Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[C@@:8]2([CH3:23])[CH2:9][CH2:10][C@@H:11]3[C@:21]4([CH3:22])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=O)[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].C(O)=O.CCCCC>C(Cl)Cl.[Zn]>[CH3:1][C:2](=[O:3])[C@@H:4]1[C@:8]2([CH3:23])[C@H:7]([C@H:12]3[C@H:11]([CH2:10][CH2:9]2)[C@:21]2([CH3:22])[C@@H:15]([CH:16]=[CH:17][CH2:19][CH2:20]2)[CH2:14][CH2:13]3)[CH2:6][CH2:5]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Zn]
Solvent: O=CO
Solvent: CCCCC
Solvent: ClCCl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C=CCC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.5 %

Procedure:
A mixture of 250 mg of progesterone, 7.5 g of zinc dust, 18.75 ml of methylene chloride and 6.25 ml of 90% formic acid was shaken at room temperature for 18 hours, whereupon it was worked up by the procedure described in Example 36. Concentration of a solution of the crude product in methylene chloride with intermittent addition of pentane gave 99.18 mg of 5β-pregn-3-en-20-one, mp 135°-136.5°, 139.5° C., nmr (CDCl3,δ) 5.5 (2, broadened dd; 3--H, 3--H, 4--H), 2.12 (3, S; 21--H) 0.96 (3, S; 19--H), 0.77 (trace, S; 19--H of 5α-isomer?) and 0.61 (3, S; 18--H) ppm.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:35][S-:36].[Na+]>C(O)C.C(OCC)(=O)C>[CH:26]1([NH:25][C:23]([C:8]2[N:9]=[N:10][N:11]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:17]=3)[C:7]=2[CH2:6][S:36][CH3:35])=[O:24])[CH2:27][CH2:28]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COS(C)(=O)=O)cc1
Reactant: C[S-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CSC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)methyl methanesulfonate (196 mg, 0.481 mmol) obtained in Example 126a), potassium carbonate (33.2 mg, 0.241 mmol, 0.5 eq.) and 15% aqueous sodium thiomethoxide solution (0.449 ml, 0.962 mmol, 2.0 eq.) were dissolved in ethanol (3.5 ml), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (30 ml), washed twice with 2% aqueous sodium carbonate solution and with saturated brine, dried over anhydrous sodium sulfate and concentrated. Diethyl ether was added and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (160 mg, 0.445 mmol, 92.5%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13](B4OC(C)(C)C(C)(C)O4)[CH:12]=3)=[CH:9][N:10]=[C:4]2[N:3]=1.Br[C:27]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:28]=1[C:29]#[N:30]>>[F:35][C:32]1[CH:31]=[C:28]([C:29]#[N:30])[C:27]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:8]3[N:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[N:3][C:4]4=[N:10][CH:9]=3)[CH:12]=2)=[CH:34][CH:33]=1
Reactant: N#Cc1cc(F)ccc1Br
Reactant: Cc1ccn2c(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)cnc2n1
Product: Cc1ccn2c(-c3cccc(-c4ccc(F)cc4C#N)c3)cnc2n1
Yield: 43.1 %

Procedure:
7-Methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-imidazo[1,2-a]pyrimidine (0.2 g, 0.6 mmol) was coupled to 2-bromo-5-fluorobenzonitrile (179 mg, 0.9 mmol) as described in Example 26 to give 4-fluoro-3′-(7-methylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile as a white solid (85 mg): δH (400 MHz, CDCl3) 2.67 (3H, s), 6.83 (1H, d, J 7), 7.20 (1H, dt, J 8.9 and 3), 7.50-7.70 (6H, m), 7.84 (1H, s), 8.76 (1H, d, J 7); m/z (ES+) 329 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[C:23]([CH:24]=O)=[CH:22][CH:21]=[CH:20][N:19]=1.N1CCC[C@H]1C(O)=O>C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Nc1ncccc1C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3cccnc3n2)CC1
Yield: 24.9 %

Procedure:
3.14 g of 1-tert-butoxycarbonyl-4-acetyl-piperidine and 1.83 g of 2-amino-3-formyl-pyridine were refluxed with 0.25 g of L-proline in n-butanol for 72 hours. After removing the solvent in vacuo the residue was combined with the residue obtained in an identical reaction and chromatographed on silica gel with ethyl acetate/n-heptane (1:1) to give 1.08 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH:22]2[CH2:24][CH2:23]2)[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([F:14])[CH:10]([NH:15]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=O)(C)(C)C>>[NH2:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH:22]2[CH2:23][CH2:24]2)[C:6]=1[N:7]1[CH2:13][CH2:12][C@H:11]([F:14])[C@@H:10]([NH2:15])[CH2:9][CH2:8]1)=[O:47]
Reactant: Nc1cnn(C2CC2)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnn(C2CC2)c1N1CC[C@H](N)[C@@H](F)CC1

Procedure:
Following the procedure for Example 107 starting from N-(1-(4-amino-1-cyclopropyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonyl-amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid gave, after purification via preparative HPLC, 278 as the monoformate salt as an off-white solid (209 mg, 50% over two steps). 1H NMR (400 MHz, d4-MeOD) δ 8.54 (s, 1H), 7.52 (s, 1H), 7.51-7.44 (m, 1H), 7.19-7.12 (m, 2H), 4.86 (dtd, J=48.0, 9.3, 3.0 Hz, 1H), 3.61-3.47 (m, 2H), 3.48-3.36 (m, 4H), 2.46-2.32 (m, 1H), 2.26-2.05 (m, 2H), 1.99-1.86 (m, 1H), 1.23-1.11 (m, 2H), 1.13-1.05 (m, 2H). LCMS (ES+) m/z 492 (M+1)
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][SH:3].[CH2:6](O)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:4])[CH2:2][SH:3]
Reactant: CCCCCCO
Reactant: O=C(O)CS
Product: CCCCCCOC(=O)CS
Reaction time: 2.5 h
Yield: 95.9 %

Procedure:
Thioglycolic acid obtained from Evans Chemetics, Inc. (75 ml, 1.0785 mole) was added dropwise to hexanol obtained from Continental Oil Company (135.6 ml, 1.0785 mole) with 12% Dowex cation exchange resin 50W×12 50/100 (12% cross-linking, 13.2 g) as a catalyst. The solution was stirred and a nitrogen atmosphere maintained. The mixture was thereafter heated, and the byproduct, water, was distilled over as an azeotrope with hexanol at 95° C. and collected. A 10 ml excess of hexanol was added to the reaction mixture to replace that lost in the azeotrope. After 2.5 hours, an 89% yield was obtained. A vacuum of 60 mm Hg was then applied to further the reaction without increasing the temperature. After an additional hour, a 95.9% yield of hexyl thioglycolate was obtained.
Reaction SMILES: N1C=CC=NC=1.CS([C:11]1[N:12]=[C:13]([N:26]2[CH2:31][CH2:30][CH:29]([CH2:32][O:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:28][CH2:27]2)[C:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][O:17][C:15]=2[N:16]=1)(=O)=O.[BH4-].[Na+]>C(O)C>[C:20]1([C:19]2[C:14]3[C:13]([N:26]4[CH2:31][CH2:30][CH:29]([CH2:32][O:33][CH2:34][CH2:35][N:36]5[CH2:37][CH2:38][CH2:39][CH2:40]5)[CH2:28][CH2:27]4)=[N:12][CH:11]=[N:16][C:15]=3[O:17][CH:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)c1nc(N2CCC(COCCN3CCCC3)CC2)c2c(-c3ccccc3)coc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1cncnc1
Solvent: CCO
Product: c1ccc(-c2coc3ncnc(N4CCC(COCCN5CCCC5)CC4)c23)cc1
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
2-Methylsulphonyl-5-phenyl-4 [4-2-pyrrolidin-1-ylethoxymethyl-1-piperidyl]furo[2,3-d]-pyrimidine pyrimidine (75 mg, 0.15 mmol) in ethanol (5.0 mL) was treated with sodium borohydride (15 mg, 0.38 mmol) at 20° C. with continuous stirring for 30 min. A further 30 mg of sodium borohydride was added and the reaction was stirred at 20° C. for a further 1 h. A further 60 mg of sodium borohydride was added and the reaction was stirred at 20° C. for a further 1 hr then concentrated in vacuum to a gum and the residue partitioned between dichloromethane and water. The dichloromethane layer was separated, dried over sodium sulphate and concentrated in vacuum to a gum. The gum was purified by preparative HPLC to give 5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]furo[2,3-d]pyrimidine (53 mg, 0.13 mmol, 84%). 1H NMR (CDCl3) δ: 1.02 (2H, m), 1.5 (2H, m), 1.75 (6H, m), 2.45-2.8 (9H, m), 3.2 (2H, d, J=8 Hz), 3.5 (2H, t, J=8 Hz), 3.95 (2H, d, J=12 Hz), 7.35-7.45 (5H, m), 7.52 (1H, s), 8.45 (1H, s). LCMS RT=5.14 min. M+1=407.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=C[C:6]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]3[C:23]([CH3:28])=[N:24][O:25][C:26]=3[CH3:27])=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[N+:29]([O-])=O)(C)(C)[CH3:2]>C(O)C.C1COCC1>[CH3:28][C:23]1[C:22]([C:18]2[CH:17]=[C:16]3[C:21]([C:12]([NH:11][CH2:6][C:5]4[CH:1]=[CH:2][CH:8]=[CH:9][CH:10]=4)=[C:13]([NH2:29])[CH:14]=[N:15]3)=[CH:20][CH:19]=2)=[C:26]([CH3:27])[O:25][N:24]=1
Reactant: Cc1noc(C)c1-c1ccc2c(Nc3ccccc3C(C)(C)C)c([N+](=O)[O-])cnc2c1
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2c(NCc3ccccc3)c(N)cnc2c1
Yield: 100.6 %

Procedure:
To a solution of N-[2-(tert-butyl)phenyl]-7-(3,5-dimethyl-4-isoxazolyl)-3-nitro-4-quinolinamine (see Intermediate 19, 2.4 g, 5.77 mmol) in a mixture of ethanol (60 ml) and THF (20 ml), was added SnCl2,2H2O (7.81 g, 34.6 mmol). The reaction mixture was refluxed for 3 h and then concentrated to dryness. The resulting residue was poured into aqueous sodium hydroxide. The organic phase was extracted with EtOAc, washed with water, dried and concentrated to give the title compound as a yellow solid (2 g, 71%). [APCI-MS] m/z: 387 MH+, Rt 3.37 min.
Reaction SMILES: C1(CCCC2C=C[N+]([O-:16])=CC=2)C=CC=CC=1.Cl[O-].[Na+].[Br:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][CH2:27]2)=[CH:23][CH:22]=1>C(Cl)Cl.O.[Cl-].[Na+].O.CC(C1C=C(C=N[C@@H]2[C@@H](N=CC3C([O-])=C(C(C)(C)C)C=C(C(C)(C)C)C=3)CCCC2)C([O-])=C(C(C)(C)C)C=1)(C)C.[Cl-].[Mn+3]>[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[CH:25]3[O:16][CH:26]3[CH2:27][C:28]=2[CH:29]=1
Reactant: [O-][n+]1ccc(CCCc2ccccc2)cc1
Reactant: Brc1ccc2c(c1)CC=C2
Agent: [Mn+3]
Agent: CC(C)(C)c1cc(C=N[C@H]2CCCC[C@@H]2N=Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2[O-])c([O-])c(C(C)(C)C)c1
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Brc1ccc2c(c1)CC1OC21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-(3-phenylpropyl)pyridine N-oxide (68.88 mg, 0.323 mmol) in methylene chloride (6.00 mL) was added (S,S)-(+)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino-manganese(III) chloride (58.62 mg, 0.09.23 mmol) and 2.0 M of sodium hypochlorite in water (4.00 mL) at 0° C. The resulting brown suspension was stirred at 0° C. for 15 min. To the cooled suspension was added a solution of 6-bromo-1H-indene (900 mg, 4.6141 mmol) in methylene chloride (6.00 mL) at 0° C. with simultaneous addition of 2.0 M of sodium hypochlorite in water (4.00 mL) at 0° C. The reaction was kept at 0° C. for 1 h. The reaction was allowed to warm up to room temperature and then stirred at room temperature overnight. The reaction mixture was poured into brine and then extracted with methylen chloride (4×40 mL). The combined extracts were dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude product was used directly for the next reaction. The ratio of the two diastereomers was 8/1.
Reaction SMILES: CCCCCC.[H-].[Na+].[O:9]1[C:13]([CH2:14][OH:15])=[CH:12][CH:11]=[C:10]1[CH2:16][OH:17].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(OCC)C.O1CCCC1>[Si:18]([O:15][CH2:14][C:13]1[O:9][C:10]([CH2:16][OH:17])=[CH:11][CH:12]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: OCc1ccc(CO)o1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CO)o1
Reaction time: 1 h

Procedure:
According to the method of P. G. McDougal, et al., J. Org. Chem., 5, 3388-3390 (1986), combine hexane washed sodium hydride (20 mmol) and tetrahydrofuran (40 mL). Slowly add 2,5-furandimethanol (20 mmol). After gas evolution ceases, add t-butyldimethylsilyl chloride (20 mmol) and stir vigorously. After about 1 hour, pour the reaction mixture into diethyl ether and extract with a saturated aqueous solution of sodium carbonate, water, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give 5-(t-butyldimethylsilyloxy)methyl-2-hydroxymethylfuran. Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (10 mmol), 5-(t-butyldimethylsilyloxy)-methyl-2-hydroxymethylfuran (10 mmol), and triphenylphosphine (10 mmol) in tetrahydrofuran (100 mL). Add diethyl azodicarboxylate (10 mmol). After 18 hours, evaporate the reaction mixture in vacuo to give a residue. Partition the residue between ethyl acetate and water. Separate the organic layer and extract with water and brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel to give 1-(t-butoxycarbonyl)-4-(1-(5-(t-butyldimethylsilyloxy)-methylfur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](O)([CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:9]([N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]3=[O:30])[C:8]=2[CH:31]=1)([O-:3])=[O:2].[H-].[Na+].O.C(OCC)(=O)C>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:19])[F:20])=[C:9]([N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]3=[O:30])[C:8]=2[CH:31]=1)([O-:3])=[O:2]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)C1(O)CNC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CNC(=O)C(F)(F)F
Yield: 27.2 %

Procedure:
A solution of 6-nitro-2,2-dimethyl-3-hydroxy-3,4-dihydro-3-(trifluoroacetamido)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.5 g, 1.13 mmol) in tetrahydrofuran (20 ml) containing sodium hydride (80%, 0.034 g, 1.13 mol) was refluxed for one hour. Water and ethyl acetate were added to the cooled solution and the organic phase was separated and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane/acetone (95/5), to give 0.13 g of 6-nitro-2,2-dimethyl-3-(trifluoroacetamido)methyl-4-(2-oxo- 1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 189° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH:15]1[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[O:18][C:17]([CH3:25])([CH3:24])[C:16]1=[O:26].O.[OH-].[Li+].[C:30]1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:31]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COCCOC>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:30]=[CH2:31])=[C:3]([CH:15]3[C:16](=[O:26])[C:17]([CH3:25])([CH3:24])[O:18][C:19]([CH3:23])([CH3:22])[C:20]3=[O:21])[CH:4]=2)=[CH:13][CH:12]=1
Reactant: CC1(C)OC(C)(C)C(=O)C(c2cc(-c3ccc(Cl)cc3)ccc2Br)C1=O
Reactant: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C
Yield: 275.7 %

Procedure:
A solution of 4-(4-bromo-4′-chlorobiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.314 g, 0.72 mmol), vinylboronic anhydride pyridine complex (0.175 g, 0.73 mmol), lithium hydroxide monohydrate (0.177 g, 4.22 mmol), 1,3-bis(diphenylphosphino)propane (0.015 g, 0.036 mmol) and palladium acetate (0.010 g, 0.044 mmol) is stirred in a mixed solvent system of 1,2-dimethoxyethane (5 ml) and distilled water (1 ml) at 80° C. for 3 hours. After cooling to room temperature the mixture is filtered through diatomaceous earth, followed by washing with ethyl acetate and distilled water. The aqueous phase is acidified with 2M aqueous hydrochloric acid to pH3, then the organic phase is separated and the aqueous phase extracted again with ethyl acetate. All organic fractions are combined, then dried over anhydrous magnesium sulphate and filtered. After concentration in vacuo the crude oil is purified by preparative reverse phase HPLC then triturated with hexanes to afford 4-(4′-chloro-4-vinylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.038 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:21]=[C:22]=[O:23])[CH:19]=[CH2:20]>>[CH2:18]([NH:21][C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23])[CH:19]=[CH2:20]
Reactant: C=CCN=C=O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: C=CCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 95.8 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.1 mg (0.131 mMol) allyl isocyanate, 19.6 mg (96%) of the title compound were recovered.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=O.[Br-].[CH3:10][CH:11]([CH3:34])[C:12](=[O:33])[CH2:13][As+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH3:10][CH:11]([CH3:34])[C:12](=[O:33])[CH:13]=[CH:7][C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1]
Reactant: CC(C)C(=O)C[As+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ncsc1C=O
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ncsc1C=CC(=O)C(C)C

Procedure:
The title compound was prepared as described in General Method 1 using 1.4 g (11.0 mmol) of 4-methyl-5-thiazolecarbaldehyde (Example A-12), 6.2 g (13.1 mmol) of (3-methyl-2-oxobutyl)triphenylarsonium bromide, 1.8 g (13.1 mmol) of potassium carbonate, 75 mL of acetonitrile, and 0.75 mL of H2O. Chromatography of the residue, eluting with 3:1 hexane:EtOAc gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[CH:12]3[O:21][CH2:22][CH2:23][O:24][CH:11]3[CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.N.[Cl-].[Li+]>[C-]#[W].C(O)C>[CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]3[CH2:10][CH:11]2[O:24][CH2:23][CH2:22][O:21][CH:12]21
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C3OCCOC3C[C@@H]12
Agent: [C-]#[W]
Agent: N
Agent: [Cl-]
Solvent: CCO
Product: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)C4OCCOC4C[C@@H]32)C1

Procedure:
1.0 g. of 3-methoxy-17-ethylenedioxy-1,3,5(10)-estratriene in 10 ml. of ethanol is added to 200 ml. of liquid ammonia, 2 g. of lithium chloride, and electrolyzed for 1 hour at 1 ampere on a tungsten carbide electrode in a cell divided by a cation exchanger membrane. After the mixture has been worked up, 0.9 g. of 3-methoxy-17-ethylenedioxy-2,5(10)-estradiene is produced, m.p. 115°-120° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:25]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:26]C([O-])=O.Cl>O1CCCC1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH2:26][C:25]([O:31][CH2:32][CH3:33])=[O:30])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1ccc(F)c(F)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 129.7 %

Procedure:
To a solution of 3,4-difluorobenzoic acid (10 g, 63.3 mmol) in tetrahydrofuran (300 ml) was added 1,1′-carbonylbis-1H-imidazole (11.3 g, 69.6 mmol) and the mixture was stirred at room temperature for 30 min. To the reaction solution was added monoethyl malonate magnesium salt (10 g, 34.8 mmol) and the mixture was stirred at room temperature for 2 hrs. To the reaction solution were added ethyl acetate (50 ml) and water (50 ml), and conc. hydrochloric acid was added until the aqueous layer showed acidic pH. The reaction solution was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(3,4-difluorophenyl)-3-oxopropionate (10.3 g, 77%) as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@H:10]2[CH2:14][CH2:13][C@H:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=3)[N:11]2[C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.ClCCl>[F:33][C:30]([F:31])([F:32])[C:27]1[CH:26]=[CH:25][C:24]([N:11]2[C@@H:12]([C:15]3[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=3)[NH2:21])[CH2:13][CH2:14][C@@H:10]2[C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[NH2:1])=[CH:29][CH:28]=1
Reactant: O=[N+]([O-])c1cccc([C@H]2CC[C@H](c3cccc([N+](=O)[O-])c3)N2c2ccc(C(F)(F)F)cc2)c1
Solvent: ClCCl
Solvent: CO
Product: Nc1cccc([C@H]2CC[C@H](c3cccc(N)c3)N2c2ccc(C(F)(F)F)cc2)c1

Procedure:
The product from Example 205B was processed using the method described in Example 55E. The title compound was isolated by flash chromatography (silica gel, methanol/dichloromethane). MS (ESI) m/z 398 (M+H)+, 396 (M−H)+.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:15]=2[CH:16]=1)SC)#[N:2].[NH3:25]>C(O)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:15]=2[CH:16]=1)=[NH:25])#[N:2]
Reactant: N
Reactant: CSC(=NCCSCc1cc2ccc(CN(C)C)cc2o1)NC#N
Solvent: CCO
Product: CN(C)Cc1ccc2cc(CSCCNC(=N)NC#N)oc2c1

Procedure:
A solution of N-cyano-N'-[2-(6-dimethylaminomethyl)-2-benzofuranylmethylthio)ethyl]-S-methylisothiourea (Example 1, Step F) (6.27 g., 0.0173 mole) and ammonia (12 g.) in ethanol (65 ml.) is heated in a sealed vessel for 36 hours at 55°-60° C. Volatile materials are then removed by distillation at reduced pressure. The residual oil consisting of the nearly pure product is purified by column chromatography on 85 g. of silica gel with elution by a 10% solution of methanol in chloroform affording N-cyano-N'-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]guanidine.