Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[OH:19])=[C:8]([Cl:20])[CH:7]=1)[CH3:5].[OH-].[Na+].Cl>CO>[Cl:20][C:8]1[CH:7]=[C:6]([CH:4]([CH3:5])[C:3]([OH:21])=[O:2])[CH:11]=[CH:10][C:9]=1[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[OH:19]
Reactant: COC(=O)C(C)c1ccc(C[C@@H]2CCCC[C@H]2O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)c1ccc(C[C@@H]2CCCC[C@H]2O)c(Cl)c1

Procedure:
3 g of methyl-2-[3-chloro-4-(trans-2-hydroxycyclohexane-1-yl methyl)phenyl]propionate were incorporated with 80 ml of an aqueous methanol containing 1.2 g of sodium hydroxide and then refluxed under heat for two hours. After the end of the reaction, the reaction mixture was treated to concentrate the solvent at a reduced pressure, incorporated with 50 ml of water and washed with 50 ml of ethyl acetate, after which the aqueous layer obtained was adjusted to a pH of 2 with conc. hydrochloric acid. The aqueous layer so adjusted was extracted with 50 ml of ethyl acetate, washed with water, dried and then freed of the solvent to obtain a residue. The thus obtained residue was recrystallized from isopropyl ether thereby to obtain 2.5 g (yield of 2-[3-chloro-4-(trans-2-hydroxycyclohexane-1-yl methyl)phenyl]propionic acid having the following melting point and instrumental analyses.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[C:4]([C:18]([F:21])([F:20])[F:19])=[CH:5][C:6]2[N:10]=[C:9]([CH3:11])[N:8]([CH2:12][CH3:13])[C:7]=2[C:14]=1[N+:15]([O-])=O>[Pt]=O>[NH2:15][C:14]1[C:7]2[N:8]([CH2:12][CH3:13])[C:9]([CH3:11])=[N:10][C:6]=2[CH:5]=[C:4]([C:18]([F:21])([F:19])[F:20])[C:3]=1[N:2]([CH3:22])[CH3:1]
Reactant: CCn1c(C)nc2cc(C(F)(F)F)c(N(C)C)c([N+](=O)[O-])c21
Agent: O=[Pt]
Product: CCn1c(C)nc2cc(C(F)(F)F)c(N(C)C)c(N)c21

Procedure:
6-Dimethylamino-1-ethyl-2-methyl-7-nitro- 5-trifluoromethylbenzimidazole (1.5g.) was hydrogenated in the presence of platinum oxide catalyst according to the procedure of Example IV to give 0.83g. of the desired product, m.p. 141°-142.5°C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([C:12]2[N:17]=[C:16]3[C:18]([C:21](O)=[O:22])=[CH:19][NH:20][C:15]3=[N:14][CH:13]=2)=[N:3]1.[NH2:24][C:25]1([CH2:28][OH:29])[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([C:12]2[N:17]=[C:16]3[C:18]([C:21]([NH:24][C:25]4([CH2:28][OH:29])[CH2:27][CH2:26]4)=[O:22])=[CH:19][NH:20][C:15]3=[N:14][CH:13]=2)=[N:3]1
Reactant: NC1(CO)CC1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)nn(C)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC5(CO)CC5)c4n3)nn(C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.8 %

Procedure:
To a stirred mixture of 2-(1,6-dimethyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (80 mg, 0.26 mmol) and (1-aminocyclopropyl)methanol (34 mg, 0.39 mmol) in DMF (3 mL), was added EDCI (100 mg, 0.52 mmol) followed by DMAP (63 mg, 0.52 mmol). The mixture was stirred at room temperature for 16 hours. Then the mixture was poured into water (5 mL) and filtered. The crude product was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 35% acetonitrile/65% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 45% acetonitrile/55% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(1,6-dimethyl-1H-indazol-3-yl)-N-(1-(hydroxymethyl)cyclopropyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (35 mg, 36%) as a white solid. MS: (M+H)+=377; 1H NMR (300 MHz, DMSO): δ 13.84 (s, 1H), 9.12 (s, 1H), 8.74 (s, 1H), 8.43-8.40 (m, 2H), 7.56 (s, 1H), 7.21 (d, 1H, J=8.4 Hz), 4.89 (brs, 1H), 4.16 (s, 3H), 3.62 (s, 2H), 2.55 (s, 3H), 0.97-0.86 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[C:17]([OH:19])[C:16]3[C:20]4[CH2:21][NH:22][CH2:23][CH2:24][C:25]=4[C:26]([CH3:29])([CH3:28])[O:27][C:15]=3[CH:14]=2)[CH3:12])=[CH:4][CH:3]=1.Cl[CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[C:17]([OH:19])[C:16]3[C:20]4[CH2:21][N:22]([CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:23][CH2:24][C:25]=4[C:26]([CH3:28])([CH3:29])[O:27][C:15]=3[CH:14]=2)[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Reactant: CN(C)C(=O)CCl
Product: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)N(C)C)CC1

Procedure:
The above-titled compound was prepared by reacting 8-[5-(4-fluorophenyl)-2-pentyl]-10-hydroxy-5,5-dimethyl- 1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with 2-chloro-N,N-dimethylacetamide according to the method of Example 3.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][C:16]1[C:17]([C:27](Cl)=[O:28])=[N:18][N:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27]([C:17]1[C:16]([CH3:15])=[N:20][N:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:18]=1)=[O:28]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: Cc1nn(-c2ccccc2)nc1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1nn(-c2ccccc2)nc1C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Yield: 61.8 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0454 g, 0.193 mmol), 5-methyl-2-phenyl-2H-1,2,3-triazole-4-carbonyl chloride (0.044 g; 0.193 mmol), and triethylamine (0.0676 mL; 0.481 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 16% of ethyl acetate in dichloromethane gave 0.0453 g (62%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-methyl-2-phenyl-2H-1,2,3-triazole-4-carboxamide as a solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:16][O:17][CH3:18])[C:9]([N:11]1[CH2:14][CH:13]([F:15])[CH2:12]1)=[O:10])(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>ClCCl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[NH2:7][C@H:8]([CH2:16][O:17][CH3:18])[C:9]([N:11]1[CH2:14][CH:13]([F:15])[CH2:12]1)=[O:10]
Reactant: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@@H](N)C(=O)N1CC(F)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In a 25 mL round-bottomed flask, [(R)-2-(3-fluoro-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (265 mg, 0.96 mmol) was dissolved in dichloromethane (5 ml). The reaction was cooled to 0° C. and trifluoroacetic acid (1.5 ml, 19.5 mmol) was slowly added. The reaction mixture was stirred at room temperature for 3 h then concentrated to provide (R)-2-amino-1-(3-fluoro-azetidin-1-yl)-3-methoxy-propan-1-one trifluoroacetate as a colorless viscous oil which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:41])[O:11][CH2:12][C:13]2([C:30](=[O:40])[NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])[CH2:18][CH2:17][N:16]([C:19](=[O:29])[CH2:20][NH:21]C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1)[CH3:2].Cl>CO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:41])[O:11][CH2:12][C:13]2([C:30](=[O:40])[NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])[CH2:18][CH2:17][N:16]([C:19](=[O:29])[CH2:20][NH2:21])[CH2:15][CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(NC(=O)OCC2(C(=O)NCc3ccccc3Cl)CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: CO
Product: CCc1ccc(NC(=O)OCC2(C(=O)NCc3ccccc3Cl)CCN(C(=O)CN)CC2)cc1
Reaction time: 2 h
Yield: 110.9 %

Procedure:
To a solution of (1-(2-(tert-butoxycarbonyl)aminoacetyl)-4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-ethylphenylcarbamate (87 mg, 0.15 mmol) in CH3OH (1 mL) was added HCl (4M in dioxane, 100 μL, 0.4 mmol, 2.6 equiv.), which was stirred for 2 h. The reaction mixture was concentrated to dryness by co-evaporating with toluene to give (1-(2-aminoacetyl)-4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-ethylphenylcarbamate (81 mg, quant.). LRMS (M+H+) m/z 487.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11].[CH:18](OCC)=[O:19]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[N:10]([CH:18]=[O:19])[CH3:11]
Reactant: CCOC=O
Reactant: CNC(Cc1ccccc1N)c1sccc1C
Product: Cc1ccsc1C(Cc1ccccc1N)N(C)C=O

Procedure:
A stirred solution of 5.00 g of 2-amino-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine and 235 ml of ethyl formate was refluxed for 8 hours. Volatile components were removed at 60° C. on a rotary evaporator. Thin layer chromatography (silica gel, ethyl acetate as the eluent) of the resultant oil indicated a multi-component mixture. HPLC of the mixture (Water's Associates Prep LC/System 500, silica gel, elution with ethyl acetate) permitted component separation. The faster eluting fractions were concentrated to an oil which crystallized upon standing. Recrystallization from methanol-water afforded 1.2 g of 2-amino-N-formyl-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine, mp 111°-112° C.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([NH2:24])[CH2:6][C:7]1[CH:8]=[C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[C:11]([CH2:13][P:14]([OH:17])([OH:16])=[O:15])[CH:12]=1)C>Cl>[NH2:24][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[C:11]([CH2:13][P:14]([OH:17])([OH:16])=[O:15])[CH:12]=1)[C:4]([OH:25])=[O:3]
Reactant: CCOC(=O)C(N)Cc1cc(CP(=O)(O)O)cc(-c2ccccc2)c1
Agent: Cl
Product: NC(Cc1cc(CP(=O)(O)O)cc(-c2ccccc2)c1)C(=O)O

Procedure:
The compound of Example 15 and 1N hydrochloric acid are heated at 60° for 2 hours. After evaporating to dryness the residue is dissolved in tetrahydrofuran/water and treated with propylene oxide, whereby the title compound is obtained, m.p. 275°-278° (decomp.). [α]D20 =0.0±0.5° (c=1 in 6N HCl), [α]36520 =+21.3° (c=1 in 6N HCl).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:14]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]=[C:12]([C:24]#[C:25][CH2:26][CH2:27][OH:28])[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[N:7]=1>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:1][C:2]1[C:3]2[N:14]([CH2:15][O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:13]=[C:12]([CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[N:7]=1
Reactant: CCCCc1nc(N)c2c(n1)c(C#CCCO)cn2COCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCc1nc(N)c2c(n1)c(CCCCO)cn2COCc1ccccc1

Procedure:
A solution of 4-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)but-3-yn-1-ol (948 mg, 2.505 mmol) in ethyl acetate (50 mL) and ethanol (50 mL) was hydrogenated using the H-cube (settings: 25° C., Full H2, 1 mL/min flow rate) and 10% Pd/C CatCart 70 as the catalyst. The reaction mixture was concentrated in vacuo at 60° C. to give the title compound as a viscous yellow oil which crystallised on standing (884 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=1.[N+:17]([O-])([OH:19])=[O:18].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[N+:17]([O-:19])=[O:18])[CH:5]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccnc(-c2ccc(O)cc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccnc(-c2ccc(O)cc2[N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(4-methoxypyridin-2-yl)phenol hydrochloride (500 mg) in acetic acid (5 ml) was added fuming nitric acid (0.09 ml), and the mixture was stirred at 40° C. for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The separated organic layer was washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, filtered, washed with diisopropyl ether and dried under reduced pressure to give 4-(4-methoxypyridin-2-yl)-3-nitrophenol (293 mg).
Reaction SMILES: [SiH](CC)(CC)CC.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:27])=[C:13]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][Br:26])=[CH:19][CH:18]=2)=O)[CH:14]=1.C(S(O)(=O)=O)(F)(F)F>C(O)(C(F)(F)F)=O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:27])=[C:13]([CH2:15][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][Br:26])=[CH:19][CH:18]=2)[CH:14]=1
Reactant: O=C(c1ccc(CCCBr)cc1)c1cc(Br)ccc1Cl
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(Br)cc1Cc1ccc(CCCBr)cc1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of Et3SiH (1.4 mL, 8.50 mmol) and (5-bromo-2-chlorophenyl)(4-(3-bromopropyl)phenyl)methanone (2.36 g, 5.67 mmol) in TFA (10 mL) at 30° C. was added CF3SO3H (0.05 mL). Within a few minutes the temperature of the solution increased causing it to reflux violently. After stirring for 2.5 h, additional Et3SiH (0.45 mL, 2.85 mmol) was added and the mixture was heated to 50° C. After stirring for 4.5 h the reaction was complete, and the volatiles were removed under reduced pressure. The residue was poured into brine and extracted 3× with ethyl acetate. The combined organic layers were washed 3× with water, 2× with aqueous Na2CO3 and 2× with brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the residue (2.3 g) was used in the next step without further purification.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])([CH3:36])[CH3:35])[C:31]([CH2:42][O:43][CH2:44][CH3:45])=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH4+:47].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl.O>[NH2:47][C:26]1[C:25]2[N:30]=[C:31]([CH2:42][O:43][CH2:44][CH3:45])[N:32]([CH2:33][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])([CH3:36])[CH3:35])[C:24]=2[C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:29][C:28]=2[N:27]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Reaction time: 8 h

Procedure:
mCPBA (11.2 g, 39.2 mmol) was added to a solution of N-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide (prepared as described in Parts A-D of Example 52, 17.2 g, 35.6 mmol) in dichloromethane (350 mL). The solution was stirred overnight and additional mCPBA (approximately 1-2 g) was added. After 20 minutes, concentrated ammonium hydroxide (150 mL) was added. The mixture was stirred for 10 minutes and p-toluenesulfonyl chloride (8.20 g, 42.8 mmol) was added in portions. The mixture was stirred at ambient temperature for 2 days, then was filtered. A white solid was obtained, which was slurried in water, filtered, and dried to yield 11.7 g of N-{2-[4-amino-7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide. A small sample, 500 mg, was purified to yield 300 mg of analytically pure N-{2-[4-amino-7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide as a white solid, mp 264-266° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:15])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1cccc(Cl)c1
Product: O=C(Nc1cccc(Cl)c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 3-chloroaniline (49 mg, 0.39 mmol). The title compound was obtained as a solid (70 mg, 47% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.79 (1H, s), 9.01 (2H, s), 8.75 (1H, s), 7.86 (1H, s), 7.67 (1H, m), 7.39 (1H, m), 7.20 (1H, m). MS m/z: 458.11, 460.09, 462.03 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.C(OCC)(=O)C>[S:21]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)(=[O:23])(=[O:22])[CH3:20]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cc(CO)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 4-chloro-3-nitrobenzyl alcohol (1 g) in methylene chloride (10 mL) were added triethylamine (1.12 mL) and methanesulfonyl chloride (0.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give (4-chloro-3-nitrobenzyl) mesylate (1.08 g). This material was dissolved in acetonitrile (4 mL)-ethanol (4 mL). To the solution were added 1,2,3,4-tetrahydroquinoline (1.62 g) and a catalytic amount of sodium iodide, and the mixture was stirred at 60° C. overnight. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1) to give 1-(4-chloro-3-nitrobenzyl)-1,2,3,4-tetrahydroquinoline (1.22 g). This material was dissolved in tetrahydrofuran (12 mL). To the solution were added methanol (12 mL), nickel (II) bromide (44 mg) and sodium borohydride (0.46 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1) to give the title compound (0.79 g).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:16]>CN(C=O)C>[C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:16]
Reactant: O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 4 °C
Reaction time: 8 h

Procedure:
To N-Teoct4 (0.017 g, 17 μmol) in 1 mL dry DMF was added dicyclohexylcarbodiimide (0.004 g, 18 μmol). After stirring for 30 minutes N-dimethyl-4-aminopyridine (0.004 g, 36 μmol) and Gly18 (SEQ ID NO: 6) (0.017 g,17 μmol) were added and the reaction stirred overnight. The cloudy solution was poured into 20 mL H2O and extracted twice with 10 mL CH2Cl2. The aqueous component was acidified to pH 3 with 1 N HCl and chilled to 4° C. The material was isolated by centrifugation and the pellet washed 3 times with 8 mL H2O. The pellet was dried in vacuum to yield dicyclohexylurea and N-TeocT4-Gly18 (SEQ ID NO:6).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3([O:20][C:19]4[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:18]=4[N:17]4[CH:26]=[CH:27][CH:28]=[C:16]34)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:29][CH3:30].[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:18]2[N:17]3[CH:26]=[CH:27][CH:28]=[C:16]3[C:13]3([CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH:31]5[CH2:33][CH2:32]5)=[C:3]([O:29][CH3:30])[CH:4]=4)=[O:9])[CH2:11][CH2:12]3)[O:20][C:19]=2[CH:21]=1
Reactant: OB(O)C1CC1
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2cccc23)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2cccc23)ccc1C1CC1
Temperature: 120 °C

Procedure:
To a microwave vial was added Pd-FibreCat (42 mg, 0.0065 mmol), (4-bromo-3-methoxyphenyl)(7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (63 mg, 0.13 mmol), cyclopropylboronic acid (17 mg, 0.19 mmol), DMF (0.7 mL), and K2CO3 (190 μL of 2.0 M, 0.39 mmol). The reaction vessel was purged with nitrogen and the mixture was heated at 120° C. overnight. The mixture was filtered and was purified by prep-HPLC (20-99% MeOH:H2O with HCl modifier) to give (7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-cyclopropyl-3-methoxyphenyl)methanone. ESI-MS m/z calc. 448.2, found 449.4 (M+1)+; Retention time: 3.32 minutes (4 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[C@H:11]([CH3:13])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C@H:11]([CH3:13])[C:10]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)[C@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C)Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2,4-dichlorophenol (compound 3; 3.0 g, 18.4 mmol), ethyl (S)-lactate (compound 8a; 2.39 g, 20.2 mmol, 1.1 eq), and triphenylphosphine (7.23 g, 27.6 mmol, 1.5 eq) in anhydrous THF (50 mL), diisopropylazodicarboxylate (5.46 g, 27.6 mmol, 1.5 eq) was added dropwise. The reaction mixture was stirred 16 hours at room temperature. The solvent was evaporated and the resulting residue was subjected to chromatography on silica gel with 2-5% EtOAc/hexanes. Product-containing fractions were pooled and evaporated to yield a pale yellow oil which was used without further purification: 1H NMR (CDCl3) δ 7.31 (d, 1H), 7.06 (dd, 1H), 6.75 (d, 1H), 4.70 (q, 1H), 4.21 (dq, 2H), 1.62 (d, 3H), 1.20 (t, 3H).