Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]=[C:4]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:7][CH2:6][N:5]1[CH2:16][C:17]([C:19]1[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=1)=[O:18].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.Cl[C:49]([O:51][CH:52]([Cl:56])[CH:53](C)C)=[O:50]>C(Cl)Cl.C(OCC)(=O)C.O>[Cl:56][CH:52]([O:51][C:49]([N:13]1[CH2:12][CH2:11][CH:10]([N:8]2[CH2:7][CH2:6][N:5]([CH2:16][C:17]([C:19]3[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=3)=[O:18])[C:4](=[O:3])[CH2:9]2)[CH2:15][CH2:14]1)=[O:50])[CH3:53]
Reactant: CC(C)C(Cl)OC(=O)Cl
Reactant: CCOC(=O)COc1ccc(C(=O)CN2CCN(C3CCNCC3)CC2=O)cc1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(C(=O)CN2CCN(C3CCN(C(=O)OC(C)Cl)CC3)CC2=O)cc1
Temperature: -40 °C
Reaction time: 0.08 h
Yield: 77.7 %

Procedure:
To a solution of 0.75 g of ethyl 4-[[2-oxo-4-(piperidin-4-yl)-piperazin-1-yl]acetyl]phenoxyacetate dihydrochloride synthesized according to the method described in WO962503 in 16 ml of methylene chloride was added 1.11 g of proton sponge under ice-cooling. After stirring for 5 minutes, the mixture was cooled to −40° C., and a solution of 0.322 g of 1-chloro-2-methylpropyl chloroformate in 2 ml of methylene chloride. After stirring for 45 minutes, the reaction mixture was diluted with ethyl acetate and water, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layer collected was washed with saturated aqueous saline, dried over sodium sulfate, and the solvent was removed by distillation. The residue was purified by chromatography on a silica gel column (methylene chloride:methanol=50:1-40:1) to give 0.624 g (74%) of ethyl 4-[[4-[1-(1-chloroethoxycarbonyl)piperidin-4-yl]-2-oxopiperazin-1-yl]acetyl]phenoxyacetate.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@H:5]([NH:12][C:13](=[O:44])[C@@H:14]([CH:41]([CH3:43])[CH3:42])[NH:15][C:16](=[O:40])[C@H:17]([CH:29](CC1C=CC=CC=1)[C:30](=[O:32])[OH:31])[NH:18]C(OCC1C=CC=CC=1)=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2]>CO.O.[Pd].[C]>[CH2:1]([O:3][CH2:4][C@H:5]([NH:12][C:13](=[O:44])[C@@H:14]([CH:41]([CH3:43])[CH3:42])[NH:15][C:16](=[O:40])[C@H:17]([CH2:29][C:30](=[O:31])[OH:32])[NH2:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC[C@H](NC(=O)[C@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)C(C)C)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCOC[C@H](NC(=O)[C@H](NC(=O)[C@@H](N)CC(=O)O)C(C)C)c1ccccc1
Temperature: 40 °C
Yield: 50.3 %

Procedure:
To a suspension of 1.20 g (1.99 mmols) of N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-valine (R)-α-ethoxymethylbenzylamide in 50 ml of methanol and 10 ml of water was added 0.30 g of 10% Pd-carbon (water content 50%). The mixture was reduced under hydrogen under heat at 40°C., 40 ml of water was added thereto, the catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure to 5 ml. The crystal thus precipitated was removed by filtration and dried to obtain 0.38 g (1.00 mmol, 50.3%) of α-L-aspartyl-D-valine (R)-α-ethoxymethylbenzylamide.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH2:13]O)[CH2:12][CH2:11]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2([CH3:13])[CH2:12][CH2:11]2)=[CH:6][N:7]=1
Reactant: Cc1ccc(O)cn1
Reactant: CC1(CO)CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(OCC2(C)CC2)cn1
Yield: 100.6 %

Procedure:
To a solution of 6-methylpyridin-3-ol (0.5 g, 4.6 mmol) in toluene (6 mL) was added (1-methylcyclopropyl)methanol (0.59 g, 6.9 mmol) and stirred under nitrogen atmosphere. The solution was added cyanomethylenetri-n-butylphosphorane (CMBP, 2.5 ml, 9.53 mmol) and stirred at 100° C. for 3 hours. The reaction mixture was evaporated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2:1 (v/v)) to give 820 mg (quantitative yield) of the title compound as a brown oil:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]2[NH:24][C:23](=[O:25])[C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[NH:20][C:19]2=[O:30])=[CH:13][C:12]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[S:7]([NH2:10])(=[O:9])=[O:8])C.CC(C)([O-])C.[K+]>C1COCC1>[CH2:32]([O:31][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][C:11]=1[N:6]1[CH2:5][C:4](=[O:3])[NH:10][S:7]1(=[O:8])=[O:9])[CH2:17][CH:18]1[NH:24][C:23](=[O:25])[C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[NH:20][C:19]1=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCOC(=O)CN(c1ccc(CC2NC(=O)c3ccccc3NC2=O)cc1OCc1ccccc1)S(N)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CN(c2ccc(CC3NC(=O)c4ccccc4NC3=O)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of the title N compound, N-[2-benzyloxy-4-(2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepin-3-ylmethyl)-phenyl]-N-[aminosulfonyl]-amino-acetic acid ethyl ester (93 mg, 0.168 mmol) in THF is cooled to 0° C. and treated dropwise with a solution of potassium t-butoxide in THF (1M, 0.244 mL, 0.244 mmol). After stirring at 0° C. for 30 min, additional potassium t-butoxide solution is added and stirring continued for another 1 h. The resulting suspension of fine solids is centrifuged, the supernatant is decanted and the cake of solids is suspended in EtOAc and centrifuged. The supernatant is decanted and the cake of solids is triturated with EtOAc and 2N aqueous HCl. The EtOAc layer is washed with brine, dried over anhydrous MgSO4, decolorized with charcoal, filtered and evaporated to give 3-[3-benzyloxy-4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-benzyl]-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dione as a foam: [M+1]+=507.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]3[NH:27][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][C:21]=4[N:20]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])C>Cl>[ClH:18].[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[CH:13][C:14]=1[C:19]1[NH:27][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:21]=2[N:20]=1
Reactant: CCOC(=O)C1CCN(c2ccc(Cl)c(-c3nc4ccncc4[nH]3)c2)CC1
Agent: Cl
Product: O=C(O)C1CCN(c2ccc(Cl)c(-c3nc4ccncc4[nH]3)c2)CC1
Temperature: 120 °C
Yield: 198.9 %

Procedure:
Method C—Step e A mixture of 1-[4-Chloro-3-(3H-imidazo[4,5-c]pyridin-2-yl)-phenyl]piperidine-4-carboxylic acid ethyl ester (0.60 g, 1.56 mmol) in 6N HCl (15 mL) was heated in microwave at 120° C. for 20 minutes; 2 cycles were needed to complete conversion. Then solvent was removed under vacuum to obtain 0.61 g of a mixture of the title compound and 2-(5-Bromo-2-chloro-phenyl)-3H-imidazo[4,5-c]pyridine (coming from the previous step), with a ratio of 7:3.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.[C:40]([O:44][C:45](=[O:57])[N:46]([C:48]1C=C(NC)C=[C:50](N)[CH:49]=1)C)([CH3:43])([CH3:42])[CH3:41]>>[C:40]([O:44][C:45](=[O:57])[N:46]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:33])[CH3:34])[C:14]2=[O:37])[CH:5]=1)[CH2:48][CH2:49][CH3:50])([CH3:43])([CH3:42])[CH3:41]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CNc1cc(N)cc(N(C)C(=O)OC(C)(C)C)c1
Product: CCCN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained as the tri-hydrochloride salt by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that (3-amino-5-methylamino-phenyl)-methyl-carbamic acid tert-butyl ester (prepared in four steps from 3,5-difluoro-nitrobenzene) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-propyl-carbamic acid tert-butyl ester (Example 41, step a) according to the method of Example 41, step b. 1H NMR (DMSO-d6) 9.83 (1H, br s), 7.55-7.45 (2H, m), 7.26-7.14 (2H, m), 6.79 (2H, br s), 6.26 (1H, s), 4.77 (2H, s), 4.31-4.26 (1H, m), 3.96-3.91 (1H, m), 3.65 (4H, br s), 2.86 (1H, m), 2.72 (6H, m), 1.84-1.64 (6H, m), 1.34-1.10 (13H, m). Found: C, 55.92; H, 6.79; N, 12.84%; C30H40N6O3.3.0HCl requires: C, 56.11; H, 6.75; N, 13.09%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH3:21]>CN(C=O)C.O>[CH2:20]([O:7][C:6](=[O:8])[C:5]1[C:9]([CH3:11])=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[O:12][CH3:13])[CH3:21]
Reactant: CCI
Reactant: COc1cc(Br)cc(C)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)cc(Br)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a stirred solution of 4-bromo-2-methoxy-6-methyl-benzoic acid (synthesized according to the methods described in sections a) to d) of example 10) (10.7 g, 43.7 mmol) in DMF (90 ml) are added potassium carbonate (12.1 g, 87.3 mmol) and ethyl iodide (17.5 ml, 218 mmol) and the resulting mixture is stirred at room temperature for 2 h. After completion of reaction the reaction mixture is diluted with water (200 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers are washed with water (2×30 ml), brine (2×30 ml), dried over sodium sulfate and concentrated in vacuo yielding 4-bromo-2-methoxy-6-methyl-benzoic acid ethyl ester (10.5 g, 39 mmol, 89%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][O:9][CH:10]=[CH:11][O:12][CH3:13].C(O)(=[O:17])C=C.[CH3:19][C:20]([C:23]([O:25]OC(C)(C)C)=[O:24])(C)C>C(C(C)=O)C>[CH3:8][O:9][CH:10]=[CH:11][O:12][CH3:13].[C:1]([OH:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:17])=[O:5].[C:23]([OH:25])(=[O:24])[CH:20]=[CH2:19]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(C)OOC(=O)C(C)(C)C
Agent: C=CC(=O)O
Agent: COC=COC
Solvent: CCC(C)=O
Product: O=C(O)/C=C\C(=O)O

Procedure:
The preparation of copolymer 4 is repeated, except that the reactor is charged with 3.9 g of maleic anhydride, 3.5 g of 1,2-dimethoxyethylene, 1.4 g of acrylic acid and 133 g of methyl ethyl ketone, and a solution of 35.3 g of maleic anhydride in 57 g of methyl ethyl ketone is then metered in at the same time as 31.7 g of 1,2-dimethoxyethylene, 13 g of acrylic acid and 1.1 g of tert-butyl perpivalate (75% strength in aliphatic hydrocarbon) in 20 g of methyl ethyl ketone. The workup leaves a solution of the polysodium salt of a copolymer of 1,2-dimethoxyethylene, maleic acid and acrylic acid having a solids content of 20%. The K value of the copolymer is 51.7. The amount of residual maleic acid in the copolymer is found to be 0.19%.
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[CH3:18][O:19][C:20]([C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][C:24]([OH:32])([CH2:25]3)[CH2:23]1)[CH2:29]2)=[O:21]>>[CH3:18][O:19][C:20]([C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][C:24]([O:32][C:1](=[O:4])[CH:2]=[CH2:3])([CH2:25]3)[CH2:23]1)[CH2:29]2)=[O:21]
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Reactant: COC(=O)C12CC3CC(CC(O)(C3)C1)C2
Product: C=CC(=O)OC12CC3CC(C1)CC(C(=O)OC)(C3)C2
Yield: 87 %

Procedure:
The reaction was conducted in the same manner as the step of Example 36 (2) except that 1-methoxycarbonyl-3-hydroxyadamantane was used instead of the 1,3-dicarboxy-5-adamantanol, and, as a result, a 1-methoxycarbonyl-3-acryloyloxyadamantane (yield: 87%, white solid) was obtained.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:47])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:46])[CH2:12][CH2:13][C@@:14]3([C:30]([N:32]4[CH2:37][CH2:36][C:35]([C:44]#[N:45])([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:34][CH2:33]4)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:49])[CH3:48])(=O)C.C1COCC1.[OH-].[Na+]>CO>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:47])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:46])[CH2:12][CH2:13][C@@:14]3([C:30]([N:32]4[CH2:37][CH2:36][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)([C:44]#[N:45])[CH2:34][CH2:33]4)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:49])[CH3:48]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(C#N)(c4ccccc4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(C#N)(c4ccccc4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.4 %

Procedure:
(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(4-cyano-4-phenylpiperidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 75, 2.0 g) was taken in MeOH: THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (1.5 g in 4 ml water) was added and the contents were stirred for about 6 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure and the residue was taken in water and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (1.45 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 10H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.15-4.18 (m, 2H); 4.56 (s, 1H); 4.71 (s, 1H); MASS: 624 (100%).
Reaction SMILES: COC1C=C2C(=CC=1)CC(CC1C=CC=CC=1NCC1C=CC(OCCN3CCCCC3)=CC=1)CC2.[CH2:37]([N:39]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[CH2:62][CH:63]1[CH2:72][CH2:71][C:70]2[C:65](=[CH:66][CH:67]=[C:68]([O:73]C)[CH:69]=2)[CH2:64]1)[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][N:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)=[CH:43][CH:42]=1)[CH3:38]>>[CH2:37]([N:39]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][N:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)=[CH:43][CH:42]=1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[CH2:62][CH:63]1[CH2:72][CH2:71][C:70]2[CH:69]=[C:68]([OH:73])[CH:67]=[CH:66][C:65]=2[CH2:64]1)[CH3:38]
Reactant: CCN(Cc1ccc(OCCN2CCCCC2)cc1)c1ccccc1CC1CCc2cc(OC)ccc2C1
Agent: COc1ccc2c(c1)CCC(Cc1ccccc1NCc1ccc(OCCN3CCCCC3)cc1)C2
Product: CCN(Cc1ccc(OCCN2CCCCC2)cc1)c1ccccc1CC1CCc2cc(O)ccc2C1
Yield: 47.2 %

Procedure:
Synthesized from [2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)phenyl][4-(2-piperidin-1-ylethoxy)benzyl]amine (600 mg) according to an analogous synthetic method to Example 786, ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)phenyl][4-(2-piperidin-1-ylethoxy)benzyl]amine (370 mg) was used according to an analogous synthetic method to Example 364 to provide the title compound (170 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([N+:16]([O-])=O)[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:6].Cl.C(O)C>O>[NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([NH2:16])[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:6]
Reactant: NCCNC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: NCCNC(=O)c1cc(N)cc(C(=O)O)c1
Reaction time: 2 h
Yield: 73.7 %

Procedure:
3-(2-Amino-ethylcarbamyl)-5-nitro-benzoic acid (200 g; 0.79 mole) is dissolved in water (1000 ml) and concentrated hydrochloric acid (75 ml). Palladium-over-charcoal (20 g) is added thereto, and the material is hydrogenated in an autoclave during 2 hours, under a hydrogen pressure of 3-4 kg. The resulting material is filtered and evaporated to dryness in vacuo, to give a solid which is taken up into ethanol (500 ml). The resulting precipitate is suction filtered, washed with ethanol and dried, to give 130 g (Yield = 74%) 3-(2-amino-ethylcarbamyl)-5-amino-benzoic acid the purity of which is controlled by:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:16](Cl)(=[O:27])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl>[C:16](=[O:27])([O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)[O:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCc1cccc(Br)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1cccc(Br)c1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
To a solution of (3-bromophenyl)methanol (10 g, 53.5 mmol) and pyridine (8.65 mL, 107 mmol) in DCM (80 mL) at 0° C. was added a solution of 4-nitrophenyl carbonochloridate (12.93 g, 64.2 mmol) in DCM (20 mL) dropwise. Upon the completion of addition, the reaction mixture was stirred at 0° C. for 2 h. After this time, the reaction was quenched with water. The organic layer was separated and washed with water, brine, dried over anhydrous MgSO4, filtered, and concentrated to afford the title compound (19.5 g, 100%). 1H NMR (400 MHz, CDCl3) δ 8.31-8.29 (m, 1H), 8.28-8.25 (m, 1H), 7.61 (t, J=1.6 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.42-7.34 (m, 3H), 7.30 (d, J=7.8 Hz, 1H), 5.26 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:43]=[CH:42][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[N:29]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:28](=[O:41])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[NH2:44][C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1>>[NH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:2]2[CH:43]=[CH:42][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[S:30](=[O:31])(=[O:32])[N:29]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:28](=[O:41])[CH2:27]5)=[CH:22][CH:21]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:47][CH:46]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S1(=O)=O
Reactant: Nc1ccc(B(O)O)cc1
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N)cc4)cc3)cc2)S1(=O)=O

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (361 mg, 0.5 mmol) was treated as described in general procedure G using 4-aminophenylboronic acid (137 mg, 1 mmol) to give 5-{-4-[2-(4′-amino-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([OH:8])=[N:6][CH:7]=1.Cl[CH2:11][CH2:12][N:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([O:8][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[N:6][CH:7]=1
Reactant: ClCCn1cccn1
Reactant: Oc1ncc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1cc(Br)cnc1OCCn1cccn1
Temperature: 90 °C

Procedure:
A vigorously stirred mixture of 5-bromo-3-fluoro-2-hydroxypyridine (440 mg, 2.3 mmol), 1-(2-chloroethyl)-1H-pyrazole (330 mg, 2.5 mmol) and K2CO3 (380 mg, 2.77 mmol) in DMF (5 mL) was heated to 90° C. for 16 h. After cooling to room temperature the solvent was removed in vacuo and the crude partitioned between water and EtOAc. The aqueous was extracted with EtOAc (×3) and the combined organics dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (gradient: 20%-100% EtOAc in pet. ether 40-60) yielded (Intermediate 6) as a clear oil.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[S:8][C:9]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([CH2:19][CH:20]3[CH2:24][CH2:23][N:22]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:21]3=[O:31])=[C:14]([Cl:32])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].CCOC(C)=O.Cl>O1CCOCC1>[Cl:32][C:14]1[CH:13]=[C:12]([C:9]2[S:8][C:7]([C:5]([OH:6])=[O:4])=[CH:11][CH:10]=2)[CH:17]=[C:16]([Cl:18])[C:15]=1[CH2:19][CH:20]1[CH2:24][CH2:23][N:22]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:21]1=[O:31]
Reactant: COC(=O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)s1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Add 1.0 mL of LiOH (2.0 N aq.) to a solution of 5-[3,5-Dichloro-4-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-phenyl]-thiophene-2-carboxylic acid methyl ester (85 mg, 0.182 mmol) in 3.0 mL of dioxane and heat to 50° C. After 3 hours, a TLC shows the reaction to be complete. Dilute the reaction with DCM /H2O (50/50), acidify with 1.0N HCl, extract with ethyl acetate, and dry the combined organic layers with sodium sulfate. Filter off the sodium sulfate and concentrate to give the title compound. LC/MS (API) m/z: 452.0 (M+1).
Reaction SMILES: [CH2:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br-].[Br:23][C:24]1[CH:25]=[CH:26][C:27]2[C:36]([CH:37]=1)=[S+:35][C:34]1[C:29](=[CH:30][CH:31]=[C:32](Br)[CH:33]=1)[N:28]=2>C(Cl)(Cl)Cl>[Br-:23].[CH2:12]([N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:24]1[CH:25]=[CH:26][C:27]2[C:36]([CH:37]=1)=[S+:35][C:34]1[C:29](=[CH:30][CH:31]=[C:32]([N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:33]=1)[N:28]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCNCCCCCCCCCC
Reactant: Brc1ccc2nc3ccc(Br)cc3[s+]c2c1
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCN(CCCCCCCCCC)c1ccc2nc3ccc(N(CCCCCCCCCC)CCCCCCCCCC)cc3[s+]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.7 g (5.72 mmol) of didecylamine in 20 mL of CHCl3 was added 0.63 g (1.43 mmol) of 22. The reaction mixture was stirred at room temperature for 2 h under argon and concentrated under diminished pressure to give 3,7-bis(didecylamino)phenothiazin-5-ium bromide (CPD-14): mass spectrum (MALDI-TOF), m/z 788.69 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)[C:5](O)=[O:6].O=S1(=O)CC(N)C2C=CC=CC=2N1.[BH4-].[Li+].Cl>O1CCCC1.C(O)C>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([CH2:5][OH:6])[CH:3]=1)[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Agent: Cl
Agent: NC1CS(=O)(=O)Nc2ccccc21
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cc(Br)cc(CO)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To an ice-cold solution of 3-bromo-5-(methoxycarbonyl)benzoic acid prepared by the method in Preparation 2 (10.3 g, 40 mmol) in anhydrous tetrahydrofuran (100 mL) is added lithium borohydride (12 g, 550 mmol) portion-wise. The reaction is stirred 4 h at this temperature. Absolute ethanol (20 mL) is added dropwise, and the reaction is stirred 1.5 h. The reaction is slowly poured on ice, and 10% hydrochloric acid (aq) is added until gas evolution ceased. The aqueous layer is extracted with chloroform, and the organic layer is washed with brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to give the title compound. ESI MS m/z 229, 231 [M−H]−.