Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:18])[C:8]=1[O:9][C:10]([F:17])=[C:11]([F:16])[C:12]([F:15])([F:14])[F:13])[NH2:5].[F:19][C:20]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:21]=1[C:22]([N:24]=[C:25]=[O:26])=[O:23]>ClCCCl.ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:25]([NH:24][C:22](=[O:23])[C:21]2[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:20]=2[F:19])=[O:26])[CH:6]=[C:7]([Cl:18])[C:8]=1[O:9][C:10]([F:17])=[C:11]([F:16])[C:12]([F:14])([F:15])[F:13]
Reactant: Nc1cc(Cl)c(OC(F)=C(F)C(F)(F)F)c(Cl)c1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(OC(F)=C(F)C(F)(F)F)c(Cl)c1
Temperature: 40 °C

Procedure:
Dissolve 0.77 g 3,5-dichloro-4-(1,2,3,3,3-pentafluoropropenoxy) aniline in 8 mL 1,2-dichloroethane under an atmosphere of nitrogen at room temperature. Add 0.50 g 2,6-difluorobenzoyl isocyanate dissolved in 5.8 mL dichloroethane dropwise over a 10 minute period. Stir and warm to 40° C. for a 2 hour period. Chill in ice water bath and filter the white solid 0.93 g, mp 177°-80° C. Proton nmr and mass spectra were consistent with the proposed structure. Anal. calcd C17 H7Cl2F7N2O3 :C, 41.57; H, 1.44; N, 5.70. Found: C, 41.65; H, 1.31; N, 5.59.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][N:20]3[C:25]=2[C:24]([NH:26][C:27]2[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=2)[N:32]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=2)[N:31]=[CH:30]4)=[N:23][CH:22]=[N:21]3)[CH2:12][CH2:11]1.C(N(CC)CC)C>C(Cl)Cl>[F:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][N:32]1[C:33]2[C:29](=[CH:28][C:27]([NH:26][C:24]3[C:25]4=[C:17]([CH2:16][N:13]5[CH2:12][CH2:11][CH:10]([NH:9][C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[O:7])[CH2:15][CH2:14]5)[CH:18]=[CH:19][N:20]4[N:21]=[CH:22][N:23]=3)=[CH:35][CH:34]=2)[CH:30]=[N:31]1
Reactant: NC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)NC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 127.9 %

Procedure:
Acetoxyacetyl chloride (46 mg, 2 equiv) was added dropwise to a solution of [5-(4-amino-piperidin-1-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (47 mg, 0.1 mmole) (80 mg, 0.17 mmole) and triethylamine (71 μL, 3 equiv.) in dry DCM (3 mL) at 0° C. under nitrogen. After stirring at 0° C. for 3 hr and at RT for 1 hr, it was diluted with DCM, washed with water and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate, gradient elution with DCM containing 0 to 2% MeOH) afforded acetic acid (1-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}-piperidin-4-ylcarbamoyl)-methyl ester as a solid (73 mg, 75%). A solution of this ester in THF (0.4 mL) was treated with aq. NaOH (IN, 0.38 mL, 3 equiv.). After 2 hr at RT it was diluted with DCM, washed with water and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate employing gradient elution with DCM containing 0 to 3% MeOH) afforded the title compound as a solid (47 mg, 70%). MS: 529 (M+H)+; HPLC Ret Time: 1.37 min (YMC Xterra ODS S7 3.0×50 mm column, 2 min gradient, 5 ml/min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[C:1]([O:5][C:6]([N:8]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1coc(-c2ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cc(-c2nc(C(=O)O)co2)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
To a solution of ethyl 2-(2-((tert-butoxycarbonyl) (2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxylate (13 g) in ethanol (100 mL) was added 2M aqueous sodium hydroxide solution (30 mL). The reaction mixture was stirred at room temperature for 16 hr, diluted with water, acidified with 1M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diisopropyl ether, and dried under reduced pressure to give the title compound (10 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Li]CCCC.CN([CH:17]=[O:18])C>CCOCC>[Br:8][C:6]1[CH:7]=[C:2]([CH:17]=[O:18])[CH:3]=[N:4][CH:5]=1
Reactant: CN(C)C=O
Reactant: Brc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1cncc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,5-dibromopyridine (1.0 eq.) in Et2O (0.1M) at −78° C. was added n-BuLi (1.05 eq.). The mixture was stirred for 30 min at −78° C. then DMF (3.0 eq.) was added. The final mixture was warmed to rt, stirred for 3 h, quenched using saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 4:1) afforded the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][Cl:20].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:18][CH2:19][Cl:20])[N:11]=[C:10]([C:13]([F:14])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: ClCCBr
Reactant: FC(F)(F)c1cc(-c2ccc(Br)cc2)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(-c2ccc(Br)cc2)n(CCCl)n1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazole (2.05 g, 7 mmol) and 1-bromo-2-chloroethane (0.71 mL, 1.2 equiv) in DMF (30 mL) was added NaH (0.42 g, 60%, 1.5 equiv) and the mixture was stirred overnight at 20° C. The reaction was quenched by water. Solid was collected and washed by water and dried under high vacuum to give a crude, which was purified by column chromatography eluting with MeOH-DCM (6:96) to give 5-(4-bromophenyl)-1-(2-chloroethyl)-3-(trifluoromethyl)-1H-pyrazole (400 mg) as a minor product. 1H-NMR (CDCl3): δ 7.64 (d, 1H), 7.31 (d, 1H), 6.54 (s, 1H), 4.41 (t, 2H), 3.93 (t, 2H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1N1CCN(C(=O)c2cnc3c(C(=O)O)cnn3c2NCc2ccccc2)CC1
Reactant: CS(N)(=O)=O
Product: Cc1ccccc1N1CCN(C(=O)c2cnc3c(C(=O)NS(C)(=O)=O)cnn3c2NCc2ccccc2)CC1
Yield: 41.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(2-methylphenyl)piperazine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.149 g, 0.317 mmol) obtained in step 2 and methanesulfonamide (0.175 g, 1.82 mmol), the title compound (0.072 g, 41%) was obtained.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:19][OH:20].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[CH2:1]([C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][C:14](=[N:19][OH:20])[NH2:15])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NO
Reactant: CCCCCCCc1ccc(OCC#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCc1ccc(OCC(N)=NO)cc1
Yield: 99.8 %

Procedure:
30.6 g (0.13 mol) of 4-n-heptyl-phenoxy-acetonitrile, 18.1 g (0.26 mol) of hydroxylamine hydrochloride and 27.6 g (0.26 mol) of sodium carbonate are stirred at reflux temperature in 100 ml of ethanol and 200 ml of water until the reaction is complete (approximately 24 hours). The entire reaction batch is subsequently introduced into water, and the mixture is extracted using methylene chloride. 34.3 g (99.8% of theory) of 4-n-heptyl-phenoxy-acetamide oxime are obtained.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:12][C:13]1([CH2:29][OH:30])[CH2:18][CH2:17][N:16]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=2)=[O:20])[CH2:15][CH2:14]1>N1C=CC=CC=1>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[F:27])[C:19]([N:16]1[CH2:17][CH2:18][C:13]([CH2:29][O:30][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])([F:12])[CH2:14][CH2:15]1)=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(c1ccc(F)c(Cl)c1)N1CCC(F)(CO)CC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2(F)CCN(C(=O)c3ccc(F)c(Cl)c3)CC2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 75.3 %

Procedure:
4.87 g of para-toluenesulfonyl chloride (25.5 mmol) are slowly added to a solution of 6.70 g of (4-fluoro-4-hydroxymethylpiperidin-1-yl)-(3-chloro-4-fluorophenyl)methanone (23.12 mmol) in 40 ml of pyridine cooled to 0° C. and maintained under a nitrogen atmosphere. The mixture is stirred for 12 hours at room temperature and then it is poured into ice-cold water, extracted with chloroform and then the organic phase is washed with a 1N aqueous solution of hydrochloric acid. The organic phase is dried over magnesium sulfate, filtered and then concentrated under vacuum. The title product is purified by recrystallization from a dichloromethane/diisopropyl ether mixture. 7.73 g of a white crystalline powder are obtained.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=1.[C:32]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]O)#[N:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:32]([C:34]1[CH:35]=[C:36]([CH2:37][O:13][C:14]2[CH:15]=[C:16]([O:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH:39]=[CH:40][CH:41]=1)#[N:33]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: N#Cc1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCc2cccc(C#N)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
Diethyl azodicarboxylate (349 mg, 2.0 mmol) was added to a solution of 2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (900 mg, 3.0 mmol), as prepared in step (c) of Example 1, 3-cyanobenzyl alcohol (400 mg, 3.0 mmol; Yoon et al., J. Org. Chem. 38:2786-2792 (1973)), and triphenylphosphine (525 mg, 2.0 mmol) in tetrahydrofuran (20 mL) at 0° C. The mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with saturated NaHCO3 (2×50 mL), brine (2×50 mL) and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (2:1 ethyl acetate/hexane) to give the title compound as a white solid (1.10 g, 89%). 1H-NMR (300 MHz, CDCl3) δ 2.26 (s, 3 H), 4.99 (s, 2 H), 6.55 (t, 1 H, J=2.3 Hz), 6.60 (t, 1 H, J=0.7 Hz), 6.67 (t, 1 H, J=0.7 Hz), 7.39 (m, 1 H), 7.50 (t, 1 H, J=7.7 Hz), 7.61 (m, 5 H), and 7.96 (d, 1 H, J=1.3 Hz).
Reaction SMILES: [Cl-].[CH2:2]([NH:6][C:7]([CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])[CH2:3][CH2:4][CH3:5].C([Li])CCC.[Na+:34].[CH:35]([C:37]1[O:41][C:40]([S:42]([O-:45])(=[O:44])=[O:43])=[CH:39][CH:38]=1)=O>O1CCCC1>[Na+:34].[CH2:2]([NH:6][C:7]([CH:9]=[CH:35][C:37]1[O:41][C:40]([S:42]([O-:45])(=[O:44])=[O:43])=[CH:39][CH:38]=1)=[O:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCNC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(S(=O)(=O)[O-])o1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCNC(=O)C=Cc1ccc(S(=O)(=O)[O-])o1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 69.1 %

Procedure:
To a suspension of (N-n-butylcarbamoyl)methyltriphenylphosphonium chloride (16.63 g, 40.38 mmol), from Example B above, in tetrahydrofuran (200 mL) at 0-5° C. was added a solution of n-butyllithium in hexanes (18 mL, 2.5 M, 45 mmol). Upon addition of the n-butyllithium solution, the solution became homogeneous and the reaction mixture was stirred for 10 min at 5° C. 5-Formylfuran-2-sulfonic acid sodium salt (8.0 g, 40.38 mmol) was then added in one portion and the reaction mixture was stirred for 45 min at 0-5° C. and then at room temperature for 1.75 h. The mixture was filtered and the solid obtained was stirred with THF (100 mL) for several hours and then filtered. The solid was mixed with ethanol (200 mL) and filtered to remove the undissolved solid. Removal of solvent provided 8.24 g (69.1% yield) of the title compound as a slightly yellowish powder, m.p.=318.1° C. (dec) (Rf =0.55 on a silica gel plate using 2:1 EtOAc/EtOH). This product consisted of 70% trans-isomer and 30% cis-isomer.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH:9]([CH3:10])[CH2:8][N:7]([C:11](=[O:24])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)[CH2:6][CH2:5][NH:4]1.Cl[C:26]1[N:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:36])[CH:32]=2)[N:27]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:10][CH:9]1[CH:3]([CH3:2])[N:4]([C:26]2[N:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([F:36])[CH:32]=3)[N:27]=2)[CH2:5][CH2:6][N:7]([C:11](=[O:24])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)[CH2:8]1
Reactant: Fc1ccc2nc(Cl)ncc2c1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCNC(C)C(C)C2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCN(c3ncc4cc(F)ccc4n3)C(C)C(C)C2)c1
Temperature: 130 °C

Procedure:
Compound 1-7 (75 mg, 0.21 mmol) was combined with 2-chloro-6-fluoroquinazoline 1-8 (39 mg, 0.21 mmol; see example 1-D), triethylamine (30 uL, 0.21 mmol), and potassium carbonate (296 mg, 2.1 mmol) in toluene (2 mL) and heated in a sealed tube to 130° C. overnight. The reaction was concentrated in vacuo and the residue purified by reverse phase preparative chromatography on a C-18 column (5 to 75% acetonitrile in water with 0.1% TFA buffer). The clean fractions were combined and made basic with 20% sodium carbonate solution. This was extracted with ethyl acetate two times and the combined organics washed with brine and dried with sodium sulfate. Concentration in vacuo gave the titled compound as a solid. Data for 1-9: LC/MS: m/z (M+Na)=460.2 found; 460.5 calculated.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:38][O:39][C:40]1[CH:41]=[C:42]([CH2:48][CH2:49][NH2:50])[CH:43]=[CH:44][C:45]=1[O:46][CH3:47]>>[CH3:38][O:39][C:40]1[CH:41]=[C:42]([CH2:48][CH2:49][NH:50][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])[CH:43]=[CH:44][C:45]=1[O:46][CH3:47]
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C)c(OC)c2)C3)cc1OC

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 2-(3,4-dimethoxyphenyl)-ethylamine. Purification was performed using HPLC with a normal phase column. Elution with a mixture of etoxynonafluorobutane and methanol gave the title compound in 97% yield, m.p. 150-154° C. MS [(+)ESI,m/z]: 616.26 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.CN(C)C=O.[CH3:15][S:16]([O-:18])=[O:17].[Na+]>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: CS(=O)[O-]
Reactant: BrCc1ccc(Br)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Cc1ccc(Br)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
A 250 mL round-bottomed flask was charged with 4-bromobenzyl bromide (5 g, 20 mmol) and N,N-dimethylformamide (10.81 mL). Sodium methanesulfinate (3.06 g, 30 mmol) was added. The reaction mixture was stirred at 65° C. for 1 hour. The reaction mixture was cooled to ambient temperature and diluted with water. The resulting suspension was stirred for 10 minutes and filtered. The solid was rinsed with water and dried under vacuum to provide the title compound (4.75 g, 95% yield).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3]>C(OCC)(=O)C.[Pt]=O>[CH3:8][C@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH2:9][CH:10]=[O:11]
Reactant: CC(C)=CCC[C@@H](C)CC=O
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CC(C)CCC[C@@H](C)CC=O
Temperature: 25 °C
Reaction time: 124 h

Procedure:
A 3 L indented flask equipped with a mechanical stirrer and a H2 inlet was charged with 205.7 g (1.333 mol) of (R)-citronellal in 7.4 L of ethyl acetate. The flask was flushed with 0.1 cu. ft. of H2 and 0.50 g (2.0 mmol) of platinum oxide were added. The reaction was stirred under a slight over-pressure of H2 at ambient temperature for 124 hours. During this time, due to relatively rapid deactivation of the catalyst, an additional 3.50 g (143. mmol) of platinum oxide had to be added in 5 portions (0.5 g at 3.5 hours., 0.5 g at 22.5 hours., 1.0 g at 96.5 hours and 0.5 g at 121 hours). The course of the hydrogenation was monitored by GC analysis. After 124 hours, GC indicated the hydrogenation to be almost complete with 1.4% of starting material remaining. A total of 1.333 cu. ft. of hydrogen (theoretically 1.166 cu. ft.) had been consumed. The catalyst was removed by filtration through a pad of Celite (diatomeaceous earth). The clear filtrate was combined with the filtrate from a previous run, analogous reduction of 10.0 g (64.8 mmol) of (R)-citronellal and concentrated on the rotovapor. Vacuum distillation of the obtained pale yellow liquid through a 30 cm Goodloe column afforded the (R)-3,7-dimethyloctanal in following fractions:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH:16]([NH:22][C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33]C(OC(C)(C)C)=O)=[CH:29][CH:28]=2)=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][NH:25][C:23](=[O:24])[NH:22][CH:16]([CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:32][CH:31]=1
Reactant: CCOC(=O)C(Cc1cccc(OCc2ccccc2)c1)NC(=O)NCc1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(Cc1cccc(OCc2ccccc2)c1)NC(=O)NCc1ccc(N)cc1
Reaction time: 1 h
Yield: 91.3 %

Procedure:
161 (469 mg) was dissolved in 4 ml of DCM and 4 ml of TFA was added then the reaction mixture was let 1 h at room temperature. The reaction mixture is concentrated and 50 ml of AcOEt are added. The organic phase are washed with saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated to afford 162 as a white solid (350 mg, 91%). 1H NMR (DMSO): δ 1.28 (t, 3H, J=6.5 Hz), 3.04 (m, 2H), 4.13 (d, 2H, J=4.1 Hz), 4.19 (q, 2H, J=6.5 Hz), 4.56 (m, 1H), 5.02 (s, 2H), 5.21 (s, 2H), 6.29 (d, 1H, J=8.3 Hz), 6.45 (m, 1H), 6.62 (d, 2H, J=7.3 Hz), 6.89 (d, 1H, J=7.3 Hz), 7.00 (m, 3H), 7.33 (t, 1H, J=7.3 Hz), 7.53 (t, 1H, J=7.3 Hz), 7.57 (d, 1H, J=6.7 Hz). HPLC method B tr=21.65 nm (97.4%). ESI-MS m/z: 448.3 [M+H]+.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Cl[CH2:12][C:13]([O-:15])=[O:14].[Na+].Cl>CO.O>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: O=C([O-])CCl
Reactant: Nc1ccc(S)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(SCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.5 %

Procedure:
Into a 500 ml three-necked flask were charged 60 ml of water, 120 ml of methanol and 75 g of sodium hydroxide. 75 g of 4-aminothiphenol and 85 g of sodium chloroacetate were then slowly added to the mixture over an ice bath. Thereafter, the reaction mixture was allowed to cool to room temperature where it was then stirred for 6 hours. After reaction, concentrated hydrochloric acid was added dropwise to the reaction mixture over an ice bath until the pH value of the solution reached 1. As a result, precipitation of a solid matter was observed. The precipitate was filtered off, thoroughly washed with water, and then dried to obtain 95 g of 4-aminophenylsulfanylacetic acid (white powder).
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:33])[NH:12][CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[N:18]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:17]2=[O:32])(C)(C)C.CC#N>C(O)=O>[O:31]=[C:25]1[CH:24]([N:18]2[C:17](=[O:32])[C:16]3[C:20](=[CH:21][CH:22]=[C:14]([CH2:13][NH:12][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:34])=[O:5])=[O:33])[CH:15]=3)[C:19]2=[O:23])[CH2:29][CH2:28][C:27](=[O:30])[NH:26]1
Reactant: CC(C)(C)OC(=O)CCCCC(=O)NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CC#N
Solvent: O=CO
Product: O=C(O)CCCCC(=O)NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 88 %

Procedure:
A solution of 5-{[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-carbamoyl}-pentanoic acid tert-butyl ester (0.85 g, 1.8 mmol) in formic acid (25 mL) was stirred at room temperature for 90 minutes. The mixture was evaporated under vacuum, and the residue was triturated in ether/ethyl acetate and filtered, providing 0.66 g, in 88% yield; mp 144-146° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 4.15 (95.81%); 1H NMR (DMSO-d6) δ 1.44-1.59 (m, 4H), 2.02-2.09 (m, 1H), 2.16-2.24 (m, 4H), 2.46-2.63 (m, 2H), 2.83-2.95 (m, 1H), 4.43 (d, J=6.0 Hz, 2H), 5.14 (dd, J=12.9 Hz, J=5.4 Hz, 1H), 7.72-7.77 (m, 2H), 7.87 (d, J=7.8 Hz, 1H), 8.51 (t, J=6.0 Hz, 1H), 11.12 (s, 1H), 12.00 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 24.1, 24.7, 30.9, 33.3, 34.9, 41.9, 48.9, 121.9, 123.5, 129.7, 131.6, 133.3, 147.8, 167.0, 167.1, 169.8, 172.2, 172.7, 174.3; Anal. Calcd for C20H21N3O7+0.2H2O: C, 57.33; H, 5.13; N, 10.03. Found: C, 57.33; H, 4.89; N, 9.81.