Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][CH:13]=[N:12][C:11]=3Br)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl-].[NH4+:17]>C1COCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][CH:13]=[N:12][C:11]=3[C:8]3[CH:9]=[CH:4][CH:5]=[CH:6][N:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: [NH4+]
Reactant: Brc1ncoc1-c1ccc2c(c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc(-c2ncoc2-c2ccc3c(c2)OCO3)nc1
Temperature: 25 °C
Yield: 46 %

Procedure:
To a degassed solution of 5-benzo[1,3]dioxol-5-yl-4-bromo-oxazole (50 mg, 0.19 mmol) and tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.009 mmol, 0.05 equiv) in THF (2 mL) was added 2-zinc bromo -pyridine (1 mL, 0.5 M in THF, 0.500 mmol, 2.6 equiv). The resulting reaction mixture was heated to reflux overnight, cooled to ambient temperature, treated with saturated aqueous ammonium chloride, and diluted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography (50% ethyl acetate in hexane) provided 2-(5-Benzo[1,3]dioxol-5-yl-oxazol4-yl)-pyridine (22.7 mg, 46%). [LCMS: Rt=1.79 min, M+H=267.1]
Reaction SMILES: C[O-].[Na+].[CH2:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([O:15]C(=O)CC2C3C=CC=CC=3OC3C2=CC=CC=3)[CH2:13][CH3:14])[C:7]=1[NH:33][C:34](=[O:50])[CH2:35][CH:36]1[C:49]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[O:43][C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:5].O>C(OCC)C>[CH2:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([OH:15])[CH2:13][CH3:14])[C:7]=1[NH:33][C:34](=[O:50])[CH2:35][CH:36]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=2[O:43][C:44]2[C:49]1=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH3:5]
Reactant: CCc1cccc(C(CC)OC(=O)CC2c3ccccc3Oc3ccccc32)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCc1cccc(C(O)CC)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 600 °C
Reaction time: 4 h

Procedure:
9.6 mg (0.18 mmol) of sodium methoxide were added to 3 ml of a methanolic solution containing 37 mg (0.060 mmol) of N-(2-ethyl-6-{1-[2-(9H-xanthen-9-yl)acetoxy]propyl}phenyl)-2-(9H-xanthen-9-yl)acetamide (prepared as described in Preparation 55). The mixture was then stirred for 4 hours at 600° C. At the end of this time, the reaction solution was diluted with diethyl ether. Water was then added to the reaction mixture, and the title compound was distributed between the organic solvent and the water. The organic layer was then separated and washed with water 3 times. The solvent was removed by distillation under reduced pressure, and the resulting residue was subjected to column chromatography through 5 g of silica gel. Elution with mixtures of methylene chloride and ethyl acetate ranging from 10:1 to 5:1 by volume afforded 21 mg (yield 89%) of the title compound as crystals, melting at 167°-168° C. (after recrystallization from a mixture of diethyl ether and hexane).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.C(O[C:16]([C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:27]=1[Cl:28])=[CH:25][CH:24]=[CH:23][C:22]=2[C:29]([F:32])([F:31])[F:30])=[O:17])C.O>C1COCC1>[Cl:28][C:27]1[C:26]2[C:21](=[C:22]([C:29]([F:30])([F:31])[F:32])[CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][C:18]=1[C:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:17]
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1Cl
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
2-Bromopyridine (0.74 mL, 7.90 mmol) was taken into THF (30 mL) and cooled to −78° C. Then BuLi (4.8 mL, 7.90 mmol, 1.6 M solution in hexane) was added dropwise and then stirred for 30 minutes. Next, 4-Chloro-8-(trifluoromethyl)-3-quinolinecarboxylic acid ethyl ester (2.0 g, 6.58 mmol) in THF (10 mL) was added rapidly and stirred at −78° C. for 4 hours. The reaction was poured into water/saturated NH4Cl solution and then extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated. The resulting material was purified via column chromatography using 15% ethyl acetate in hexane as the eluent to yield 0.823 g of (4-chloro-8-trifluoromethyl-quinolin-3-yl)-pyridin-2-yl-methanone as a yellow solid.
Reaction SMILES: [N:1]#[C:2][NH2:3].[F:4][C:5]([F:14])([F:13])[C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9].[N+:15]([O-:18])([OH:17])=[O:16]>C(O)C>[N+:15]([O-:18])([OH:17])=[O:16].[F:4][C:5]([F:13])([F:14])[C:6]1[CH:7]=[C:8]([NH:9][C:2]([NH2:3])=[NH:1])[CH:10]=[CH:11][CH:12]=1
Reactant: N#CN
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N=C(N)Nc1cccc(C(F)(F)F)c1

Procedure:
6.3 g (150 mmol) of cyanamide (50% in water) are added to a suspension of 16.1 g (100 mmol) of 3-trifluoromethyl-aniline in 35 ml of ethanol. 7.0 ml of nitric acid (65%, 0.1 mol) are then added to the brown solution and the reaction mixture is heated for 20 h under RF. It is then cooled to 0° and filtered, and the material retained on the filter is washed with ethanol and dried at 60° under HV to give 3-trifluoromethyl-phenylguanidine nitrate; 1H-NMR (dimethyl sulfoxide): 7.6 (7H,m), 9.9 (1H,br,s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([OH:12])=[O:11])[S:5][C:6]=1[CH2:7][CH2:8][CH3:9].S(=O)(=O)(O)O.O.[CH3:19]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]([O:12][CH3:19])=[O:11])[S:5][C:6]=1[CH2:7][CH2:8][CH3:9]
Reactant: CO
Reactant: CCCc1sc(C(=O)O)cc1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCc1sc(C(=O)OC)cc1Br
Temperature: 50 °C
Reaction time: 36 h
Yield: 93 %

Procedure:
To a solution of 4-bromo-5-propyl-2-thiophenecarboxylic acid (5.0 g, 20.07 mmol) in methanol (100 ml) was added sulfuric acid (5.35 ml, 100 mmol). The resulting solution stirred at 50° C. for 36 h. H2O (50 mL) was added the aqueous phase was washed several times with DCM. The combined organic fractions were washed with saturated NaHCO3, dried over Na2SO4, concentrated and used directly without further purification providing methyl 4-bromo-5-propyl-2-thiophenecarboxylate (5.1 g, 18.61 mmol, 93% yield) as a yellow oil: LCMS (ES) m/e 262, 264 (M, M+2)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([B:21]([OH:26])[OH:22])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(OCc2ccccc2)c1
Yield: 55.6 %

Procedure:
Prepared according to the method described in Example 51b) from 3-(benzyloxy)bromobenzene (2.16 g, Example 93a), n-butyllithium (2.5 M in hexanes, 3.6 ml) and triisopropyl borate (3.4 g), in tetrahydrofuran (2×10 ml). After work up the residue was purified by column chromatography over silica eluting with ethyl acetate:hexane:acetic acid (20:79.5:0.5) then methanol to give the sub-title compound as a white solid (1.04 g). This was used without analysis.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH2:25](Br)[CH3:26]>>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH3:26])[N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(CCNC(=O)c2n[nH]c3ccccc23)CC1
Reactant: CCBr
Product: CCCCN1CCN(CCNC(=O)c2nn(CC)c3ccccc23)CC1

Procedure:
The title compound was synthesized by using N-(2-(4-n-butyl-1-piperazinyl)ethyl]-1H-indazole-3-carboxamide obtained in Example 10 and ethyl bromide according to the same process as in Example 12.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1>>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: NCc1cccnc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: Clc1nc(Cl)nc(NCc2cccnc2)n1

Procedure:
Following the general procedure A, 2,4,6-trichloro-1,3,5-triazine was coupled with 3-aminomethylpyridine with reaction time of 2 h. Purification by column chromatography gave the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(O)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 193.8 %

Procedure:
To a solution of 1-benzyl-4-methyl-4-piperidinol (3.6 g, 17.5 mmol) in 75 mL of benzene was added AlCl3 (11.7 g, 87.7 mmol) in one portion at room temperature. After stirring at room temperature for 30 min, the reaction mixture was heated to reflux for 8 h. The red colored solution was allowed to cool and then poured over 100 g of ice-water. It was extracted with EtOAc (2×100 mL) and the organic layer was washed with solution of Rochelle's salt. The organic layer was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo to obtain 1-benzyl-4-methyl-4-phenylpiperidine as a red oil (4.5 g, 97% yield). It was used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1([F:17])[CH2:9][CH2:8][C:7]([CH2:15][F:16])([C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5]1>C1COCC1.CO>[F:3][C:4]1([F:17])[CH2:5][CH2:6][C:7]([CH2:15][F:16])([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]1
Reactant: CCOC(=O)C1(CF)CCC(F)(F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(CF)CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
1 N NaOH (0.994 mL, 0.994 mmol) was added to a solution of ethyl 4,4-difluoro-1-(fluoromethyl)cyclohexanecarboxylate (73.6 mg, 0.331 mmol) in THF (1 mL) and MeOH (1 ml) and the mixture was stirred at rt for 3-4 h. The reaction mixture was acidified and extracted with EtOAc, washed with brine and dried (MgSO4). Evaporation of the solvent afforded Cap-7 as a beige solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.38 (d, J=47.1 Hz, 2H), 2.30-2.16 (m, 2H), 2.11-1.98 (m, 2H), 1.96-1.76 (m, 2H), 1.65-1.51 (m, 2H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:19]1([C:25](=[O:29])[C:26](=[O:28])[CH3:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCCCCC>[OH:29][C:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:26](=[O:28])[CH3:27])[C:2]([CH3:3])([CH3:4])[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:5]
Reactant: CCCCCCCCCCCCOC(=O)C(C)C
Reactant: CC(=O)C(=O)c1ccccc1
Solvent: CCCCCC
Product: CCCCCCCCCCCCOC(=O)C(C)(C)C(O)(C(C)=O)c1ccccc1
Yield: 31.6 %

Procedure:
The reaction of dodecyl isobutyrate (6.4 g, 0.025 mole) with 1-phenyl-1,2-propanedione (3.7 g, 0.025 mole) is conducted in the manner described in Example I. Thin layer chromatography of the crude reaction mixture indicated the presence of two main reaction products. High pressure liquid chromatography on silica gel using 2% ethyl acetate in hexane as the eluant yields pure dodecyl 3-hydroxy-2,2-dimethyl-4-oxo-3-phenylpentanoate (IVa) (3.2 g, 32%), b.p. 148° C. (Kugelrohr air bath temperature) at 0.005 mm Hg. Also recovered is pure dodecyl 3-hydroxy-2,2,3-trimethyl-4-oxo-4-phenylbutyrate (IVb) (3.5 g, 35%), b.p. 145° C. (Kugelrohr air bath temperature) at 0.005 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[S:5][C:6]=1[C:7](=[O:16])[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15].[CH3:27][N:28]1[C:32]([CH2:33][NH2:34])=[CH:31][N:30]=[CH:29]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:34][CH2:33][C:32]3[N:28]([CH3:27])[CH:29]=[N:30][CH:31]=3)=[O:24])=[CH:20][CH:19]=2)[S:5][C:6]=1[C:7](=[O:16])[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15]
Reactant: Nc1nc(Nc2ccc(C(=O)O)cc2)sc1C(=O)c1c(F)cccc1F
Reactant: Cn1cncc1CN
Product: Cn1cncc1CNC(=O)c1ccc(Nc2nc(N)c(C(=O)c3c(F)cccc3F)s2)cc1

Procedure:
The title compound was prepared in a manner analogous to Step 3 of Method A, from 4-[4-amino-5-(2,6-difluoro-benzoyl)-thiazol-2-ylamino]-benzoic acid (3) and C-(3-methyl-3H-imidazol-4-yl)-methylamine. Purified via preparative HPLC.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([C:24]([C@H:26]1[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]1)=[O:25])[C:10]1[CH:14]=[C:13]([C:15]#[C:16][C:17]([CH3:20])([CH3:19])[CH3:18])[S:12][C:11]=1[C:21]([OH:23])=[O:22])(C)(C)C.CCN(CC)CC.F.F.F>C1COCC1>[CH3:19][C:17]([CH3:18])([CH3:20])[C:16]#[C:15][C:13]1[S:12][C:11]([C:21]([OH:23])=[O:22])=[C:10]([N:9]([CH2:8][CH2:7][OH:6])[C:24]([C@H:26]2[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])[CH:14]=1
Reactant: CC(C)(C)C#Cc1cc(N(CCO[Si](C)(C)C(C)(C)C)C(=O)[C@H]2CC[C@H](C)CC2)c(C(=O)O)s1
Agent: F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C#Cc1cc(N(CCO)C(=O)[C@H]2CC[C@H](C)CC2)c(C(=O)O)s1
Reaction time: 1 h

Procedure:
3-[[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid (273 mg) in THF (4 mL) was treated with triethylaminetrihydrofluoride (0.5 mL). After 1 hour, volatiles were removed under vacuum and the residue was purified by silica gel chromatography (0-10% Methanol:DCM) to provide 83 mg of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(2-hydroxy-ethyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]=[C:13]1[NH:17][CH2:16][C:15]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[S:14]1)[CH3:2].[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([N:17]2[CH2:16][C:15]3([CH2:21][CH2:20][CH2:19][CH2:18]3)[S:14][C:13]2=[N:12][C:4]2[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=2[CH2:1][CH3:2])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: BrC1CCCC1
Reactant: CCc1cc([N+](=O)[O-])ccc1N=C1NCC2(CCCC2)S1
Product: CCc1cc([N+](=O)[O-])ccc1N=C1SC2(CCCC2)CN1C1CCCC1

Procedure:
2- Ethylaniline was converted to 2-ethylacetanilide according to Method A2a, Step 1. The acetanilide was converted to 2-ethyl-4-nitroacetanilide according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 2-ethyl-4-nitroaniline. The aniline was converted to 2-ethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 2-ethyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-ethyl-4-nitrophenylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to afford 3-cyclopentyl-2-(2-ethyl-4-nitrophenylimino)-1-thia-3-azaspiro[4.4]nonane.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25](O)=[O:26])=[CH:5][C:4]=2[N:3]=1.ON1C2C=CC=CC=2N=N1.[CH3:38][N:39](C)[CH2:40]CCN=C=NCC.Cl.CNC>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]([N:39]([CH3:40])[CH3:38])=[O:26])=[CH:5][C:4]=2[N:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COCc1nc2c(N)nc3cc(CCC(=O)O)ccc3c2n1CC(C)(C)O
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: COCc1nc2c(N)nc3cc(CCC(=O)N(C)C)ccc3c2n1CC(C)(C)O
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
3-[4-Amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoic acid (1.25 g, 3.30 mmol), anhydrous pyridine (75 mL) and 1-hydroxybenzotriazole (892 mg, 6.60 mmol) were combined and the reaction was stirred for 30 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (1.27 g, 6.60 mmol) was added and the reaction mixture was stirred for an additional 15 minutes. Dimethylamine hydrochloride (540 mg, 6.60 mmol) was added in one portion and the reaction was stirred for an additional 4 hours. The solution was concentrated under reduced pressure and the resulting oil was dissolved in chloroform (50 mL) and washed with 1% aqueous sodium carbonate (3×25 mL). The combined aqueous washes were extracted with chloroform. The combined organic fractions were purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient; 0-25% CMA over 1500 mL, followed by 25-30% CMA over 1000 mL) followed by recrystallization from acetonitrile to provide 931 mg of 3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N,N-dimethylpropanamide as a white solid, mp 142-145° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH:13]([O:15]C(Cl)Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:13]=[O:15])=[C:7]([OH:11])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: ClC(Cl)OC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C=O)c(O)c1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
A stirred, cooled (ice bath) solution of 3-tert-butyl phenol (1.5 g, 10 mmol) in anhydrous dichloromethane was treated with titanium tetrachloride (1.86 mL, 17 mmol) followed by . . . ,-dichloromethyl ether (0.9 mL, 20 mmol). The reaction was allowed to warm to ambient temperature over 1 h, quenched cautiously with ice and water and extracted with dichloromethane. The organic extract was washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column_chromatography using 2-2.5% ethyl acetate in hexane as the eluent to afford the title compound (1.37 g, 77%). 1H NMR (300 MHz, CDCl3): δ 11.02(s, 1H), 9.81(s, 1H), 7.45(d, J=8.2 Hz, 1H), 7.03(dd, J=8.2, 1.7 Hz, 1H), 6.99(d, J=1.7 Hz, 1H), 1.31(s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:11][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[NH2:1]
Reactant: Nc1ncccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cccnc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
A suspension of 2-aminonicotinic acid (833 mg, 6.00 mmol) and potassium carbonate (912 mg, 6.60 mmol) in dimethylformamide (DMF, 8.5 ml) was heated to reflux. The reaction mixture was cooled to room temperature and 415 μl of iodomethane (6.60 mmol) were added. The mixture was then refluxed under stirring for 18 h; after subsequent cooling, the mixture was finally filtered and the filtrate was concentrated under reduced pressure. The crude product was purified is by flash chromatography on silica gel (ethyl acetate/petroleum ether=7/3). The isolated 2-aminonicotinic acid methyl ester was obtained in 58% yield.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:29][O:30][C@H:31]([C:33]1[NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[N:34]=1)[CH3:32]>>[CH3:29][O:30][C@H:31]([C:33]1[N:34]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:16][CH:15]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)[CH3:32]
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)ccc2n1
Reactant: CO[C@@H](C)c1nc2ccccc2[nH]1
Product: CO[C@@H](C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)ccc2n1

Procedure:
Following General procedure D, 4-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)azetidin-3-yl)morpholine from Example 126 was reacted with (S)-2-(1-methoxyethyl)-1H-benzo[d]imidazole to give 150. 1H NMR (400 MHz, DMSO) δ 8.18 (d, J=8.6 Hz, 1H), 8.01 (dd, J=6.7, 1.8 Hz, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.73 (dd, J=6.7, 2.1 Hz, 1H), 7.38-7.24 (m, 2H), 5.50 (q, J=6.4 Hz, 1H), 4.53 (br s, 4H), 3.92-3.79 (m, 6H), 3.63-3.52 (m, 4H), 3.45 (t, J=6.2 Hz, 2H), 3.09 (s, 3H), 2.97 (overlapping m, 3H), 2.25 (br s, 4H), 1.63 (d, J=6.4 Hz, 3H). LCMS: 345.3
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C@@H:17]2[CH2:22][CH2:21][C@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]2)=[CH:13][C:12]([C:31]2[CH:36]=[C:35]([F:37])[C:34]([OH:38])=[C:33]([F:39])[CH:32]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[NH2:23][C@@H:20]1[CH2:21][CH2:22][C@H:17]([NH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:31]4[CH:32]=[C:33]([F:39])[C:34]([OH:38])=[C:35]([F:37])[CH:36]=4)[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(F)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(F)c4)cc23)CC1
Yield: 60.2 %

Procedure:
Following general procedure A-2, tert-butyl cis-4-[3-(cyclopropanecarbonyl)-6-(3,5-difluoro-4-hydroxyphenyl)quinolin-4-ylamino]cyclohexylcarbamate (51 mg, 0.095 mmol) was reacted with TFA (2 mL) to afford the desired product (25 mg, 52%) as a light yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.27 (s, 1H), 8.37 (d, J=1.7 Hz, 1H), 8.06 (dd, J=8.8, 1.9 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.33 (dd, J=8.1, 1.6 Hz, 2H), 4.73 (s, 1H), 2.97-2.86 (m, 1H), 2.16 (d, J=9.1 Hz, 2H), 2.09-1.97 (m, 5H), 1.91-1.76 (m, 2H), 1.27-1.20 (m, 2H), 1.20-1.10 (m, 2H); ESI MS m/z 438 [C25H25F2N3O2+H]+; HPLC>99% (AUC), tR=5.12 min.
Reaction SMILES: [OH:1][N:2]=[C:3]([O:5][CH2:6][CH3:7])[CH3:4].[H-].[Na+].Cl[C:11]1[N:16]([C:17]2[CH:22]=[C:21]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N+:30]([O-:32])=[O:31])[C:20]([Cl:33])=[CH:19][C:18]=2[F:34])[C:15](=[O:35])[CH:14]=[C:13]([C:36]([F:39])([F:38])[F:37])[N:12]=1.O>O1CCCC1>[Cl:33][C:20]1[C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])=[CH:22][C:17]([N:16]2[C:15](=[O:35])[CH:14]=[C:13]([C:36]([F:38])([F:39])[F:37])[N:12]=[C:11]2[O:1][N:2]=[C:3]([O:5][CH2:6][CH3:7])[CH3:4])=[C:18]([F:34])[CH:19]=1
Reactant: O=c1cc(C(F)(F)F)nc(Cl)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F
Reactant: CCOC(C)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(C)=NOc1nc(C(F)(F)F)cc(=O)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F
Temperature: 0 °C
Yield: 85 %

Procedure:
Ethyl N-hydroxyacetimidate(0.23 g, 0.002 mol) was added dropwise to a suspension of sodium hydride(008 g, 0.002 mol) in tetrahydrofuran(5 ml) with stirring at 0° C. 2-Chloro-3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-4(3H)-pyrimidinone(0.93 g, 0.002 mol) was added to the mixture at 0° C., and the mixture was stirred at 0° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate solution was concentrated and purified by column chromatography on silica gel(20% ethyl acetate/hexane) to give compound II-1 (0.90 g, yield 85%) as a white solid, m.p.152-155° C.