Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:9][C:10]([O:12]CC)=[O:11])=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCC(=O)N[C@@H](CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Reaction time: 0.75 h
Yield: 96.6 %

Procedure:
To a solution of (R)-4-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (61.2 mg, 0.160 mmol) in THF (1.6 mL) and methanol (0.2 mL), aqueous 1M NaOH solution (0.638 mL, 0.638 mmol) is added at room temperature. After stirring for 45 minutes, the reaction is quenched with aqueous 0.1 M HCl and is extracted with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (R)-4-(biphenyl-4-yl)-3-(3-carboxypropanamido)butanoic acid (54.9 mg). HPLC retention time=1.33 minutes (condition A); MS (m+1)=356.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.40-2.56 (m, 6 H) 2.83-2.94 (m, 2 H) 4.43-4.50 (m, 1 H) 7.29-7.32 (m, 3 H) 7.41 (t, 2 H, J=7.7 Hz) 7.53-7.60 (m, 4 H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:13]3=[O:21])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:22]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH2:23].[OH-].[Na+].[NH4+].[Cl-]>C1COCC1.O>[CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH2:23][CH2:22][S:24]([NH2:27])(=[O:26])=[O:25])[C:13]3=[O:21])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C=CS(N)(=O)=O
Reactant: Cc1cccc2scc(Cn3c(=O)[nH]c4ccccc43)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2scc(Cn3c(=O)n(CCS(N)(=O)=O)c4ccccc43)c12
Temperature: 65 °C
Yield: 45.4 %

Procedure:
To the solution of 1-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (50 mg, 0.17 mmol) in THF (1.0 mL) are added ethenesulfonic acid amide (40 mg, 0.34 mmol) and solid NaOH (14 mg, 0.34 mmol). The mixture is warmed up to 65° C. for 24 hr and then saturated NH4Cl solution (5.0 mL) is added along with water (5.0 mL). The mixture is extracted with EtOAc (3×20 mL). The organic layers are combined, dried (Na2SO4) and concentrated to give crude product. Purification by preparative TLC using 4% MeOH in CH2Cl2 affords 31 mg (46%) of 2-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-ethanesulfonic acid amide. LCMS (ESMS): m/z 402.10 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:17]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH:10][CH:28]2[CH2:29][CH2:30][N:25]([C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:24])[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: NCc1ccccc1Oc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(c1ccccc1)N1CCC(NCc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and N-benzoyl-4-piperidone (87 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then, it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCN to DCM/MeOH 95:5 gradient as eluent gave {4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}phenylmethanone (152 mg, 84%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=5.19 min, m/z 423.35 (36), 421.34 (M++H, 100). HPLC tr=4.04 min (98.05%) 1H NMR (270 MHz, CDCl3) δ 1.24-1.44 (3H, m, CH2+NH), 1.76 (1H, m, ½CH2), 1.91 (1H, m, ½CH2), 2.72 (1H, hept, CHNH), 2.96 (1H, m, ½CH2), 3.80 (2H, m, CH2NH), 4.46 (1H, m, ½CH2), 6.84 (2H, AA′BB′, ArH), 6.86 (1H, m, ArH), 7.12 (1H, td, ArH), 7.23 (1H, m, ArH), 7.24 (2H, AA′BB′, ArH) and 7.33-7.41 (6H, m, ArH). 13C NMR (270 MHz, CDCl3) δ 32.26, 33.09, 40.78, 45.67, 46.29 (CH2), 53.81 (CH), 118.95, 119.63, 124.57, 126.86, 127.97, 128.54, 128.75, 129.58, 129.85, 130.58, 131.78, 136.33, 154.35, 156.38 (ArC), and 170.00 (C═O).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1.[CH:21](O)=O>>[CH3:20][S:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:3]3[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=3[N:1]=[CH:21]2)=[CH:14][CH:15]=1
Reactant: O=CO
Reactant: COC(=O)c1ccc(N)c(Nc2ccc(SC)cc2)c1
Product: COC(=O)c1ccc2ncn(-c3ccc(SC)cc3)c2c1
Yield: 74 %

Procedure:
A solution of methyl 4-amino-3-[[4-(methylthio)phenyl]amino]benzoate (5.78 g, 20.0 mmol) in formic acid (50 mL) was stirred at 100° C. overnight. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (4.44 g, yield 74%) as colorless crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=1.[CH:15]([PH:18][CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16].C(N(CC)CC)C>CO>[CH:15]([P:18]([CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=1)[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]
Reactant: CC(C)PC(C)C
Reactant: ClCc1cccc(-c2ccccn2)n1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)P(Cc1cccc(-c2ccccn2)n1)C(C)C
Temperature: 50 °C

Procedure:
stirring bar was added 6-chloromethyl-2,2′-bipyridine (BPy-CH2Cl) (1.03 g, 5.00 mmol), di-iso-propyl phosphine (710 mg, 6.00 mmol), and 15 mL MeOH in nitrogen glove box. The flask was sealed and heated at 50° C. for 48 hrs with stirring outside the glove box. After cooling, it was reintroduced to the glove box, triethylamine (910 mg, 9.00 mmol) was added and the reaction mixture was stirred at room temperature for 1 hr. The solvents were removed under reduced pressure to obtain a white solid. The residue was washed with ether (2×10 mL), filtered and was removed under reduced pressure to yield a pale yellow liquid. It was further purified by basic alumina chromatography under the glove box using hexane as an eluent to yield pure 6.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[C:9](I)=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[CH2:14][CH2:13][O:12][C:10]=2[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Nc1cc(OCCc2ccsc2)c(I)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)Nc1cc2c(cn1)-c1sccc1CCO2
Yield: 42 %

Procedure:
Following Scheme 4, N-tert-butyl-5-iodo-4-(2-(thiophen-3-yl)ethoxy)pyridin-2-amine was cyclized in the presence of palladium (II) acetate and triphenylphosphine to give N-tert-butyl-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepin-8-amine (42%). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.04 (d, J=5.2, 1H), 6.81 (d, J=5.2, 1H), 6.07 (s, 1H), 4.59 (s, 1H), 4.35-4.29 (m, 2H), 3.21-3.07 (m, 2H), 1.42 (s, 9H). MS: (ESI+) 275.1
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH3:8])[N:6]=1.[CH:9]1[C:22]2[CH:21]([C:23](Cl)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1>>[CH2:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:23]([CH:21]2[C:22]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][C:15]3[C:20]2=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:24])=[N:6]1)[CH3:8]
Reactant: CCn1nnc(N)n1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Product: CCn1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)n1

Procedure:
The title compound, white solid, m.p. 228° C. (dec.) and MS: (neg. ions): m/e=320.0 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-ethyl-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10][C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:29]([O:28][C:26]([CH2:25][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10][C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:27])[CH3:30]
Reactant: CCOC(=O)C(C)(Sc1cc2ccccc2[nH]1)c1ccccc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1c(SC(C)(C(=O)OCC)c2ccccc2)cc2ccccc21
Yield: 63 %

Procedure:
Starting from ethyl 2-(1H-indol-2-yl)thio-2-phenylpropionate and ethyl bromoacetate, the title compound was obtained as a pale yellow oily matter (yield: 63 %) according to the method of Example 92.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:10]([O:2][CH2:1][C:3]([CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH2:4][CH3:5])[CH2:6][OH:7])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCBr
Reactant: CCC(CO)(CO)CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CCCCCCCCCOCC(CC)(CO)COCCCCCCCCC
Temperature: 75 °C
Reaction time: 4 h

Procedure:
Under nitrogen stream, to a 2-L reactor provided with a stirrer, thermometer, condenser and gas inlet tube, 107.3 g (0.8 mol) of trimethylolpropane and 249 g (1.2 mol) of n-nonyl bromide and 11.4 g of tetrabutyl ammonium bromide were put, to which 360 g of 50 mass/volume % aqueous sodium hydroxide was added and heated at 70 to 80 degrees C. for four hours with stirring. After the reaction, the mixture was cooled and left still overnight to deposit white crystal. A liquid layer is transferred to a separating funnel by decantation. An alkali layer of an under layer was removed by separation. An organic layer was washed with 400 mL of saturated saline and 50 mL of a dilute aqueous solution of sulfuric acid. After the organic layer was further washed with distilled water until becoming neutral, 190 g of the obtained organic layer was dried with magnesium sulfate.
Reaction SMILES: [Cl-].C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[CH2:12]([O:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1)=[O:16])[CH3:13].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(=O)CC>[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCC(C)=O
Product: CCOC(=O)C1CCCNC1
Yield: 139.9 %

Procedure:
A mixture of the above crude chloride (1.14 g, 3.5 mmol), (R)-3-piperidinecarboxylic acid ethyl ester (L)-tartrate (1.05 g, 3.5 mmol), dried potassium carbonate (1.94 g, 14 mmol), sodium iodide (0.53 g, 3.5 mmol) and 2-butanone (15 ml) was heated at reflux temperature for 60 h. The reaction mixture was filtered, the filtrate washed with 2-butanone (10 ml) and the combined filtrates evapoated in vacuo. The crude product was purified by column chromatography on silica gel using a mixture of ethyl acetate and heptane (1:3) containing triethylamine (2.5%) as eluent. This afforded the product, (R)-1-(3-2-chloro-12H-dibenzo[d,g][1,3,6]dioxazocin-12-yl)-1-propyl)-3-piperidinecarboxylic acid ethyl ester (0.77 g, 49%) as an oil.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:35]=[CH:36][CH:37]=1)[C:11]([NH:13][CH:14]([C:16]1[N:21]=[N:20][C:19]([NH:22][C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=2)=[N:18][CH:17]=1)[CH3:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:15][C:14]1[N:13]=[C:11]([C:10]2[CH:35]=[CH:36][CH:37]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=2)[N:21]2[C:16]=1[CH:17]=[N:18][C:19]([NH:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=1)=[N:20]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Oc4ccccc4)c3)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Oc5ccccc5)c4)n3n2)cc(OC)c1OC
Yield: 50.8 %

Procedure:
In a similar manner as described for Example 9, 3-phenoxy-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 31) (58 mg, 0.11 mmol), and 1,2,4-triazole (55 mg, 0.80 mmol) in pyridine (2 mL) and phosphorous oxychloride (0.037 mL, 0.40 mmol) gave 5-methyl-7-(3-phenoxyphenyl)-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (27 mg, 49%) as a tan-yellow solid. 1H NMR (CD3OD): δ8.99 (s, 1H), 8.08 (d, J=7.87 Hz, 1H), 7.96 (t, J=1.92 Hz), 7.44 (t, J=8.06 Hz, 1H), 7.31 (t, J=7.87 Hz, 2H), 7.00-7.11 (m, 6H), 3.77 (s, 6H), 3.72 (s, 3H), 2.54 (s, 3H). MS m/z 448 (M+1).
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:11]=1>CO>[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][N:27]([C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[CH2:26][CH2:25]2)[N:11]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C(Cl)C1CCCC1
Solvent: CO
Product: COc1cc2nc(N3CCN(C(=O)C4CCCC4)CC3)nc(N)c2cc1OC
Reaction time: 4 h

Procedure:
Cyclopentylcarbonyl chloride (0.1 mole) is added to 0.1 mole of 4-amino-2-(1-piperazinyl)-6,7-dimethoxyquinazoline in 300 ml. of methanol with vigorous stirring at room temperature. Stirring is continued for a period of 2 to 6 hours and the product is isolated according to the procedure of Example 1(a) to provide 4-amino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline. If the hydrochloride salt is desired, the base treatment is omitted and evaporation of the solvent provides 4-amino-2-[4-(cyclopentylcarbonyl)-piperazinyl]-6,7-dimethoxyquinazoline hydrochloride, m.p. 279°-280° C. (dec.)(corr.) crystallized from methanol-isopropanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:34](=[CH:35][CH:36]=1)[CH2:33][C:8]1([CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[CH2:14][CH2:15][CH2:16][C:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:18][C:19]#[N:20])[CH2:7][CH2:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:34](=[CH:35][CH:36]=1)[CH2:33][C:8]1([CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[CH2:14][CH2:15][CH2:16][C:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:18][CH2:19][NH2:20])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC1(CCCCN1CCCC(CC#N)(c1ccccc1)c1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CCC1(CCCCN1CCCC(CCN)(c1ccccc1)c1ccccc1)C2
Temperature: 60 °C
Yield: 89.2 %

Procedure:
To a solution of 3,4-dihydro-6-methoxy-1'-(5-cyano-4,4-diphenylpentyl)spiro[naphthalene-2(1H),2'-piperidine] (0.6 g) in tetrahydrofuran (15 ml) was added lithium aluminum hydride (95 mg) portionwise under ice-cooling and stirring. After completion of dropwise addition, the mixture was heated at 60° C. for 6 hours. To this reaction mixture were serially added water (0.25 ml), 15% sodium hydroxide solution (0.75 ml) and water (0.25 ml) under ice-cooling and stirring and the precipitate which separated out was filtered off. The filtrate was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness to provide the title compound (0.54 g) as light-yellow syrup.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:9]2[O:10][CH2:11][C@H:12]([O:13]C(C3C=CC=CC=3)=O)[C@@H:8]2[O:7][C@@H:4]1[O:5][CH3:6].[OH-].[Na+]>CO.C(OCC)(=O)C>[CH3:1][O:2][C@H:3]1[C@@H:9]2[O:10][CH2:11][C@@H:12]([OH:13])[C@@H:8]2[O:7][C@@H:4]1[O:5][CH3:6]
Reactant: CO[C@H]1O[C@@H]2[C@@H](OC[C@@H]2OC(=O)c2ccccc2)[C@@H]1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CO[C@H]1O[C@@H]2[C@@H](OC[C@H]2O)[C@@H]1OC
Yield: 85 %

Procedure:
A solution of methyl 3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-β-L-glucofuranoside (820 mg, 3.1 mmol) and 50% sodium hydroxide (248 mg, 3.1 mmol) in methanol (10 mL) was stirred at room temperature for 30 minutes. The material was adsorbed on silica gel (5 g) and passed through a short column (15% ethyl acetate in hexanes to 5% methanol in ethyl acetate) to give methyl 3,6-anhydro-2-O-methyl-α-D-idofuranoside as a colorless oil, 420 mg, 85% yield. 1H NMR (400 MHz; CDCl3): 5.04 (s, 1H), 5.84-5.81 (tr, 1H), 4.44-4.42 (tr, 1H), 4.25-4.19 (m, 1H), 3.85-3.75 (m, 1H), 3.49 (s, 3H), 3.43 (s, 3H), 2.75-2.72 (d, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[C:8]([C:10]1[CH:14]=[CH:13][NH:12][CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](I)[CH3:26]>CN(C)C=O>[CH2:25]([N:12]1[CH:13]=[CH:14][C:10]([C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)=[CH:11]1)[CH3:26]
Reactant: CCI
Reactant: CC(C)(C)c1cc(C(=O)c2cc[nH]c2)cc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1
Reaction time: 0.5 h

Procedure:
2 G (6.6 mmol) of 3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole were added to a cooled, stirred suspension of 0.70 g of sodium hydride (50% in mineral oil) in 50 ml of anhydrous dimethylformamide under nitrogen. After 30 minutes at room temperature, 0.7 ml of ethyl iodide was added, and stirring at room temperature was continued for an additional 2 hours. The reaction mixture was poured over a 10% HCl--ice mixture, then extracted three times with 250 ml ethyl acetate. The organic layer was washed five times with 200 ml water, dried and evaporated to dryness. The residue was purified by chromatography on alumina (3% water, 100 g) eluting with hexane:ethyl acetate (9:1). Crystallization from methylene chloride-hexane gave 1.11 g of N-ethyl-3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole (mp 73°-75° C.).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[I:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].[Al+3].[Cl-].[Cl-].[Cl-].CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[S:3][C:4]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([I:12])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C(Cl)c1ccc(I)c([N+](=O)[O-])c1
Reactant: COC(=O)Cc1ccsc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(C(=O)c2ccc(I)c([N+](=O)[O-])c2)sc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a stirred solution of 230 mg (1 mmol) methyl (2-bromothiophene-3-yl)acetate and 310 mg (1 mmol) 4-iodo-3-nitrobenzoyl chloride in 15 mL of dry CH2Cl2 was added 432 mg of AlCl3 (4 mmol) in four portions at room temperature. The resulting mixture was stirred overnight. The reaction mixture was slowly poured onto 5 g of ice and allowed to warm to room temperature. The organic layer was dried over MgSO4, filtered, and then concentrated in vacuo. The residue was purified by flash chromatography. (Hex/EtOAc=1:5) to give 310 mg of product as a light yellow solid (yield 60%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][N:15]([CH3:30])[CH2:16][CH2:17][C:18]1[S:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]=1[C:27](=[O:29])[CH3:28]>C(Cl)Cl.CCCCCC>[CH3:30][N:15]([CH3:14])[CH2:16][CH2:17][C:18]1[S:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]=1[C:27]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)([OH:29])[CH3:28]
Reactant: CC(=O)c1c(CCN(C)C)sc2ccccc12
Reactant: Fc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: ClCCl
Product: CN(C)CCc1sc2ccccc2c1C(C)(O)c1ccc(F)cn1
Temperature: -78 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
2-Bromo-5-fluoropyridine (5 g, 0.03 mol) was dissolved in methylene chloride (18 mL) and was cooled at −78° C. 1.6 M of n-butyllithium in hexane (18 mL) was added dropwise in 5 minutes and the reaction was stirred for 120 minutes at −78° C. Then a solution of 1-[2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-ethanone (1.75 g, 7.1 mmol) dissolved in methylene chloride (9 mL) and added dropwise and the mixture was allowed to warm to room temperature gradually overnight. The reaction was quenched with aq NH4Cl, followed by water and ammonium hydroxide. The organic layer was extracted with Methylene chloride, and dried over sodium sulfate. Silica gel column chromatography (eluent: 9:1 DCM/MeOH) afforded 1.656 g of 1-[2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-1-(5-fluoro-pyridin-2-yl)-ethanol (Compound 7-1) (68%).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][C@@H:17]3[C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:21]4=[CH:20][CH:19]=[C:18]3[C@@H:13]2[CH2:12][CH2:11]1)[CH2:3][CH2:4][C@@H:5]([CH:7]([CH3:9])[CH3:8])[CH3:6].O.C(O)C>C(OCC)C.C1C=CC=CC=1>[CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][CH2:17]/[C:18](=[CH:19]\[CH:20]=[C:21]3\[CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23][C:22]\3=[CH2:28])/[C@@H:13]2[CH2:12][CH2:11]1)[CH2:3][CH2:4][C@@H:5]([CH:7]([CH3:8])[CH3:9])[CH3:6]
Reactant: CC(C)[C@@H](C)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CC[C@H](C)C(C)C)CC[C@@H]12

Procedure:
22,23-dihydroergosterol (VIII) (2.0 g, 5.0 mmol) was dissolved in a solution of diethyl ether and benzene (4:1, 600 ml) and irradiated (Hannovia immersion lamp, 450 watts) with stirring under argon in a water-cooled quartz vessel for three hours. The solution was concentrated in vacuo to yield a gummy solid, which was redissolved in 100 ml. of ethanol and heated at reflux under argon for eight hours. Then, the solution was concentrated in vacuo and the residue was adsorbed on a silica gel column and eluted with 30% ethyl acetate in hexane to afford vitamin D4 (22,23-dihydroergocalciferol) (IX) with a yield of 1.2 g. (60%) and with the following characteristics: 1H NMR: (400 MHz, CDCl3), δppm 0.55 (3H, s, 18--H3) 0.78 (6H, dd, 26--H3 and 27--H3) 0.87 (3H, d, 21--H3) 0.93 (3H, d, 28--H3) 3.94 (1H, m, 3--H) 4.82 (1H, m (sharp), 19--H), 5.04 (1H, m (sharp), 19--H), 6.04 (1H, d, 7--H) 6.24 (1H, d, 6--H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1>C(O)C.[Pd]>[CH3:15][O:14][CH:3]([O:2][CH3:1])[C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: COC(OC)c1ccc2cccnc2n1
Agent: [Pd]
Solvent: CCO
Product: COC(OC)c1ccc2c(n1)NCCC2
Reaction time: 12.5 h

Procedure:
A solution of 8-1 (10 g, 0.049 mol) in ethanol (100 ml) was treated with 10% Pd on C (1.5 g) and the resulting mixture stirred under a H2 filled balloon for 12.5 h. The catalyst was removed by filtration through celite and the solution concentrated to afford 8-2 as a yellow crystalline solid.