Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[NH:15][C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=1)(=[O:6])=[O:5].Cl[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22].[Cl-].[Cl-].[Ca+2]>CN(C=O)C.CO>[CH3:3][S:4]([C:7]1[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:9]2[C:10]([N:15]=1)=[N:11][CH:12]=[CH:13][CH:14]=2)(=[O:5])=[O:6]
Reactant: CS(=O)(=O)c1nc2cccnc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Ca+2]
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2ncccc21
Yield: 25.1 %

Procedure:
Sodium hydride (146 mg) was added to a solution of 2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (600 mg) and [2-(chloromethoxy)ethyl]trimethylsilane (609 mg) in DMF (3 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 1 h. The reaction mixture was diluted with MeOH (2 mL), and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-30% EtOAc in hexane) to give 2-(methylsulfonyl)-1-[{2-(trimethylsilyl)ethoxy}methyl]-1H-imidazo[4,5-b]pyridine (250 mg) as light brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)[C:7]([OH:10])=[N:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)[C:7]([OH:10])=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cnc(O)c(-c2cncs2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cnc(O)c(-c2cncs2)c1
Yield: 90.1 %

Procedure:
A solution of 5-nitro-3-thiazol-5-ylpyridin-2-ol (218 mg, 0.977 mmol) and 10% Pd/C (100 mg) in methanol (5 mL) was hydrogenated under 1 atm at rt for 5 h. The resulting mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give 170 mg of the title compound, which was used directly in the next step without purification. 1H-NMR (DMSO-d6, 400 MHz): δ=4.38 (s, br, 2H), 6.78 (d, J=2.8 Hz, 1H), 7.80 (d, J=2.8 Hz, 1H), 8.41 (s, 1H), 8.97 (s, 1H), 11.52 (s, br, 1H). MS (ES+): m/z 194.15 [MH+]. HPLC: tR=0.49 and 0.90 min (ZQ2000, polar—5 min).
Reaction SMILES: [ClH:1].[NH2:2][C:3]([CH3:17])([C:13]([F:16])([F:15])[F:14])[CH2:4][NH:5]C(=O)OC(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[F:14][C:13]([F:16])([F:15])[C:3]([CH3:17])([NH2:2])[CH2:4][NH2:5]
Reactant: CC(C)(C)OC(=O)NCC(C)(N)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: CC(N)(CN)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
188 ml of 4 M hydrogen chloride in dioxane were added to 15 g (61.9 mmol) of rac-tert-butyl (2-amino-3,3,3-trifluoro-2-methylpropyl)carbamate from Example 245A in dioxane (188 ml). The reaction mixture was stirred at RT for 16 h and then concentrated and kept under argon. This gave 14.4 g (108% of theory) of the target compound which was not purified any further.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:36]=[CH:35][C:6]([C:7]([N:9]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:34])[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:8])=[CH:5][CH:4]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]([CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])[C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:36][CH:35]=3)[CH2:21][CH2:22]2)=[O:34])=[CH:32][CH:31]=1
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(CN)cc1
Reactant: CS(=O)(=O)Cl
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(CNS(C)(=O)=O)cc1
Yield: 57.3 %

Procedure:
Using 4-aminomethyl-N-{2-[4-(4-fluorobenzoyl)piperidino]-ethyl}-N-(2-methoxyphenyl)benzamide (60 mg, 0.123 mmol) and methanesulfonyl chloride (11 μl, 0.142 mmol), the procedure of Inventive Example 94 was repeated to obtain 40 mg (57.5%) of the title compound in a colorless amorphous form.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[CH3:6][C:7](=[O:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>P(=O)(O)(O)O>[CH2:9]([C:8]([C:7](=[O:19])[CH3:6])=[CH:2][C:1]([OH:5])=[O:4])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=CC(=O)O
Reactant: CCCCCCCCCCCC(C)=O
Agent: O=P(O)(O)O
Product: CCCCCCCCCCC(=CC(=O)O)C(C)=O

Procedure:
Prepared from glyoxylic acid (4.94 g, 6.5 mmol), 2-tridecanone (12.9 g, 6.5 mmol) and orthophosphoric acid (20 ml). 1H n.m.r. δ (CDCl3) 0.87, t J 7.2 Hz, 3H, CH3; 1.30, m, 16H, CH2; 2.39, s, 3H, CH3; 2.77, t J 7.0 Hz, 2H, CH2; 6.50, s, CH.
Reaction SMILES: C(N1C2C=CC=C(C)C=2C=NC(C2C=CC(O)=CC=2)C1=O)(C)C.[N+:24]([C:27]1[CH:28]=[CH:29][C:30]2[N:36](C)[C:35](=[O:38])[CH:34]([C:39]3[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=3)[N:33]=[C:32]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:31]=2[CH:52]=1)([O-:26])=[O:25]>>[N+:24]([C:27]1[CH:28]=[CH:29][C:30]2[NH:36][C:35](=[O:38])[CH:34]([C:39]3[CH:40]=[CH:41][C:42]([OH:45])=[CH:43][CH:44]=3)[N:33]=[C:32]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:31]=2[CH:52]=1)([O-:26])=[O:25]
Reactant: CN1C(=O)C(c2ccc(O)cc2)N=C(c2ccccc2)c2cc([N+](=O)[O-])ccc21
Agent: Cc1cccc2c1C=NC(c1ccc(O)cc1)C(=O)N2C(C)C
Product: O=C1Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1c1ccc(O)cc1

Procedure:
1,3-dihydro-1-isopropyl-6-methyl-3-(4-hydroxyphenyl)-2H-1,4-benzodiazepin-2-one; 7-nitro-1,3-dihydro-1-methyl-3-(4-hydroxyphenyl)-5-phenyl-2H-1,4-benzodiazepin-2-one;
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14].C[O-].[Na+].Cl>CO.CCOC(C)=O>[CH3:4][O:3][C:1](=[O:2])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:14][C:13](=[O:15])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C=CC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-carbomethoxybenzaldehyde (79 mg, 0.48 mmol) and acetophenone (56 μL, 0.48 mmol) in anhydrous methanol (1.6 mL), was added neat sodium methoxide (26 mg, 0.48 mmol). The mixture was stirred at room temperature overnight then heated to reflux for 1 hour, cooled down to room temperature and added HCl 1N and EtOAc. The layers were separated and the organic layer dried over anhydrous MgSO4 and filtered. The solvent was evaporated under vacuum to afford a yellow solid, which was recrystallized from acetonitrile/water to give a pale yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][C:31]([O:37][CH3:38])=[N:32]3)(O)[C@@H:9]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][C:31]([O:37][CH3:38])=[N:32]3)[C@@H:9]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCC[C@H](c1ccc(C(=O)OC(C)(C)C)cc1)C(O)(c1ccc(Cl)cc1)c1cccc2nc(OC)ccc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: CCC[C@H](c1ccc(C(=O)O)cc1)C(c1ccc(Cl)cc1)c1cccc2nc(OC)ccc12
Temperature: -78 °C

Procedure:
The product of step A (85 mg, 0.160 mmol) was dissolved in CH2Cl2 (15 mL) and triethylsilane (0.26 ml, 1.6 mmol) was added. The solution was cooled to −78° C., then BF3 gas was slowly bubbled through the solution until it was saturated (less than one minute, at the time fuming BF3 was observed from a small needle venting from the flask). The mixture was allowed to warm gradually to −20° C. When all starting material was consumed by LC/MS analysis, 1N HCl (aq) was added and the mixture was allowed to warm to room temperature. The mixture was extracted twice with CH2Cl2. The combined organic extracts were washed with water, dried over MgSO4, then concentrated. This afforded the title compound, which was used in the next step without purification: LC1 2.29 min. (M+H) 460.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.NC1C(C(C2C=C(F)C=CC=2OC)=O)=CN=C(S(CC)(=O)=O)N=1.[NH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]1>CN1CCCC1=O.O>[C:56]([O:55][C:53]([N:50]1[CH2:51][CH2:52][CH:47]([NH:46][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[CH:6][N:5]=2)[CH2:48][CH2:49]1)=[O:54])([CH3:59])([CH3:57])[CH3:58]
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)ccc2OC)c(N)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCS(=O)(=O)c1ncc(C(=O)c2cc(F)ccc2OC)c(N)n1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1N
Temperature: 70 °C
Yield: 95 %

Procedure:
A solution composed of a 9:1 mixture of (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone and (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (11.6 g, 36 mmol, Example 163) and 4-amino-1N-Boc-piperidine (Astatech Inc.) (10.8 g, 54 mmol) in 1-methyl-2-pyrrolidinone (50 mL, Aldrich) was heated at 70° C. for 30 minutes. The reaction was diluted with water and extracted with ethyl acetate. The dried (Na2SO4) organic solution was evaporated and the residue was triturated with ethyl ether/hexane to give 95% yield of 4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless solid, mp 122-124 dec. Mass Spectrum (LR-ES) M+: 445.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[N:35]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:36][CH3:37])[C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[CH:9]=1.O.C(=O)(O)[O-].[Na+]>Cl.C(OCC)(=O)C>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1)[CH2:6][N:7]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[N:35]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:36][CH3:37])[C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:9]=1
Reactant: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(NCCC(=O)OC(C)(C)C)ncn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(NCCC(=O)O)ncn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 103 %

Procedure:
Tert-butyl 3-(6-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-4-ylamino)-propionate (60 mg) is dissolved in a 4N-hydrochloric acid in ethyl acetate (0.5 ml) and the mixture is stirred at room temperature for 1.5 hours. To the reaction solution are added ethyl acetate and water, and followed by a further addition of a saturated aqueous sodium bicarbonate solution to make the pH of aqueous layer to be about 4, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate and the mixture is concentrated under reduced pressure to give 3-(6-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-4-ylamino)-propionic acid (57 mg). MS (m/z): 666 [M+H]+
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH:10]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:11]2=[O:14])=[CH:7][C:6]=1[O:20][CH3:21])([CH3:4])([CH3:3])[CH3:2].O.O.O.C([O-])(=O)C.[Na+].O.[Br:31]Br>[N+](CC)(CC)(CC)CC.[I-].ClCCl>[Br:31][C:7]1[C:6]([O:20][CH3:21])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:13]=[C:12]2[C:8]=1[CH2:9][CH:10]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:11]2=[O:14]
Reactant: COc1cc2c(cc1C(C)(C)C)C(=O)C(CC(C)(C)C)C2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Solvent: O
Solvent: ClCCl
Product: COc1c(C(C)(C)C)cc2c(c1Br)CC(CC(C)(C)C)C2=O
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 42.4 g (0.146 mol) of 6-tert-butyl-2-(2,2-dimethylpropyl)-5-methoxy-1-indanone, 58.0 g (0.426 mol) of sodium acetate, trihydrate, 0.93 g of Et4NI, 130 ml of dichloromethane, and 250 ml of water 23.5 g (0.147 mol) of bromine was added dropwise by vigorous stirring for 5 min at 5° C. The resulting mixture was stirred for additional 1 h at this temperature. Further on, this mixture was washed by aqueous Na2SO3 to remove an excess of bromine, and then 500 ml of dichloromethane was added. The organic layer was separated, and the aqueous layer was extracted with 2×250 ml of dichloromethane. The combined organic extract was dried over K2CO3 and then evaporated to dryness to give 54.8 g of yellowish oil which crystallizes on storage at room temperature. This product was further used without an additional purification.
Reaction SMILES: [C:1]([CH2:4][CH2:5][S:6][C:7]1[N:12]=[C:11]([C:13](=O)[CH2:14]Br)[CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[C:23]([NH2:25])=[S:24])[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[S:24][CH:14]=[C:13]([C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([S:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])[N:12]=3)[N:25]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH3:18]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: O=C(O)CCSc1cccc(C(=O)CBr)n1
Product: CCOc1ccc(-c2nc(-c3cccc(SCCC(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 6-(2-carboxyethylthio)-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide, to obtain 2-(3,4-diethoxyphenyl)-4-[6-(2-carboxyethylthio)-2-pyridyl]thiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[CH2:24][C@H:23]([OH:25])[CH2:22]2)=[CH:17][CH:16]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([C@H:21]2[CH2:24][C@H:23]([OH:25])[CH2:22]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc([C@H]4C[C@H](O)C4)cc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc([C@H]4C[C@H](O)C4)cc3)cc12
Temperature: 90 °C
Reaction time: 5 h
Yield: 53.5 %

Procedure:
To a solution of methyl 6-chloro-5-[4-(trans-3-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylate (290 mg, 0.82 mmol) in methanol/water (20 mL, v/v=1/1) was added sodium hydroxide (326 mg, 8.17 mmol). The mixture was stirred at 90° C. for 5 hours. The mixture was then acidified with 1M HCl to pH ˜5. The resulting suspension was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to give the title compound (150 mg, 54%) as a white solid. MS (AP+) 342.0 (M+H)+: 1H NMR (500 MHz, CD3OD) δ 8.03 (s, 1H), 8.02 (s, 1H), 7.59 (s, 1H), 7.41 (d, 2H), 7.34 (d, 2H), 4.53-4.50 (m, 1H), 3.67-3.65 (m, 1H), 2.55-2.43 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.O1CCCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cn2)CC1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
5-nitro-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (400 mg) from above was dissolved in methanol (50 mL) and tetrahydrofuran (10 mL). To this mixture was added 10% palladium on carbon (100 mg). The mixture was hydrogenated at 50 psi for 2 hrs. The mixture was filtered and the solvents were evaporated to give 5-amino-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester as a white solid (363 mg). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:22]=[C:21]([C:23]([OH:25])=O)[O:20][N:19]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:26][CH2:27][C@H:28]([NH:33][S:34]([CH2:37][CH2:38][CH2:39][CH3:40])(=[O:36])=[O:35])[C:29]([O:31][CH3:32])=[O:30].C1C=CC2N(O)N=NC=2C=1.N(CC)(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[CH3:32][O:31][C:29](=[O:30])[C@@H:28]([NH:33][S:34]([CH2:37][CH2:38][CH2:39][CH3:40])(=[O:36])=[O:35])[CH2:27][NH:26][C:23]([C:21]1[O:20][N:19]=[C:18]([O:17][CH2:16][CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2])[CH2:13][CH2:12]2)[CH:22]=1)=[O:25]
Reactant: CCCCS(=O)(=O)N[C@@H](CN)C(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC(CCCOc2cc(C(=O)O)on2)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCS(=O)(=O)N[C@@H](CNC(=O)c1cc(OCCCC2CCN(C(=O)OC(C)(C)C)CC2)no1)C(=O)OC

Procedure:
A stirred solution of 3-7 (142 mg, 0.4 mmol), 2-9 (110 mg, 0.4 mmol), HOBT (61 mg, 0.4 mmol), N(i-Pr)2Et (216 μL, 1.2 mmol) and DMF (7 mL) at -15° C. was treated with EDC (77 mg, 0.4 mmol) followed by removal of the cooling bath. After 20 h. the reaction mixture concentrated followed by dilution with EtOAc. The EtOAc solution was washed with 1M NaHSO4, and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 10% to 20% acetone/CH2Cl2) to give 3-8 as a viscous gum. Rf 0.64 (silica, 20% acetone/CH2Cl2).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:31][O:32][CH2:33][CH3:34])[N:21]([CH2:22][C:23]([CH3:30])([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][C:13]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43](=[O:66])[CH2:44][CH2:45][S:46]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:12][C:11]=2[N:10]=1.C([SiH](CC)CC)C>ClCCl>[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:31][O:32][CH2:33][CH3:34])[N:21]([CH2:22][C:23]([CH3:30])([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][C:13]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43](=[O:66])[CH2:44][CH2:45][SH:46])=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCCCCCNC(=O)CCSC(c4ccccc4)(c4ccccc4)c4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOCc1nc2c(N)nc3cc(OCCCCCCNC(=O)CCS)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Reaction time: 1 h
Yield: 3.3 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a 0° C. solution of N-{6-[(4-amino-2-(ethoxymethyl)-1-{2-methyl-2-[(methylsulfonyl)amino]propyl}-1H-imidazo[4,5-c]quinolin-7-yl)oxy]hexyl}-3-(tritylthio)propanamide (0.22 g, 2.63 mmol) and triethylsilane (0.46 mL, 2.89 mmol) in dichloromethane (7 mL). The solution was stirred for 1 hour; then additional triethylsilane (0.05 mL) was added. After an additional hour at 0° C., the solution was concentrated under reduced pressure. The residue was concentrated under reduced pressure from ethyl acetate and toluene. The material was purified by HPFC on silica gel (gradient elution with 25-100% CMA in chloroform) and then subjected to the procedure described in Part D of the synthesis of IRM Compound 1 to provide 51 mg of N-{6-[(4-amino-2-(ethoxymethyl)-1-{2-methyl-2-[(methylsulfonyl)amino]propyl}-1H-imidazo[4,5-c]quinolin-7-yl)oxy]hexyl}-3-mercaptopropanamide, mp 152-157° C. MS (ESI) m/z 595 (M+H)+. Anal. Calcd for C27H42N6O5S2: C, 54.52; H, 7.12; N, 14.13; S, 10.78. Found: C, 54.41; H, 7.13; N, 13.85; S, 10.63.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[N:9]1[C:22](=[O:43])[CH2:23][NH:24][C:25](=[O:42])[NH:26][C:27]1[CH:28]=[C:29]([CH:39]=[CH:40][CH:41]=1)[C:30]([O:32]CC[Si](C)(C)C)=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[N:9]1[C:22](=[O:43])[CH2:23][NH:24][C:25](=[O:42])[NH:26][C:27]1[CH:28]=[C:29]([CH:39]=[CH:40][CH:41]=1)[C:30]([OH:32])=[O:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](c2c[nH]c3ccccc23)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCC[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](c2c[nH]c3ccccc23)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 43.1 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 41, but starting from 0.25 g of 2-trimethylsilylethyl (2S,5S)-3-{3-{2-[2-tert-butoxycarbonyl-5-(3-indolyl)-1-pyrrolidinyl]-2-oxoethyl}ureido}benzoate and 1.5 cm3 of a 1M solution of tetrabutylammonium fluoride. The crude product is dissolved in 25 cm3 of ethyl acetate and extracted with 2 times 10 cm3 of 0.1N aqueous sodium hydroxide solution. The aqueous phases are brought to a pH of 2 by addition of a 1N aqueous hydrochloric acid solution. The product precipitated is separated by filtration, washed with 2 times 5 cm3 of distilled water and dried in air. 0.09 g of (2S,5S)-3-{3-{2-[2-tert-butoxycarbonyl-5-(3-indolyl)-1-pyrrolidinyl]-2-oxoethyl}ureido}benzoic acid is thus obtained in the form of an amorphous product, [α]D20 =-42.9°±1.5° (C=0.503%; CH3OH), [proton NMR (300 MHz, DMSO D6, δ in ppm, J in Hz); 1.44 (s, 9H, --C(CH3)3 ; 1.7 to 2.4 (m, 4H, --CH2 --CH2 --); 3.59 and 3.99 (2dd, J=18 and 6, 2H, N--CO--CH2 --N); 4.55 (d, J=9 Hz, 1H, N--CH--COO--); 5.53 (d, J=8, 1H, N--CH--Ar); 6.3 (t, J=6.1 Hz, 1H, --NH--CO--); 6.9 to 7.6 (m, 7H, aromatic); 7.15 (bs, 1H, N--CH=); 7.94 (broad s, 1H, in position 2 on NH--Ph--COO); 8.95 (broad, 1H, Ph--NH--CO--); 11.02 (broad, 1H, --NH--), 12.75 (broad, 1H, COOH). Two NOE effects have been observed between N--CH= of indole and the protons in positions 2 and 5 of pyrrolidine], [infrared spectrum (KBr), characteristic bands in cm-1 : 3385, 2975, 2930, 2700 to 2250 (broad band), 1730, 1690, 1640, 1560, 1490, 1460, 1395, 1370, 1155, 740, 685].
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[C:6]([I:8])[CH:7]=1>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([I:8])[CH:7]=1)[NH2:9]
Reactant: O=[N+]([O-])c1cc(I)cc(I)c1
Solvent: CCO
Product: Nc1cc(I)cc(I)c1

Procedure:
A mixture of 61.5 G (0.164M) of 3,5-diiodonitrobenzene, from step (a), and 111.1 G (0.4924M) of stannous chloride in 900 ml of absolute ethanol was heated to reflux 1.5 hours under nitrogen. Most of the solvent was removed. The residue was stirred with ethylacetate, 5 normal sodium hydroxide and ice. organic phase was separated and washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, solvent was removed to afford a crude oil, which was chromatographed on silica gel using 8:1:1 mixture of hexane:methylene chloride:ethyl acetate. The desired aniline was obtained as 35 G of light tan colored solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11]C)[C:9]=1[OH:10])[CH:5]=[O:6].[Al+3].[Cl-].[Cl-].[Cl-].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: COc1cc(C=O)cc(F)c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c(F)c1
Yield: 81.8 %

Procedure:
To the solution of 3-fluoro-4-hydroxy-5-methoxybenzaldehyde (800 mg, 4.7 mmol) in DCM (50 mL) was added AlCl3 (680 mg, 5.1 mmol) portionwise, and at 0° C., pyridine (950 mg, 9.4 mmol) was added, and the resulting mixture was refluxed overnight. The reaction mixture was quenched with HCl ice-water solution, and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the 3-fluoro-4,5-dihydroxybenzaldehyde as a pale solid (600 mg, yield 81%), which was used directly in the next step without further purification.