Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1([C:6]2[CH2:14][CH2:13][C:12]3([C:15]([O:17][CH3:18])=[O:16])[C:8](=[CH:9][CH2:10][CH2:11]3)[CH:7]=2)CCCC1.C([O-])(=[O:21])C.[Na+]>C1(C)C=CC=CC=1.CC(O)=O.O.CCOC(C)=O>[O:21]=[C:6]1[CH:7]=[C:8]2[C:12]([C:15]([O:17][CH3:18])=[O:16])([CH2:11][CH2:10][CH2:9]2)[CH2:13][CH2:14]1
Reactant: COC(=O)C12CCC=C1C=C(N1CCCC1)CC2
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C12CCCC1=CC(=O)CC2
Yield: 48.3 %

Procedure:
The crude enamine from Step 2 was dissolved in toluene (20 mL) and a solution of sodium acetate (1.360 ml, 25.3 mmol) in AcOH/water (4/4 mL) was added and the resulting mixture was heated to reflux under N2 atmosphere for 2 h. The reaction went to completion, diluted with EtOAc, washed with water, sat. NH4Cl, sat. NaHCO3, brine, dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-30% heptane/EtOAc to afford methyl 6-oxo-2,3,3a,4,5,6-hexahydro-1H-indene-3a-carboxylate (1.32 g, 6.80 mmol, 48.3% yield) as a bright yellow oil. MS m/z=195.2 [M+H]+.
Reaction SMILES: [C:1](O)(=O)CCCCCCCC(O)=O.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:1])=[O:23]
Reactant: O=C(O)CCCCCCCC(=O)O
Reactant: O=C(O)CCCCCCCBr
Product: COC(=O)CCCCCCCBr

Procedure:
Methyl 8-bromooctanoate is prepared from azelaic acid essentially as described in U.S. Pat. No. 3,852,419, or by direct esterification of 8-bromooctanoic acid as follows:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16]C2C3C(=C(Br)C=CC=3)C=CC=2OC)[C:12]2[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)N[C@@H]1C(=O)NC2C=CC=CC=2NC1)(C)(C)C.BrC[C:57]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[N:59]([C:66]2[CH:73]=[CH:72][CH:71]=[CH:70][C:67]=2[C:68]#[N:69])[N:58]=1>>[C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:57]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[N:59]([C:66]3[CH:73]=[CH:72][CH:71]=[CH:70][C:67]=3[C:68]#[N:69])[N:58]=2)[C:12]2[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=2[NH:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccccc1-n1nc(CBr)c2ccccc21
Reactant: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Agent: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(Cc2nn(-c3ccccc3C#N)c3ccccc23)C1=O
Yield: 72.9 %

Procedure:
In a similar manner to that described for the preparation of [(S)-1-(5-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester (Intermediate 5), ((S)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester (Intermediate 2)(500 mg, 1.8 mmol) and 2-(3-bromomethyl-indazol-1-yl)-benzonitrile (Intermediate 1) (676.18 mg, 2.16 mmol) were converted to the title compound (670 mg, 72.9%) which was obtained as light yellow solid. LC-MS: 509 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[F:35][C:36]1[CH:37]=[C:38]([OH:42])[CH:39]=[CH:40][CH:41]=1>>[Cl:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][C:23]=2[O:42][C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([F:35])[CH:37]=2)[CH:17]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:34])=[C:8]([CH3:33])[CH:9]=1
Reactant: Oc1cccc(F)c1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(Cl)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2cc(Cl)cc(Oc3ccc(C(F)(F)F)cc3Oc3cccc(F)c3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepare by reacting the compound of 3-{4-[3-(2-Bromo-4-trifluoromethyl-phenoxy)-5-chloro-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 3-fluorophenol as in Example 45 to afford 0.025 g (23%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H21O5F4Cl 560, found 578 and 580 (M+NH4, 100%).
Reaction SMILES: [CH2:1]([CH2:8][CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O)(=O)=O.[C:16]([C-:18]([C:21]#[N:22])[C:19]#[N:20])#[N:17].[K+]>>[NH2:22][C:21]([NH:10][CH2:9][CH2:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:18]([C:19]#[N:20])[C:16]#[N:17]
Reactant: N#C[C-](C#N)C#N
Reactant: NCCCc1ccccc1
Agent: CS(=O)(=O)O
Agent: [K+]
Product: N#CC(C#N)=C(N)NCCCc1ccccc1
Yield: 70.8 %

Procedure:
In a similar manner 27.4 g of benzylethylamine and 13 ml (19.2 g) of methanesulfonic acid were allowed to react. The resulting salt was treated with 25.8 g of potassium tricyanomethanide to yield an additional 32 g of 3-amino-3-(benzylethylamino)-2-cyanopropenenitrile, mp 165°-167°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:36][CH2:37][CH2:38][CH2:39][C:40]([NH:42][CH3:43])=[O:41])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([NH:17][C@@H:18]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:19][N:20](C)[C:21](=O)OC(C)(C)C)=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:36][CH2:37][CH2:38][CH2:39][C:40]([NH:42][CH3:43])=[O:41])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([NH:17][C@H:18]([CH2:19][NH:20][CH3:21])[CH2:29][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)CCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCCC(=O)NC)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
tert-butyl (S)-2-((R)-3-((R)-(3-chlorophenyl)(4-(methylamino)-4-oxobutoxy)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate (50 mg, 0.08 mmol) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (10 mL). The reaction mixture was stirred at rt for 1 h, a solution of saturated sodium bicarbonate was added dropwise to adjust pH=7-8. The resulting mixture was extracted with CH2Cl2 (3×15 mL), washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative HPLC to afford (R)-3-((R)-(3-chlorophenyl)(4-(methylamino)-4-oxobutoxy)methyl)-N—((S)-1-cyclohexyl-3-(methylamino)propan-2-yl)piperidine-1-carboxamide (3.30 mg, yield 8%). 1H NMR (CD3OD, 400 MHz) δ 7.30-7.34 (m, 3H), 7.20 (d, 1H), 4.30 (d, 1H), 4.05 (m, 1H), 3.97 (m, 2H), 2.76 (m, 3H), 2.69 (s, 3H), 2.53 (s, 3H), 2.27 (m, 3H), 1.83 (m, 3H), 1.71 (m, 5H), 1.13-1.28 (m, 10H), 0.89 (m, 4H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31][C:32]1[S:44][C:35]2=[N:36][C:37]([Cl:43])=[C:38]([C@H:40](O)[CH3:41])[CH:39]=[C:34]2[CH:33]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:31][C:32]1[S:44][C:35]2=[N:36][C:37]([Cl:43])=[C:38]([C@@H:40]([N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])[CH3:41])[CH:39]=[C:34]2[CH:33]=1
Reactant: C[C@@H](O)c1cc2cc(Cl)sc2nc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](c1cc2cc(Cl)sc2nc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a reaction flask was combined phthalimide (1.530 g, 10.40 mmol), triphenylphosphine (2.73 g, 10.40 mmol), (R)-1-(2,6-dichlorothieno[2,3-b]pyridin-5-yl)-ethanol (2.15 g, 8.66 mmol) and tetrahydrofuran (57.8 mL). The reaction was cooled to 0° C. and diisopropyl azodicarboxylate (2.043 mL, 10.40 mmol) was added dropwise. The reaction was removed from the ice bath and allowed to warm to rt and stir overnight. The reaction was diluted with ethyl acetate and washed with NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated. Purification using 5-10% ethyl acetate in hexanes afforded (S)-2-(1-(2,6-dichlorothieno[2,3-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione. 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.82 (m, 2H), 7.73*m, 2H), 7.18 (s, 1H), 5.90 (q, 7.3 Hz, 1H), 1.90 (d, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].I[C:23]1[C:27]([CH2:28][N:29]([CH3:41])[CH2:30][CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:26][N:25]([CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[N:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC>[CH3:12][CH:10]([C:8]1[CH:7]=[C:6]([C:23]2[C:27]([CH2:28][N:29]([CH3:41])[CH2:30][CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:26][N:25]([CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)[N:24]=2)[CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:9]=1)[CH3:11]
Reactant: CC(C)c1cc(B2OC(C)(C)C(C)(C)O2)cc(C(C)C)c1
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)c1cc(-c2nn(C3CCCCO3)cc2CN(C)CCN(C)C(=O)OC(C)(C)C)cc(C(C)C)c1
Temperature: 25 °C
Yield: 19.5 %

Procedure:
A mixture of 2-(3,5-diisopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (288 mg, 1.00 mmol, 1.00 equiv), tert-butyl N-[2-([[3-iodo-1-(oxan-2-yl)-1H-pyrazol-4-yl]methyl](methyl)amino)ethyl]-N-methylcarbamate (479 mg, 1.00 mmol, 1.00 equiv), K3PO4 (636 mg, 3.00 mmol, 3.00 equiv) and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (65 mg, 0.10 mmol, 0.10 equiv) in ethylene glycol dimethyl ether (5 mL) was stirred under nitrogen in a 10-mL sealed tube for 12 h at 85° C. The resulting mixture was cooled to room temperature and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (39:1 with 0.1% triethylamine) to obtain 100 mg (20%) of tert-butyl N-[2-[([3-[3,5-bis(propan-2-yl)phenyl]-1-(oxan-2-yl)-1H-pyrazol-4-yl]methyl)(methyl)amino]ethyl]-N-methylcarbamate as a black solid. 1H NMR (300 MHz, DMSO-d6): δ 7.83 (s, 1H), 7.49 (s, 2H), 7.07 (s, 1H), 5.45-5.35 (m, 1H), 4.01-3.88 (m, 1H), 3.71-3.60 (m, 1H), 3.40 (s, 2H), 3.24 (s, 2H), 3.00-2.80 (m, 2H), 2.68 (s, 3H), 2.49-2.40 (m, 2H), 2.23 (s, 3H), 2.15-1.85 (m, 3H), 1.80-1.60 (m, 1H), 1.31 (s, 9H), 1.23 (d, J=6.9 Hz, 12H) ppm. LCMS (method D, ESI): RT=1.41 min, m/z=513.5 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH:6]1[CH2:8][CH2:7]1)=[O:4].[P:9]([O:16]CC)([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>>[CH2:11]([O:10][P:9]([CH2:2][C:3](=[O:4])[NH:5][CH:6]1[CH2:8][CH2:7]1)(=[O:16])[O:13][CH2:14][CH3:15])[CH3:12]
Reactant: O=C(CCl)NC1CC1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CC(=O)NC1CC1)OCC
Temperature: 155 °C
Yield: 14.7 %

Procedure:
2-Chloro-N-cyclopropylacetamide (20 g, 0.15 moles) was added in portions with stirring to triethyl phosphite (28 g, 0.17 moles, Aldrich) at 110° C. The solution was then heated to 155° C. for 30 minutes, cooled to 125° C., and the volatiles were removed by distillation under aspirator vacuum (15 mm Hg) at this temperature. The residual oil was stirred with pentane (200 mL) while cooling in an ice bath to induce crystallization. Filtration gave 5.2 g (14%) of diethyl((cyclopropylcarbamoyl)methyl)phosphonate as white crystals; m.p. 51°-56° C. The liquor was concentrated and cooled to give 25.3 g (71%) of a second crop; m.p. 50°-56° C. Recrystallization from dichloromethane/hexanes gave the analytical sample, m.p. 55°-57° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:36])[CH2:16][NH:17][CH:18]([CH3:35])[CH2:19][C:20]2[CH:34]=[CH:33][C:23]3[O:24][C:25]([C:30](O)=[O:31])([C:27]([OH:29])=[O:28])[O:26][C:22]=3[CH:21]=2)[CH:12]=[CH:13][CH:14]=1.[K+].[Br-].Cl>>[OH:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][O:5][C:30]([C:25]1([C:27]([O:29][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][OH:1])=[O:28])[O:24][C:23]2[CH:33]=[CH:34][C:20]([CH2:19][C@H:18]([NH:17][CH2:16][C@@H:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=3)[OH:36])[CH3:35])=[CH:21][C:22]=2[O:26]1)=[O:31]
Reactant: CC(C)(CO)CO
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC(C)(C)CO)(C(=O)OCC(C)(C)CO)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid 3-hydroxy-2,2-dimethyl-propanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) δ0.78 (s, 12H, 4×CH3), 1.09 (d, J=6.4 Hz, 3H, CH3), 2.6 (m, 1H, CH), 3-3.3 (m, 7H, CH, CH2), 3.4 (brs, 1H, CH), 4.04 (s, 4H, OCH2, OCH2),4.65 (m, 2H, OH), 5.05 (m, 1H, CH), 6.34 (d, J=4.17 Hz, 1H, OH), 6.85 (dd, J=7.9, 1.53 Hz, 1H, Ar--H), 7.07 (m, 2H, Ar--H), 7.37-7.42 (m, 3H, Ar--H), 7.48 (s, 1H, Ar--H), 8.78 (brs, 1H, NH), 9.2 (brs, 1H, NH); IR (KBr, cm-1) 3400 (OH), 2900 (NH), 1760 (CO); MS m/e 594 (M+H)+ ; Analysis for: C30H40ClNO9 ×HCl: Calc'd: C, 57.14; H, 6.55; N, 2.22; Found: C, 56.44; H, 6.62; N, 2.38.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:42])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:41])[CH2:32][NH:33]C(=O)OC(C)(C)C)[CH:25]=3)=[CH:15][CH:14]=2)[N:7]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][CH2:32][C:31]([NH:30][C:26]1[CH:25]=[C:24]([O:23][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]([NH:12][C:11]([NH:10][C:8]3[N:7]([C:43]4[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=4)[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=3)=[O:42])=[CH:14][CH:15]=2)[CH:29]=[CH:28][N:27]=1)=[O:41]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(NC(=O)CNC(=O)OC(C)(C)C)c3)c3ccccc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(NC(=O)CN)c3)c3ccccc23)cc1
Temperature: 0 °C

Procedure:
To a stirred solution of tert-butyl 2-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-ylamino)-2-oxoethylcarbamate (187 mg, 92% pure, 0.259 mmol) in dry DCM (6 mL) 0° C. under nitrogen was added TFA (2.0 mL) and the reaction mixture maintained at 0° C. for 20 min and then warmed to RT for 3 hr. The resulting mixture was evaporated in vacuo and the residue was purified by SCX capture and release to afford the title compound, Intermediate G1, as a brown solid (130 mg, 87%); Rt 1.82 min (Method 2); m/z 564 (M+H)+ (ES+).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32][CH2:33][NH2:34])=[O:6])[CH:2]=[CH2:3].[Cl-:35].[N+]([C:39]1[CH:44]=[C:43]([N+]([O-])=O)C=[CH:41][C:40]=1[N+]1C=CC=CC=1)([O-])=O>C(O)CCC>[Cl-:35].[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32][CH2:33][N+:34]1[CH:43]=[CH:44][CH:39]=[CH:40][CH:41]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: O=[N+]([O-])c1ccc(-[n+]2ccccc2)c([N+](=O)[O-])c1
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CCN
Agent: [Cl-]
Solvent: CCCCO
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC[n+]1ccccc1
Yield: 84.2 %

Procedure:
A solution of (2R,4S)-1-allyloxycarbonyl-2-(2aminoethyl)4-(triphenylmethylthio) pyrrolidine (5.78 g) and 1-(2,4-dinitrophenyl)pyridinium chloride (4.19 g) in n-butanol (60 ml) was stirred under reflux condition for 4 hours, and then evaporated under reduced pressure. The residue was column chromatographed on silica gel (chloroform:methanol=5:1 to 4:1) to give (2R,4S)-1-allyloxycarbonyl-2-{2-(1-pyridinio)ethyl}-4(triphenylmethylthio)pyrrolidine chloride (5.88 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([Cl:11])=[C:5]([OH:10])[C:6]([CH3:9])=[CH:7][CH:8]=1.Cl.Cl.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]2)=[CH:17][CH:16]=1.[OH-].[NH4+].OO>O.C(O)C>[NH2:2][C:3]1[C:8](=[N:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[C:6]([CH3:9])[C:5](=[O:10])[C:4]=1[Cl:11]
Reactant: Cc1ccc(N)c(Cl)c1O
Reactant: Nc1ccc(N2CCC(O)C2)cc1
Agent: Cl
Agent: OO
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC1=CC(=Nc2ccc(N3CCC(O)C3)cc2)C(N)=C(Cl)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
1.94 g of 3-amino-2-chloro-6-methylphenol hydrochloride are added to 2.51 g of 1-(4-aminophenyl)pyrrolidin-3-ol dihydrochloride in solution in 20 ml of water and 20 ml of ethanol. The pH is adjusted to 9.5 with 20% ammonium hydroxide and then 18 ml of 9% aqueous hydrogen peroxide solution are added. The mixture is left stirring at ambient temperature for 8 hours and then the precipitate formed is filtered off. 2.79 g of 3-amino-2-chloro-4-{[4-(3-hydroxypyrrolidin-1-yl)phenyl]imino}-6-methylcyclohexa-2,5-dien-1-one (11) are thus obtained.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[C:9](B(O)O)=[CH:8][CH:7]=[CH:6][N:5]=1.Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:2][O:3][C:4]1[C:9]([C:14]2[CH:15]=[C:16]([NH2:17])[CH:18]=[CH:19][CH:20]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: COc1ncccc1B(O)O
Reactant: Nc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ncccc1-c1cccc(N)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
2-methoxypyridine-3-boronic acid hydrate (0.133 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in DME (3 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.610 mL, 1.22 mmol) and Pd(PPh3)4 (0.02 g, 0.017 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (10-100% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.092 g in 80% yield.
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[C]=O.[CH2:13]([NH2:16])[CH:14]=[CH2:15].[C:17]1([CH3:23])C=CC=C[CH:18]=1>>[CH2:13]([NH2:16])[CH:14]=[CH2:15].[NH2:16][CH:17]([CH3:23])[CH2:18][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2]
Reactant: CCO[SiH](OCC)OCC
Reactant: Cc1ccccc1
Agent: [C]=O
Solvent: C=CCN
Product: CCO[Si](CC(C)N)(OCC)OCC
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A 200 ml. flask equipped with a stirrer, thermometer, dropping funnel, CO inlet tube and reflux condenser having a CO outlet tube, was charged with 41 grams of triethoxy silane (0.25 mole), 1.9 milligrams of tetrahodium dodecacarbonyl (2.5×10-6 mole) and 30 ml. of toluene. While passing carbon monoxide through the flask at a rate of 10 ml./min., the mixture was heated to a temperature of 110° C. under stirring. To the mixture 14 grams of allylamine (0.25 mole) was dropwise added in 2 minutes. After the addition of the allylamine the CO flush, heating and stirring were continued for 30 minutes. It was revealed by gas chromatography that gamma-aminopropyl triethoxy silane was obtained in a yield of 62% on an allylamine basis, while the yield of beta-aminopropyl triethoxy silane was 4% on an allylamine basis.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:14][NH2:15]>C(O)C>[CH3:10][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:15][N:14]=1
Reactant: NN
Reactant: CC(=O)CC(=O)c1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2ccccc2)[nH]n1
Yield: 80 %

Procedure:
To a solution of 1-phenylbutane-1,3-dione (5.0 g, 30.8 mmol) in ethanol (50 mL), was added hydrazine hydrate (1.54 g, 30.8 mmol) at ambient temperature. The reaction was refluxed for 5 h. After cooling, the reaction was concentrated under reduced pressure and extracted with ethyl acetate. The extract was dried over MgSO4 and concentrated under reduced pressure. The residue was added 10% ethyl acetate in hexane. The precipitate was filtered and washed with hexane. The white solid was dried in air to give the title compound (3.9 g). LCMS m/z=159.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H), 6.65 (s, 1H), 7.34 (m, 1H), 7.42 (m, 2H), 7.82 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)=[C:4]([C:7](OCC)=[O:8])[NH:5][CH:6]=1>CC(O)=O.[Fe]>[CH3:1][C:2]1[C:3]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]=[C:7]([OH:8])[C:4]=2[NH:5][CH:6]=1
Reactant: CCOC(=O)c1[nH]cc(C)c1-c1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1c[nH]c2c(O)nc3ccccc3c12
Temperature: 100 °C
Yield: 86.5 %

Procedure:
A solution of ethyl 4-methyl-3-(2-nitrophenyl)-1H-pyrrole-2-carboxylate (3.2 g, 11.67 mmol) in AcOH (117 mL) was treated at 20° C. with iron dust (6.52 g, 117 mmol). The reaction mixture was heated at 100° C. for 3 h. The white precipitate was removed by filtration, and the filtrates were concentrated to give a residue that was purified on silica gel (gradient elution, 50-100% MeOH/acetone) to afford the title compound (2.0 g, 86%) as a solid. LCMS (ES+) m/z 199 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[C:8]([C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[C:15](Cl)=[O:16])([CH3:11])([CH3:10])[CH3:9].[OH-].[Na+]>C(Cl)Cl.O>[C:22]([C:19]1[CH:18]=[C:14]([CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:20]=1[OH:21])[C:15]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[O:16])([CH3:25])([CH3:24])[CH3:23]
Reactant: CN(C)CCCO
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CN(C)CCCOC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.8 %

Procedure:
A solution of 41.3 g (400 mmol) of 3-dimethylaminopropanol in 200 ml of methylene chloride was added to a solution of 107.3 g (400 mmol) of 3,5-di-tert-butyl-4-hydroxybenzoyl chloride prepared as described in Example 1 in 400 ml of methylene chloride over a period of seven minutes. The reaction was exothermic. The reaction mixture was stirred for 90 minutes at room temperature and then washed with a solution of 16.0 g (400 mmol) of NaOH in 600 ml of water and then with water. The solution was dried over magnesium sulfate and concentrated to a residue on a rotary evaporator. The residue was then heated to reflux in 800 ml of heptane and filtered through supercel. The filtrate was cooled and the white solid was collected, washed with heptane and dried to give 92.3 g (68.8% of theory) of 3-dimethylaminopropyl 3,5-di-tert-butyl-4-hydroxybenzoate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:8])[CH2:5][CH2:6][OH:7].S=[C:10]1[CH2:14][S:13][C:12](=[O:15])[NH:11]1>C(O)C>[OH:7][CH2:6][CH2:5][N:4]([CH3:8])[CH2:3][CH2:2][NH:1][C:10]1[CH2:14][S:13][C:12](=[O:15])[N:11]=1
Reactant: CN(CCN)CCO
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: CN(CCO)CCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98 %

Procedure:
To a solution of 2-[(2-aminoethyl)(methyl)amino]ethanol (1.00 g) in ethanol (30 mL) was added 4-thioxo-1,3-thiazolidin-2-one (1.07 g). The reaction mixture was stirred at room temperature for 3 days, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (1.71 g).