Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCBr.[Mg].Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][CH2:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])=[CH:9][CH:8]=1.[CH2:21]([N:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH:30]([CH2:35][O:36][C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:21]([N:28]1[CH2:33][CH2:32][C:31]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14][CH2:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])=[CH:9][CH:8]=2)([OH:34])[CH:30]([CH2:35][O:36][C:37]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC[C@H](C)COCc1ccc(Br)cc1
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC[C@H](C)COCc1ccc(C2(O)CCN(Cc3ccccc3)CC2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.32 mmol of 1,2-dibromoethane are added to a suspension of 156.518 mmol of magnesium in 20 ml of tetrahydrofuran under argon at room temperature. The reaction mixture is warmed until the magnesium starts to react and then 3 ml of a solution of 151.509 mmol of 1-bromo-4-((S)-3-methoxy-2-methyl-propoxymethyl)-benzene in 170 ml of tetrahydrofuran, followed by the rest of the solution, is added while maintaining a gentle reflux. After 2 hours, the reaction mixture is cooled to room temperature and then a solution of 125.214 mmol of 1-benzyl-3-trityloxymethyl -piperidin-4-one [234757-27-8] in 170 ml of tetrahydrofuran is slowly added, taking care to keep the internal reaction temperature under 40° C. After overnight stirring at room temperature, the reaction mixture is quenched with saturated aqueous ammonium chloride solution. Ethyl acetate is added to the reaction mixture and the phases separated—the organic phase is washed successively with water and brine. The combined aqueous phases are back-extracted with ethyl acetate—the combined organic phases are dried with sodium sulfate and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound as a yellow oil. Rf=0.30 (EtOAc-heptane-25% ammonia conc. 100:100:1); Rt=5.43 (gradient I).
Reaction SMILES: ClC1C=CC=C(F)C=1C=O.ClC1C=CC=C(F)C=1C=C.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C@H:29]1[CH2:31][C@H:30]1[N:32]=[C:33]=[O:34].[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][N:37]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C@H:29]1[CH2:31][C@H:30]1[NH:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][N:37]=1)=[O:34]
Reactant: N#Cc1ccc(N)nc1
Reactant: O=C=N[C@@H]1C[C@@H]1c1c(F)cccc1Cl
Agent: C=Cc1c(F)cccc1Cl
Agent: O=Cc1c(F)cccc1Cl
Product: N#Cc1ccc(NC(=O)N[C@@H]2C[C@@H]2c2c(F)cccc2Cl)nc1

Procedure:
2-chloro-6-fluorobenzaldehyde (Aldrich), was converted to 2-chloro-6-fluorostyrene according to the method described in Example 377 of WO 93/03022 and then to cis-2-(2-chloro-6-fluorophenyl) cyclopropylisocyanate analogously to the method described in Example 348 of WO 93/03022. This compound was then condensed with 2-amino-5-cyanopyridine of Example 41 in a manner analogous to the method in Example 7 to provide N-(cis-2-(2-chloro-6-fluorophenyl)-cyclopropyl)-N'-(5-cyanopyrid-2-yl)-urea: Mp 189° C. 1H-NMR (250 MHz, DMSO-d6): 1.2 (m, 1H), 1.45-1.55 (m, 1H), 2.2-2.3 (m, 1H), 3.3-3.4 (m, 1H), 7.35-7.6 (m, 4H), 7.9-8.1 (m, 2H), 9.5 (s, 1H).
Reaction SMILES: Br.[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][CH2:6][C:7]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:11]2[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:10]=2[CH2:9][O:8]1.[NH3:26]>C(O)C.[Cu](Cl)Cl>[CH3:25][N:3]([CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:11]2[CH:12]=[CH:13][C:14]([C:16](=[NH:26])[NH2:17])=[CH:15][C:10]=2[CH2:9][O:8]1
Reactant: N
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Agent: Cl[Cu]Cl
Agent: Br
Solvent: CCO
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C(=N)N)ccc21
Temperature: 80 °C

Procedure:
A mixture of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile hydrobromide (citalopram hydrobromide, 300 mg, 1.0 equiv), copper(II) chloride (1.5 equiv) and ammonia (2.8 equiv) in ethanol (6 mL) was heated at 80° C. for 48 h. The mixture was cooled to room temperature and concentrated to dryness to give crude product (M/Z 342 [M++H]). This material was purified by re-suspending the crude product in fresh ethanol, filtration to remove insoluble material and slow evaporation under N2 to give the title product, 90 mg (23%) of a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].[F:16][C:17]([F:29])([F:28])[C:18]1[CH:19]=[C:20](O)[CH:21]=[CH:22][C:23]=1OCC.[C:30]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:31]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:30][CH2:31][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:28])[F:29])[CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CCOc1ccc(O)cc1C(F)(F)F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc(CCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)c1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
To a solution of 0.30 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 0.20 g of 3-(trifluoromethyl)phenetyl alcohol and 0.27 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran was added dropwise a solution of 0.21 g of diisopropylazodicarboxylate dissolved in 5 ml of tetrahydrofuran, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to obtain a residue. The residue was subjected to silica gel chromatography, which afforded 0.39 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(2-(3-(trifluoromethyl) phenyl)ethoxy)benzene (81% yield), nD26.0 1.5497.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:1][C:2]1([CH3:18])[C@H:17]2[C@H:9]([NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CC1(C)c2ccccc2-c2[nH]c3ccccc3c21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)c2ccccc2[C@H]2Nc3ccccc3[C@H]21
Reaction time: 0.5 h

Procedure:
5,10-Dihydro-10,10-dimethylindeno [1,2-b]indole (1.00 g, 4.29 mmol) was reacted with sodium cyanoborohydride (1.0 g, 16 mmol) in glacial acetic acid (20 cm3), for 10 minutes. The solution was poured into water, stirred for 30 minutes, and extracted into diethylether. The organic phase was washed 10 times with water, dried (Na2SO4), and the solvent removed in vacuo. The residue was dissolved in 5% ethylacetate/petrol (60°-80° C.) and filtered through a pad of "flash" silica, yielding, on removal of solvent, a gum which solidified on the oil pump, to give the title compound as a colourless solid. Yield: 0.98 g, (98%) M.p. 57°-59° C. 1H NMR (CDCl3) δ: 1.17 (3H, s,), 1.43 (3H, s,), 3.86 (1H, d,), 3.9 (1H, br,), 5.29 (1H, d,), 6.59 (1H, d,), 6.71 (1H, ddd,), 7.02 (1H, ddd,), 7.2-7.3 (5H, m,).
Reaction SMILES: [Li]CCCC.[CH2:6]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[I:17]I.O>O1CCCC1>[CH2:6]([C:12]1[O:13][C:14]([I:17])=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCc1ccco1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCc1ccc(I)o1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
A solution of n-BuLi (24.7 mL, 1.6 M in hexanes, 39.5 mmol, 1.4 equivalents) was added dropwise to a solution of 2-hexylfuran (4.3 g, 28.3 mmol) in dry tetrahydrofuran (THF, 50 mL) at −78° C. under N2. The reaction mixture was warmed to 0° C., stirred for 10 min and cooled again to −78° C. To this solution was added slowly iodine (9.3 g, 36.7 mmol) in 25 mL of THF, and the solution was warmed slowly to 0° C. and stirred for 2 h at 0° C. After addition of 100 mL of water, the solution was extracted with hexane. The organic layer was washed with aqueous Na2S2O3 solution (30 mL) and water, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (elution with hexane) to afford 6 g of 2-hexyl-5-iodofuran (76%) as a pale brownish oil. 1H NMR (300 MHz, CDCl3): δ6.37 (d, J=3.14 Hz, 1H), 5.88 (d, J=3.16 Hz, 1H), 2.60 (t, J=7.56, 7.56 Hz, 2H), 1.58 (td, J=15.11, 7.66, 7.66 Hz, 2H), 1.24-1.39 (m, 6H), 0.86 (t, J=6.77, 6.77 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 162.3, 120.6, 108.0, 84.3, 31.6, 28.8, 28.3, 27.8, 22.6, 14.1 ppm. HRMS (FD): m/z calcd for C10H15IO: 278.0168. Found 278.0172.
Reaction SMILES: [NH2:1][C:2]1([C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH2:6][CH:5]([O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])[CH2:4][CH:3]1[CH2:15][OH:16].[C:31]([N:39]=[C:40]=[S:41])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[Si:8]([O:7][CH:5]1[CH2:6][C:2]([NH:1][C:40]([NH:39][C:31](=[O:38])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[S:41])([C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH:3]([CH2:15][OH:16])[CH2:4]1)([C:11]([CH3:13])([CH3:12])[CH3:14])([CH3:9])[CH3:10]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cccc(-c2cccc(C3(N)CC(O[Si](C)(C)C(C)(C)C)CC3CO)c2)c1
Solvent: C1CCOC1
Product: COc1cccc(-c2cccc(C3(NC(=S)NC(=O)c4ccccc4)CC(O[Si](C)(C)C(C)(C)C)CC3CO)c2)c1
Yield: 77.5 %

Procedure:
A solution of (2-amino-4-(tert-butyldimethylsilyloxy)-2-(3′-methoxybiphenyl-3-yl)cyclopentyl)methanol (9.44 g, 22.1 mmol) and benzoyl isothiocyanate (3.49 g, 21.0 mmol) in THF (88 mL) is stirred for 1.5 hours at room temperature and concentrated under reduced pressure. The crude product is purified by silica gel chromatography eluting with a linear gradient of 0% to 5% methanol in dichloromethane over 27 minutes to give the title compound (9.61 g, 70%). ES/MS m/e: 589 (M−1).
Reaction SMILES: C[C:2]1(O)[CH:6]([CH3:7])[S:5](=[O:9])(=[O:8])[C:4]2[CH:10]=[CH:11][CH:12]=[CH:13][C:3]1=2.[NH:15]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]=[CH:16]1.[C:24]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl.O1CCOCC1>C1COCC1>[CH3:23][O:22][C:20]([C:18]1[N:17]([CH:2]2[C:6]([CH3:7])([CH3:24])[S:5](=[O:8])(=[O:9])[C:4]3[CH:10]=[CH:11][CH:12]=[CH:13][C:3]2=3)[CH:16]=[N:15][CH:19]=1)=[O:21]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC1C(C)(O)c2ccccc2S1(=O)=O
Reactant: COC(=O)c1c[nH]cn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1c2ccccc2S(=O)(=O)C1(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3,2-dimethyl-1,1-dioxo-2,3-dihydro-1H-1lambda*6*-benzo[b]thiophen-3-ol (3.1 g, 14.6 mmol) in THF (100 mL) is added methyl 4-imidazolecarboxylate (CAS#17325-26-7, 2.76 g, 2.1.9 mmol), and triphenylphosphine (5.73 g, 21.9 mmol). The reaction is cooled to 0° C. and di-t-butyl azodicarboxylate (5.04 g, 21.9 mmol) is added. The reaction is placed at room temperature and permitted to stir for three hours. The reaction mixture is cooled to 0° C. and quenched with 4 N HCl in dioxane (5 mL, 20 mmol) and stirred for 30 minutes. The reaction is concentrated to near dryness and diluted with ethyl acetate. The organic layer is extracted three times with 1 N aqueous HCl. The aqueous extracts are combined, neutralized with Na2CO3, and extracted three times with ethyl acetate. The combined organic layers are dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 3:7) to furnish 3-(2,2-dimethyl-1,1-dioxo-2,3-dihydro-1H-1lambda*6*-benzo[b]thiophen-3-yl)-3H-imidazole-4-carboxylic acid methyl ester; MS: (ESI) m/z 321 (M+H)+; 1H NMR: (400 MHz, CDCl3) δ ppm 1.18 (s, 3 H), 1.62 (s, 3 H), 3.96 (s, 3 H), 6.69 (s, 1 H), 7.29 (s, 1 H), 7.38-7.46 (m, 1 H), 7.68-7.76 (m, 2 H), 7.84 (s, 1 H), 7.91-7.97 (m, 1 H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24]C)[CH2:6][CH:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[NH:8]1.B(Br)(Br)[Br:27].CO>C(Cl)Cl>[BrH:27].[OH:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[OH:24])[CH2:6][CH:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[NH:8]1
Reactant: COc1ccc(CC2CCC(CCc3ccc(Cl)cc3)N2)cc1OC
Reactant: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Br
Product: Oc1ccc(CC2CCC(CCc3ccc(Cl)cc3)N2)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (-70° C.) solution of 24.2 g (0.67 mole) of 2-(3',4'-dimethoxybenzyl)-5-[2-(4-chlorophenyl)ethyl]pyrrolidine in 600 cc of methylene chloride was added dropwise 46.5 g (0.186 mole) of boron tribromide. After the addition the reaction mixture was gradually warmed to room temperature over a period of 2 hours. The mixture was cooled again to -70° C. and 300 ml of methanol was carefully added. Solvent was removed in vacuo. An additional 100 ml of methanol was added and removed in vacuo. The gummy residue was boiled in ethyl acetate and decanted, then triturated with ethyl acetate and left in the refrigerator overnight to give a solid. After recrystallization from a minimum amount of methanol there was obtained 7.05 g.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([OH:15])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2.Cl.[CH3:17][O:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH2:21].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[CH3:17][O:18][C:19](=[O:29])[C@@H:20]([NH:21][C:13]([C:3]1[C:2]([OH:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:12])[CH:4]=1)=[O:15])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1cc2cccc(O)c2cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1cc2cccc(O)c2cc1O
Yield: 60.5 %

Procedure:
A solution of 3,5-dihydroxy-2-naphthoic acid (4.08 g), L-phenylalanine methyl ester hydrochloride (4.74 g), WSC.HCl (4.22 g), HOBT (2.97 g) and N-methylmorpholine (2.41 ml) in DMF (200 ml) was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous citric acid solution, water, a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1 v/v) to give the title compound (4.42 g, yield 61%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:17][CH:18]=[C:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]([OH:17])=[C:10]2[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: O=C1CNCCN1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccccc1)CC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 1-benzylpiperazin-2-one (0.29 g, 1.54 mmol) and diethyl ethoxymethylenemalonate (0.35 g, 1.63 mmol) in toluene was heated in a sealed tube at 80° C. for 4 hours. The resultant mixture was concentrated under vacuum. The residue was dissolved in anhydrous DMF (10 mL), cooled to 0° C. under an atmosphere of nitrogen, and treated with a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 2.0 mL, 2.0 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was partitioned between ethyl acetate and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with diethyl ether, and the solid precipitated was filtered to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:41]2[CH:45]=[CH:44][S:43][C:42]=2[CH:46]=[O:47])O1>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:41]2[CH:45]=[CH:44][S:43][C:42]=2[CH:46]=[O:47])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(I)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CC1(C)OB(c2ccsc2C=O)OC1(C)C
Product: COc1cc(-c2csc3c(-c4ccsc4C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
N-[4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carbaldehyde were reacted together according to general procedure A to furnish the title compound. LCMS (Conditions a): MH+=539.0, RT=4.10 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.77 (s, 1H), 9.53 (s, 1H), 8.29 (d, J=5.3 Hz, 1H), 7.98 (m, 2H), 7.63 (m, 6H), 7.36 (m, 1H), 7.24 (s, 1H), 7.15 (m, 1H), 5.85 (br, 2H), 4.04 (s, 3H), 3.92 (s, 3H).
Reaction SMILES: C(Br)CCC.FC1C=CC=CC=1C1C2C=C([N+]([O-])=O)C=CC=2N(C)C(=O)C(C)(C)N=1.C([N:35]1[C:41]2[CH:42]=[CH:43][C:44]([N+:46]([O-:48])=[O:47])=[CH:45][C:40]=2[C:39]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:55])=[N:38][C:37]([CH3:57])([CH3:56])[C:36]1=[O:58])CCC>CCOCC.CCCCCC>[Cl:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[C:39]1[C:40]2[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:41]=2[NH:35][C:36](=[O:58])[C:37]([CH3:57])([CH3:56])[N:38]=1
Reactant: CCCCN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc21
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCCCBr
Product: CC1(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O

Procedure:
From 25 g (0.073 mol) of 5-(o-chlorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one and n-butyl bromide there is obtained, in analogy to the details in paragraph (c) of Example 1, with a reaction period of 4 days, 1-butyl-5-(o-chlorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 129° (ether/n-hexane).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]1[CH2:11][C@H:10]2[CH:12]([NH2:15])[CH2:13][CH2:14][C@H:9]2[CH2:8]1.C(N(CC)CC)C.[F:28][C:29]([F:41])([F:40])[C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>ClCCl>[F:41][C:29]([F:28])([F:40])[C:30]1[CH:31]=[C:32]([S:36]([NH:15][C@@H:12]2[C@H:10]3[C@H:9]([CH2:8][N:7]([CH2:6][C:5]4[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:19])([F:1])[F:20])[CH:4]=4)[CH2:11]3)[CH2:14][CH2:13]2)(=[O:37])=[O:38])[CH:33]=[CH:34][CH:35]=1
Reactant: NC1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@@H]12
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (3aS*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E (200 mg, 0.703 mmol) in dichloromethane (2 mL) was added triethylamine (0.147 mL, 1.055 mmol) followed by 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.124 mL, 0.774 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with dichloromethane. The organics were reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-24). The title compounds were eluted with a gradient of 0% to 10% methanol (2 N ammonia)/dichloromethane over 20 minutes.
Reaction SMILES: CC(C)=O.[CH3:5][O:6][C:7](=[O:39])[CH2:8][N:9]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]([OH:38])[C:27]1[CH:35]=[C:34]([O:36][CH3:37])[C:30]2[O:31][CH2:32][O:33][C:29]=2[CH:28]=1)(=[O:19])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>C(OCC)(=O)C>[CH3:5][O:6][C:7](=[O:39])[CH2:8][N:9]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([C:27]1[CH:35]=[C:34]([O:36][CH3:37])[C:30]2[O:31][CH2:32][O:33][C:29]=2[CH:28]=1)=[O:38])(=[O:18])=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]
Reactant: COC(=O)CN(c1ccccc1C)S(=O)(=O)c1ccccc1C(O)c1cc(OC)c2c(c1)OCO2
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COC(=O)CN(c1ccccc1C)S(=O)(=O)c1ccccc1C(=O)c1cc(OC)c2c(c1)OCO2
Reaction time: 0.25 h
Yield: 59 %

Procedure:
To acetone (225 mL) was added ({2-[hydroxy-(7-methoxy-benzo[1,3]dioxol-5-yl)-methyl]-benzenesulfonyl}-o-tolyl-amino)-acetic acid methyl ester (4.17 g, 8.35 mmol), and 8N Jones reagent (4 mL). The mixture was stirred 15 minutes giving a suspended solid. Isopropanol (20 mL) was added followed by stirring for 15 minutes. The mixture was filtered, saturated sodium bicarbonate solution was added, and the solvent was removed in vacuo giving a paste. The paste was resuspended in ethyl acetate and water, filtered, and washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. The solution was filtered and evaporated to a solid which was crystallized from ethyl acetate and ethyl ether giving a white solid, 2.41 g, 59% yield, mp 159-170° C. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1.CCOCC>[C:4]1([C:2](=[CH2:3])[C:1]([NH:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:11])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NCc1ccccc1
Reactant: C=C(C(=O)O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: C=C(C(=O)NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
A stirred solution of atropic acid (10.3 g, 69.5 mmol) in dry tetrahydrofuran (100 ml) was treated under nitrogen with N-methylmorpholine (7.7 ml, 70.0 mmol), cooled to -10°, treated dropwise with iso-butylchloroformate (9 ml, 69.4 mmol), treated dropwise with benzylamine (7.6 ml, 69.6 mmol), warmed to room temperature over 1 hour, filtered and evaporated in vacuo to give a yellow oil which was dissolved in ether (100 ml). The solution was washed with 0.1N-HCl (200 ml), brine (100 ml), 0.1N-NaOH (100 ml) and brine (100 ml), dried (MgSO4), and evaporated in vacuo to give a yellow liquid. Purification by chromatography (silica; di-iso-propyl ether) gave the product as white crystals (7.3 g), m.p. 84°-86° (from di-iso-propyl ether).