Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[C:16]([N:21]2[CH:25]=[C:24]([C:26]([OH:28])=O)[N:23]=[CH:22]2)[CH:17]=[CH:18][C:19]=1[Cl:20].N.O>CN(C=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([N:21]2[CH:25]=[C:24]([C:26]([NH2:3])=[O:28])[N:23]=[CH:22]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cn(-c2ccc(Cl)c(Cl)c2)cn1
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cn(-c2ccc(Cl)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Carbonyldiimidazole (0.49 g, 3 mmol) was added to a stirred suspension of 1-(3,4-dichloro-phenyl)-1H-imidazole-4-carboxylic acid (0.64 g, 2.5 mmol) in DMF (10 ml). After 1 h at 60° C., the reaction mixture was cooled to rt, aqueous ammonia (25%, 20 ml) was added and stirring was continued for 12 h. Then H2O (100 ml) was added and the precipitated product was filtered. Recrystallisation from EtOH afforded the title compound as off-white crystals. Mp. 244-245° C. (EtOH), MS: m/e=255 (M+).
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)(C)=O.[CH2:13]([C@@:15]12[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][C@H:16]1[CH2:17][CH2:18][CH2:19][C:20]1[C:21]2=[CH:22][C:23]2[CH:24]=[N:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:27]=2[CH:28]=1)[CH3:14]>C1COCC1>[CH2:13]([C@@:15]12[CH2:39][CH2:38][C@@:37]3([CH2:8][O:40]3)[CH2:36][C@H:16]1[CH2:17][CH2:18][CH2:19][C:20]1[C:21]2=[CH:22][C:23]2[CH:24]=[N:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:27]=2[CH:28]=1)[CH3:14]
Reactant: CC[C@@]12CCC(=O)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC[C@@]12CC[C@@]3(CO3)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 65 °C

Procedure:
Sodium hydride (60 wt % in oil, 0.023 g, 0.967 mmol) was added carefully to a flask containing about 3 mL DMSO then heated to about 65° C. for about 30 min. The reaction was cooled to rt then diluted with 2 mL THF. The reaction was further cooled in an ice water bath and trimethylsulfoxonium iodide (0.213 g, 0.967 mmol) was added in one portion and stirred about 15 min. (4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3 (2H)-one (9, R1=4-Fluorophenyl, R2=Ethyl) (0.182, 0.483 mmol) in 2 mL THF was introduced via syringe and allowed to warm to rt over about 18 hrs. THF was removed in vacuo and the residue was diluted with 15 mL water and extracted with EtOAc (15 mL×3). The combined organics were washed with sat. aq. NaCl. The organic layer was dried over MgSO4 filtered and concentrated to a crude viscous oil.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([F:14])=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:27]2[CH:41]=[CH:40][C:30]([CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:29][CH:28]=2)O1>>[F:14][C:9]1[C:8]2[NH:7][C:6](=[O:15])[C:5]3[S:16][CH:17]=[CH:18][C:4]=3[C:3]=2[C:2]([C:27]2[CH:41]=[CH:40][C:30]([CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:29][CH:28]=2)=[C:11]([O:12][CH3:13])[CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1cc(F)c2[nH]c(=O)c3sccc3c2c1Br
Product: COc1cc(F)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Yield: 44 %

Procedure:
Following General Procedure B, 9-bromo-6-fluoro-8-methoxythieno[2,3-c]quinolin-4(5H)-one (150 mg, 0.50 mmol) was reacted with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (200 mg, 0.60 mmol) to afford the desired product (100 mg, 48%) as a brown solid: ESI MS m/z 455 [C24H23FN2O4S+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]([F:31])([CH3:30])[CH2:25][CH2:26][CH2:27][Mg]Cl>C1COCC1>[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C@@:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)([OH:22])[CH2:27][CH2:26][CH2:25][C:24]([F:31])([F:23])[CH3:30])[CH2:9]1)([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(F)(F)CCC[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2)C1
Solvent: C1CCOC1
Product: CC(F)(F)CCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h

Procedure:
A solution of (3R)-1-(tert-butoxycarbonyl)-3-(3-chlorobenzoyl)piperidine (100 mg, 0.33 mmol) in THF (2 mL) was cooled to −20° C. and 4,4-difluoropentylmagnesium chloride (˜0.79M in THF, 5.0 mL, 4.0 mmol) was added. The mixture was stirred for 2 h and quenched with sat'd NH4Cl. The aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was removed on a roto-evaporator. The crude product was purified using flash chromatography (hexanes/EtOAc). N-Boc-(S)-1-(3-chlorophenyl)-5,5-difluoro-1-((R)-piperidin-3-yl)hexan-1-ol was isolated as an oil (70 mg) MS m/z 454 (M+Na).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:35])[C@H:7]([CH3:34])[CH2:8][C@H:9]([OH:33])[C@@H:10]([NH2:32])[CH2:11][C:12]([CH3:31])([CH3:30])[CH2:13][C:14]([N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19][CH:18]([C:26]([O:28][CH3:29])=[O:27])[CH2:17]1)=[O:15])[CH2:2][CH2:3][CH3:4].[CH:36](OC1C=CC([N+]([O-])=O)=CC=1)=[O:37]>>[CH2:1]([NH:5][C:6](=[O:35])[C@H:7]([CH3:34])[CH2:8][C@H:9]([OH:33])[C@@H:10]([NH:32][CH:36]=[O:37])[CH2:11][C:12]([CH3:30])([CH3:31])[CH2:13][C:14]([N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19][CH:18]([C:26]([O:28][CH3:29])=[O:27])[CH2:17]1)=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC(C)(C)CC(=O)N1CC(C(=O)OC)Sc2ccccc21
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(C(=O)OC)Sc2ccccc21)NC=O

Procedure:
195 mg of 5(S)-amino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[2(R,S)-methoxycarbonyl-3,4-dihydro-2H-1,4-benzothiazin-4-ylcarbonyl]-octanoic acid (N-butyl)amide (Example 18)) are reacted with 128 mg of 4-nitrophenyl formate in a manner analogous to that described in Example 17) and the product is purified over 30 g of silica gel (mobile phase M). The title compound is obtained as a yellowish-coloured solid: Rf (N)=0.20; FAB-MS: (M+H)+ =536.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CC#N>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: C1COCCN1
Reactant: COc1ccc(Nc2nccc(-c3sc(NC(=O)CCBr)nc3C)n2)cc1
Solvent: CC#N
Product: COc1ccc(Nc2nccc(-c3sc(NC(=O)CCN4CCOCC4)nc3C)n2)cc1

Procedure:
By treatment of 3-bromo-N-{5-[2-(4-methoxy-phenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide with morpholine. Anal. RP-HPLC: tR=12.7 min (0-60% MeCN, purity >90%). 1H-NMR (CDCl3) δ: 1.20 (m, 2H, CH2), 2.54-2.63 (m, 7H, CH3 and CH2), 3.34 (m, 2H, CH2), 3.80 (m, 5H, CH3 and CH2), 4.03 (m, 2H, CH2), 6.87-6.92 (m, 3H, pyrimidinyl-H and Ph-H), 7.17 (brs, 1H, NH), 7.53 (m, 2H, Ph-H), 8.35 (m, 1H, pyrimidinyl-H), 10.33 (brs, 1H, NH).
Reaction SMILES: [CH3:1][O-].[Na+].C[O:5][C:6](=O)[CH:7]([CH:13]([CH3:15])C)[NH:8][S:9]([NH2:12])(=[O:11])=[O:10]>CO>[CH2:13]([CH:7]1[NH:8][S:9](=[O:11])(=[O:10])[NH:12][C:6]1=[O:5])[CH2:15][CH3:1]
Reactant: C[O-]
Reactant: COC(=O)C(NS(N)(=O)=O)C(C)C
Agent: [Na+]
Solvent: CO
Product: CCCC1NS(=O)(=O)NC1=O
Reaction time: 6 h
Yield: 116489.3 %

Procedure:
A solution of freshly prepared sodium methoxide (6.41 g, from 2.3 g of Na) in 100 ml of methanol was added a solution of N-(aminosulfonyl)-DL-valine methyl ester (16.6 g; 0.079 mmol) in methanol (150 ml) and the resulting reaction mixture was stirred for 6 hours. The mixture was cooled, neutralized with BIO-RAD® 50W-X8 H+ ion exchange resin, and filtered. The filtrate was concentrated in vacuo to afford 16.4 g of a crude 4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IV: R1 =H; R2 =isopropyl; R3 =H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](F)=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:23][S-:24].[Na+].Cl>CN(C)C=O>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:24][CH3:23])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C[S-]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(SC)c(C(F)(F)F)c1
Temperature: 105 °C
Yield: 32.7 %

Procedure:
A solution of 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid methyl ester (7.0 g, 21.9 mmol) in N,N-dimethylformamide (50 mL) was treated with sodium methanethiolate (2.61 g, 33.0 mmol). The reaction mixture was then heated at 100-110° C. for 24 h. At this time, the reaction was poured onto a mixture of ice and a 2N aqueous hydrochloric acid solution (100 mL). This mixture was extracted into ethyl acetate (3×75 mL) and diethyl ether (1×50 mL). The combined organic layers were then washed with water (1×75 mL) and a saturated aqueous sodium chloride solution (3×100 mL). The organic layer was dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionic acid methyl ester (2.48 g, 35.5%) as a pale yellow oil: EI-HRMS m/e calcd for C17H21F3O2S (M+) 346.1214, found 346.1212.
Reaction SMILES: [S:1]1[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[CH3:14][Sn:15](Cl)([CH3:17])[CH3:16]>C1COCC1>[CH3:14][Sn:15]([CH3:17])([CH3:16])[C:7]1[S:6][C:5]2[S:1][C:2]([Sn:15]([CH3:17])([CH3:16])[CH3:14])=[CH:3][C:4]=2[CH:8]=1
Reactant: c1cc2ccsc2s1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cc2cc([Sn](C)(C)C)sc2s1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
A solution of thieno[2,3-b]thiophene (2.81 g, 20 mmol) was dissolved in anhydrous THF (100 ml) and cooled to −78° C. under nitrogen. A solution of n-butyllithium (17.6 ml of a 2.5M solution in hexanes, 44 mmol) was added dropwise over 15 min, and the resulting solution was allowed to warm to RT and stirred at that temperature for 16 h. The resulting suspension was cooled to −78° C. and trimethyltin chloride (10.0 g, 50 mmol) was added at once as a solid. The reaction was allowed to warm to RT over 4 h and stirred at that temperature for an additional 20 h. The reaction was quenched by the addition of saturated sodium hydrogen carbonate (100 ml). Ethyl acetate (50 ml) was added and the layers separated. The organic layer was washed-with sodium carbonate (80 ml of a 2M aqeous solution) and brine (80 ml), dried (sodium sulfate), filtered and concentrated under reduced pressure. The resulting crude product was dry loaded onto a 20 g reverse phase silica column and eluted with acetonitrile. The first fraction was collected, concentrated and recrystallised from acetonitrile to afford the product as white flakes (4.15 g, 45%). M/Z cluster centred at 466 (M+). Found C, 31.1; H, 4.4; S,13.8, Calc. for C12H20S2Sn2 C, 30.9; H, 4.3; S, 13.8. 1H NMR (300 MHz, CDCl3) δ 7.23 (s, 2H), 0.38 (s,18H). 13C NMR (75 MHz, CDCl3) δ 152.4, 147.7, 142.7, 126.3, −8.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([O:17][CH2:18][CH3:19])[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([OH:16])=[CH:8][CH:7]=1.[CH3:21][C:22]1[S:26][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH2:37]CO.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[CH:4]([O:17][CH2:18][CH3:19])[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([O:16][CH2:21][C:22]2[S:26][C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[N:24][C:23]=2[CH3:37])=[CH:8][CH:7]=1
Reactant: CCOC(Cc1ccc(O)c2c1CCCC2)C(=O)OC
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)c2c1CCCC2)C(=O)OC

Procedure:
In analogy to the procedure described in example 14 b], [rac]-2-ethoxy-3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid methyl ester (example 2 c]) was reacted with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole [PCT Int. Appl. (2001), WO 01/00603 A1] in N,N-dimethylformamide in the presence of cesium carbonate to give [rac]-2-ethoxy-3-{4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 1 e], to yield [rac]-2-ethoxy-3-{4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-propionic acid as colorless solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:64][N:65]1[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:13][CH2:14]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][N:65]5[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NN2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.9 %

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (22 mg, 0.05 mmol, 1 eq), DIPEA (17 μl, 0.10 mmol, 2 eq) and TBTU (18 mg, 0.055 mmol, 1.1 eq) were added to 0.5 mL DMF and the resulting solution stirred at rt for 30 min before the addition of 1-amino-4-methylpiperazine (12 μl, 0.1 mmol, 2 eq). The RM was then stirred at rt for 4 hours before purifying by preparative RP-HPLC-MS (Preparative—1) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxy-N-(4-methylpiperazin-1-yl)benzamide (white solid, 8 mg, 30%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:20]=[C:21](/[CH3:27])\[C:22]([O:24]CC)=[O:23])[C:6]2[C:11]([C:12]=1[O:13][CH2:14][O:15][CH3:16])=[C:10]([CH2:17][CH2:18][CH3:19])[CH:9]=[CH:8][CH:7]=2.[OH-].[K+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:20]=[C:21](/[CH3:27])\[C:22]([OH:24])=[O:23])[C:6]2[C:11]([C:12]=1[O:13][CH2:14][O:15][CH3:16])=[C:10]([CH2:17][CH2:18][CH3:19])[CH:9]=[CH:8][CH:7]=2
Reactant: CCCc1cccc2c(/C=C(/C)C(=O)OCC)cc(OC)c(OCOC)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1cccc2c(/C=C(/C)C(=O)O)cc(OC)c(OCOC)c12
Temperature: 10 °C
Yield: 96.1 %

Procedure:
170 g of ethyl (Z)-3-(3-methoxy-4-methoxymethoxy-5-propyl-1-naphthyl)-2-methylpropenoate was dissolved in 850 ml of ethanol and a potassium hydroxide aqueous solution (potassium hydroxide 60 g/water 120 ml) was added, followed by refluxing for 1 hour. After cooling to 10° C., 2.5N hydrochloric acid was added to make it pH~5, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant crystals were filtered to obtain 151 g of the titled compound as yellow crystals.
Reaction SMILES: [CH3:1][C:2](=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:22]=1[N:30]=[C:31]=[O:32])([CH3:20])[CH3:19].C([N-]C(C)C)(C)C.[Li+]>>[CH3:20][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:28])[CH3:29])[C:22]=1[NH:30][C:31](=[O:32])[CH2:1][C:2](=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:19]
Reactant: CCCCCCCCCCCCCCC(C)=O
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCCCCCCCCC(=O)CC(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
The title compound was prepared from 2-hexadecanone (5.0 g, 0.018 ml), 2,6-diisopropylphenyl isocyanate (3.72 g, 0.018 mol), and lithium diisopropylamide (0.018 mol) using the procedure described in Example 1. The desired product was obtained in 80% yield (6.38 g, 0.014 mol). MS: 443 (M+).
Reaction SMILES: [C:1]1(=O)[C:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2]1.Cl.[NH2:15][OH:16].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:1]1(=[N:15][OH:16])[C:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCc2oc3ccccc3c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: ON=C1CCc2oc3ccccc3c21
Yield: 101.2 %

Procedure:
A mixture of 2,3-dihydro-1H-cyclopenta[b]benzofuran-1-one (1.0g) and hydroxylamine hydrochloride (1.21g), in dry pyridine was stirred at 60° under nitrogen for 24h. The solution was poured into 8% sodium bicarbonate solution (150ml) and extracted with dichloromethane (3×50 ml). The combined extracts were washed with water (2×10 0 ml), dried, and evaporated to give the title compound (1.1 g) as a foam, t.l.c. (System B, 1:2) Rf 0.46.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH2:13]([C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[C:16]=1[C:17](Cl)=[O:18])[CH3:14]>>[CH2:13]([C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[C:16]=1[C:17]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:18])[CH3:14]
Reactant: CN1CCc2c(N)cccc2C1
Reactant: CCc1cccc(CC)c1C(=O)Cl
Product: CCc1cccc(CC)c1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline was reacted with 2,6-diethylbenzoyl chloride according to the procedure of Example 19 to yield 5-(2,6-diethylbenzamido)-2-methyl-1,2,3,4-tetrahydroisoquinoline; m.p. 185.5°-187.5° C. after purification from ethanol.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[C:26]2=[CH:19][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:7](=[O:18])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Reactant: COc1ccc2c(c1)CC(=O)N2
Product: COc1ccc2c(c1)C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCCC1)CC3)C(=O)N2
Yield: 33 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-methoxy-1,3-dihydro-indol-2-one (prepared according to U.S. Pat. No. 6,114,371) as starting materials to give 2-(5-methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetra hydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 33.0%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[CH:3]=1.[CH2:17]([C@@H:19]1[O:21][CH2:20]1)[Cl:18]>>[Cl:18][CH2:17][C@@H:19]([OH:21])[CH2:20][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[CH:3]=1
Reactant: CCCC(CCC)COc1cccc(Br)c1
Reactant: ClC[C@H]1CO1
Product: CCCC(CCC)COc1cccc(C[C@H](O)CCl)c1

Procedure:
Metallation of 1-bromo-3-(2-propylpentyloxy)benzene followed by addition of (R)-(−)-epichlorohydrin gave (S)-1-chloro-3-(3-(2-propylpentyloxy)phenyl)propan-2-ol Yield (1.52 g, 58%): 1H NMR (400 MHz, DMSO-d6) δ 7.14 (t, J=7.8 Hz, 1H), 6.77-6.72 (m, 3H), 5.14 (d, J=5.6 Hz, 1H), 3.88-3.81 (m, 1H), 3.78 (d, J=5.6 Hz, 2H), 3.52 (dd, J=10.8, 4.4 Hz, 1H), 3.43 (dd, J=11.2, 5.6 Hz, 1H), 2.74 (dd, J=13.6, 5.2 Hz, 1H), 2.60, (dd, J=13.6, 7.6 Hz, 1H), 1.75-1.69 (m, 1H), 1.39-1.25 (m, 8H), 0.85 (t, J=7.0 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:33][C:31]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:24])[CH:32]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(C#N)c(F)c4)ncnc32)CC1

Procedure:
4-[4-(4-Cyano-3-fluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 2-fluoro-4-hydroxybenzonitrile (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.94-2.04 (m, 4H), 2.99-3.07 (m, 2H), 4.08-4.11 (m, 2H), 5.01-5.05 (m, 1H), 7.47-7.50 (m, 1H), 7.75-7.79 (m, 1H), 8.08-8.12 (m, 1H), 8.42 (s, 1H), 8.60 (s, 1H). Mass spectrum MH+=439.
Reaction SMILES: [CH2:1]1[C@:7]([OH:10])([CH2:8][OH:9])[C@@H:6]([OH:11])[C@H:5]([OH:12])[C@@H:4]([OH:13])[C:2]1=O.[NH2:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17].Cl>CN(C=O)C.CO>[CH2:1]1[C@:7]([OH:10])([CH2:8][OH:9])[C@@H:6]([OH:11])[C@H:5]([OH:12])[C@@H:4]([OH:13])[C@H:2]1[NH:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17]
Reactant: O=C1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: NC(CO)CO
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5 mmol of valiolone and 5 mmol of 2-amino-1,3-propanediol in 25 mL DMF or methanol is added a catalytic amount of HCl. After 1 hour at room temperature, 2.5 mmol of solid Na(CN)BH3 is added and the reaction mixture is stirred over night at room temperature. The reaction mixture is then concentrated under reduced pressure and the residue is dissolved in water and applied to a Dowex 50 (H+) column. The column is washed with water and the product is eluted with 0.5 N NH4OH. After concentrating the eluate, the residue is dissolved in water and applied successively first to a Amberlite CG-50 (NH4+) or Diaion WK-100 (NH4+) and then a Dowex 1 (OH-) column and each time the product is eluted with water to give voglibose.