Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])CCC=C.[CH2:9]([O:25][C:26]1[CH:35]=[C:34](C)[CH:33]=[CH:32]C=1S([O-])(=O)=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O>CN(C)C=O.O1CCCC1>[CH2:9]([O:25][CH2:26][CH:35]([CH2:34][CH:33]=[CH2:32])[CH2:3][OH:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: C=CCCCO
Reactant: CCCCCCCCCCCCCCCCOc1cc(C)ccc1S(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC(CO)COCCCCCCCCCCCCCCCC
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 10.9 %

Procedure:
To a suspension of 19.1 g of 50% sodium hydride under argon in 300 ml of N,N-dimethylformamide is added dropwise over a period of 1 hour, with stirring a solution of 37 g of 4-penten-1-ol, 2-methanol (prepared as described by B. K. Wasson, et. al., J. Chem. Soc., 39, 923 (1961)) in 200 ml of tetrahydrofuran. After stirring another 30 minutes, 126.34 g of hexadecyloxytosylate is added followed by 500 ml of tetrahydrofuran. This mixture is stirred for 2.5 hours, then heated to 80° C. for 20 minutes and then at room temperature overnight. Water is added and the mixture extracted with ether. The ether extract is dried and then evaporated. The residue is distilled using a Kugelrohr. The fraction distilling at 200°-210° C. 1 mm is collected, purified by chromatography and then redistilled, to give 11.35 g of the desired compound.
Reaction SMILES: N[C:2]1[C:3]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.N[C:13]1C=CC(S(O)(=O)=O)=C[CH:14]=1.CO>C(O)(C)C>[CH2:13]=[CH:14][C:6]1[CH:5]=[CH:4][C:3]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:2][CH:7]=1
Reactant: Nc1ccccc1S(=O)(=O)O
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CC(C)O
Product: C=Cc1ccc(S(=O)(=O)O)cc1
Yield: 73 %

Procedure:
Example 13 was repeated, but instead of aniline-2-sulphonic acid the same amount of aniline-4-sulphonic acid and instead of methanol the same volume of iso-propanol were used. 15.0 g (73%) of styrene-4-sulphonic acid, Na salt, were obtained.
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[CH2:24]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)[CH2:25][CH2:26][CH3:27].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:24]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=2)=[CH:30][CH:29]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1ccc(B(O)O)cc1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCc1ccc(-c2nc(C)ccc2Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 4-n-butylphenylboronic acid (178 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (55 mg, yield 64%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:34])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[C:24]([O:29][C:30]([F:33])([F:32])[F:31])[CH:23]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH2:19][CH2:18]2)=[O:34])=[CH:23][C:24]=1[O:29][C:30]([F:31])([F:32])[F:33]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)Nc3ccc(Br)c(OC(F)(F)F)c3)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Br)c(OC(F)(F)F)c1)N1CCN(C2CCNCC2)CC1

Procedure:
A solution of 4-[4-(4-bromo-3-trifluoromethoxy-phenylcarbamoyl)-piperazin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (61.8 mg, 0.11 mmol) in 4 M of HCl in 1,4-dioxane (2.8 mL) was stirred at RT for 1 h to provide the title intermediate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([OH:9])=O)=[N:4][S:5][N:6]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[F:18])[NH2:14].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.[Cl-].[Na+].O.Cl>[NH2:1][C:2]1[C:3]([C:7]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([F:18])=[C:11]([Br:10])[CH:12]=2)=[O:9])=[N:4][S:5][N:6]=1
Reactant: Nc1ccc(F)c(Br)c1
Reactant: Nc1nsnc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Nc1nsnc1C(=O)Nc1ccc(F)c(Br)c1
Reaction time: 16 h
Yield: 76.8 %

Procedure:
A solution of 4-amino-1,2,5-thiadiazole-3-carboxylic acid (250 mg, 1.7 mmol) and 3-bromo-4-fluoroaniline (393 mg, 2.1 mmol) in N,N-dimethylformamide (5 mL) was treated with O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (784 mg, 2.1 mmol) followed by N,N-diisopropylethylamine (0.36 mL, 2.1 mmol) and stirred for 16 h. The reaction mixture was diluted with brine (50 mL) and 0.1 N HCl (100 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with brine (50 mL), dried with sodium sulfate, filtered, and concentrated. Purification of the crude reaction mixture on silica gel gave the desired product (414 mg, 76%). LCMS for C9H7BrFN4OS(M+H)+: m/z=316.9, 318.8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([N+:16]([O-])=O)[CH:3]=1>[Ni].CO>[Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1NCCN1CCCC1
Agent: [Ni]
Solvent: CO
Product: Nc1cc(Br)ccc1NCCN1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
100 mg Raney Nickel are added to a solution of 1.00 g (3.18 mmol) (4-bromo-2-nitro-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amine in 100 mL MeOH. The reaction solution is stirred for 15 min at 3 bar H2 and RT. After filtration the solvent is eliminated i.vac. and the product is further reacted without purification.
Reaction SMILES: [NH2:1][C@H:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][CH2:4][NH:5][C:6]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:8]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:7]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CO>[C:33]([NH:1][C@H:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][CH2:4][NH:5][C:6]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[C:8]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:7]=1)(=[O:35])[CH3:34]
Reactant: Cn1c(NCC[C@H](N)c2ccccc2)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)N[C@@H](CCNc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)n1C)c1ccccc1

Procedure:
A solution of 2-(((S)-3-amino-3-phenylpropyl) -amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone (23.8 mg, 0.055 mmol) and acetic anhydride (20 μl, 0.21 mmol) in methanol(1 ml) was kept for 30 min at room temperature. Evaporation was followed by column chromatography (dichloromethane-methanol-ammonium hydroxide=93:7:0.7) to provide the title compound. MS (m/z): 472.2 (M+H)+; C27H26FN5O2requir. 471.5.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[NH2:19]>N1C=CC=CC=1>[C:1]1([N:7]2[C:12](=[O:11])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3[NH:19][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccnc1N
Reactant: O=C=Nc1ccccc1
Solvent: c1ccncc1
Product: O=c1[nH]c2ncccc2c(=O)n1-c1ccccc1
Yield: 61.2 %

Procedure:
17.22 g (144.6 mmol, 15.7 ml) phenylisocyanate was added to a suspenssion of 7.00 g (46.0 mmol) 2-aminonicotinic acid methyl ester in dry pyridine. The mixture was refluxed for 16 hours. The pyridine is was removed under reduced pressure and the residue was treated with 280 ml ethanol. The mixture is refluxed for 10 minutes. Upon cooling down 3-phenyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione crystallized from the medium and was recrystallized from methoxypropanol. 6.73 g (61%) 3-phenyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione was isolated (m.p. 304° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][C:4]=1[NH:12][C:13](=[S:21])OC1C=CC=CC=1.[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([CH3:29])[CH:28]=1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][C:4]=1[NH:12][C:13]([N:33]1[CH2:34][CH2:35][N:30]([C:25]2[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH3:22])[CH:24]=2)[CH2:31][CH2:32]1)=[S:21]
Reactant: COc1nc2c(cc1NC(=S)Oc1ccccc1)CCC2
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc2c(cc1NC(=S)N1CCN(c3cc(C)cc(C)c3)CC1)CCC2
Yield: 53 %

Procedure:
Phenyl N-(2-methoxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)thiocarbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:21]=[CH:20][C:10]([O:11][CH:12]([CH2:17][O:18][CH3:19])[C:13]([O:15]C)=[O:14])=[CH:9][CH:8]=2)[C:5]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[CH:25][C:4]=2[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH:12]([CH2:17][O:18][CH3:19])[C:13]([OH:15])=[O:14])=[CH:20][CH:21]=2)[C:5]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:27])[F:28])=[CH:25][C:4]=2[N:3]=1
Reactant: COCC(Oc1ccc(-n2c(C)nc3cc(C(F)(F)F)ccc32)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCC(Oc1ccc(-n2c(C)nc3cc(C(F)(F)F)ccc32)cc1)C(=O)O

Procedure:
A solution of 4.5 g of 10 and 0.5 g of sodium hydroxide in 50 ml of aqueous methanol was refluxed for 2 hours. The resulting mixture was concentrated to dryness, the residue was acidified with dilute hydrochloric acid and extracted with ether. The extract was dried and concentrated. The residue was crystallized from ether-hexane to give 11, as a light tan crystalline solid, m.p.: 111°-112° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(N(CC)CC)C>[CH3:29][S:30]([NH:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CNS(C)(=O)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1

Procedure:
To a solution of (2S,4R)-2-aminomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2 g) were successively added triethylamine (0.82 ml) and methanesulfonyl chloride (0.42 ml) under ice-cooling with stirring, and the mixture was stirred at the same temperature for 1 hour. The reaction mexture was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give (2S,4R)-2-methanesulfonylaminomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.15 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][OH:19])[CH:14]=3)[N:9]=2)=[CH:5][CH:4]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH:18]=[O:19])[CH:14]=3)[N:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccc3cc(CO)ccc3n2)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: Ic1ccccc1
Product: COc1ccc(Oc2ccc3cc(C=O)ccc3n2)cc1
Yield: 98 %

Procedure:
To a CH2Cl2 (38 mL) solution of [2-(4-methoxyphenoxy)quinolin-6-yl]methanol (1.11 g) and iodobenzene diacetate (1.33 g) was added 2,2,6,6-tetramethyl-1-piperidinyloxy radical (61.0 mg), then the resultant mixture was stirred over night at room temperature. The reaction mixture was quenched by addition of saturated aqueous Na2S2O3 and NaHCO3, and extracted with CH2Cl2. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=10/1 to 5/1) to afford 2-(4-methoxyphenoxy)quinoline-6-carbaldehyde (1.08 g) as a colorless solid.
Reaction SMILES: ClC1C=CC(N2[C:17]3[C:12](=[C:13]([CH3:21])[C:14]([OH:20])=[C:15]([CH3:19])[C:16]=3C)[CH2:11]C3(CCC3)C2)=CC=1.[N+:25]([O-:28])(O)=[O:26]>C(O)(=O)C>[CH3:21][C:13]1[C:12]([CH3:11])=[C:17]([N+:25]([O-:28])=[O:26])[CH:16]=[C:15]([CH3:19])[C:14]=1[OH:20]
Reactant: Cc1c(C)c2c(c(C)c1O)CC1(CCC1)CN2c1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c(C)c(C)c1O
Reaction time: 0.5 h

Procedure:
2,3,6-trimethyl phenol 1 (19.1 g) was dissolved in acetic acid (190 mL). This solution was added to an acetic acid solution of HNO3 (150 mL, 1M) at room temperature in 4.5 hours. After another 0.5 hour, the mixture was evaporated, and the residue was taken up by EtOAc (350 mL). This solution was washed with water (150 mL×2), and brine (150 mL), dried and evaporated. Elution on a silica column (Hexane: EtOAc, 5:1-5:2), gave 2,3,6-trimethyl-4-nitrophenol (7.56 g), as a yellow solid. 1H-NMR, (300 MHz, CDCl3) δ=7.61 6, (br s, 1H), 2.432 (s, 3H), 2.275 (s, 3H), 2.242 (s, 3H) ppm.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[C:6]([O:16][CH2:17][CH3:18])[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.O=[Mn]=O>[CH2:17]([O:16][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])[CH:7]=1)[CH:3]=[O:2])[CH3:18]
Reactant: CCOc1cc(OCC(F)(F)F)cc(C(=O)OC)c1
Agent: O=[Mn]=O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOc1cc(C=O)cc(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
To a solution of 3-ethoxy-5-(2,2,2-trifluoro-ethoxy)-benzoic acid methyl ester (0.8 g, 2.88 mmol, 1.0 equiv) in anhydrous THF (20 mL) was added lithium aluminium hydride (0.273 g, 7.19 mmol, 2.5 equiv) and the reaction mixture stirred at rt for 4 h. The crude reaction mixture was filtered over Hyflo Super Cel, the filtrate extracted with diethyl ether (3×50 mL) and the combined organic phases dried over MgSO4 providing 0.75 g (99%) of the benzyl alcohol. The crude reaction product (0.75 g, 3.0 mmol, 1.0 equiv) was dissolved in THF (20 mL) and activated MnO2 (2.61 g, 30.00 mmol, 10.0 equiv) was added. After stirring at rt for 3 h, the reaction mixture was filtered over Hyflo Super Cel and the solvent removed by evaporation under reduced pressure. A conc. solution of sodium chloride (100 mL) was added, the mixture extracted with ethyl acetate (3×100 mL) and the combined organic phases dried over MgSO4. Purification of the crude material with column chromatography on silica eluting with heptane/ethyl acetate (4:1) provided 0.54 g (72%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.35 (t, J=7.0 Hz, 3H), 4.00 (q, J=7.0 Hz, 2H), 4.31 (q, J=8.1 Hz, 2H), 6.66-6.67 (m, 1H), 6.91-6.92 (m, 1H), 6.99-7.00 (m, 1H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:22]2[C:21](=[O:27])[CH2:20][C@@:19]2([CH3:28])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:18])[CH2:16][OH:17])[CH2:6]1)(=[O:3])[CH3:2].[CH3:29]I>[Ag]=O>[C:1]([O:4][C@@H:5]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:22]2[C:21](=[O:27])[CH2:20][C@@:19]2([CH3:28])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:18])[CH2:16][O:17][CH3:29])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@H](CC[C@H]3[C@@H]4CC[C@H](C(=O)CO)[C@@]4(C)CC(=O)[C@@H]32)C1
Agent: O=[Ag]
Product: COCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 8 h

Procedure:
Freshly prepared silver oxide (690 mg.) was added to a solution of 3α-acetoxy-21-hydroxy-5β-pregnane-11,20-dione (68.3 mg.) in methyl iodide (1.5 ml.) and the resulting mixture was refluxed for 1 hour, allowed to stand overnight and then refluxed for a further 3 hours. The reaction was partitioned between water and chloroform and the chloroform layer was washed with water, dried (Na2SO4) and evaporated to give 3α-acetoxy-21-methoxy-5β-pregnane-11,20-dione (69 mg.) as a foam. This was dissolved in methanol (1.25 ml.) and refluxed with 10% aqueous potassium bicarbonate solution (0.6 ml.) for 2.5 hours. The reaction mixture was allowed to cool and was partitioned between water and ether. The ether layer was washed with water, dried (Na2SO4) and evaporated. The product was purified by preparative t.l.c. (ethyl acetate:chloroform; 1:1) to give the title compound as a foam, [α]D + 80°, (c 2.36).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[CH:11][CH:10]=1.Cl[C:15]([O:18]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl>C1(C)C=CC=CC=1.C1COCC1>[O:18]=[C:15]1[N:13]2[N:12]=[CH:11][CH:10]=[C:9]2[C:3]2[CH:4]=[C:5]([CH:7]=[O:8])[S:6][C:2]=2[NH:1]1
Reactant: Nc1sc(C=O)cc1-c1ccn[nH]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1cc2c([nH]c(=O)n3nccc23)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
5-Amino-4-(1H-pyrazol-5-yl)thiophene-2-carbaldehyde (12 mg, 0.06 mmol) and bis(trichloromethyl)carbonate (55 mg, 0.19 mmol) were dissolved in toluene (3 mL) and THF (0.5 mL), and the reaction heated in a sealed tube at 100° C. for 3 h. The reaction was cooled to room temperature, hexanes (10 mL) added, suspension stirred at room temperature for 30 min, precipitate washed with additional hexanes (10 mL), dried under reduced pressure to yield 5-oxo-4,5-dihydropyrazolo[1,5-c]thieno[3,2-e]pyrimidine-2-carbaldehyde as a powder (11 mg, 81%). 1H NMR (400 MHZ, DMSO-d6) δ 6.99 (s, 1H), 8.12 (s, 1H), 8.45 (s, 1H), 9.93 (s, 1H), 13.06 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:21])[C:5]([CH2:8][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])=[N:6][CH:7]=1.FC1C=C(CN)C=CC=1[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:20][O:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[CH2:10][NH:9][CH2:8][C:5]1[N:6]=[CH:7][C:2]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=2)=[CH:3][C:4]=1[CH3:21]
Reactant: Cc1cc(-c2ccc(CN)cc2F)ccn1
Reactant: COc1ccc(CNCc2ncc(Br)cc2C)c(OC)c1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(CNCc2ncc(-c3ccnc(C)c3)cc2C)c(OC)c1
Temperature: 120 °C

Procedure:
To a round bottom flask was added 1-(5-bromo-3-methylpyridin-2-yl)-N-(2,4-dimethoxybenzyl)methanamine 81-3 (1.5 g, 4.3 mmol), 2-methylpyridin-4-ylboronic acid 15-1 (589 mg, 4.3 mmol), Pd(PPh3)4 (248 mg, 0.22 mmol), saturated Na2CO3 (10 mL), ethanol (10 mL) and toluene (30 mL). The reaction was refluxed at 120° C. for 30 hours. After cooling to room temperature, the reaction was diluted into ethyl acetate and washed with brine. The solvent was removed by rotary evaporation. The crude product was purified by silica gel flash chromatography to give N-(2,4-dimethoxybenzyl)-1-(2′,5-dimethyl-3,4′-bipyridin-6-yl)methanamine 81-4. MS m/z 364.2 (M+1).
Reaction SMILES: O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:21][C@@H:22]1[CH:31]=[CH:30][CH2:29][C:24]2([CH2:28][CH2:27][CH2:26][CH2:25]2)[C@H:23]1[C:32](=[O:36])/[CH:33]=[CH:34]/[CH3:35]>C1C=CC=CC=1>[CH3:21][C@@H:22]1[CH:31]=[CH:30][CH2:29][C:24]2([CH2:28][CH2:27][CH2:26][CH2:25]2)[C@H:23]1[C:32](=[O:36])[CH2:33][CH2:34][CH3:35]
Reactant: C/C=C/C(=O)[C@H]1[C@H](C)C=CCC12CCCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCC(=O)[C@H]1[C@H](C)C=CCC12CCCC2
Reaction time: 0.08 h
Yield: 39.6 %

Procedure:
After argon bubbling, a mixture of benzene (70 ml) and water (0.15 ml) was treated with triphenylphosphine-cooper (I)-hydride hexamer (3.3 g, 1.68 mmol). The resulting mixture was stirred for five min., treated with a solution of (E)-1-(rel-(6S,7R)-7-methylspiro[4.5]dec-8-en-6-yl)but-2-en-1-one (2 g, 9.16 mmol) in benzene (10 ml) and stirred for 2 h at 20° C. The reaction mixture was then stirred for 30 min under air, filtered, and concentrated. FC (SiO2, hexane/MTBE 70:1) of the crude product (4.07 g) gave 1-(rel-(6S,7R)-7-methylspiro[4.5]dec-8-en-6-yl)butan-1-one (0.80 g, 40%). Boiling point: 100° C. (0.08 mbar).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[CH:29]=[C:28]([CH3:30])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]4[O:11][CH2:1][O:2][C:3]=4[CH:4]=3)[C:24]3[CH:29]=[C:28]([CH3:30])[S:27][C:25]=3[N:26]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C)sc3n2)cc1
Reactant: NCc1ccc2c(c1)OCO2
Product: COC(=O)c1ccc(-c2nc(NCc3ccc4c(c3)OCO4)c3cc(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxy-benzylamine is reacted with 4-(4-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxybenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[C:12]([F:30])[C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:11]1[C:12]([F:30])=[C:13]([O:16][C@H:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCCC[C@@H]3c3ccnn3C)c(F)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCCCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1F
Yield: 71 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,3-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (190 mg, 0.310 mmol) prepared in Example 51a, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (102 mg, 71%) as a colorless solid.