Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].O.[CH2:7]1[CH:12]2[C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:11]2[CH2:10][CH2:9][NH:8]1>C(O)C>[OH:3][CH:2]([CH2:4][OH:5])[CH2:1][N:8]1[CH2:9][CH2:10][N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][C:14]3[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=3[CH:12]2[CH2:7]1
Reactant: OCC1CO1
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNCC21
Solvent: CCO
Solvent: O
Product: OCC(O)CN1CCN2c3ccccc3Cc3ccccc3C2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.6 %

Procedure:
A mixture of 0.41 g of glycidol and 0.9 ml of water was added, whilst ice-cooling, to a solution of 1 g of 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine dissolved in 2 ml of ethanol, and the mixture was stirred at room temperature for 5 hours; it was then concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and ethanol as the eluent, to afford 0.72 g (yield 56%) of the title compound as a colorless foam.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][N:4]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl.FC(F)(F)S(O[C:33]1[C:45]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][C:37]=2[CH:36]=[CH:35][CH:34]=1)(=O)=O>O1CCOCC1.O>[CH:36]1[C:37]2[NH:38][C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:45]=2[C:33]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=2)=[CH:34][CH:35]=1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: O=S(=O)(Oc1cccc2[nH]c3ccccc3c12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cccc3[nH]c4ccccc4c23)cn1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
0.72 g of 2-cyano-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)pyridine, 3.3 g of caesium carbonate and 92 mg of 1,1′-bis(diphenyl-phosphino)ferrocenepalladium(II) dichloride as a complex with dichloromethane (1/1) [PdCl2(dppf).CH2Cl2] are successively added, under argon, to a solution of 0.8 g of 4-trifluoromethanesulphonyloxycarbazole, obtained in stage 1 of Example 1, in a mixture of 37 ml of dioxane and 12 ml of water. The reaction mixture is refluxed for 4 hours, cooled to ambient temperature, filtered through celite and concentrated under reduced pressure. The residue is subsequently purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (85/15 by volume), so as to give 0.24 g of 5-(9H-carbazol-4-yl)pyridine-2-carbonitrile in the form of a yellow solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.Cl.[NH2:14][OH:15].C(=O)([O-])O.[Na+].O>CO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:11][O:15][NH2:14])=[CH:6][CH:5]=1
Reactant: NO
Reactant: COC(=O)c1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C=NON)cc1
Yield: 81 %

Procedure:
In 200 ml of methanol were dissolved 16.5 g of 4-cyanobenzoic acid methyl ester and 7.2 g of hydroxylamine hydrochloride. To the solution was added 8.82 g of sodium hydrogencarbonate at room temperature. The mixture was heated for 3 hours under reflux. The reaction mixture was cooled, to which was added 400 ml of water. Resulting crystalline precipitate was collected by filtration, which was washed with water and ether, followed by drying under reduced pressure to afford 16.1 g of the titled compound as colorless needles.
Reaction SMILES: [Cl-:1].[C:2]([C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:8][NH+:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2F)[C:12](=[O:20])[CH:11]=[N:10]1)([OH:4])=[O:3].Cl.[Li+].[OH-:27]>>[Cl-:1].[C:2]([C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:8][NH+:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[OH:27])[C:12](=[O:20])[CH:11]=[N:10]1)([OH:4])=[O:3]
Reactant: [OH-]
Reactant: O=C(O)c1cc(C[NH+]2N=CC(=O)c3cccc(F)c32)ccc1F
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Product: O=C(O)c1cc(C[NH+]2N=CC(=O)c3cccc(O)c32)ccc1F

Procedure:
A solution of D5 in 9% LiOH (0.05 M) was heated at 160° C. under microwaves irradiation for 15 min. The aqueous phase was made acidic with 37% HCl. The resulting precipitate was collected by filtration affording the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.CCN(CC)CC>C(Cl)Cl.CCOC(C)=O.O>[O:44]1[CH2:45][CH2:46][N:41]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]3)=[CH:17][CH:16]=2)=[O:15])[CH2:42][CH2:43]1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2ccc(C(=O)N3CCOCC3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (200 mg, 0.806 mmol) in CH2Cl2 (10 mL) was subsequently added EDCl (232 mg, 1.21 mmol), HOBt (163 mg, 1.21 mmol), morpholine (0.11 mL, 1.21 mmol), and Et3N (0.22 mL, 1.61 mmol). The mixture was stirred at room temperature overnight, treated with EtOAc/H2O, and extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography to give the title compound (207 mg, 81% yield). MS (m/z): 318 (M+H)+
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[C:14]2[O:13][CH2:12][O:11][C:10]=2[C:9]([CH3:15])=[CH:8][CH:7]=1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C(OC(=O)C)(=O)C>[N+:1]([C:8]1[CH:7]=[C:6]([CH3:5])[C:14]2[O:13][CH2:12][O:11][C:10]=2[C:9]=1[CH3:15])([O-:4])=[O:2]
Reactant: Cc1ccc(C)c2c1OCO2
Reactant: O=[N+]([O-])O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CC(=O)OC(C)=O
Product: Cc1cc([N+](=O)[O-])c(C)c2c1OCO2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.92 mL of concentrated nitric acid in 17 mL of acetic arthydride is added dropwise to a stirred solution of 2.20 g of 4,7-dimethyl-1,3-benzodioxole in 60 mL of acetic anhydride at -5° C. After 30 minutes, the mixture is poured over 100 g of crushed ice and allowed to stir for 30 minutes as a white precipitate falls out of solution. The solid is filtered, taken up in ether, dried over magnesium sulfate and concentrated under reduced pressure to afford 2.1 g of 5-nitro-4,7-dimethyl-1,3-benzodioxole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([NH2:18])=[O:17])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9](I)[CH:8]=3.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:31][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([NH2:18])=[O:17])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([C:27]1[CH:32]=[N:31][C:30]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[CH:29][CH:28]=1)[CH:8]=3
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(I)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: NC(=O)c1cc(Br)cc2c1[nH]c1cc(-c3ccc(N4CCOCC4)nc3)ccc12
Temperature: 105 °C

Procedure:
3-Bromo-7-iodo-9H-carbazole-1-carboxamide 481A (100 mg, 0.241 mmol), 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (84 mg, 0.289 mmol), PdCl2(dppf)-CH2Cl2 adduct (39.4 mg, 0.048 mmol), and Na2CO3 (2M) (0.602 mL, 1.205 mmol) were mixed with DME (4 mL) in a sealed microwave vial. The mixture was flushed with N2 and heated at 105° C. in an oil bath for 5 hrs. The mixture was used as it is. MS (ESI) m/z 450.97 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@@H:14]([CH2:37][C:38]([NH:40][C:41]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C:15]([N:17]([CH2:27][C:28]1[C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[S:31][CH:32]=1)[C@@H:18]([CH3:26])[CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[O:16]>>[S:31]1[CH:32]=[C:28]([CH2:27][N:17]([C@@H:18]([CH3:26])[CH:19]([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])[C:15](=[O:16])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH2:37][C:38](=[O:39])[NH:40][C:41]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]1=2
Reactant: CCNC(=O)NN(C)CC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N(Cc1csc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 40 mg (0.23 mmol) was coupled with (S)-2-amino-N1-(benzo[b]thiophen-3-ylmethyl)-N1—((S)-1,1-diethoxy-propan-2-yl)-N4-tritylsuccinamide (Compound IV-21) 100 mg (0.15 mmol) to obtain the title compound.
Reaction SMILES: [O:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:10]=[CH:9][S:8][C:7]=2[NH2:11])=[N:2]1.[F:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[F:23])[N:19]([CH2:24][C:25](O)=[O:26])[C:18](=[O:28])[CH:17]=[CH:16]2>>[O:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:10]=[CH:9][S:8][C:7]=2[NH:11][C:25](=[O:26])[CH2:24][N:19]2[C:20]3[C:15](=[CH:14][C:13]([F:12])=[C:22]([F:23])[CH:21]=3)[CH:16]=[CH:17][C:18]2=[O:28])=[N:2]1
Reactant: O=C(O)Cn1c(=O)ccc2cc(F)c(F)cc21
Reactant: Nc1sccc1-c1ncon1
Product: O=C(Cn1c(=O)ccc2cc(F)c(F)cc21)Nc1sccc1-c1ncon1

Procedure:
The title compound was prepared from 3-(1,2,4-oxadiazol-3-yl)thiophen-2-amine (18 mg, 108 umol) and 2-(6,7-difluoro-2-oxoquinolin-1(2H)-yl)acetic acid (32 mg, 134 umol) using protocol A. The crude product was purified by HPLC to yield N-(3-(1,2,4-oxadiazol-3-yl)thiophen-2-yl)-2-(6,7-difluoro-2-oxoquinolin-1(2H)-yl)acetamide. Method [7] retention time 5.34 min by HPLC (M+=389) and (M+Na=411). 1H NMR (300 MHz, CDCl3) δ 11.06 (s, 1H), 8.69 (s, 1H), 7.74 (d, J=9.9 Hz, 1H), 7.42 (m, 2H), 7.35 (m, 1H), 6.98 (d, J=5.4 Hz, 1H), 6.86 (d, J=9.3 Hz, 1H), 5.22 (s, 2H).
Reaction SMILES: C(B(CC)[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)C.FC(F)(F)S(O[C:18]1[C@:19]2([CH2:36][CH2:35][C@H:34]3[C@@H:24]([CH2:25][CH:26]=[C:27]4[C@:32]3([CH3:33])[CH2:31][CH2:30][C@H:29]([O:37][C:38](=[O:40])[CH3:39])[CH2:28]4)[C@@H:21]2[CH2:22][CH:23]=1)[CH3:20])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:38]([O:37][C@H:29]1[CH2:30][CH2:31][C@@:32]2([CH3:33])[C:27](=[CH:26][CH2:25][C@@H:24]3[C@@H:34]2[CH2:35][CH2:36][C@@:19]2([CH3:20])[C@H:21]3[CH2:22][CH:23]=[C:18]2[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:28]1)(=[O:40])[CH3:39]
Reactant: CCB(CC)c1cccnc1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(OS(=O)(=O)C(F)(F)F)=CC[C@@H]32)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
Diethyl(3-pyridyl)borane (3.38 g, 23 mmol) from Aldrich Chemical Co. Ltd. was added to a stirred solution of 3β-acetoxyandrosta-5,16-dien-17-yl trifluoromethanesulphonate (6.94 g, 15 mmol) in THF (75 ml) containing bis(triphenylphosphine)palladium(II) chloride (0.105 g, 0.15 mmol). An aqueous solution of sodium carbonate (2M, 30 ml) was then added and the mixture heated, with stirring, by an oil bath at 80° C. for 1 h, and allowed to cool. The mixture was partitioned between diethyl ether and water, the ether phase was dried (Na2CO3), filtered through a short plug of silica, and concentrated. Chromatography, on elution with light petroleum-diethyl ether (2:1), afforded the title compound (4.95 g, 84%) which crystallised from hexane, m.p. 144°-145° C., 1H-NMR(CDCl3) inter alia δ1.05(3H,s, 19-CH3), 1.08(3H,s,18-CH3), 2.04(3H,s,CH3CO2), 4.60(1H,m,3α-H), 5.42(1H,dm, J 4.7 Hz,6-H), 5.99(1H,m,16-H), 7.23(1H,m,Py 5-H) 7.65(1H,m,Py 4-H), 8.46(1H,m,Py 6-H), 8.62(1H,m,Py 2-H). Anal. Calcd: C, 79.75; H, 8.50; N, 3.58. Found: C, 79.78; H, 8.52; N, 3.54%.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1

Procedure:
5-Bromo-2-furoic acid (1 g, 5.25 mmol) was coupled to 4-chloro-phenylboronic acid (819 mg, 5.23 mmol) acid using Method F to give the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C:13]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22](O)=[O:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>ClCCl>[C:16]([O:15][C:13]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([NH:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=[O:23])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Cc1c(N)cccc1C(=O)O
Agent: Cl
Solvent: ClCCl
Product: Cc1c(NC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cccc1C(=O)O
Reaction time: 18 h
Yield: 45 %

Procedure:
HCl salt (3.1 g, 16.6 mmol) was added to a suspension of 3-amino-2-methylbenzoic acid (2.5 g, 16.6 mmol) and N-Boc-L-proline (3.5 g, 16.6 mmol) in dichloromethane (40 mL). The reaction mixture was stirred under nitrogen for 18 h, diluted with solvent (1 vol) and washed with 1N HCl, brine, and dried (MgSO4). Concentration gave a foam with was applied to a 40 M Biotage SiO2 column, and eluted by gradient 20%-60% B (1000 mL); A=1% acetic acid/hexanes; B=1% acetic acid/ethyl acetate to give J.36 (S)-3-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)-2-methylbenzoic acid 2.6 g (45%). 1H NMR (300 MHz, DMSO-d6) δ: 12.5 (br. s, 1H), 9.52/9.46 (s, 1H), 7.57 (d, J=7.3 Hz, 1H), 7.44-7.40 (m, 1H), 7.29-7.24 (m, 1H), 4.32-4.28 (m, 1H), 3.47-3.48 (m, 1H), 3.34-3.29 (m, 1H), 2.33 (s, 3H), 1.93-1.80 (m, 4H), 1.41/1.36 (s, 9H). LC (Cond.-J1): 1.55 min; LCMS: Anal. Calcd. for [M+H]+ C18H25N2O5: 349.18; found 349.33.
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH2:7][C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2].[CH2:11]1CCN2C(=NCCC2)C[CH2:12]1.ICC.O>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:10])[CH:7]([C:8]#[N:9])[CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(C)OC(=O)CC#N
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(C#N)C(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
To a solution of cyanoacetic acid tert-butyl ester (10.0 mL, 69.99 mmoL) (TCI America, Portland Oreg.) and DBU (10.5 mL, 69.99 mmol) in DMF (70 mL) was added iodoethane (6.8 mL, 84.00 mmol) dropwise at 0° C. The resulting mixture was heated to 70° C. for 20 hours. After cooling to room temperature, H2O (350 mL) and EtOAc (350 mL) were added. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% EtOAc/hexanes) to give the title compound in 5 g. 1H NMR (CDCl3, 200 MHz): δ=3.36 (dd, 1H, J=6.3 Hz and 6.3 Hz), 2.06-1.88 (m, 2H), 1.49 (s, 9H), 1.11 (t, 3H, J=7.3 Hz).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1([O:21][C:22]([O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=O)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][O:24][C:22]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:21])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)COC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A suspension of 5.09 g (25.42 mmol) of 1,1-dimethylethyl 4-aminopiperidine-1-carboxylate and 13.45 g (59.99 mmol) of ethyl [(phenyloxycarbonyl)oxy]acetate (J. Med. Chem., 1999, 42, 277-90) in 300 ml of toluene is heated at reflux for 30 hours.
Reaction SMILES: O.[O:2]=[C:3]1[CH:11]([Br:12])[CH2:10][CH2:9][C:8]2[N:7]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:6]=[CH:5][C:4]1=2.[Cl:22][CH2:23][CH:24](O)[CH2:25][OH:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:22][CH2:23][CH:24]1[CH2:25][O:26][C:3]2([CH:11]([Br:12])[CH2:10][CH2:9][C:8]3[N:7]([S:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)(=[O:15])=[O:14])[CH:6]=[CH:5][C:4]2=3)[O:2]1
Reactant: OCC(O)CCl
Reactant: O=C1c2ccn(S(=O)(=O)c3ccccc3)c2CCC1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2c1CCC(Br)C21OCC(CCl)O1
Yield: 97 %

Procedure:
In a three necked flask equipped with a thermometer, a stirrer and a reflux condenser having Widmer-type water trap filled with Molecular Sieves are placed 4-oxo-5-bromo-1-benzenesulfonyl-4,5,6,7-tetrahydroindole (100 parts), 3-chloro-1,2-propanediol (311 parts), p-toluenesulfonic acid monohydrate (3 parts) and toluene (4500 parts), and the mixture is refluxed for 7 hours 20 minutes while drying the refluxing azeotropic mixture. After cooling, the reaction mixture is adjusted to pH 9 with 2.5N aqueous sodium hydroxide with stirring, and the formed toluene layer is separated. The water layer is washed with benzene (200 parts). Toluene layer and benzene washing are combined, washed twice with water (500 parts) and dried over anhydrous sodium sulfate (500 parts). The drying agent is filtered off, and the filtrate is concentrated under reduced pressure. The obtained residue (143 parts) is dissolved in benzene (300 parts), stirred with active charcoal (50 parts) for 30 minutes and filtered through a filter-bed of siliceous earth. The filtrate is concentrated under reduced pressure, and stirring of resulted residue with a small amount of ether and hexane affords amorphous powder. This is collected by filtration, washed with a mixture of ether and hexane, and dried to give 4'-chloromethyl-5-bromo-1-benzenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]-dioxolane diastereomer mixture (122 parts) in 97% yield.
Reaction SMILES: Cl.Cl[C:3]1[N:7]([CH3:8])[N:6]=[C:5]([CH3:9])[C:4]=1[CH2:10][NH2:11].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH3:8][N:7]1[CH:3]=[C:4]([CH2:10][NH2:11])[C:5]([CH3:9])=[N:6]1
Reactant: Cc1nn(C)c(Cl)c1CN
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(C)cc1CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 4 (120 mg, 0.61 mmol) in THF (5 mL) was added LAH (43 mg, 3.78 mmol). The resulting mixture was stirred at room temperature overnight. Water was added and the resulting mixture was filtered. Organic layer was separated and then concentrated in vacuum to give a white solid (crude product). LCMS (ESI) m/z=126 (M+H)+.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.C(S)CCS.S1CCCCS1.[Li]CCCC.[C:27](OC)(=[O:36])[CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN1CCN(C)C1=O>C(Cl)Cl>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:2]=1[CH2:1][CH:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][C:27]2=[O:36]
Reactant: COc1ccccc1C=O
Reactant: COC(=O)C=Cc1ccccc1
Agent: C1CCSSC1
Agent: SCCCS
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CN1CCN(C)C1=O
Product: COc1cccc2c1CC(c1ccccc1)CC2=O

Procedure:
o- Anisaldehyde (20.5 g) was treated with 1,3-propanedithiol (24 ml) in the presence of BF. etherate (4 ml) and CH2Cl2 (300 ml). This dithiane derivative (4.7 g) was reacted with n-BuLi (2.5 M hexane solution) (7.3 ml), methyl cinnamate (3.4 g) and 1,3-dimethyl-2-imidazolidone (4.6 ml) affording the desired product (M+H)+ 389. Desulfurization was accomplished with Raney Nickel and EtOH, followed by hydrolysis to the desired carboxylic acid. Cyclization to the desired 5-methoxy-3-phenyl-1-tetralone was accomplished by heating with polyphosphoric acid, (M+H)+ 253.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[S:8](=O)[C:7]=2[CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si](Cl)(C)(C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[S:8][C:7]=2[CH:33]=1
Reactant: COC(=O)/C=C/c1ccc(OC2=C(c3ccc(OC)cc3)S(=O)c3cc(OC)ccc32)cc1
Agent: C[Si](C)(C)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(Oc2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Temperature: 75 °C
Yield: 58.1 %

Procedure:
To a 30 mL vial containing (E)-methyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (200 mg, 0.43 mmol) was added THF (5 mL), triphenylphosphine (420 mg, 1.60 mmol) and TMS-Cl (0.553 mL, 4.32 mmol). The reaction was heated to 75° C. for 18 h after which time the mixture was cooled to room temperature, quenched with sat. aq. NaHCO3 and diluted with DCM. The organic phase was collected (phase separator) and concentrated in vacuo to afford the crude product which was purified by column chromatography (SiO2, 0-60% EtOAc/Heptane) to afford (E)-methyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (110 mg, 0.25 mmol, 57% yield) as a white solid. 1H NMR (400 MHz, CDCl3) 8 ppm=7.58-7.73 (m, 3H), 7.38-7.50 (m, J=8.59 Hz, 2H), 7.28 (t, J=2.27 Hz, 2H), 6.96-7.05 (m, J=8.59 Hz, 2H), 6.85-6.96 (m, 3H), 6.32 (d, J=15.66 Hz, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.[CH3:10][NH2:11].CCO>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([NH:11][CH3:10])=[N:6][CH:7]=1
Reactant: Fc1cc(Br)cnc1F
Reactant: CN
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1ncc(Br)cc1F
Temperature: 100 °C

Procedure:
A mixture of 5-bromo-2,3-difluoropyridine (Matrix, Columbia, USA, 2.53 mmol) and 8 M methylamine in EtOH (Aldrich, Buchs, Switzerland, 2 ml, 16 mmol) was sealed in a vial and heated with microwave irradiation at 100° C. for 30 min. The cooled RM was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title product as an off-white solid. (HPLC: tR 1.94 min (Method A); M+H=205, 207, M−H=203, 205 MS-ES)