Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:11]=[CH:10]2.[CH3:25][CH2:26][O:27][C:28]([C:30]([C:33](OCC)=[O:34])([CH3:32])[CH3:31])=[O:29]>C1COCC1>[CH2:26]([O:27][C:28](=[O:29])[C:30]([CH3:32])([CH3:31])[C:33]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:13]=2)[CH:8]=1)=[O:34])[CH3:25]
Reactant: CCOC(=O)C(C)(C)C(=O)OCC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C(=O)c1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
t-Butyl lithium 1.7 M (99.7 mL, 169.5 mmol) was added slowly to a solution of (6-bromo-naphthalen-2-yloxy)-tert-butyl-dimethyl-silane (26.0 g, 77.1 mmol) in THF (400 mL) cooled to −78° C. under a nitrogen atmosphere. The reaction was stirred at −78° C. for 1 h, and then diethyl dimethyl malonate (43.5 g, 231.2 mmol) was added rapidly. The reaction was stirred an additional 0.5 h, warmed to room temperature, and partitioned between water saturated with KH2PO4 and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated to give 3-[6-(tert-butyl-dimethyl-silanyloxy)-naphthalen-2-yl]-2,2-dimethyl-3-oxo-propionic acid ethyl ester as an oil.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([O:31][CH3:32])[CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.CO>[CH3:32][O:31][CH:5]([CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][CH:8]=1)[C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Yield: 90.3 %

Procedure:
0.184 g of 2-Methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid ethyl ester (0.40 mmol) was dissolved in 1 ml of THF/MeOH=1/1 and treated with 0.670 ml of 3N NaOH. The reaction mixture was kept over night at RT and then quenched by pouring onto crashed ice/HCl. Twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents left a crude product, which was purified by crystallisation from AcOEt/hexane to yield 0.158 g of the title compound as white solid, mp.121-122°.
Reaction SMILES: [CH2:1]([N:5]([C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1)[C:6](Cl)=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH2:1]([N:5]([C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1)[C:6](=[O:7])[NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Product: CCCCN(C(=O)Nc1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 40 °C
Reaction time: 15 h
Yield: 52.9 %

Procedure:
A solution of butyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-carbamoyl chloride (9) (368 mg, 0.55 mmole) in 30 mL pyridine was treated with 272 mg of ethyl p-aminobenzoate (3 eq.) and stirred at 40° C. for 15 hours. The reaction mixture was concentrated in vacuo to provide an orange oil which was purified by flash chromatography (SiO2, 2.5% methanol/dichloromethane) which yielded 131 mg (54%) of ethyl 4-[3-butyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (11) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10](Cl)=[O:11].[NH2:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[OH:30]>C(OCC)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([NH:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[OH:30])=[O:11]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3c(Cl)cccc3Cl)O2)c(=O)[nH]c1=O
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
A solution of 1.12 g of (2,6-dichlorophenyl)acetyl chloride in 15 ml of diethyl ether was added to a solution of 1.275 g of 5'-amino-2',5'dideoxy-5-ethyluridine in 15 ml of 0.33M sodium hydroxide solution. The mixture was shaken vigorously for 10 minutes and then filtered. The solid was washed with 150 ml of water, 20 ml of ethanol and 40 ml of diethyl ether, and then recrystallized from 2.5 l of ethanol to give 1.53 g of 5'-[2-(2,6-dichlorophenyl)acetamido]-2', 5'-dideoxy-5-ethyluridine in the form of a white solid of melting point 296°-297° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([NH2:29])[C:23]=1[NH2:30]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:7]=[CH:6][C:3]=1[C:4]1[NH:29][C:24]2[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[C:23]=2[N:30]=1
Reactant: Cc1cc(C)c(N)c(N)c1
Reactant: CN1CCC(CCCOc2ccc(C=O)c(Cl)c2)CC1
Product: Cc1cc(C)c2nc(-c3ccc(OCCCC4CCN(C)CC4)cc3Cl)[nH]c2c1
Yield: 86.3 %

Procedure:
This compound was prepared by the method described in Example 2, using 2-chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyde (106 mg, 0.36 mmol, 1.0 equiv), 3,5-dimethyl-benzene-1,2-diamine (49 mg, 0.36 mmol, 1.0 equiv), and Na2S2O5 (88 mg, 0.47 mmol, 1.3 equiv) in Step C. Purification by Method 2 afforded 128 mg (87%) of the title compound. MS (electrospray): mass calculated for C24H30ClN3O, 411.21; m/z found, 412.4 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.68 (d, J=8.5 Hz, 1H), 7.21 (br s, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.01 (dd, J=8.7, 2.5 Hz, 1H), 6.90 (s, 1H), 4.05 (t, J=6.3 Hz, 2H), 2.92-2.88 (m, 2H), 2.54 (s, 3H), 2.43 (s, 3H), 2.29 (s, 3H), 2.09-2.03 (m, 2H), 1.85-1.76 (m, 4H), 1.47-1.11 (m, 5H).
Reaction SMILES: [CH3:1][CH:2]([CH3:37])[C@H:3]([NH:24][C:25](=[O:36])[C@@H:26]([NH:28]C(=O)OC(C)(C)C)[CH3:27])[C:4](=[O:23])[N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][C@H:6]1[C:14](=[O:22])[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C@@H:26]([CH3:27])[C:25]([NH:24][C@@H:3]([CH:2]([CH3:37])[CH3:1])[C:4]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][C@H:6]1[C:14]([NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:22])=[O:23])=[O:36]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
In a 100 mL round-bottomed flask, tert-butyl (S)-1-((S)-3-methyl-1-oxo-1-((S)-2-(phenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)butan-2-ylamino)-1-oxopropan-2-ylcarbamate (75 mg, 147 μmol, Eq: 1.00) was combined with DCM (6 mL) to give a colorless solution. TFA (1.9 mL, 24.9 mmol, Eq: 169) was added. The reaction was stirred for 30 min and then concentrated in vacuo. The residue was taken up in DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated in vacuo to give (S)-1-((S)-2-((S)-2-aminopropanamido)-3-methylbutanoyl)-N-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (55 mg) which was used without further purification.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([C@@H:7]2[CH2:11][C@H:10]([CH3:12])[CH2:9][N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:5][CH:6]=1.[CH3:20][Si:21]([CH3:34])([CH3:33])[C:22]#[C:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(O)(C)C>[CH3:12][C@@H:10]1[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:7]([C:4]2[NH:5][CH:6]=[C:2]([C:27]3[CH:28]=[CH:29][C:24]([C:23]#[C:22][Si:21]([CH3:20])([CH3:34])[CH3:33])=[CH:25][CH:26]=3)[N:3]=2)[CH2:11]1
Reactant: C[C@H]1C[C@@H](c2nc(I)c[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: C[Si](C)(C)C#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: C[C@H]1C[C@@H](c2nc(-c3ccc(C#C[Si](C)(C)C)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 85 °C
Yield: 99.7 %

Procedure:
To a solution of tert-butyl (2S,4S)-2-(4-iodo-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (150 mg, 0.3976 mmol) and ([4-(2-trimethylsilylethynyl)phenyl]boronic acid (130 mg, 0.6 mmol) in isopropanol (3 mL) are added sequentially Pd(DPPF)(Cl)2.CH2Cl2 (16 mg, 0.02 mmol), and 2 M NaHCO3 (600 uL, 1.2 mmol). The mixture is heated to 85° C. in a sealed tube overnight. After reaction, the solvent is removed under reduced pressure and the residue is purified by flash column chromatography on silica gel using methanol/CH2Cl2 0-5% to provide tert-butyl (2S,4S)-4-methyl-2-[4-[4-(2-trimethylsilylethynyl)phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (168 mg, 95%).
Reaction SMILES: [BH3-]C#N.[Na+].C(O)(=O)C.[C:9]([O:13][C:14]([NH:16][N:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:15])([CH3:12])([CH3:11])[CH3:10]>C1COCC1>[C:9]([O:13][C:14]([NH:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CCCCC=NNC(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCNNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
6.65 g of NaBH3CN are solubilized in acetic acid (10.5 g; 175 mmoles). The solution is cooled at 0° C. and a solution in anhydrous THF (35 mL; 0.15 M) of t-butyl-2-pentylidenhydrazincarboxylate (7.00 g; 35 mmoles) prepared in example 11a is dropwise added. The reaction mixture is then let to warm to room temperature under stirring for 24 hours. The organic phase is washed with a 10% NaHCO3 solution and then extracted with chloroform. The organic phase is recovered and the solvent removed under vacuum. The obtained residue is purified by chromatography on silica gel using as eluent a chloroform/methanol 90:1 volume/volume mixture. 6.3 g of t-butyl-2-pentylhydrazincarboxylate are obtained (white solid; yield 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.Br[C:37]#[C:38][C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1>C1(C)C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:37]#[C:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Fc1ccc(C#CBr)cc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Product: CN1CCc2c(c3cc(Cl)ccc3n2C#Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 16.4 %

Procedure:
To a stirred solution of 8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 0.00090 mol) and copper sulfate (0.026 g, 0.00009 mol) in toluene (5 mL) was added potassium carbonate (0.25 g, 0.0018 mol) and 1,10 phenanthroline (0.032 g, 0.000018 mol). The reaction mixture was stirred for 5 min at RT. A solution of 1-bromoethynyl-4-fluoro-benzene (0.199 g, 0.00099 mol) in toluene (2 mL) was added to the reaction mixture. After addition, the reaction mixture was stirred for 2 h at 80° C. After completion of reaction (monitored by TLC), solvent was removed under reduced pressure, and the product obtained was purified by column chromatography (2% MeOH:DCM as eluent on silica (100-200 mesh), diameter of column—5.0 cm, height of silica—approx. 5 inch) to provide the desired compound as a yellow colored oil (0.05 g, 16% yield). The free base was converted to its oxalate salt by treatment with oxalic acid (1 equiv) in THF. 1H NMR (DMSO, oxalate salt) δ (ppm): 7.65 (m, 4H), 7.30 (m, 3H), 4.20 (m, 2H), 3.40 (m, 2H), 3.10 (m, 2H), 2.80 (s, 3H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH:12]1[CH2:17][CH2:16][N:15](CC2C=CC=CC=2)[CH2:14][CH2:13]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H][H]>C(O)C.O.[C].[Pd]>[CH3:2][N:3]([CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: CN(CCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN(CCc1ccccc1)C1CCNCC1
Yield: 70.1 %

Procedure:
60 ml of concentrated hydrochloric acid and 13.3 g of 10% palladium-carbon were added to a solution of 266 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-benzylpiperidine in 1 liter of ethanol and 500 ml of water. The mixture was stirred at a hydrogen pressure of 1 atm. at 60° C. for 5 hours. 10% palladium-carbon was removed by filtration and then washed with ethanol. The filtrate and the washings were combined and concentrated under reduced pressure. The residue was added to ice water. The mixture was made alkaline with a 25% aqueous sodium hydroxide solution and then extracted with methylene chloride. The extract was water-washed and then concentrated under reduced pressure. The residue was subjected to vacuum distillation to obtain 131.9 g of 4-[N-methyl-N-(2-phenylethyl)amino]piperidine as a colorless oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]=[C:2]1[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][N:10]1[C:20](=[O:21])[CH2:19][N:18]=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[CH:16]=[C:11]12.IC1C=CC=C2C=1CCN1C(=O)CN=C(C3C=CC=C(OC)C=3)C=C12.C([Sn](CCCC)(CCCC)C1OCCC=1)CCC>O1CCOCC1.CCOC(C)=O.CCCCCCC.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>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([C:17]2[CH:16]=[C:11]3[C:12]4[C:7]([CH2:8][CH2:9][N:10]3[C:20](=[O:21])[CH2:19][N:18]=2)=[C:6]([CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[CH:15]=[CH:14][CH:13]=4)[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cccc(C2=NCC(=O)N3CCc4c(C5=CCCO5)cccc4C3=C2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Agent: COc1cccc(C2=NCC(=O)N3CCc4c(I)cccc4C3=C2)c1
Solvent: CCCCCCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cccc(C2=NCC(=O)N3CCc4c(cccc4C4CCCO4)C3=C2)c1
Temperature: 150 °C

Procedure:
9-(4,5-dihydrofuran-2-yl)-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one. 57-1. A mixture of 9-iodo-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (Example 30) (1.0 g, 2.25 mmol), tributyl(4,5-dihydrofuran-2-yl)stannane (1.21 g, 3.38 mmol) and Pd(PPh3)4(0.13 g, 0.11 mmol) in 1,4-dioxane (10 mL) was heated in a microwave reactor at 150° C. for 90 min. The mixture was then diluted with AcOEt and filtered. The filtrate was concentrated in vacuo and the crude product obtained was purified by flash chromatography (SiO2, heptane to heptane/AcOEt 1:1) to give a brown solid, which was suspended in heptane and heated to reflux. The suspension was then allowed to cool to RT and then filtered. The filter cake was then dried in vacuo to afford the title compound (543 mg) as a beige solid. UPLC-MS: MS 387.2 (M+H+); UPLC rt 1.10 min.
Reaction SMILES: CS(Cl)(=O)=O.O[C@@H:7]1[C@H:13]2[C@H:14]3[C@H:23]([CH2:24][CH2:25][C@:10]2([CH2:11][CH3:12])[C:9](=[O:27])[CH2:8]1)[C@@H:22]1[C:17](=[CH:18][C:19](=[O:26])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3.CN(C)C=O.C([O-])(=O)C.[Na+]>N1C=CC=CC=1>[CH3:12][CH2:11][C@:10]12[CH2:25][CH2:24][C@H:23]3[C@@H:14]([CH2:15][CH2:16][C:17]4[C@@H:22]3[CH2:21][CH2:20][C:19](=[O:26])[CH:18]=4)[C@@H:13]1[CH:7]=[CH:8][C:9]2=[O:27]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](O)CC2=O
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1C=CC2=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
At 0° C., 77.5 ml of methanesulfonyl chloride is added dropwise within 10 minutes to 250 g of 15α-hydroxy-18-methyl-4-estrene-3,17-dione in 704 ml of pyridine. After 3.5 hours, 350 ml of dimethylformamide and 283 g of anhydrous sodium acetate are added, the mixture is stirred under argon for 20 hours at room temperature, and the reaction mixture is introduced into ice water. The thus-precipitated product is suctioned off, washed with water, and dried under vacuum. For purposes of purification, the crude product (212 g) is treated with 21 g of active carbon in 1,500 ml of ethyl acetate and 0.4 ml of pyridine. After concentrating the solution to 420 ml, 188 g of 18-methyl-4,15-estradiene-3,17-dione is crystallized at 0° C. Melting point 156.9° C. (from acetone/hexane).
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)#[CH:22].C(N(CC)CC)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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:22]#[C:21][C:23]2([OH:31])[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[CH:12][CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2ccncc2)nc1Cc1ccccc1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1(C#Cc2ccc(-c3ccncc3)nc2Cc2ccccc2)CN2CCC1CC2
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of 196 mg of 2-benzyl-3-bromo-6-(4-pyridyl)pyridine, 100 mg of 3-ethynyl-3-quinuclidinol, 70 mg of tetrakis(triphenylphosphine)palladium(0), 11 mg of cuprous iodide, 0.25 ml of triethylamine and 3.0 ml of N,N-dimethylformamide was heated under stirring in an oil bath kept at 85° C. for one hour in a nitrogen atmosphere. After cooling as it was, the mixture was extracted with ethyl acetate-dilute aqueous ammonia. The organic phase was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel column chromatography and eluted with hexane/ethyl acetate (1:1) and then with methanol/ethyl acetate (20:1). After removing the solvent, the residue was recrystallized from hexane/ethyl acetate, to give 178 mg of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=O.N(C1C=COC=1C=O)=[N+]=[N-].[C:19]([O:29][CH2:30][CH3:31])(=[O:28])[CH2:20][C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=O>C(O)C.N1CCCCC1>[O:4]1[C:3]2[C:2](=[N:1][C:20]([C:19]([O:29][CH2:30][CH3:31])=[O:28])=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]=2)[CH:6]=[CH:5]1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: Nc1ccoc1C=O
Agent: [N-]=[N+]=Nc1ccoc1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2occc2nc1C(=O)OCC
Reaction time: 3 h
Yield: 24 %

Procedure:
3-Amino-2-formylfuran, prepared from 3-azido-2-formylfuran (8.9 g 0.065 mol) is dissolved in ethanol and to this solution diethyl oxalacetate (12.23 g, 0.065 mol) and ten drops of piperidine are added. In addition pulverized 3A° molecular sieve is added and the reaction stirred at 65°-60° C. for three hours, then additional diethyl oxalacetate (2.2 g) is added. The reaction is essentially complete after 12 hours at 55°-60° C. On cooling the reaction is filtered, and the filtrate concentrated and then dissolved in ethyl acetate, water washed, then brine washed, dried over anhydrous magnesium sulfate and stripped to dryness. The residue is dissolved in 3:1 hexane:ethyl acetate and passed through a flash chromatographic column in two stages. First it is filtered by vacuum through a four to five inch pad of silica from which the last three fractions containing the required product are collected and combined. These combined fractions are then passed through a six inch column eluting under pressure with ethyl acetate:hexane 3:1 and 2.1. Diethyl furo[3,2-b]-pyridine-5,6-dicarboxylate 4.15 g (24%) is obtained after crystallization from hexane-ether, of mp 60°64° C., and with a mas spectrum m/e of 264.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:19]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:14][N:15]=2)=[O:9])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: ClCCN1CCCCC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: O=C(Nc1ncc(SCCN2CCCCC2)s1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 1-(2-chloroethyl)-piperidine
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].[NH2:21][NH2:22]>CO>[NH:21]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)(=[O:14])=[O:13])[NH2:22]
Reactant: NN
Reactant: COC(=O)c1ccc(F)c(S(=O)(=O)N2CCOCC2)c1
Solvent: CO
Product: COC(=O)c1ccc(NN)c(S(=O)(=O)N2CCOCC2)c1
Temperature: 65 °C
Yield: 64.1 %

Procedure:
Methyl 4-fluoro-3-(morpholinosulfonyl)benzoate (30 mg, 0.099 mmol) was added to hydrazine (4.44 mg, 0.138 mmol) in methanol (8 mL) and refluxed for 5 h at 65° C. The reaction was monitored by TLC. Upon completion of the reaction and cooling, the solvent was removed by vacuum, and the compound was purified by column chromatography affording the title compound (20 mg). 1H NMR (400 MHz, CD3OD): δ 8.15 (d, 1H, J=2.0 Hz), 8.03 (dd, 1H, J=2.4 & 9.2 Hz), 7.48 (d, 1H, J=9.2 Hz), 3.86 (s, 3H), 3.67 (m, 4H), 3.04 (m, 4H). ESI-MS: 316.1 [M+H]+.