Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Li].C(Br)CCC.[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.[CH2:21]1[O:23][CH2:22]1>CCOCC.O>[CH:12]1([CH2:21][CH2:22][OH:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1
Reactant: C1=Cc2ccccc2C1
Reactant: C1CO1
Agent: [Li]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCBr
Product: OCCC1C=Cc2ccccc21

Procedure:
The above compound is prepared as described by Howell & Taylor, J.C.S., 1957, 3013. To butyl-lithium, prepared from lithium (20.0 g.) and butyl bromide (234 g.) in ether, indene (116 g., 1.0 M) is added with stirring under nitrogen at -10°. After 1 hour at -10° ethylene oxide (88 g.) in ether (300 ml.) is added in one-half hour. After warming to 10°, 500 ml. water is added cautiously and stirring is continued until there is no lithium remaining. The layers are separated and the organic layer is washed once with dilute HCl and three times with water. After drying, the ether is removed and the product distilled, collecting 76 g. (48%) at 125-135/0.2 mm. N.M.R. establishes the position of the double bond as 2,3.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1Br.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)(Cl)Cl>C1COCC1.CCOC(C)=O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:3]2[S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[Br:1])=[CH:16][CH:15]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1sc2ccccc2c1Br
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3ccccc3c2Br)cc1
Yield: 77.7 %

Procedure:
A mixture of the dibromobenzothiophene (11 g, 37.7 mmol), p-methoxyphenylboronic acid (5.7 g, 37.7 mmol), Pd(OAc) to (58 mg, 0.26 mmol) and tri-ortho-tolyl phosphine (237 mg) in 38 mL THF was treated with 38 mL 2 M Na2CO3 and refluxed in the absence of light overnight. Diluted with 100 mL EtOAc and separated the layers. The aqueous layer was extracted with EtOAc (50 mL). The combined organic layer was dried over MgSO4 and concentrated to an oil which was purified by chromatography (SiO2 ; stepwise 5 then 8% CHCl3 in hexanes) to recover 9.34 g (29.3 mmol, 78%) of the desired compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C:10](=[NH:13])[O:11][CH3:12])[N:3]=1.[CH3:14][O-:15].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:15][CH3:14])[N:5]=[C:4]([NH:9][C:10](=[NH:13])[O:11][CH3:12])[N:3]=1
Reactant: COC(=N)Nc1nc(Cl)cc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)Nc1nc(Cl)cc(OC)n1
Reaction time: 12 h
Yield: 85.6 %

Procedure:
9.1 g (0.041 mol) of N-(4,6-dichloro-pyrimidin2-yl)-O-methyl-isourea are initially introduced in 80 ml of methanol. 2.2 g of sodium methoxide (0.041 mol), dissolved in 20 ml of methanol, are then added dropwise at 20° C. The mixture is subsequently stirred for 12 hours and concentrated, the residue is taken up in methylene chloride, and the solution is washed three times with water and concentrated again. 7.6 g (86% of theory) of N-(4-chloro-6-methoxy-pyrimidin-2-yl) -O-methyl-isourea are obtained in the form of white crystals of melting point 118°-120° C.
Reaction SMILES: [CH3:1][C:2](=[CH:4][C:5](=[O:10])[C:6]([CH3:9])(O)C)[CH3:3].[CH:11](C=C1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(C)C(C[C@@H](O)CC1)=CC3)=O.C(C=C1CC[C@H]2[C@H]3[C@H](CC[C@]12C)C1CCC(=O)CC=1CC3)=O.CCC1C[C@@H]2[C@H](CC[C@@H]3[C@@H]4C(=CC(=O)CC4)CC[C@H]32)C1=CC=O>>[CH3:3][C:2](=[CH:4][C:5](=[O:10])[CH2:6][CH2:9][CH3:11])[CH3:1]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=CC=O)CC[C@@H]12
Reactant: CC(C)=CC(=O)C(C)(C)O
Agent: CCC1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@H]2C1=CC=O
Agent: C[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC2=CC=O)CC(=O)CC4
Product: CCCC(=O)C=C(C)C

Procedure:
2,5-dimethyl-hex-2-en-5-ol-4-one; 17-(formylmethylene)-androst-5-en-3 β -ol; 17-(formylmethylene)-estr-5(10)-en-3-one; 13 β-ethyl-17-(formylmethylene)-gon-4-en-3-one; and
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([N:23]([CH3:27])[C:24](=[O:26])[CH3:25])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:28])[O:11]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[OH:8][CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([N:23]([CH3:27])[C:24](=[O:26])[CH3:25])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:28])[O:11]1
Reactant: CC(=O)N(C)c1ccc2c(c1)OC[C@H]1[C@H](CO[Si](C)(C)C(C)(C)C)OC(=O)N21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(=O)N(C)c1ccc2c(c1)OC[C@H]1[C@H](CO)OC(=O)N21
Yield: 86.4 %

Procedure:
Using N-((3R,3aS)-3-(((t-butyldimethylsilyl)oxy)methyl)-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-7-yl)-N-methylacetamide (0.617 g, 1.52 mmol), and TBAF (1M, 2 ml) as starting materials, preparation following the method as described in Example 1 (b) afforded white solid 0.384 g, yield: 86.53%.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.Br[CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.O>CN(C=O)C>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([O:3][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]2)=[CH:5][CH:6]=1)#[N:9]
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil; 316 mg, 7.91 mmol) in DMF (10 mL) was added in portions 4-hydroxybenzonitrile (856 mg, 7.19 mmol). After stirring for 15 min at rt, tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (2.00 g, 7.19 mmol) was added, and the reaction mixture was stirred at 80° C. for 1 h and at 150° C. for a further 1 h. After cooling to rt, water was added, and the mixture was stirred for 15 min. The solid was filtered off, water was added again, and the mixture was stirred for further 15 min and then filtered again. This procedure was repeated once again. Finally, the solids obtained were dried in vacuo to give the title compound (1.47 g, 59%): ES-MS m/z 317, HPLC RT (Method F) 2.54 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[N:18]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]([CH2:30][CH2:31][C:32]1[CH:40]=[CH:39][C:35]([CH2:36][CH2:37]Br)=[CH:34][CH:33]=1)=[O:29].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[N:18]2[CH2:25][CH2:24][CH2:23][N:22]([CH2:37][CH2:36][C:35]3[CH:39]=[CH:40][C:32]([CH2:31][CH2:30][C:28]([O:27][CH3:26])=[O:29])=[CH:33][CH:34]=3)[CH2:21][CH2:20][CH2:19]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Cn2c(N3CCCNCCC3)nc3ccccc32)cc1
Reactant: COC(=O)CCc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(CCN2CCCN(c3nc4ccccc4n3Cc3ccc(F)cc3)CCC2)cc1
Temperature: 100 °C
Yield: 61.5 %

Procedure:
To a solution of 1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane (12.1 g) in N,N-dimethylformamide (70 ml) were added 4-(2-methoxycarbonylethyl)phenethyl bromide (9.49 g), sodium carbonate (3.71 g) and potassium iodide (0.58 g), and the mixture was heated at 100° C. for 1 hour. The reaction mixture was poured into an ice-water (200 ml), and the mixture was extracted with methylene chloride (200 ml). The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of methylene chloride, diethyl ether and methanol (1:1:0.25) as eluent to give 1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-(2-methoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane (11.38 g) as a colorless oily liquid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][C:13]3[CH:25]=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:15]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=4)[CH:14]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][C:13]3[CH:25]=[CH:24][C:16]([C:17]([OH:19])=[O:18])=[C:15]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=4)[CH:14]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccc3c(c2)OCCO3)cc1Nc1cccc(O)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CCc2ccc3c(c2)OCCO3)cc1Nc1cccc(O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 4-(2-(2,3-dihydro[1,4]benzodioxin-6-yl)ethyl)-2-((3-hydroxyphenyl)amino)benzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 55-75% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 4-(2-(2,3-dihydro[1,4]benzodioxin-6-yl)ethyl)-2-((3-hydroxyphenyl)amino)benzoic acid 8.1 mg of a white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[C:23]([Cl:35])=[CH:22][N:21]=1>>[Cl:35][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])=[N:25][C:20]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][C:2]([F:17])([F:18])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:21][CH:22]=1
Reactant: Nc1ccc2c(c1)CCC(NCC(F)(F)F)CC2
Reactant: COc1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)(F)F)CC3)ncc1Cl
Yield: 23 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2,2-Trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine) was combined with (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-phenyl)-amine to yield 5-Chloro-N*4*-(2-methoxy-phenyl)-N*2*-[7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]-pyrimidine-2,4-diamine (34.40 mg, 23% yield) as a white powder. 1H-NMR (CDCl3) δ 8.44 (d, J=7.8 Hz, 1H), 8.04 (s, 1H), 7.85 (s, 1H), 7.37 (s, 1H), 7.23 (m, 1H), 7.05 (m, 2H), 6.92 (m, 3H), 3.94 (s, 3H), 3.24 (q, J=18.8, 9.4 Hz, 2H), 2.83 (m, 3H), 2.67 (m, 2H), 2.07 (m, 2H), 1.33 (m, 2H). LC/MS (ESI+)=492 (M+H). MP=182-183.5° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].N[C@H](C(O)=O)CC(=O)O.N[C@@H](C(O)=O)CC(=O)O.N[C@H](C(O)=O)CCC(=O)O.N[C@@H](C(O)=O)CCC(=O)O.N[C@H](C(O)=O)CCC(=O)N.N[C@@H](C(O)=O)CCC(=O)N>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: NC(=O)C[C@@H](N)C(=O)O
Agent: NC(=O)CC[C@@H](N)C(=O)O
Agent: NC(=O)CC[C@H](N)C(=O)O
Agent: N[C@@H](CC(=O)O)C(=O)O
Product: NC(=O)C[C@H](N)C(=O)O

Procedure:
replace with: D-Asn, Asp, D-Asp, Glu, D-Glu, Gln, D-Gln;
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1.[F:23][C:24]1[CH:29]=[C:28]([O:30]C)[C:27]([F:32])=[CH:26][C:25]=1[N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:42])[CH2:35][CH2:34]1>>[F:23][C:24]1[CH:29]=[C:28]([OH:30])[C:27]([F:32])=[CH:26][C:25]=1[N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:42])[CH2:35][CH2:34]1
Reactant: COc1cc(F)c(N2CCN(CCC(=O)c3ccccc3)CC2)cc1F
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1
Product: O=C(CCN1CCN(c2cc(F)c(O)cc2F)CC1)c1ccccc1
Yield: 101 %

Procedure:
Production Example 2 was repeated except that 1-(4-methoxyphenyl)-4-phenethylpiperazine was replaced with 3-[4-(2,5-difluoro-4-methoxyphenyl)piperazin-1-yl]-1-phenylpropan-1-one (344 mg), to provide crude 3-[4-(2,5-difluoro-4-hydroxyphenyl)-piperazin-1-yl]-1-phenylpropan-1-one (334 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:27])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=[C:19]4[C:18](I)=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:28][CH3:29].C([Mg]Cl)(C)C.[Cl-].[NH4+]>ClCCl.C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:27])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=[C:19]4[CH:18]=[N:17]3)[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(I)c4cc(Cl)cnc43)CC2)ccc1Cl
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(N2CCN(C(=O)Cn3ncc4cc(Cl)cnc43)CC2)ccc1Cl
Temperature: 25 °C
Yield: 32.2 %

Procedure:
To a solution of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(3-iodo-5-chloro-pyrazolo[3,4-b]pyridine-1-yl)-ethanone (0.037 mmol, 1 eq.) in 1.5 mL of dichloromethane under a nitrogen atmosphere cooled to −40° C., was added dropwise, 30 μl of 2.0 M solution of isopropyl magnesium chloride (0.056 mmol, 1.5 eq.) in THF. The resultant mixture was for 30 minutes at −40° C. followed by dropwise addition of an ammonium chloride aqueous (aq) solution at low temperature. The reaction solution was warmed to rt, diluted with 200 mL of EtOAc, washed with 50 mL of water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by HPLC to provide 5-mg final product: 1H NMR (400 MHz, CDCl3) δ 8.44 (d, 1H), 8.05(m, 1H), 7.23 (d, 1H), 6.50 (d, 1H), 6.43 (dd, 1H), 5.42 (s, 2H), 3.89 (s, 3H), 3.76 (m, 4H), 3.20 (m, 4H). LCMS observed for (M+H)+: 421.1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:16]([O:15][C:13](=[O:14])[C:12]([C:10]#[N:11])=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2])[CH3:17]
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=C(C)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of acetophenone (50 mmole), ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), ammonium acetate (400 mg), and benzene (50 mL) was heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract was concentrated in vacuo and the desired product, as a mixture of E- and Z-isomers, was isolated by column chromatography on silica gel, eluting with 5% ethyl acetate/petroleum ether, affording an oil that solidified on standing at room temperature.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][C:8]=1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)COc1ccc(OCc2ccccc2)cc1CCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COc1ccc(O)cc1CCc1ccccc1

Procedure:
A solution of (4-benzyloxy-2-phenethylphenoxy)acetic acid ethyl ester (1.77 mmol) in ethanol (15 mL) was treated with 5% Pd/C (70 mg) and hydrogen (60 psi) at ambient temperature for 18 h. The mixture was filtered and concentrated in vacuo to give the desired product.
Reaction SMILES: C(OC(=O)C[C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][C:9](=O)[NH:8][CH2:7]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:25](OCC)(=[O:27])[CH3:26].CCCCCC.ClCCl>O1CCCC1>[C:12]1([CH:6]2[CH2:10][CH2:9][NH:8][CH:7]2[CH2:26][CH2:25][OH:27])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC1(c2ccccc2)CNC(=O)C1
Reactant: CCOC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCCC1NCCC1c1ccccc1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
Combine (3-phenyl-5-oxopyrrolidin-3-yl)acetic acid ethyl ester (301 g, 1.25 mol) and tetrahydrofuran (3.5 L). Cool to about 5° C. Slowly, add portionwise over about 45 minutes a solution of lithium aluminum hydride in tetrahydrofuran (3.9 L, 1 M, 3.9 mol). After the addition is complete heat to 60° C. After 18 hours, cool in an ice-bath. Add water/tetrahydrofuran 1/1 (1.95 L) dropwise at such a rate that the temperature of the reaction mixture does not rise above 20° C. Dilute the reaction mixture with tetrahydrofuran (2.25 L) and stir. After 1.5 hours, filter the reaction mixture. Suspend the solids in diethyl ether (3 L) and filter. Combine the filtrates and concentrate the in vacuo to give a residue. Combine the residue and dichloromethane (4 L) and extract three times with water (1 L). Dry the organic layer over MgSO4, filter, and concentrate in vacuo to obtain a solid. Triturate the solid with diethyl ether (0.3 L), collect by filtration, rinse with diethyl ether, and dry to give the title compound: Rf=0.12 (silica gel dichloromethane/methanol/concentrated aqueous ammonia, 9/1/0.1).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1[N:24]=[C:25]=[S:26])(=[O:3])[CH3:2].[NH2:27][C:28]1[S:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1>C1(C)C(C)=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[NH:24][C:25]([NH:27][C:28]1[S:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1)=[S:26])(=[O:3])[CH3:2]
Reactant: Nc1nc2ccccc2s1
Reactant: CC(=O)OC[C@H]1OC(N=C=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: Cc1ccccc1C
Product: CC(=O)OC[C@H]1O[C@@H](NC(=S)Nc2nc3ccccc3s2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 110 °C

Procedure:
To 10 ml of anhydrous xylene were added 390 mg (1 mmol) of 2,3,4,6-tetra-O-acetyl-D-glucopyranosyl isothiocyanate and 150 mg (1 mmol) of 2-aminobenzothiazole (MW 150) and the mixture was heated at 110° C. for 40 minutes and allowed to cool to room temperature. Crystals formed were filtered off and recrystallized from methanol to give colourless needles melting between 179° and 181° C. (uncorrected). Yield: 230 mg (42%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].[CH:18]([NH2:21])([CH3:20])[CH3:19]>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:21][CH:18]([CH3:20])[CH3:19])[CH:7]=1
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)Nc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 13 h
Yield: 88.3 %

Procedure:
To a stirred mixture of 2,4-difluoro-1-nitrobenzene (4.77 g, 30 mmol) and K2CO3 (4.14 g, 30 mmol) in THF (30 mL) was added isopropyl amine (1.77 g, 30 mmol) in THF (10 mL) at 0° C. After being stirred for 13 h, the insoluble materials were removed by pad of Celite and the filtrate was consentrated under reduced pressure to give title compound (5.25 g, 88%) as a pale yellow oil.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:14])[CH:11]=2)[CH2:6]1)=[O:4]>CC(O)=O>[F:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:13]2
Reactant: COC(=O)C1Cc2ccc(F)cc2C1
Solvent: CC(=O)O
Product: O=C(O)C1Cc2ccc(F)cc2C1

Procedure:
5-fluoro-indan-2-carboxylic acid methyl ester in HOAc containing 20% HCl was hydrolyzed according to the protocols as outlined in general procedure G to give the desired title acid. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ 3.02-3.16 (m, 4H), 3.25-3.37 (m, 1H), 6.90-6.98 (m, 1H), 7.01-7.07 (m, 1H), 7.17-7.25 (m, 1H), 12.3 (br s, 1H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].C1N=C[N:12]([C:15](N2C=NC=C2)=[S:16])C=1.N>C1COCC1>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:15](=[S:16])[NH2:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)N1CCNCC1
Agent: N
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.1 %

Procedure:
To a suspension of 1-isopropylpiperazine (1.5 g, 11.70 mmol) in THF (24 mL) was added 1,1-thiocarbonyldiimidazole (2.398 g, 13.45 mmol). The reaction mixture was stirred at ambient temperature for about 8 h. Upon addition of the 1,1-thiocarbonyldiimidazole, the reaction mixture slightly warmed. A solution of ammonia (7.0 M in MeOH, 20 mL) was added and the reaction mixture was stirred overnight at ambient temperature. Additional ammonia (7.0 M in MeOH, 20 mL) was added and the reaction mixture was stirred overnight at about 40° C. The reaction mixture was cooled to ambient temperature and solvent was removed under reduced pressure. The residue was triturated with Et2O (15 mL) and filtered to give the title compound (2.5 g, 97%) as a yellow solid: LC/MS (Table 1, Method a) Rt=0.74 min; MS m/z: 188.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>>[CH2:18]([N:13]1[C:12]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[F:28])=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: OB(O)c1ccccc1F
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCn1nc2c(c1-c1ccccc1F)CCNCC2
Yield: 94.1 %

Procedure:
The title compound (121 mg) was prepared according to Example 263 using 205 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 97 mg of 2-fluorophenylboronic acid. MS (ESI): exact mass calculated for C15H18FN3, 259.15; found, m/z 260.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.61-7.55 (m, 1H), 7.39-7.30 (m, 3H), 4.01-3.91 (m, 2H), 3.43-3.41 (m, 2H), 3.18-3.16 (m, 2H), 2.79-2.73 (m, 2H), 1.28 (t, J=9.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]2[CH:20]=C[N+](C)=C2)=[O:15])[C@H:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]=1.NC1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1.CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([NH:16][CH:20]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:31][CH2:30]2)=[O:15])[C@H:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]=1
Reactant: C[n+]1ccn(C(=O)N2CC(c3cc(F)ccc3F)=C[C@H]2c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)N2CC(c3cc(F)ccc3F)=C[C@H]2c2ccccc2)CC1
Reaction time: 6 h

Procedure:
Crude 18-2 (115 mg, 0.24 mmol) was suspended in anhydrous CH2CL2 (3 mL) and treated successively with 4-amino-1-tert-butyloxycarbonyl-piperidine (235 mg, 1.17 mmol) and Et3N (0.1 mL, 0.7 mmol). The suspension was stirred for 6 hours and complete dissolution was observed. Upon completion, the reaction was diluted further with CH2Cl2 (20 mL) and washed with 1N HCl to remove all unbound amine and Et3N. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to yield crude 18-3 as a yellow oil: LRMS m/z (N C(CH3)3+H) 427.9 found, 428.1 required.