3][CH:4]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: O=C1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1ccc(N2CCCC2=O)cc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
2.61 g (0.01 mole) of 4-bromobenzophenone and 1.13 ml of butyrolactam (0.015 mole) are fused together at 180° C., and 1.4 g of K2CO3 and 0.63 g of Cu powder are added. The mixture is stirred at this temperature for 2 h, allowed to cool to 140° C. and then dissolved in ethyl acetate. Chromatography on silica gel eluting with toluene/ethyl acetate provides N-(4-benzoylphenyl)-2-pyrrolidinone of melting point 162°-164° C., which is immediately dissolved in 10 ml of methanol and 10 ml of 5 N NaOH and boiled under reflux for about 2 h. After the methanol has been removed by distillation, the mixture is acidified to pH 5, and the product is filtered off with suction. Melting point: 156°-158° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[OH:13].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:21]([CH3:23])[CH3:22]>CC(C)=O>[CH:21]([O:13][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9]2)([CH3:23])[CH3:22]
Reactant: COc1ccc2c(c1O)CCCC2
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1ccc2c(c1OC(C)C)CCCC2
Yield: 92.6 %

Procedure:
33 (4.55 g, 25.5 mmol) was charged in a 250 mL round bottom flask, equipped with a reflux condenser, under nitrogen gas. 50 mL of anhydrous acetone was added followed by cesium carbonate (66.55 g, 204.3 mmol). 2-bromopropane (23.94 mL, 255.0 mmol) was added and the reaction mixture was refluxed for 12 h. The solvent was filtered and evaporated in vacuo and purified by flash column chromatography (silica gel, 1:99 EtOAc:Hexanes) to afford 5.2 g (93%) of 5-isopropoxy-6-methoxy-1,2,3,4-tetrahydronaphtalene (34). Rf value: 0.615 (15:85 EtOAc:Hexanes).
Reaction SMILES: CC1(C)COC(C([C@@H]2[C@]3(C)[C@H](C4[C@H](CC3)[C@]3(C)C(C[C@@H](OC(OC)=O)C[C@@H]3O)=CC=4)CC2)C)[O:4][CH2:3]1.[CH3:36][O:37][C:38]([O:40][C@@H:41]1[C@@:59]2([CH3:60])[C:45](=[CH:46][CH:47]=[C:48]3[C@@H:58]2[CH2:57][CH2:56][C@@:55]2([CH3:61])[C@H:49]3[CH2:50][CH2:51][C@@H:52]2[CH2:53][CH3:54])[CH2:44][C@@H:43]([O:62]C(OC)=O)[CH2:42]1)=[O:39]>>[OH:62][C@H:43]1[CH2:42][C@H:41]([O:40][C:38]([O:37][CH3:36])=[O:39])[C@@:59]2([CH3:60])[C:45](=[CH:46][CH:47]=[C:48]3[C@@H:58]2[CH2:57][CH2:56][C@@:55]2([CH3:61])[C@H:49]3[CH2:50][CH2:51][C@@H:52]2[CH:53]([CH:3]=[O:4])[CH3:54])[CH2:44]1
Reactant: CC[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(=O)OC)C[C@H](OC(=O)OC)[C@]4(C)[C@H]3CC[C@]12C
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O)C1
Product: COC(=O)O[C@H]1C[C@H](O)CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@]21C

Procedure:
The reaction and workup procedures of Example 156 were repeated except that 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl )-3β-(methoxycarbonyl)oxypregna-5,7-dien-1α-ol was used in lieu of 100 mg of 20-(5,5-dimethoxycarbonyl)oxypregna-1,3-dioxan-2-yl)-1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene to give 55 mg of 3β-hydroxy-1α-(methoxycarbonyl)oxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:18]1([CH2:24]Br)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[CH:18]1([CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CCCCC2)cc1
Temperature: 50 °C

Procedure:
To a solution of methyl 4-hydroxybenzoate 23-1 (24.3 g, 160 mmol) in 250 mL of DMF was added 62 g (190 mmol) of Cs2CO3 followed by 20.4 mL (146 mmol) of cyclohexylmethyl bromide. The resulting slurry was then heated at 50° C. for 20 h. The solvent was distilled under reduced pressure and the residue was taken up in 500 mL of EtOAc. The organic phase was extracted with 1N NaOH (2×150 mL), water (5×150 mL) and brine (150 mL), dried (MgSO4) and concentrated to afford product 23-2 as a white solid.