Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.O>C1(C)C=CC=CC=1>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([N:16]=[C:14]([CH:5]2[CH:6]([C:11]([OH:13])=[O:12])[CH:7]3[CH2:10][C:4]2([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]3)[OH:15])=[CH:18][CH:19]=1
Reactant: Nc1ccc(O)cc1
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=Nc1ccc(O)cc1

Procedure:
A solution of 101 g of allylbicylo[2.2.1]hept-5-ene-2,3-dicarboxylic acid anhydride and 54.5 g of 4-aminophenol in 155 g of toluene is heated to boiling point, and the water formed during imidation is separated in a Hahn stillhead.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH:20]=[N+:21]=[N-:22]>C1C=CC=CC=1>[CH:8]1([N:7]2[C:5]([CH2:4][CH2:3][CH2:2][Cl:1])=[N:22][N:21]=[N:20]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(CCCCl)NC1CCCCC1
Reactant: [N-]=[N+]=N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: ClCCCc1nnnn1C1CCCCC1
Reaction time: 2 h

Procedure:
Into 200 ml of dried benzene, 30.6 g of N-γ-chlorobutyrylcyclohexylamine was added. While the inside temperature is kept below 20° C. by ice-cooling the outside of the reaction vessel, 30 g of PCl5 was added under stirring condition. After completion of the addition, the stirring is continued for 2 hours at a room temperature, then the reaction mixture is concentrated to a half volume thereof by using an evaporator with a bath temperature of below 50° C. To the concentrated reaction mixture was added dropwise 140 ml of benzene containing 10% of HN3 under stirring condition for 90 minutes while keeping the inside temperature below 15° C. After the addition operation, the reaction mixture is allowed to stand overnight at room temperature. Then the reaction mixture is refluxed for 3 hours with stirring and is concentrated. The thus obtained concentrate is extracted with 200 ml of chloroform. The chloroform layer is washed with 5% NaHCO3 aqueous solution and with water and dried with Na2SO4. After removal of the drying agent, the mother liquor is concentrated and the residue thus obtained is recrystallized from water-containing isopropanol to obtain 28 g of 1-cyclohexyl-5-γ-chloropropyltetrazole in the form of colorless needle like crystals. Melting point: 82°-85° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][CH2:16][Cl:17])=[CH:9][CH:8]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:17][CH2:16][CH2:15][C:14]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[C:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][OH:3])=[CH:12][CH:11]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)COc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCOc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1

Procedure:
[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-acetic acid ethyl ester (Example 7) was dissolved in tetrahydrofuran at room temperature under nitrogen atmosphere. Lithium aluminium hydride was added to the solution in small portions until the reaction was complete. The reaction was quenched by adding saturated ammonium chloride solution to the mixture. The product was extracted into toluene, which was dried and evaporated in vacuo. The yield 100 mg, 43%.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][C@@H:4]1[F:36].[C:37](Cl)(=[O:39])[CH3:38]>>[C:37]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:33][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][C@@H:4]1[F:36])(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)[C@@H](F)C1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1F

Procedure:
Starting from N-[(1S*,3S*,4S*)-4-amino-3-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f62) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[O:20][C:7]1([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:24].[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][N:26]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]3[C:21](=[CH:22][CH:23]=2)[O:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:9][CH2:8]2)[CH2:6][C:5]3=[O:24])[CH:28]=[N:27]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)O3)cn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Tert-butyl 6-bromo-4-oxospiro-[chroman-2,4′-piperidine]-1′-carboxylate (1 g) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (682 mg) were dissolved in dioxane in a nitrogen atmosphere, and aqueous 2 M sodium carbonate solution (3.8 mL) and tetrakis(triphenylphosphine)palladium (144 mg) were added thereto, and degassed. The reaction liquid was stirred overnight at 100° C., cooled to room temperature, then water was added thereto, and filtered through Celite. The filtrate was extracted with chloroform, and the organic layer was dried with sodium sulfate. Sodium sulfate was removed through filtration, the filtrate was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate=100/0 to 0/100) to obtain the intended product as a pale yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.FC1C(O)=C(F)C(F)=C(F)C=1F.C(N=C=NC(C)C)(C)C.Cl.[OH:33][CH:34]1[O:42][C@H:41]([CH2:43][OH:44])[C@@H:39]([OH:40])[C@H:37]([OH:38])[C@H:35]1[NH2:36].CCN(CC)CC>CN(C=O)C.CN(C=O)C.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:34]2([O:42][C@H:41]([CH2:43][OH:44])[C@@H:39]([OH:40])[C@H:37]([OH:38])[C@H:35]2[NH2:36])[OH:33])=[O:8])=[CH:9][CH:10]=1
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=C(O)c1ccc(I)cc1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1(O)C(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-iodobenzoic acid (1 mmol) in DMF (2 mL) was added pentafluorophenol (2 mmol) and diisopropylcarbodiimide (1.2 mmol). The solution was stirred at room temperature for 6 hours and then added to a solution of glucosamine hydrochloride (1 mmol) and NEt3 (2 mmol) in DMF/H2O (1 mL, 1:10 v/v). The reaction was stirred for 16 hours and then crystallized from hot water to yield 4-iodobenzoyl glucosamine, compound TP010. The structure of TP010 is shown below (R is I).
Reaction SMILES: FC(F)(F)S(O[C@H:7]1[C@H:12]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][CH2:9][C:8]1([F:22])[F:21])(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[N:25]([C@H:7]1[C:8]([F:22])([F:21])[CH2:9][CH2:10][CH2:11][C@H:12]1[NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N+:26]=[N-:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@H]1OS(=O)(=O)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@@H]1N=[N+]=[N-]
Temperature: 100 °C
Yield: 56.2 %

Procedure:
A solution of (1S,6R)-6-[(tert-butoxycarbonyl)amino]-2,2-difluorocyclohexyl trifluoromethanesulfonate 26 (2.32 g, 6.05 mmol) and sodium azide (2.36 g, 36.3 mmol) in DMF was sealed and heated to 100° C. for 3 hours in a microwave reactor. The reaction was partitioned between water and ethyl acetate. The organics were washed with water, dried over magnesium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (0-15% ethyl acetate in hexanes) gave 0.94 g (56%) of tert-butyl [(1R,2R)-2-azido-3,3-difluorocyclohexyl]carbamate 28 as a white solid: 1H NMR (500 MHz, CDCl3) δ 4.75 (1H, m), 3.98 (1H, bs), 3.88 (1H, bm), 1.96 (2H, m), 1.70 (2H, m), 1.46 (9H, s), 1.37 (2H, m).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=3)=[O:25])[CH:20]=[CH:19][C:18]=2[F:34])([CH:14]([F:16])[F:15])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=3)=[O:25])[CH:20]=[CH:19][C:18]=2[F:34])([CH:14]([F:16])[F:15])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)(C(F)F)COC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C(=O)Nc2ccc(F)c([C@]3(C(F)F)COCC(N)=N3)c2)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
((R)-5-{5-[(5-Cyano-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (44.47 g, 91.0 mmol) was dissolved in 450 ml DCM and mildly chilled with a rt water bath. TFA (150 ml) was added. The reaction was slightly exothermic. The mixture was stirred for 1.5 h at it. The volatiles were removed with vacuum at rt. The residue was taken up in DCM and the procedure repeated twice. The residue was taken up in 3 L EtOAc and washed with 10% aqueous Na2CO3 and brine. The organic phase was dried with sodium sulfate and partially evaporated. iPrOH was added and the mixture chilled. The title compound was collected as snow-white crystals. Yield 30.56 g.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CO.CCO[CH2:18][CH3:19].O=O>N1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:18][CH3:19]
Reactant: C#CCCCCCCCCCC
Reactant: CCOCC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: c1ccncc1
Solvent: CO
Product: CCCCCCCCCCC#CC#CCCCCCCCCCC
Reaction time: 72 h

Procedure:
Dodec-1-yne (EGA 24,440-6) (1.2 g) was heated in the presence of copper acetate (4 g) in a mixture of pyridine (100 cm3) , methanol 300 cm3) and ether (400 cm3), for 72 h, at 30°-32° C., in the presence of a gentle stream of pure oxygen. The ether and methanol were then evaporated off under reduced pressure after the excess dissolved oxygen had been removed by the passage of argon, in the presence of 1 g of CuCl. The solution was taken up by fresh anhydrous pyridine (400 cm3) for 72 h at 47° C. (reflux). Part of the pyridine was then evaporated off under reduced pressure, after which the mixture was acidified with a 10% aqueous solution of HCl. After extraction with ether and evaporation, an oily liquid was obtained which crystallized in the cold. The oil was chromatographed in CHCl3 on SiO2 to give an oil which was transparent at room temperature (0.877 g, y=73%). The product was checked by NMR, gas chromatography (purity 97%) and mass spectroscopy (peak 330).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:18][C:6]2=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:19])[CH2:3]1.ClC1C=C(C=CC=1)C(OO)=[O:26]>C(Cl)Cl>[CH3:1][C:2]1([CH3:20])[CH2:18][C:6]2=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[S:8][C:9]([S:10]([CH3:11])=[O:26])=[C:5]2[C:4](=[O:19])[CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1sc(-c2ccccn2)c2c1C(=O)CC(C)(C)C2
Solvent: ClCCl
Product: CS(=O)c1sc(-c2ccccn2)c2c1C(=O)CC(C)(C)C2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
6,6-Dimethyl-3-methylthio-1-(pyrid-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (200 mg, 0.66 mmol) was dissolved in CH2Cl2 (20 mL) and cooled to −78° C. Meta-chloroperoxybenzoic acid (82 mg of 70% (w/w); 0.66 mmol) was dissolved in CH2Cl2 (5 mL) and added dropwise to the solution, which was allowed to stir at −50° C. for 1 h, then warmed to room temperature. The mixture was diluted with dichloromethane and washed with saturated sodium hydrogen carbonate solution, water and brine. After drying (Na2SO4), the solution was evaporated to dryness and the residue was purified by chromatography on silica gel, eluting with ethyl acetate:hexane (1:1). The title compound was isolated as a white solid (160 mg, 79%). 1HNMR (360 MHz, CDCl3)δ 1.08 (3H, s), 1.11 (3H, s), 2.43 (1H, d, J=18 Hz), 2.53 (1H, d, J=18 Hz), 3.00 (3H, s), 3.03 (2H, s), 7.24-7.28 (1H, m), 7.52-7.54 (1H, m), 7.76-7.80 (1H, m), 8.64-8.66 (1H, m). MS (ES+) 320 (M+1).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:30])[CH2:22][NH:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=O)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:30])[CH2:22][NH:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(N)cc2)cc1
Temperature: 25 °C
Yield: 12 %

Procedure:
N-2-(4-(4-t-butoxycarbonylaminophenyl)phenyl)propyl 2-propane-sulfonamide: A degassed solution of 0.9 g (2.9 mmol) of material from Example 39, 1.4 g (2.8 mmol) of material from Preparation 51 and 0.2 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium(0) in 10 mL of toluene was heated to reflux for 5 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. Chromatography (100 g of silica gel, 30% ethyl acetate/hexane) of the residue afforded 0.15 g (12%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[NH2:7][CH2:8][CH2:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][CH2:11]1>CO>[O:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH:10]([CH2:9][CH2:8][N:7]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:11]1
Reactant: NCCC1COc2ccccc2C1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCN(CCC(=O)OC)CCC1COc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
6.63 g (77 mmol) of acrylic acid methyl ester are added at room temperature to a solution of 6.2 g (35 mmol) of 3-(2-aminoethyl)chroman in 50 ml of methanol and the whole is stirred for 16 hours at room temperature. The reaction mixture is then concentrated by evaporation in vacuo and yields 12.23 g (100%) of N-[2-(chroman-3-yl)ethyl]-N,N-bis(2-methoxycarbonylethyl)-amine in the form of a reddish oil.
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[C:3](=[O:9])[CH2:2]1.[BH4-].[Na+].Cl.N(CCO)CCO>C(O)C>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([OH:9])[CH2:2]1
Reactant: O=C1COC2OCCC12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: OCCNCCO
Solvent: CCO
Product: OC1COC2OCCC12
Reaction time: 1 h
Yield: 155.3 %

Procedure:
Generally in accordance with the procedure described by Ghosh et al in J. Org. Chem. 2004, 69, 7822-7829, tetrahydrofuro[2,3-b]furan-3(2H)-one (950 mg, 7.42 mmol, 1 eq.) was dissolved at 0° C. in 50 mL of ethanol. NaBH4 (302.4 mg, 8 mmol, 1.07 eq.) was added in one portion to the mixture. After a 1 hour stirring period, diethanolamine hydrochloride salt (3.2 g, 8 mmol, 1.07 eq.) was added and the mixture was stirred overnight at room temperature. The heterogeneous mixture was filtered over dicalite and washed with 20 mL of warm AcOEt. After evaporation of the organic solvents under reduced pressure to afford 1500 mg of hexahydrofuro[2,3-b]furan-3-ol with a quality (area %) of 40%; max yield: 60%. diastereoisomeric excess: exo(3S,3aS,6aR)/endo (3R,3aS,6aR): 18.5/81.5.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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]>[NH2:8][C:5]1[N:6]=[N:7][C:2]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Nc1ccc(Cl)nn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(N)nn2)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 48.9 %

Procedure:
A mixture of 6-chloropyridazin-3-amine (3.24 g, 25 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (9.8 g, 37.4 mmol), Pd2(dba)3 (0.72 g, 1.25 mmol), X-phos (1.19 g, 2.5 mmol) and Na2CO3 (7.95 g, 75 mmol) in dioxane (150 mL) and water (15 mL) was heated to 100° C. with stirring for 4 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=20:1) to give methyl 4-(6-aminopyridazin-3-yl)benzoate (2.8 g, 48%) as a white solid. LC-MS: [M+H]+, 230.1, tR=1.213 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@H:14]3[C:18]([CH3:20])([CH3:19])[C@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.I[CH3:23]>CN1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@H:14]3[C:18]([CH3:20])([CH3:19])[C@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[N:9]1[CH3:23]
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccccc3Cl)c(=O)c12
Reactant: CI
Agent: CN1CCCC1
Product: Cn1c2c(c(=O)n1-c1ccccc1Cl)[C@@H]1CC[C@@]2(C)C1(C)C
Yield: 66.9 %

Procedure:
A solution of (4R,7S)-2-(2-chloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 39; 151.5 mg, 0.5 mmol) and iodomethane (0.16 mL, 2.55 mmol) in N-methylpyrrolidine (1 mL) was heated at 100° C. in a sealed tube for 2 h. The reaction mixture was purified by preparative HPLC to give (4R,7S)-2-(2-chloro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (106 mg, 67%) as an off-white solid. ES(+)-MS (M+H) 317.
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9]CC(Cl)(Cl)Cl)=[O:8])[N:5]1[C:16](=[O:32])[CH:17]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C@H:4]1[S:3]2>[Zn].C(O)(=O)C>[CH3:1][C:2]12[CH2:15][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:16](=[O:32])[CH:17]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=3)(=[O:20])=[O:21])[C@H:4]1[S:3]2
Reactant: CC(=O)Nc1ccc(S(=O)(=O)NC2C(=O)N3[C@@H]2SC2(C)CC32C(=O)OCC(Cl)(Cl)Cl)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(S(=O)(=O)NC2C(=O)N3[C@@H]2SC2(C)CC32C(=O)O)cc1
Yield: 60.5 %

Procedure:
2,2,2-Trichloroethyl 2-methyl-2,3-methylene-6-(4-acetamidobenzenesulfonamido)penam-3-carboxylate (1.09 g.), acetic acid (1.5 ml.) and zinc powder (1.2 g.) were treated in the similar manner as described in Example 1 and the residue was crystallized using ethyl acetate to give 2-methyl-2,3-methylene-6-(4-acetamidobenzenesulfonamido)penam-3-carboxylic acid (0.5 g.), mp. 230°C (dec.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23].CCN(C(C)C)C(C)C>C(O)CCC>[CH2:22]([N:24]([CH2:25][CH3:26])[C:2]1[C:11]2[C:6](=[C:7]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)[CH3:23]
Reactant: O=S(=O)(Nc1cccc2c(Cl)ccnc12)c1ccccc1
Reactant: CCNCC
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1ccnc2c(NS(=O)(=O)c3ccccc3)cccc12
Yield: 26.4 %

Procedure:
In a similar fashion using route 48 general procedure 114, N-(4-chloro-quinolin-8-yl)-benzenesulfonamide 224 (100 mg, 0.32 mmol), diethyl amine (0.097 ml, 0.94 mmol), DIPEA (0.11 ml, 0.63 mmol) and n-butanol (1 ml) gave the title compound (30 mg, 27%) after purification by column chromatography with chloroform/MeOH (1 drop NH3) (97:3) as the eluent.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].CO[C:15](=O)[NH:16][C:17]1[CH:18]=[N:19][C:20]([N:31]2[CH2:36][CH2:35][S:34][CH2:33][CH2:32]2)=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH3:30].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:15][NH:16][C:17]1[CH:18]=[N:19][C:20]([N:31]2[CH2:32][CH2:33][S:34][CH2:35][CH2:36]2)=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH3:30]
Reactant: COC(=O)Nc1cnc(N2CCSCC2)cc1-c1ccc(F)cc1C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CNc1cnc(N2CCSCC2)cc1-c1ccc(F)cc1C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 103 %

Procedure:
43.7 ml Red-Al (3.5 M in toluene) was diluted in 25 ml toluene and added dropwise to a solution of 13 g (30.6 mmol) [4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-pyridin-3-yl]-carbamic acid methyl ester in 55 ml toluene at 10° C. (the addition was exothermic). The yellow solution obtained was stirred for 40 minutes at room temperature and 1.5 hours at 50° C. It was cooled to 0° C. and poured slowly onto a mixture of 150 ml 4 N aqueous sodium hydroxide and 50 ml ice (very exothermic). After 10 minutes stirring, the phases were separated, the aqueous phase was extracted with tert-butyl-methyl-ether and the organic phases were washed with brine. The combined organic extracts were dried and concentrated under reduced pressure to yield 10 g methyl-[4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-pyridin-3-yl]-amine as a brown oil which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]=[C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][N:11]1[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14]
Reactant: CC(Br)c1ccccc1
Reactant: COC(=O)c1ccnc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(C(C)c2ccccc2)c(=O)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 17.5 %

Procedure:
To a solution of methyl 2-hydroxyisonicotinate (306 mg, 2 mmol) in N,N-dimethylformamide (30 mL) was added (1-bromoethyl)benzene (0.37 g, 2 mmol) and potassium carbonate (0.55 g, 4 mmol). The mixture was heated to 110° C. and stirred at the same temperature for 12 hours. The solvent was evaporated in vacuum and the residue was purified by preparative-HPLC to give methyl 2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylate (90 mg, 17%) The product was used directly in the next step.