Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:18][CH:19]([CH3:36])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:24]=1)=[O:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:33]2[CH2:34][CH2:35][CH:30]([C:25]3[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:36])[CH:28]=[CH:27][C:26]=3[CH3:29])[CH2:31][CH2:32]2)=[CH:8][CH:7]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCNCC1
Reactant: O=Cc1ccc(Oc2ccc(F)c(F)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(Cc2ccc(Oc3ccc(F)c(F)c3)cc2)CC1
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of 4-(3,4-Difluorophenoxy)benzaldehyde (41.0 mg, 0.170 mmol) and 2-methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide (45.0 mg, 0.170 mmol) in 1,2-dichloroethane (5.00 mL) was added sodium triacetoxyborohydride (110 mg, 0.520 mmol) and AcOH (10.0 μL, 0.170 mmol) at room temperature. The mixture was stirred overnight. The reaction mixture was quenched by saturated NaHCO3 solution (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, concentrated in vacuo. The crude product was purified by preparative TLC using 5% NH3 {2.0 M in MeOH) in CH2Cl2 to give the desired product N-(3-{1-[4-(3,4-difluorophenoxy)benzyl]-4-piperidinyl}-4-methylphenyl)-2-methylpropanamide (44.0 mg, 54.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:19])[C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:20]Br>C(Cl)(Cl)(Cl)Cl>[Br:20][C:11]1[C:12]([C:13]#[N:14])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]([CH3:19])[C:10]=1[C:15]([F:18])([F:16])[F:17]
Reactant: BrBr
Reactant: Cn1c(C(F)(F)F)cc(C#N)c1-c1ccc(Cl)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1c(-c2ccc(Cl)cc2)c(C#N)c(Br)c1C(F)(F)F
Yield: 94 %

Procedure:
A solution of 2-(p-chlorophenyl)-1-methyl-5-(trifluoromethyl)pyrrole-3-carbonitrile (5.0 g, 0.0176 mol) in carbon tetrachloride is treated with bromine (56 g, 0.0351 mol), heated at reflux temperature for 8 hours, cooled, washed sequentially with water, aqueous sodium metabisulfite and water, dried over sodium sulfate and concentrated in vacuo to give a solid residue. The residue is recrystallized from heptane to give the title produce as a white solid, 6.0 g (94% yield), mp 126°-129° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1F)[N:13]([CH3:18])[C:12](=[O:19])[N:11]([OH:20])[C:10]2=[O:21].C(N(CC)CC)C>C(#N)C>[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[N:13]([CH3:18])[C:12](=[O:19])[N:11]([OH:20])[C:10]2=[O:21]
Reactant: C1CCNC1
Reactant: Cn1c(=O)n(O)c(=O)c2cc(F)c(F)cc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1c(=O)n(O)c(=O)c2cc(F)c(N3CCCC3)cc21
Yield: 38 %

Procedure:
Pyrrolidine (0.07 mL, 0.8 mmol) was added to a solution of 6,7-difluoro-3-hydroxy-1-methyl-1H-quinazoline-2,4-dione (Example L, 0.15 g, 0.66 mmol) and triethylamine (1.2 mL, 8.6 mmol) in 30 mL of acetonitrile. The solution was warmed to reflux for 18 hours, cooled, and filtered to give a solid. The solid was triturated with chloroform, filtered, and dried to give 0.07 g of the title compound as a solid, mp>250° C.
Reaction SMILES: II.[OH:3][CH2:4]/[CH:5]=[C:6](/[CH2:8][CH2:9]/[CH:10]=[C:11](/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])\[CH3:12])\[CH3:7].[CH2:19]([Sn:23]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24]I)[CH2:20][CH2:21][CH3:22]>O1CCCC1>[CH2:30]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][O:3][CH2:4][CH:5]=[C:6]([CH3:7])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:12])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:31][CH2:32][CH3:33]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: II
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 108.3 %

Procedure:
A 1.15 g (10.0 mmol) of 35% KH in mineral oil was washed with three 5 mL portions of dry hexane and suspended in 15 mL of dry tetrahydrofuran (THF) under argon. A solution of 242 mg (0.95 mmol) of iodine in 10 mL of THF was added over 50 minutes and the reaction was allowed to stir for an additional 40 minutes at room temperature to give a white suspension. (E,E)-Farnesol (1.5 g, 6.75 mmol) in 10 mL of THF was added dropwise over 15 minutes, and after 75 minutes, a solution of 2.43 g (5.64 mmol) of tributyl(iodomethyl)tin was added rapidly in 6 mL of THF. The mixture was stirred for three hours and carefully quenched with methanol Upon dilution with diethyl ether, the organic layer was washed with water and brine, dried (MgSO4) and evaporated to give 3.21 g of a pale yellow liquid The crude material was chromatographed on 720 g of silica gel eluted with 0.5:99.5 diethyl ether: petroleum ether, and the impure fractions were further purified on 150 g of silica gel eluted with 0.33:99.67 diethyl ether:petroleum ether to provide a total of 2.09 g (71%) of pure title stannane as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]([CH3:27])[C:9](=[O:26])[CH2:10][NH:11][C:12](=[O:25])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)=[CH:6][CH:5]=[C:4]([CH3:28])[C:3]=1[CH2:29]O.CS([Cl:35])(=O)=O.O>CN(C)C=O>[Cl:35][CH2:29][C:3]1[C:4]([CH3:28])=[CH:5][CH:6]=[C:7]([N:8]([C:9](=[O:26])[CH2:10][NH:11][C:12](=[O:25])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)[CH3:27])[C:2]=1[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(C)c(CO)c2C)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(C)c(CCl)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of 2,6-dimethyl-1-hydroxymethyl-3-[N-methyl-N-[4-(methylcarbamoyl) cinnamoylglycyl]amino]benzene (2.00 g) in N,N-dimethylformamide (100 ml) was added methanesulfonyl chloride (784 mg) under ice-cooling, and the mixture was stirred for 2 hours at the same temperature and overnight at ambient temperature. To the mixture was added water and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was pulverized with diethyl ether to give 1-chloromethyl-2,6-dimethyl-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzene (2.00 g) as white powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1.[NH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25].C(NC(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1
Reactant: COC(=O)CN
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)CNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(6-chloropyrimidine-4-carboxamido)-3-methylbenzene-1-sulfonyl chloride (Intermediate 30, 1.2g; 3.47 mmol) in THF (100ml) was treated with methyl 2-aminoacetate (540 mg; 4.34 mmol) and diisopropylamine (2 ml; 14.3 mmol). After stirring at RT for 18 hours the solvent was removed in vacuo and the residue redissolved in DCM and washed with water. The organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc. The title product was obtained as a white solid (1.05 g, 76%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 5.00 g (19.8 mmol) of (4′-trifluoromethylbiphenyl-4-yl)methanol in 40 ml of chloroform is mixed with 2.89 ml (39.7 mmol) of thionyl chloride dissolved in 10 ml of chloroform, and the mixture is stirred at room temperature over 12 hours. After reaction is complete, the reaction mixture is concentrated to dryness, and the residue is taken up ethyl acetate and washed with saturated sodium carbonate solution. The organic phase is subsequently separated off, dried over sodium sulfate and concentrated after filtration. The resulting crude product is purified by flash chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 9:1). 5.26 g (19.4 mmol, 98% of theory) of the title compound are obtained.
Reaction SMILES: ClC(Cl)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][C:7]=1[C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2([C:29]([F:32])([F:31])[F:30])[N:28]=[N:27]2)=[CH:22][CH:21]=1)=[O:19])=O.[C-]#[N:35].[K+]>CCO.O>[NH2:35][C:3]1[C:18]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3([C:29]([F:32])([F:31])[F:30])[N:28]=[N:27]3)=[CH:24][CH:25]=2)([OH:19])[C:7]2[C:6](=[CH:11][CH:10]=[C:9]([C:12]#[C:13][Si:14]([CH3:15])([CH3:16])[CH3:17])[CH:8]=2)[N:5]=1
Reactant: [C-]#N
Reactant: C[Si](C)(C)C#Cc1ccc(NC(=O)C(Cl)Cl)c(C(=O)c2ccc(C3(C(F)(F)F)N=N3)cc2)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)C#Cc1ccc2c(c1)C(O)(c1ccc(C3(C(F)(F)F)N=N3)cc1)C(N)=N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
2,2-dichloro-N-[2-({4-[3-(trifluoromethyl)diazirin-3-yl]phenyl}carbonyl)-4-[2-(trimethylsilyl)ethynyl]phenyl]acetamide (57 mg, 0.11 mmol, 1 eq.) was dissolved in EtOH (3 mL). Potassium cyanide (9.4 mg, 0.14 mmol, 1.3 eq.) in water (1 mL) was added to the reaction, and the reaction was stirred at room temperature for 16 hours. The EtOH was evaporated, and additional water (8 mL) was added. The reaction was then extracted three times with 5% isopropanol in DCM (20 mL each), and the organic layer was dried over sodium sulfate. The solvent was evaporated, and the residue was purified on silica column (DCM/MeOH, 39:1→19:1→9:1→4:1) to result in 39.2 mg (82%) of the title compound as a yellow solid. 1H NMR (500 MHz, CD3OD) δ 7.44 (d, J=8.5, 2H, Ar—H), 7.29 (dd, J=1.8, 8.8, 1H, Ar—H), 7.22 (d, J=8.3, 2H, Ar—H), 7.02-6.94 (m, 2H, Ar—H), 0.18 (s, 9H, SiC3H9). 13C NMR (126 MHz, CD3OD) δ 180.56 (C—NH2), 156.85 (C—Ar), 144.59 (C—Ar), 140.89 (C—Ar), 135.13 (C—Ar), 129.58 (C—Ar), 127.89 (d, J=0.88, C—Ar), 127.66 (C—Ar), 126.99 (C—Ar), 123.70 (q, J=273.80, CF3), 117.82 (C—Ar), 116.69 (C—Ar), 107.08 (CSi(CH3)3), 92.94 (CCSi(CH3)3), 84.20 (Ar—COH), 29.55 (q, J=40.25, CN2), 0.23 (Si(CH3)3). Exact Mass, 428.13.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:10]=2[C:11](O)=[O:12])=O)=[CH:5][CH:4]=1.O.[NH2:22][NH2:23]>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]2[C:9]3[C:10](=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[C:11](=[O:12])[NH:23][N:22]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc(C)cc2C(=O)O)cc1
Reactant: NN
Solvent: O
Product: COc1ccc(-c2n[nH]c(=O)c3cc(C)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 2-(4-methoxybenzoyl)-5-methylbenzoic acid with hydrazine hydrate.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:36])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]=3[CH2:27][CH2:28][CH3:29])=[O:21])[CH:14]=2)[CH:9]=1.O.Cl>CO>[C:30]1([N:25]2[C:26]([CH2:27][CH2:28][CH3:29])=[C:22]([C:20]([NH:19][CH2:18][C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH:9]=[C:8]([O:7][CH2:6][C:5]([OH:36])=[O:4])[CH:17]=[CH:16]4)=[O:21])[CH:23]=[N:24]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCc1c(C(=O)NCc2ccc3cc(OCC(=O)OC)ccc3c2)cnn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCc1c(C(=O)NCc2ccc3cc(OCC(=O)O)ccc3c2)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
1 N NaOH (431 μL, 0.431 mmol) was added under nitrogen to a solution at room temperature of (6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic acid methyl ester (170 mg, 0.359 mmol), prepared in the previous step, in 25 mL of MeOH plus 10 mL of water. After the addition the reaction was stirred at room temperature for 18 h (overnight). The reaction was acidified with 1 N HCl and then concentrated under reduced pressure to remove the MeOH. The solid present was collected by filtration and dried under reduced pressure to give the title compound (146 mg, 92%) as an off-white solid, mp 175-177° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=[O:7].C1CCN2C(=NCCC2)CC1.[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[C:24]([S:29][CH3:30])[N:23]=1.Cl>CN(C=O)C>[Cl:21][C:22]1[CH:27]=[C:26]([NH:9][NH:8][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[N:25]=[C:24]([S:29][CH3:30])[N:23]=1
Reactant: NNC(=O)c1ccco1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CSc1nc(Cl)cc(NNC(=O)c2ccco2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
Into 150 mL of DMF, 65 g (515 mmol) of 2-furoic hydrazide and 70 mL (510 mmol) of DBU were dissolved, and a DMF solution of 4,6-dichloro-2-methylthiopyrimidine (50.0 g (256 mmol)/100 mL) was slowly added dropwise thereto at room temperature (inner temperature was controlled at 45° C. or lower). After stirring at room temperature for about 2 hours, the reaction solution was poured into ice-water and the pH was adjusted to 6 to 7 with a 2 mol/L hydrochloric acid solution, followed by collecting the resulting solid through filtration. The collected solid was dissolved into an organic solvent (chloroform/methanol=10/1) and, after washing with water, the solution was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was triturated twice with chloroform to obtain 56.9 g of Compound A as white flocculent crystals (yield: 78%). The residue obtained by concentrating the filtrate was purified by silica gel column chromatography (hexane/ethyl acetate=6/4) to additionally recover Compound A in about 10% yield.
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][CH:34]4[CH2:38][O:37][C:36]([CH3:40])([CH3:39])[O:35]4)[C:31]([CH2:41][O:42][CH2:43][CH3:44])=[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+:46].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][CH:34]4[CH2:38][O:37][C:36]([CH3:39])([CH3:40])[O:35]4)[C:31]([CH2:41][O:42][CH2:43][CH3:44])=[N:30][C:25]=3[C:26]([NH2:46])=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC1COC(C)(C)O1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC1COC(C)(C)O1
Reaction time: 2 h

Procedure:
3-Chloroperoxybenozic acid (mCPBA) (75% pure, 11.57 g, 50.27 mmol, 1.5 eq) was added to a solution of 7-benzyloxy-1-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (15.00 g, 33.52 mmol. 1 eq) in dichloromethane (200 mL), and the reaction mixture was stirred for two hours. Analysis by thin layer chromatography indicated the reaction was incomplete and additional mCPBA (1.2 g) was added and the reaction was stirred overnight. The reaction mixture was diluted with dichloromethane (300 mL), washed sequentially with 4% aqueous sodium carbonate solution (2×300 mL) and brine (300 mL), and concentrated under reduced pressure to afford a residue. Concentrated ammonium hydroxide (75 mL) was then added to a mixture of the residue in dichloromethane (200 mL) and cooled to 4° C. p-Toluenesulfonyl chloride (2.75 g, 14.44 mmol, 1.1 eq) was added in portions to the reaction mixture and stirred at ambient temperature for 16 hours. The reaction mixture was then diluted with dichloromethane (200 mL), washed with 4M aqueous sodium carbonate solution and separated. The aqueous layer was re-extracted with dichloromethane (200 mL) and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a brown solid. The crude material was purified by crystallization from diethyl ether to provide 9.8 g of 7-benzyloxy-1-[(2,2-dimethyl[1,3]dioxolan-4yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-ylamine as white plates of solid, mp 186-187° C. 1H-NMR (300 MHz, CDCl3) δ 7.89 (d, J=9.1 Hz, 1H), 7.53-7.29 (m, 6H), 7.05 (dd, J=9.0, 2.6 Hz, 1H), 5.42 (br s, 2H), 5.18 (s, 2H), 4.94 (d, J=12.6 Hz, 1H), 4.83-4.69 (m, 3H), 4.68-4.58 (m, 1H), 4.15 (dd, J=8.6, 6.2 Hz, 1H), 3.86 (dd, J=8.6, 6.1 Hz, 1H), 3.62 (q, J=7.0 Hz, 2H), 1.45 (s, 3H), 1.29 (s, 3H), 1.25 (t, J=7.0 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 158.3, 151.7, 149.0, 147.1, 136.8, 134.7, 128.6, 128.0, 127.6, 125.4, 120.9, 113.8, 110.2, 109.7, 108.9, 74.6, 70.0, 66.7, 66.3, 65.3, 48.2, 26.7, 25.1, 15.0; MS (APCI) m/z 463.1 (M+H)+; Anal, calcd for C26H30N4O4: C, 67.51; H, 6.54; N, 12.11. Found: C, 67.29; H, 6.33; N, 12.03.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([NH:10][CH:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[O:20][CH3:21])[CH2:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=1>>[CH3:21][O:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:11]([NH:10][C:7]1[O:8][CH2:9][C:4]3[CH:3]=[C:2]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[N:26]=4)[CH:23]=[CH:22][C:5]=3[N:6]=1)[CH2:12][CH2:13]2
Reactant: COc1cccc2c1C(NC1=Nc3ccc(Br)cc3CO1)CC2
Reactant: Nc1cccc(C(F)(F)F)n1
Product: COc1cccc2c1C(NC1=Nc3ccc(Nc4cccc(C(F)(F)F)n4)cc3CO1)CC2
Yield: 63.4 %

Procedure:
The title compound (144 mg, 63%), light brown foam, MS (ISP): m/e=455.3 (M+H+), was prepared in accordance with the general method of Example 35 from rac-(6-bromo-4H- benzo[d][1,3]oxazin-2-yl)-(7-methoxy-indan-1-yl)-amine (Example 74) (187 mg, 0.5 mmol) an commercially available 2-amino-6-trifluoromethyl-pyridine (162 mg, 1.0 mmol).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:3][NH:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[NH:17]1[C:21](=[O:22])[CH2:20][CH2:19][C@H:18]1[C:23](O)=[O:24].O.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:15][CH:14]([CH3:16])[CH2:13][CH:2]([NH:1][C:23]([CH:18]1[CH2:19][CH2:20][C:21](=[O:22])[NH:17]1)=[O:24])[CH2:3][NH:4][CH2:5][C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: CC(C)C[C@H](N)CNCC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC(CNCC(=O)OC(C)(C)C)NC(=O)C1CCC(=O)N1
Reaction time: 0.5 h

Procedure:
A solution of 1.54 g of (S)-N-(2-amino-4-methylpentyl)glycine, 1,1-dimethylethyl ester, 890 mg of L-pyroglutamic acid, and 904 mg of hydroxybenzotriazole, hydrate in 30 ml of N,N-dimethylformamide is cooled in ice and treated dropwise with a solution of 1.4 g of N,N'-dicyclohexylcarbodiimide in 5 ml of N,N-dimethylformamide. After stirring at 0° for 0.5 hours, the mixture is kept at room temperature overnight. The mixture is filtered and the solvent distilled off under high vacuum. The residue is taken up in ethyl acetate and the ethyl acetate washed two times with water. The water is adjusted to pH 6 and lyophilized. The residue is chromatographed on 95 g of silica gel eluting with chloroform/methanol, (94:6). Combining the appropriate fractions gives 1.2 g of [S-(R*,R*)]-N-[4-methyl-2-[[(5-oxo-2-pyrrolidinyl]carbonyl)amino]pentyl]glycine, 1,1-dimethylethyl ester. The product is homogeneous by thin layer chromatography.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](Cl)=[O:10])=[CH:5][CH:4]=1.[CH:16]([N:19]([CH3:30])[C:20]1[S:21][C:22]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=2[N:24]=1)([CH3:18])[CH3:17]>>[CH:16]([N:19]([CH3:30])[C:20]1[S:21][C:22]2[CH:28]=[C:27]([NH:29][C:9](=[O:10])[CH:8]=[CH:7][C:6]3[CH:12]=[CH:13][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=3)[CH:26]=[CH:25][C:23]=2[N:24]=1)([CH3:18])[CH3:17]
Reactant: O=C(Cl)C=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)N(C)c1nc2ccc(N)cc2s1
Product: CC(C)N(C)c1nc2ccc(NC(=O)C=Cc3ccc(C(F)(F)F)cc3)cc2s1
Yield: 25.9 %

Procedure:
Prepare according to Method D (Example 17), using 4-trifluoromethylcinnamoyl chloride (526 mg, 2.24 mmol) (Example 17) and N2-isopropyl-N2-methyl-benzothiazole-2,6-diamine (332 mg, 1.50 mmol), to afford the title compound (163 mg, 26%). mass spectrum (m/e): 420.2 [M+H], 418.2 [M−H]. 1H NMR (400 MHz, DMSO-d6): δ 10.30 (s, 1H), 8.25 (d, 1H, J=1.8 Hz), 7.87-7.78 (m, 4H), 7.64 (d, 1H, J=15.8 Hz), 7.43 (dd, 1H, J=8.6, 1.9 Hz), 7.39 (d, 1H, J=8.4 Hz), 6.96 (d, 1H, J=15.4 Hz), 4.32 (m, 1H), 2.97 (s, 3H), 1.22 (d, 6H, J=7.0 Hz).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:17]([N+:18]([O-])=O)=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH:22][C:23]1[CH:33]=[CH:32][C:26]([C:27](=N)OCC)=[CH:25][CH:24]=1>CO>[CH:1]1([N:7]2[C:8]3=[N:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:16]=[C:17]3[N:18]=[C:27]2[C:26]2[CH:32]=[CH:33][C:23]([OH:22])=[CH:24][CH:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=N)c1ccc(O)cc1
Reactant: COC(=O)c1cnc(NC2CCCCC2)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cnc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A solution of intermediate 58 (5.0 g, 20.0 mmol) and ethyl 4-hydroxybenzimidate hydrochloride (6.0 g, 30.0 mmol) in methanol (67 mL) was heated at reflux for 22 h. The reaction mixture was then cooled to rt and the precipitated solid was collected by vacuum filtration and washed sparingly with cold methanol to afford intermediate 59 as a white solid (6.13 g, 88%). ESI-MS m/e 352.2 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[CH3:40][CH:41]([CH3:45])[CH2:42][CH2:43][NH2:44]>CN(C)C=O>[F:1][C:2]1[C:3]([C:8]([NH:44][CH2:43][CH2:42][CH:41]([CH3:45])[CH3:40])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1F
Reactant: CC(C)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)c1ncccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of 3-fluoro-pyridine-2-carboxylic acid (0.50 g, 3.54 mmol) in dimethylformamide (6 ml) are added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (3.41 g, 10.63 mmol) and N-methylmorpholine (1.56 ml, 14.2 mmol) at 0° C. followed by the addition of 3-methyl-butyl-amine (0.61 ml, 5.32 mmol). The reaction mixture is stirred at RT for 2 h. After completion of the reaction, the mixture is poured onto ice-water, extracted with EtOAc (3×50 ml). The combined organic layers are washed with brine (50 ml), dried over sodium sulfate and evaporated to dryness to yield the crude product, which is purified by column chromatography (silica gel, 50% EtOAc/hexane) affording 3-fluoro-N-(3-methyl-butyl)-pyridine-2-carboxylic acid amide (0.31 g, 1.47 mmol, 42%).