Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[C:16]1[N:12]([CH:13]=[C:14]([C:20]3[N:24]([CH2:25][CH:26]([O:28][CH3:29])[CH3:27])[N:23]=[CH:22][N:21]=3)[N:15]=1)[CH2:11][CH2:10][O:9]2)=[CH2:5])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:29][O:28][CH:26]([CH3:27])[CH2:25][N:24]1[C:20]([C:14]2[N:15]=[C:16]3[N:12]([CH:13]=2)[CH2:11][CH2:10][O:9][C:8]2[C:17]3=[CH:18][CH:19]=[C:6]([C:4](=[O:3])[CH3:5])[CH:7]=2)=[N:21][CH:22]=[N:23]1
Reactant: C=C(OCC)c1ccc2c(c1)OCCn1cc(-c3ncnn3CC(C)OC)nc1-2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: COC(C)Cn1ncnc1-c1cn2c(n1)-c1ccc(C(C)=O)cc1OCC2
Temperature: 60 °C
Reaction time: 1.25 h
Yield: 90.7 %

Procedure:
A mixture of 12-(1-ethoxyethenyl)-4-[1-(2-methoxypropyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (190 mg, 0.480 mmol) and p-toluenesulfonic acid (11 mg, 0.060 mmol) in acetone (10 mL) was stirred at 60° C. for 75 min. The solid was filtered off and the filtrate was concentrated. The residue was purified by reverse phase Combiflash eluting with a 0-40% gradient of CH3CN in 0.3% NH4HCO3 to afford 1-{4-[1-(2-methoxypropyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-12-yl}ethan-1-one (160 mg, 91% yield). LCMS (ESI) m/z: 368.1 [M+H+]
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[N:7][C:8]=1[Cl:9].CCN(CC)CC.Cl[C:31]([O:33][CH3:34])=[O:32]>C(Cl)Cl>[C:16]([N:13]1[CH2:14][CH2:15][C@H:12]1[CH2:11][O:10][C:5]1[CH:6]=[N:7][C:8]([Cl:9])=[C:3]([CH2:2][NH:1][C:31]([O:33][CH3:34])=[O:32])[CH:4]=1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CN)c1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
5-Aminomethyl-3-(1-BOC-2-(S)-azetidinylmethoxy)-6-chloropyridine (0.23 g, 0.70 mmol) from Example 92b in CH2Cl2 (5 mL) at 0° C. was treated with NEt3 (0.2 mL, 1.40 mmol) and methyl chloroformate (0.061 mL, 0.80 mmol). The mixture was allowed to warm to room temperature and stir for 1 h. The volatile components were evaporated and the residue was chromatographed (silica gel; MeOH/CH2Cl2, 1:19) to afford the title compound as a yellow oil (0.22 g, 82%). 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.28-2.35 (m, 2H), 3.71 (s, 3H), 3.89 (t, J=7.5 Hz, 2H), 4.10 (dd, J=3.0, 10.0 Hz, 1H), 4.36 (m, 1H), 4.40 (d, J=6.5 Hz, 2H), 4.54 (m, 1H), 7.35 (d, J=3.5 Hz, 1H), 8.01 (d, J=3.0 Hz, 1H); MS (CI/NH3) m/z 386 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.[OH-].[K+]>CN(C=O)C.O.[Cu-]=O>[Cl:1][C:2]1[CH:7]=[C:6]([S:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: COc1ccc(S)cc1
Reactant: CC(=O)c1c(C)cc(I)cc1Cl
Agent: O=[Cu-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Sc2cc(C)c(C(C)=O)c(Cl)c2)cc1
Yield: 13.5 %

Procedure:
A mixture of 1-(2-chloro-4-iodo-6-methylphenyl)ethanone (3-1, 0.720 g, 2.44 mmol), 4-methoxybenzenethiol (0.45 mL, 3.7 mmol), copper(I) oxide (17.0 mg, 0.12 mmol), and potassium hydroxide (0.34 g, 6.1 mmol) in DMF (2.2 mL) and H2O (0.5 mL) was heated at reflux for 20 h. The mixture was quenched with H2O and extracted with ethyl acetate. The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to provide 1-(2-chloro-4-(4-methoxyphenylsulfanyl)-6-methylphenyl)ethanone (3-2, 0.10 g, 0.33 mmol) as yellow oil in 13% yield: 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J=8.7 Hz, 2 H), 6.94 (d, J=8.7 Hz, 2 H), 6.86 (d, J=8.2 Hz, 2 H), 3.85 (s, 3 H), 2.50 (s, 3 H), 2.17 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[C:22]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:34]([O:36]C)=O)[CH3:9].[NH3:38]>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[C:22]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29])[N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:34]([NH2:38])=[O:36])[CH3:9]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@H](C)c1ccccc1Br
Reactant: N
Solvent: CO
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1Br

Procedure:
In a similar manner as described for example A5, 2.11 g of methyl 3-[(1R)-1-(2-bromophenyl)ethoxy]-5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxylate and 168 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[F:30][C:31]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:32]=1[CH2:33]Br>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH2:33][C:32]2[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:31]=2[F:30])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:25][CH:26]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)c1
Reactant: Fc1ccc(CBr)c(F)c1
Product: C=CCOc1cccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 61D and 2,4-difluorobenzyl bromide were processed as described in Example 6B to provide the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][C:12]([CH3:16])([CH3:15])[C:13]#[CH:14])[CH:8]=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18]>ClC1C=CC=CC=1Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([N+:17]([O-:19])=[O:18])=[CH:7][C:8]2[CH:14]=[CH:13][C:12]([CH3:15])([CH3:16])[O:11][C:9]=2[CH:10]=1
Reactant: C#CC(C)(C)Oc1ccc([N+](=O)[O-])c(OCOC)c1
Solvent: Clc1ccccc1Cl
Product: COCOc1cc2c(cc1[N+](=O)[O-])C=CC(C)(C)O2
Yield: 77 %

Procedure:
A solution of 2-methoxymethoxy-4-(1,1-dimethyl-2-propynyloxy)-1-nitro-benzene (2.1 g, 7.92 mmol) in 1,2-dichlorobenzene (21 mL) was stirred at 20° C. for 0.5 hour. Upon the completion of the reaction, the resulting mixture was concentrated and purified by silica gel column (hexane/ethyl acetate=5/1). Thereby, a mixture (1:1) of the aimed product and the regioisomer was obtained (yield: 77%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:26]=[C:27]([S:29]([CH3:31])=[O:30])[N:28]=2)[C:21]([NH:23][O:24][CH3:25])=[O:22])[CH2:14][CH2:13]1)=[O:10].C1C=C(Cl)C=C(C(OO)=[O:40])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:19]=[C:20]([CH:26]=[C:27]([S:29]([CH3:31])(=[O:40])=[O:30])[N:28]=2)[C:21]([NH:23][O:24][CH3:25])=[O:22])[CH2:16][CH2:17]1)=[O:10]
Reactant: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(S(C)=O)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.8 %

Procedure:
2-(4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-N-methoxy-6-(methylsulfinyl)isonicotinamide (Example 152) (90 mg, 0.185 mmol) was dissolved in anhydrous DCM (5 ml). mCPBA (32 mg, 0185 mmol) was added and the mixture was stirred at room temperature for 12 h. The crude mixture was diluted and washed with 10% sodium thiosulfate, water, brine and dried over sodium sulfate and concentrated in vacuo. The brown oil was purified by flash chromatography eluting with acetonitrile/water (0.1% TFA) to give the title compound (11 mg).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C@H:20]([OH:29])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:8][C@@H:9]([C@H:20]([OH:29])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11]
Reactant: COc1ccc([C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc([C@@H](O)[C@H](N)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 101.8 %

Procedure:
To (2S,3R)-benzyl 2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(4-methoxyphenyl)propanoate (3.0 g, 7.5 mmol) in DCM (30 mL) was added TFA (15 mL) and the mixture was stirred at 0° C. After 30 min it was diluted with DCM (100 mL). Saturated aqueous NaHCO3 (100 mL) was added and the two layers were separated. The aqueous layer were extracted with DCM (100 mL×2) and the combined organics were dried over anhydrous sodium sulfate and concentrated to afford crude (2S,3R)-benzyl 2-amino-3-hydroxy-3-(4-methoxyphenyl)propanoate (2.3 g, quant.) as an oil, which was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:12][NH2:13])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC(C)([O-])C.[Na+]>CN1CCCC1=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:14]1([C:11]2[C:3]3=[C:4]4[CH:10]=[CH:9][NH:8][C:5]4=[N:6][CH:7]=[C:2]3[NH:13][N:12]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NN=C(c1c(Cl)cnc2[nH]ccc12)C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN1CCCC1=O
Product: c1cc2c(ncc3[nH]nc(C4CCCCC4)c32)[nH]1
Yield: 33.1 %

Procedure:
A mixture of 5-chloro-4-(cyclohexyl(hydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine (0.125 g, 0.452 mmol), sodium tert-butoxide (0.104 g, 1.08 mmol), palladium acetate (0.001 g, 0.0045 mmol) and (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl di-tert-butyl phosphine (0.0025 g, 0.0045 mmol) was heated in N-methyl-2-pyrrolidinone (2 mL) at about 160° C. in a CEM Discover microwave for about 30 min. The insoluble residue was removed by filtration and the filtrate was subjected to purification by preparative RP-HPLC (Table 2, Method h) to yield 1-cyclohexyl-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine as a white solid (0.036 g, 33%); LC/MS (Table 2, Method d) Rt=2.04 min; MS m/z: 241 (M+H)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[CH:12]=[C:11]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:10]=1>>[CH3:22][O:21][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][C:16]=1[O:19][CH3:20])[C:9]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[N:10][C:11]([NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1)=[CH:12]2
Reactant: Oc1ccccc1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Oc3ccccc3)c2cc1OC

Procedure:
Similar procedure as described in example 10 was used, starting from phenol and (1-chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (6,7-dimethoxy-1-phenoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 367(MH+).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]([CH2:25][CH2:26][O:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:9]1[C:10]([N+:22]([O-:24])=[O:23])=[C:11]([C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)[C:12]([O:14]C)=[O:13])(=[O:4])=[O:3].[OH-].[K+]>O1CCOCC1>[CH3:31][S:28]([O:27][CH2:26][CH2:25][N:8]([CH2:7][CH2:6][O:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:9]1[C:10]([N+:22]([O-:24])=[O:23])=[C:11]([C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:29])=[O:30]
Reactant: COC(=O)c1c([N+](=O)[O-])ccc(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)c1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1ccc([N+](=O)[O-])c(C(=O)O)c1[N+](=O)[O-]

Procedure:
Hydrolysis of 16 (10.6 g, 21.9 mmol) with 3 N KOH (40 mL) in dioxane (200 mL) at room temperature for 15 min, followed by acidification with 1 N HCl and extraction with EtOAc, gave a quantitative yield of crude 3-(bis{2-[(methylsulfonyl)oxy]ethyl}amino)-2,6-dinitrobenzoic acid (17):
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CO.Cl>O>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A mixture of methyl 4,5-diphenyl-2-oxazoleoctanoate (7.00 g, 18.5 mmol), 5N sodium hydroxide solution (7.42 mL), water (100 mL) and methanol (20 mL) was heated on a steam bath for 45 minutes. After stirring at room temperature for 75 minutes, the mixture was diluted with water (150 mL), heated on a steam bath for 10 minutes and then allowed to stir overnight at room temperature. The mixture was heated to reflux for 1 hour, cooled, acidified with 2N hydrochloric acid solution and extracted with CH2Cl2. The combined extracts were dried over sodium sulfate and concentrated in vacuo to give an oil that crystallized. Recrystallization from a mixture of diethyl ether, CH2Cl2 and hexanes furnished 4,5-diphenyl-2-ozazoleoctanoic acid (5.25 g, 77%), m.p. 70°-73° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]=2)[N:3]=1.[F:21][CH:22]([F:31])[O:23][C:24]1[CH:25]=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=1.CCN(CC)CC>C1COCC1>[F:21][CH:22]([F:31])[O:23][C:24]1[CH:25]=[C:26]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[C:4]([C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]=3)[N:3]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: O=[N+]([O-])c1ccc2nc(-c3cnccn3)nc(Cl)c2c1
Reactant: Nc1cccc(OC(F)F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2nc(-c3cnccn3)nc(Nc3cccc(OC(F)F)c3)c2c1
Temperature: 75 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
A mixture of 4-chloro-6-nitro-2-(pyrazin-2-yl)quinazoline (1.00 g, crude, 3.7 mmol, 1.0 eq.), 3-(difluoromethoxy)benzenamine (600 mg, 3.7 mmol, 1.0 eq.) and Et3N (1.00 g, 10 mmol, 3.0 eq) in THF (80 mL) was stirred at 75° C. for 18 h. After cooling, the volatiles were removed in vacuo and the residue was washed with H2O (100 mL×2). The solid was dried in vacuo to afford 1.40 g of N-(3-(difluoromethoxy)phenyl)-6-nitro-2-(pyrazin-2-yl)quinazolin-4-amine as a black solid (90.2% of two steps). LCMS m′ z=411.0 (M+1) (Method A) (retention time=1.61 min).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([CH2:30]O)[CH2:25]1.C(P(CCCC)CCCC)CCC>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:30][CH:26]4[CH2:27][CH2:28][CH2:29][N:24]([CH3:23])[CH2:25]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: CN1CCCC(CO)C1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC1CCCN(C)C1
Reaction time: 18 h
Yield: 32.5 %

Procedure:
1,1′-Azodicarbonyl)dipiperidine (560 mg, 2.2 mmol) was added in portions to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (240 mg, 0.75 mmol), (prepared as described for the starting material in Example 2), 1-methyl-3-piperidinemethanol (115 mg, 0.89 mmol) and tributylphosphine (440 mg, 2.2 mmol) in methylene chloride (10 ml). The mixture was stirred for 18 hours, diluted with ether and the resulting precipitate was removed by filtration. The volatiles were removed from the filtrate by evaporation, and the residue was dissolved in acetone and ethereal hydrogen chloride 1.5 ml of a 1M solution, 1.5 mmol) was added. The precipitated product was collected by filtration and purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (75/8/1). The purified solid product was triturated with ether collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-ylmethoxy)quinazoline (105 mg, 33%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH:11]1[CH2:15][O:14]C(C)(C)[O:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+]>C1COCC1>[CH2:1]([NH:8][CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH:11]([OH:12])[CH2:15][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OCC(C(CNCc2ccccc2)c2ccc(Cl)c(Cl)c2)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: OCC(O)C(CNCc1ccccc1)c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 105.4 %

Procedure:
To a solution of (2RS)—N-benzyl-2-(3,4-dichlorophenyl)-2-[(4RS)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanamine (7.95 g) in THF (32 mL) was added 1.0 N hydrochloric acid (31.4 ml) at room temperature, and the mixture was stirred under nitrogen purging at 50° C. for 3 hr. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (7.50 g) as a pale-brown oil. This was used without purification for the next step.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:12]3[C:21]([OH:22])=[C:20]4[C:15]([CH:16]=[CH:17][CH:18]=[N:19]4)=[CH:14][N:13]=3)=[N:10][N:11]=2)=[CH:4][CH:3]=1.[OH:25]C1C(C#N)=NC=C2C=1N=CC=C2>>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]([NH:11][NH2:10])=[O:25])=[CH:4][CH:3]=1.[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:12]3[C:21]([OH:22])=[C:20]4[C:15]([CH:16]=[CH:17][CH:18]=[N:19]4)=[CH:14][N:13]=3)=[N:10][N:11]=2)=[CH:23][CH:24]=1
Reactant: N#Cc1ncc2cccnc2c1O
Agent: Oc1c(-c2nnc(Cc3ccc(F)cc3)[nH]2)ncc2cccnc12
Product: NNC(=O)Cc1ccc(F)cc1

Procedure:
7-[5-(4-Fluorobenzyl)-4H-1,2,4-triazol-3-yl]-1,6-naphthyridin-8-ol. In a similar manner to that described in example 1 from of 8-hydroxy-1,6-naphthyridine-7-carbonitrile (30 mg, 0.18 mmol) and 2-(4-fluorophenyl)acetic hydrazide (147 mg, 0.90 mmol) was formed the title compound (9 mg, 16%) as a yellow solid. 1H NMR (CDCl3/CD3OD): δ 9.14 (m, 1 H), 8.80 (s, 1 H), 8.28 (m, 1 H), 7.61 (dd, J=8.4, 4.5 Hz, 1 H), 7.33 (dd, J=8.7, 5.7 Hz, 2 H), 6.99 (t, J=8.7 Hz, 2 H), 4.17 (s, 2 H); 9F NMR (CDCl3/CD3OD): δ −116.72; MS m/z 344 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>ClCCl>[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NS(=O)(=O)c1ccc(F)cc1)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To an ice-cold mixture of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (60 mg, 0.19 mmol, 1.0 eq.) and pyridine (0.3 mL, 3.8 mmol, eq.) in dichloro methane (5 mL) was added 4-fluorobenzene-1-sulfonyl chloride (51 mg, 0.29 mmol, 1.5 eq.) under nitrogen. Then the reaction mixture was stirred at room temperature for two hours. Thin layer chromatography and LC-MS indicated that the starting material was consumed completely. The reaction was quenched with 20 mL water extracted with ethyl acetate (20 mL×2). The combined organic layers were concentrated and the residue was purified by silica gel (petroleum ether/ethyl acetate=2:1) to afford 66 mg of methyl 2-(2-(4-fluorophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid; yield: 74%; MS (ESI+APCI) M+1=469.
Reaction SMILES: Cl[Si](Cl)(Cl)Cl.[N-:6]=[N+:7]=[N-:8].[Na+].[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=O)[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:26]=1)[C:19]([CH3:42])([CH3:41])[CH2:18]2)=[O:14])[CH3:11]>C(#N)C>[CH2:10]([O:12][C:13]([C:15]1[CH:24]=[C:23]2[C:22](=[CH:17][CH:16]=1)[NH:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]3[C:32]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:8][N:7]=[N:6]3)[CH:26]=1)[C:19]([CH3:18])([CH3:42])[CH2:41]2)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)Cc3ccccc3)c1)N2
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-n3nnnc3Cc3ccccc3)c1)N2
Temperature: 25 °C
Yield: 57.6 %

Procedure:
To a stirred solution of tetrachlorosilane (6.0 mL, 52 mmol), sodium azide (5.1 g, 78.1 mmol) in dry acetonitrile (20 mL) was added 3,3-dimethyl-2-(3-phenylacetylamino-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.3 g, 5.2 mmol) at room temperature. Then the mixture solution was stirred at room temperature for over night. LC/MS showed that reaction finished completely. The reaction mixture was poured into ice-cold saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (40% ethyl acetate/hexanes) afforded 2-[3-(5-benzyl-tetrazol-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.4 g, 58.3%) as a white solid: LC/MS m/e calcd for C28H29N5O2 (M+H)+: 468.58, observed: 468.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([CH:9]=[N:10][OH:11])=[CH:7][CH:6]=1)=[O:4].[ClH:14].OOS([O-])=O.[K+]>CN(C)C=O.O1CCOCC1>[Cl-:14].[CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([CH:9]=[N:10][OH:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: Cl
Agent: COC(=O)c1ccc(C=NO)cc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-methoxycarbonylbenzaldehyde oxime (896 mg) in N,N-dimethylformamide (10 ml) was added 4N-hydrochloride acid in 1,4-dioxane (1.38 ml) and oxone® (1.69 g). The suspension was stirred at ambient temperature for 16 hours and poured into ice-water. The object compound was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate. The solvents were removed under reduced pressure to give 4-Methoxycarbonylbenzaldehyde oxime chloride (1.05 g).