Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:23])[C:9]=1[N:10]2C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:23])[C:9]=1[NH:10]2
Reactant: CC(C)(C)OC(=O)n1c2c(c3c(Cl)c(Cl)ccc31)CCCC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCCc2c1[nH]c1ccc(Cl)c(Cl)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
tert-Butyl 5,6-dichloro-1-oxo-3,4-dihydro-1H-carbazole-9(2H)-carboxylate (intermediate 1b) (0.9 g, 2.5 mmol) was dissolved in DCM (15 mL), cooled to 0° C., and TFA (1.6 mL) was added. The reaction mixture was stirred at 0° C. for 1 h, neutralized with saturated NaHCO3 (20 mL) and extracted with DCM (2×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the title compound as a white solid (450 mg, 70%) which was directly in the next step without further purification. 1H NMR (500 MHz, CDCl3, δ in ppm) 9.18 (bs, 1H), 7.38 (d, J=9.0 Hz, 1H), 7.28 (d, J=9.5 Hz, 1H), 3.37 (t, J=6.0 Hz, 2H), 2.67 (t, J=7.0 Hz, 2H), 2.30-2.25 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[N:9][C:10]([CH:23]3[CH2:28][CH2:27][N:26](C(OCC4C=CC=CC=4)=O)[CH2:25][CH2:24]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:3][CH:2]=1.Br.CC(O)=O>Cl>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[N:9][C:10]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:14]=2)=[CH:3][CH:2]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2cc(-c3cccc(C(F)(F)F)c3)c(-c3ccncc3)nn2)CC1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2cc(C3CCNCC3)nnc2-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.6 %

Procedure:
Under Ar, a mixture of 35 (0.68 g, 1.3 mmol) and 30% HBr—AcOH (10 mL) was stirred at room temperature. After 3 h, 3N HCl (50 mL) was added and the solution extracted with Et2O (2×). The aqueous layer was basified with saturated Na2CO3 and extracted with EtOAc (6×). The organic extracts were dried, filtered and concentrated to dryness. The residue was crystallzed from EtOAc-hexanes to yield 73 mg (15%) of 36 mp 148-50° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:8][C:9](=S)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2F)[CH:5]=[CH:6][CH:7]=1.[NH2:19][NH2:20]>CS(C)=O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:8][C:9]2[C:10]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:20][N:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: Cc1c(Br)cccc1NC(=S)c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(Br)cccc1Nc1n[nH]c2ccccc12
Temperature: 150 °C

Procedure:
Step 3 A yellow solution of N-(3-bromo-2-methylphenyl)-2-fluorobenzothioamide (500 mg, 1.542 mmol) in DMSO (5 mL) was treated with anhydrous hydrazine (0.484 mL, 15.42 mmol) and heated at 150° C. After 2 h 20 min the solution was cooled to rt, diluted with NaHCO3 (aq) and extracted twice with EtOAc. The combined organic phases were washed twice with water and once with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 85:15 to 50:50 hexane-EtOAc) to provide N-(3-bromo-2-methylphenyl)-1H-indazol-3-amine as a tan waxy solid (162 mg, 35%). 1H NMR (400 MHz, chloroform-d) δ 9.38 (1 H, br. s.), 7.49 (1 H, d, J=8.1 Hz), 7.45 (1 H, d, J=7.9 Hz), 7.40 (2 H, d, J=3.5 Hz), 7.19 (1 H, dd, J=7.9, 0.9 Hz), 7.10 (1 H, dt, J=8.1, 4.0 Hz), 6.98 (1 H, t, J=8.1 Hz), 6.10 (1 H, s), 2.49 (3 H, s). Mass spectrum m/z 302, 304 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][N:31]1[CH:36]2[CH2:37][CH2:38][CH:32]1[CH2:33][NH:34][CH2:35]2>>[CH3:28][N:26]([CH3:27])[C:25]([C:7]1[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:34]4[CH2:35][CH:36]5[N:31]([CH3:30])[CH:32]([CH2:38][CH2:37]5)[CH2:33]4)=[O:22])=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:29]
Reactant: CN1C2CCC1CNC2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C)cn3)nc2n1C1CCCC1
Yield: 60.3 %

Procedure:
Following general amide formation method 1, 6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (100 mg, 0.254 mmol, 1.0 eq) was combined with 8-Methyl-3,8-diaza-bicyclo[3.2.1]octane (55.5 mg, 0.279 mmol, 1.1 eq) which gave 7-cyclopentyl-2-[5-(8-methyl-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as solid (77 mg) in 60% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56-1.76 (m, 4H) 2.01 (br. s., 6H) 2.44 (br. s., 4H) 3.06 (br. s., 8H) 3.33 (br. s., 4H) 3.49 (br. s., 4H) 4.76 (quin, J=8.84 Hz, 1H) 6.66 (s, 1H) 7.82-7.88 (m, 1H) 8.33-8.41 (m, 2H) 8.85 (s, 1H) 10.05 (s, 1H)
Reaction SMILES: C(O[C:4](=[O:18])[C:5]([C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)=[CH:6]O)C.[NH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[NH2:20].C([O-])C.[Na+].Cl>C(O)C>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:19]1[C:4](=[O:18])[C:5]([C:8]2[CH:9]=[N:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=2)=[CH:6][NH:20]1
Reactant: CCOC(=O)C(=CO)c1ccc(C(F)(F)F)nc1
Reactant: NNc1ccccn1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1c(-c2ccc(C(F)(F)F)nc2)c[nH]n1-c1ccccn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
261 mg (1.00 mmol) of the compound from Example 41A and 115 mg (1.05 mmol) 2-hydrazinopyridine are dissolved in 5 ml anhydrous ethanol under argon and the mixture is stirred at RT for 20 h. 68 mg (1.00 mmol) sodium ethanolate are added, the mixture is stirred at RT for 30 min and 1 M hydrochloric acid and a little ethanol are then added, a precipitate separating out. This is filtered off, washed with a little ethanol and dried in vacuo.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][C:7]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]([N+:21]([O-])=O)=[CH:13][N:12]=1)([CH3:10])[C:8]#[N:9].[OH-].[Na+]>CC(=O)OCC>[NH2:21][C:14]1[CH:15]=[C:16]([C:17]([F:20])([F:18])[F:19])[C:11]([C:7]([CH3:10])([CH3:6])[C:8]#[N:9])=[N:12][CH:13]=1
Reactant: CC(C)(C#N)c1ncc([N+](=O)[O-])cc1C(F)(F)F
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C#N)c1ncc(N)cc1C(F)(F)F
Reaction time: 4 h
Yield: 40.8 %

Procedure:
Tin(II) chloride dihydrate (449 mg, 1.991 mmol) was added to a solution of 2-methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (129 mg, 0.498 mmol) in EA (15 mL). The mixture was at 60° C. for 4 h. Then the solution was adjusted to pH=8-9 with 2N NaOH. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, basic condition) to yield a white solid of 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)-2-methylpropanenitrile (46.48 mg, 0.203 mmol, 40.7% yield). TLC (PE/EA=1:1, Rf=0.3): 1H NMR (400 MHz, DMSO-d6) δ 8.04-8.17 (m, 1H), 7.31 (d, J=2.43 Hz, 1H), 5.97 (s, 2H), 1.70 (s, 6H); ES-LCMS m/z 230.1 (M+H).
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:36]=[CH:35][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24](/[CH:28]=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:25][C:26]=3[CH3:27])=[C:18]([O:37][CH3:38])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:39]([P:48](=[O:55])([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:53]([O:52][P:48](/[CH:39]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:36]=[CH:35][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24](/[CH:28]=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:25][C:26]=3[CH3:27])=[C:18]([O:37][CH3:38])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)([O:49][CH2:50][CH3:51])=[O:55])[CH3:54]
Reactant: CCOC(=O)/C=C/c1nc(COc2ccc(COc3nn(-c4ccccc4)cc3C=O)cc2OC)c(C)o1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1nc(COc2ccc(COc3nn(-c4ccccc4)cc3/C=C/P(=O)(OCC)OCC)cc2OC)c(C)o1
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To a mixture of ethyl (2E)-3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate (0.80 g), tetraethyl methylenediphosphonate (0.49 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.07 g) at room temperature, and the mixture was stirred at the same temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl (2E)-3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-propenoate as colorless crystals (0.70 g, yield 71%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 130-131° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:22][C:23]1[C:28]([Br:29])=[CH:27][C:26]([S:30][CH2:31][CH2:32][CH2:33][NH:34][CH3:35])=[CH:25][C:24]=1[Br:36]>>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:34]([CH3:35])[CH2:33][CH2:32][CH2:31][S:30][C:26]3[CH:27]=[C:28]([Br:29])[C:23]([NH2:22])=[C:24]([Br:36])[CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCCl)CC2
Reactant: CNCCCSc1cc(Br)c(N)c(Br)c1
Product: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCN(C)CCCSc1cc(Br)c(N)c(Br)c1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl)-propyl chloride and N-[3-(4-amino-3,5-dibromo-phenylthio)-propyl]-methylamine analogously to Example 1.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]1([CH3:21])[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[C:13]1[N:18]=[C:17](Cl)[N:16]=[C:15](Cl)[N:14]=1.[C:22]1([CH:29]=[CH:28][CH:27]=[C:25]([OH:26])[CH:24]=1)[OH:23].Cl>S1(CCCC1)(=O)=O>[C:5]1([CH3:21])[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[C:13]1[N:18]=[C:17]([C:27]2[CH:28]=[CH:29][C:22]([OH:23])=[CH:24][C:25]=2[OH:26])[N:16]=[C:15]([C:27]2[CH:28]=[CH:29][C:22]([OH:23])=[CH:24][C:25]=2[OH:26])[N:14]=1
Reactant: Cc1cc(C)c(-c2nc(Cl)nc(Cl)n2)c(C)c1
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S1(=O)CCCC1
Product: Cc1cc(C)c(-c2nc(-c3ccc(O)cc3O)nc(-c3ccc(O)cc3O)n2)c(C)c1
Reaction time: 14 h
Yield: 84.6 %

Procedure:
148.7 g (1.21 mol) of anhydrous aluminium trichloride (purity 98%) are added with stirring to a suspension of 130.0 g (0.485 mol) of 2-mesityl-4,6-dichloro-1,3,5-triazine (i) in 300 ml of petroleum ether with a boiling range of 110°-140° C. and 385 ml of sulfolane. During this addition, the mixture warms to 45° C. A solution of 133.5 g (1.21 mol) of resorcinol (purity 98%) in 155 ml of sulfolane is added to the mixture over the course of 45 minutes. The mixture is warmed at 80°-85° C. for 5 hours 30 minutes with evolution of HCl. The upper phase (petroleum ether) is removed, and the lower, viscous phase is transferred while still hot into a stirred mixture of 2.1 l of methanol and 2.1 l of water. After the mixture has been stirred for 14 hours, the solid is filtered off, stirred in 2.2 l of 1 molar HCl for 1 hour and re-filtered. The filter cake is suspended in 1000 ml of water, stirred for 30 minutes and re-filtered. This operation is repeated twice. The filter cake is dried for 24 hours at 80° C. and a pressure of 60 mmHg (8000 Pa), giving 170.5 g of the title product (ii) of the formula ##STR65## of m.p. 230°-234° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][C:15]1[CH2:21][C:20]2[CH:22]=[C:23]3[O:28][CH2:27][O:26][C:24]3=[CH:25][C:19]=2[C:18]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[N:17][N:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:57]1(=[O:67])[NH:61][C:60](=[O:62])[C:59]2=[CH:63][CH:64]=[CH:65][CH:66]=[C:58]12>C1COCC1>[N+:35]([C:32]1[CH:33]=[CH:34][C:29]([C:18]2[C:19]3[CH:25]=[C:24]4[O:26][CH2:27][O:28][C:23]4=[CH:22][C:20]=3[CH2:21][C:15]([CH2:14][N:61]3[C:60](=[O:62])[C:59]4=[CH:63][CH:64]=[CH:65][CH:66]=[C:58]4[C:57]3=[O:67])=[N:16][N:17]=2)=[CH:30][CH:31]=1)([O-:37])=[O:36]
Reactant: O=[N+]([O-])c1ccc(C2=NN=C(CO)Cc3cc4c(cc32)OCO4)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Reaction time: 24 h

Procedure:
A solution of 1.25 ml (8.05 mmol) of diethyl azodicarboxylate in 7 ml of THF is added in drops to a stirred solution of 2.60 g (7.66 mmol) of 8-hydroxymethyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine (starting compound III.), 2.11 g (8.05 mmol) of triphenylphosphine and 1.18 g (8.05 mmol) of phthalimide in 130 ml of dry THF at room temperature. The mixture is stirred for 24 hours at this temperature. Then, the precipitated product is suctioned off and washed with ethanol. 2.87 g (80%) of the title compound, which can be further processed without further purification, is obtained.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:7][C:8]([C:10]1[NH:11][C:12]([C:15]2[CH:20]=[C:19]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:16]=2)=[CH:13][CH:14]=1)=[O:9])[C@H:4]([OH:6])[CH3:5].[CH:38]([Si:41]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])Cl)([CH3:40])[CH3:39].C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[OH:6][C@H:4]([CH3:5])[C@H:3]([NH:7][C:8]([C:10]1[NH:11][C:12]([C:15]2[CH:20]=[C:19]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:23]([CH3:24])[CH3:25])[CH:26]([CH3:27])[CH3:28])[CH:18]=[C:17]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:16]=2)=[CH:13][CH:14]=1)=[O:9])[CH2:2][O:1][Si:41]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[CH:38]([CH3:40])[CH3:39]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@H](CO)[C@@H](C)O)[nH]2)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)[C@@H](C)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
N-[(2R,3R)-1,3-Dihydroxybutan-2-yl]-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrole-2-carboxamide (2.10 g, 3.93 mmol) synthesized in Example (110a) was dissolved in methylene chloride (50 mL), and triisopropylchlorosilane (1.50 mL, 7.01 mmol), 4-dimethylaminopyridine (1.50 g, 12.27 mmol) and triethylamine (5.00 mL, 35.87 mmol) were added, followed by stirring at room temperature for 1 day under nitrogen atmosphere. To the reaction solution, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=25-40%) to afford the desired compound (2.52 g, yield 93%) as a white solid.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1.C(N(C(C)C)C(C)C)C.[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1)[O:32][CH2:31][CH2:30][CH:29]2[C:46]([O:48][CH2:49][CH3:50])=[O:47].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>ClCCl>[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](=[O:42])[NH:15][CH:12]3[CH2:13][CH2:14][N:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=4)[CH2:11]3)=[CH:39][CH:38]=1)[O:32][CH2:31][CH2:30][CH:29]2[C:46]([O:48][CH2:49][CH3:50])=[O:47]
Reactant: NC1CCN(c2cccc(Cl)c2)C1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCN(c5cccc(Cl)c5)C4)cc3)c(Cl)cc21
Reaction time: 5 h
Yield: 94.7 %

Procedure:
Crude 1-(3-chlorophenyl)pyrrolidin-3-amine dihydrochloride (53.7 mg, 0.199 mmol) in dichloromethane was treated sequentially with N-ethyl-N-isopropylpropan-2-amine (78.6 μl, 0.451 mmol), 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (50 mg, 0.133 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.5 mg, 0.159 mmol), and 1-hydroxy-7-azabenzotriazole (5.42 mg, 0.0398 mmol) at ambient temperature. After 5 hours, the reaction was applied directly to a silica gel column. Elution with a gradient of 20-70% ethyl acetate-hexanes provided the title compound (70 mg, 0.126 mmol, 95.0% yield) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:1][C:2]2[CH:11]=[C:10]([O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1ccc(OCC(F)(F)F)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: COC(=O)c1ccc(OCC(F)(F)F)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 82.6 %

Procedure:
Using a procedure similar to that of Example 26-B, methyl 2-hydroxy-4-(2,2,2-trifluoroethoxy)benzoate (2.0 g, 7.99 mmol) is alkylated with 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.61 g, 7.99 mmol) to afford methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(2,2,2-trifluoroethoxy)benzoate (2.86 g).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])C1=S)[CH:2]=[CH2:3].[CH2:19](N)C(C)C>O>[Cl:16][C:15]1[C:10]([NH:6][CH2:7][CH2:8][CH2:9][NH:4][CH2:1][CH:2]([CH3:3])[CH3:19])=[C:11]([CH3:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)CN
Reactant: C=CCN1CCCN(c2c(C)cccc2Cl)C1=S
Solvent: O
Product: Cc1cccc(Cl)c1NCCCNCC(C)C
Temperature: 85 °C

Procedure:
Under cooling the hydrobromide salt of Example 12, Step B (6.82 g) was mixed with isobutylamine (5.85 g). The mixture was warmed to 85° C. under nitrogen until homogeneous and then refluxed for 2.5 hours. After cooling, it was diluted with water and the basic solution extracted with dichloromethane. The extracts were washed with 20% aqueous sodium chloride, dried over anhydrous potassium carbonate and evaporated to a brown oil which was flash chromatographed (on Merck-60 flash silica gel). The less polar impurities were eluted with 1:1 hexane- EtOAc and the desired material with 95:5:0.1 dichloromethane-methanol-ammonium hydroxide. The low melting material (3.82 g, 75%) was used as such in the next step.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[CH:4][C:3]=1[CH3:10].[F:11][CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.N1C(C)=CC=CC=1C>CC(N(C)C)=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][CH2:13][CH2:12][F:11])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: Cc1cc(N)cc(C)c1Br
Solvent: Cc1cccc(C)n1
Solvent: CC(=O)N(C)C
Product: Cc1cc(NCCF)cc(C)c1Br
Temperature: 120 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
A solution of 4-bromo-3,5-dimethyl-phenylamine (400 mg, 2 mmol), toluene-4-sulfonic acid 2-fluoro-ethyl ester (567 mg, 2.6 mmol) and 2,6-lutidine (429 mg, 4.0 mmol) in DMA (5 ml) was heated with stirring at 120° C. for four hours. The mixture was quenched with water and then extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give (4-bromo-3,5-dimethyl-phenyl)-(2-fluoro-ethyl)-amine (262 mg, 53%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.[CH3:15]O>>[CH3:15][O:2][C:1](=[O:3])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CO
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Product: COC(=O)c1ccc(S(N)(=O)=O)cc1

Procedure:
A slurry of 30.2 g (0.15 mole) of p-carboxybenzenesulfonamide in 500 ml of methanol was treated with 30 g of anhydrous hydrogen chloride and the mixture was heated at reflux temperature for 3 hr. The solution was concentrated under vacuum to give 32.3 g of white, crystalline residue. A 5.0 g portion of this residue was recrystallized from 25 ml of methanol to give 3.3 g of title compound as a white powder, mp 174°-178° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:38])[N:7]([CH2:16][CH2:17][S:18][S:19][CH2:20][CH2:21][N:22]3[C:31](=[O:32])[C:30]4[CH:33]=[CH:34][C:35](Cl)=[C:28]5[C:29]=4[C:24](=[CH:25][CH:26]=[CH:27]5)[C:23]3=[O:37])[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3.[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][CH2:43][NH2:44]>>[S:19]([CH2:20][CH2:21][N:22]1[C:31](=[O:32])[C:30]2[CH:33]=[CH:34][C:35]([NH:44][CH2:43][CH2:42][CH2:41][N:40]([CH3:45])[CH3:39])=[C:28]3[C:29]=2[C:24](=[CH:25][CH:26]=[CH:27]3)[C:23]1=[O:37])[S:18][CH2:17][CH2:16][N:7]1[C:6](=[O:38])[C:5]2[CH:4]=[CH:3][C:2]([NH:44][CH2:43][CH2:42][CH2:41][N:40]([CH3:45])[CH3:39])=[C:13]3[C:14]=2[C:9](=[CH:10][CH:11]=[CH:12]3)[C:8]1=[O:15]
Reactant: CN(C)CCCN
Reactant: O=C1c2cccc3c(Cl)ccc(c23)C(=O)N1CCSSCCN1C(=O)c2cccc3c(Cl)ccc(c23)C1=O
Product: CN(C)CCCNc1ccc2c3c(cccc13)C(=O)N(CCSSCCN1C(=O)c3cccc4c(NCCCN(C)C)ccc(c34)C1=O)C2=O
Temperature: 110 °C
Reaction time: 12 h

Procedure:
4 g of (6-chloro-2-(2-{[2-(6-chloro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)ethyl]-disulphanyl}ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione are suspended in 40 ml of N,N-dimethylpropane-1,3-diamine. The mixture is heated with stirring at 110° C. for 12 hours. After cooling, a yellow precipitate is collected, and 500 ml of a 1/1 ethanol/water mixture are added dropwise to the filtrate. The yellow paste obtained is isolated and triturated with 200 ml of acetone. The solids obtained are washed with 300 ml of water and dried. 4.5 g of yellow powder are recovered. The analyses show that the product is in accordance with the expected product.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][N:9]([C:12]3[C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=[CH:14][N:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:22][CH:23]([CH2:29][CH2:30][CH2:31][CH3:32])[CH:24]([OH:28])[C:25]([NH2:27])=[O:26]>>[NH2:27][C:25](=[O:26])[C:24]([CH:23]([NH:22][C:18](=[O:20])[C:17]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:9]1[CH:10]=[CH:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1)[CH2:29][CH2:30][CH2:31][CH3:32])=[O:28]
Reactant: CCCCC(N)C(O)C(N)=O
Reactant: O=C(O)c1cccnc1-n1ccc(-c2ccccc2)n1
Agent: Cl
Product: CCCCC(NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1)C(=O)C(N)=O

Procedure:
Preparation in analogy to Example 5 by coupling 2-(3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxylic acid and 3-amino-2-hydroxyheptanamide hydrochloride and subsequent oxidation afforded 40 mg of the title compound as a white solid.