Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:46]=[CH:45][C:6]2[NH:7][C:8](=[O:44])[N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([C:24]([C:26]5[CH:27]=[C:28]6[C:32](=[C:33]([CH3:35])[CH:34]=5)[N:31](COCC[Si](C)(C)C)[N:30]=[CH:29]6)=[O:25])[N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl.N.O>CO.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:46]=[CH:45][C:6]2[NH:7][C:8](=[O:44])[N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([C:24]([C:26]5[CH:27]=[C:28]6[C:32](=[C:33]([CH3:35])[CH:34]=5)[NH:31][N:30]=[CH:29]6)=[O:25])[N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(cnn5COCC[Si](C)(C)C)c4)ncn3)CC1)C(=O)N2
Agent: Cl
Agent: N
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]ncc5c4)ncn3)CC1)C(=O)N2

Procedure:
65 mg (0.10 mmol) 7-methoxy-3-(1-{6-[7-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-5-carbonyl]-pyrimidin-4-yl}-piperidin-4-yl)-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one in 0.4 mL MeOH and 0.6 mL (2.4 mmol) of a 4 molar HCl solution in dioxane was stirred overnight at RT. The mixture was neutralised with 0.4 mL of a 6 molar methanolic ammonia solution, mixed with some water and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [CH:1]1([C:7]#[CH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)S(O[C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:25][CH3:26])=[C:20]([O:27][CH3:28])[CH:19]=2)(=O)=O.[NH4+].[OH-]>C1COCC1.C(Cl)(Cl)Cl.[Cl-].[Cl-].[Zn+2].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>[CH:1]1([C:7]#[C:8][C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([O:25][CH3:26])=[C:20]([O:27][CH3:28])[CH:19]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc2cc(OS(=O)(=O)C(F)(F)F)cnc2cc1OC
Reactant: C#CC1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc2cc(C#CC3CCCCC3)cnc2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
This reaction is carried out under anhydrous conditions. Cyclohexylacetylene (700 mg; 6.47 mmol) in 10 mL. THF is cooled to 0° C. To this is added 2.5M n-BuLl (3.0 mL; 7.44 mmol) and stirred for 30 min. at 0° C. under N2 atm and then 1.0M ZnCl2 (7.4 mL; 7.44 mmol). This is allowed to warm to room temperature and stirred for 3/4 hour. The reaction mixture is transferred via cannula to a flask containing 6,7-dimethoxyquinolin-3-yl trifiuoromethane sulfonate (500 mg; 1.48 mmol) and Pd(PPh3)4 (83 mg; 0.074 mmol) in 4 mL of THF. This is then heated to 50° C. under N2 for 41/2 hours. The reaction mixture is then poured into 90 mL of 10% NH4OH, diluted with CHCl3 and stirred for 20 min. The aqueous layer is separated, and the organic layer washed with brine, dried over MgSO4, filtered, evaporated and chromatographed with 4:1 hexane: EtOAc to obtain 3-cyclohexylethynyl-6,7-dimethoxyquinoline, which is recrystallized from hexane, identified by NMR and used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.C(N(CC)CC)C.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.Cl.[CH3:50][C:51]1[S:52][CH:53]=[C:54]([CH2:56][O:57][NH2:58])[N:55]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:58][O:57][CH2:56][C:54]1[N:55]=[C:51]([CH3:50])[S:52][CH:53]=1)=[O:8]
Reactant: COc1cccc(C(=O)O)c1NCc1ccncc1
Reactant: Cc1nc(CON)cs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)NOCc2csc(C)n2)c1NCc1ccncc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
3-Methoxy-2-[(pyridin-4-ylmethyl)-amino]-benzoic acid (200 mg, see preparation 1D) was dissolved in DMF (20 ml) and triethylamine (0.65 ml) at 50-60° C. N,N,N′,N′-Tetramethyl-O-(benzotriazole-1-yl)uronium-tetrafluoroborate (250 mg) was added and after 5 minutes O-(2-methyl-thiazol-4-ylmethyl)-hydroxylamine hydrochloride (209 mg, see preparation 12) was added. The reaction mixture was heated to 90° C. and stirred at this temperature for 2 hours. The mixture was cooled to room temperature and water was added. The mixture was extracted several times with EtOAc and the combined organic layers were washed with water, saturated aqueous sodium bicarbonate, water, and brine. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The remaining material was purified by column chromatography on silica gel (elution with 1 to 4% methanol in EtOAc) and gave the title compound as an yellow oil. 13C-NMR (DMSO-d6) δ 165.3, 150.4, 150.0, 149.8, 149.3, 137.8, 122.2, 120.5, 118.8, 117.9, 114.0, 71.8, 55.7, 48.3, 18.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15](Cl)[CH:14]=[C:13]([Cl:18])[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:19]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>C(O)CCC>[Cl:18][C:13]1[N:12]=[C:11]([NH:10][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)[N:16]=[C:15]([NH:26][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:14]=1
Reactant: COc1ccc(Nc2nc(Cl)cc(Cl)n2)cc1Cl
Reactant: NC1CCCCCC1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2nc(Cl)cc(NC3CCCCCC3)n2)cc1Cl
Yield: 60 %

Procedure:
To a solution of compound (3-chloro-4-methoxy-phenyl)-(4,6-dichloro-pyrimidin-2-yl)-amine (0.08 g, 0.26 mmol) in butanol (3 mL) was added to cycloheptylamine (0.03 g, 0.26 mmol) at 25° C. with stirring. To this was added triethylamine (0.14 mL, 1.04 mmol), and the mixture was stirred for 30 minutes at 25° C. and then heated and refluxed for 12 hours under nitrogen atmosphere. The mixture was concentrated under vacuum, diluted with cold water, and extracted with ethyl acetate. The organic layers were collected, combined, washed with brine, dried over anhydrous sodium sulphate, and concentrated under vacuum to give the desired compound. Yield: 60%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].Br[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]
Reactant: COC(=O)c1ccc(Br)c(O)c1
Reactant: O=C(CBr)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)c(OCC(=O)N2CCOCC2)c1
Temperature: 80 °C
Yield: 14.5 %

Procedure:
Methyl 4-bromo-3-hydroxybenzoate (71 mg) and 4-(bromoacetyl)morpholine (71 mg) were combined in DMF (5 ml). Sodium hydride (14 mg, 60% dispersion in mineral oil) was added and the reaction heated at 80° C. under nitrogen for 16 hours. The reaction was quenched with water (2 ml) and solvent the evaporated in vacuo. The residue was partitioned between water (10 ml) and ethyl acetate/chloroform (1:1, 2×10 ml). The organic layers were combined, dried using a hydrophobic filter and evaporated under vacuum. The residue was partially purified by SPE (2 g, Si), eluting with a methanol/chloroform gradient (0.5% to 5%), and the product fractions further purified by mdap, to give methyl 4bromo-3{[2-(4-morpholinyl)-2-oxoethyl]oxy}benzoate as a white solid (16 mg).
Reaction SMILES: BrC1C2C1CNC1C=CC=CC=12.BrC1C2C3CC3C(=O)NC=2C=CC=1.[Br:26][C:27]1[CH:28]=[N:29][N:30]([CH2:32][C:33]2[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=2)[C:36]([NH2:38])=O)[CH:31]=1>>[Br:26][C:27]1[CH:28]=[N:29][N:30]([CH2:32][C:33]2[CH:34]=[C:35]([CH2:36][NH2:38])[CH:39]=[CH:40][CH:41]=2)[CH:31]=1
Reactant: NC(=O)c1cccc(Cn2cc(Br)cn2)c1
Agent: BrC1C2CNc3ccccc3C12
Agent: O=C1Nc2cccc(Br)c2C2CC12
Product: NCc1cccc(Cn2cc(Br)cn2)c1

Procedure:
The title compound was prepared using a procedure analogous to bromo-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinoline except that 7-bromo-3,7b-dihydro-1H-cyclopropa[c]quinolin-2(1aH)-one was replaced with 3-((4-bromo-1H-pyrazol-1-yl)methyl)benzamide. LCMS, [M+H]+=266.1. 1H NMR (500 MHz, CDCl3) δ 7.47 (s, 1H), 7.36 (s, 1H), 7.33-7.25 (m, 2H), 7.18 (s, 1H), 7.09 (d, J=7.4 Hz, 1H), 5.24 (s, 2H), 3.85 (s, 2H), 1.78 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]=2[CH:4]=1)#[CH:2].Br[C:33]1[CH:34]=[C:35]([C:47]2[O:48][C:49]([C:52]3[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])=[CH:54][CH:53]=3)=[N:50][N:51]=2)[CH:36]=[C:37]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=1>>[CH2:24]([C:6]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]2[CH:4]=[C:3]([C:1]#[C:2][C:33]3[CH:34]=[C:35]([C:47]4[O:48][C:49]([C:52]5[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])=[CH:54][CH:53]=5)=[N:50][N:51]=4)[CH:36]=[C:37]([C:39]#[C:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:38]=3)[CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: C#Cc1ccc2c(c1)C(CCCCCCCC)(CCCCCCCC)c1ccccc1-2
Reactant: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Br)cc(C#Cc4ccccc4)c3)o2)cc1
Product: CCCCCCCCOc1ccc(-c2nnc(-c3cc(C#Cc4ccccc4)cc(C#Cc4ccc5c(c4)C(CCCCCCCC)(CCCCCCCC)c4ccccc4-5)c3)o2)cc1

Procedure:
According to the general procedure of Example 1, the reaction of 2-ethynyl-9,9-dioctyl-9H-fluorene (Example 8) with a molar equivalent of 2-(3-bromo-5-phenylethynylphenyl)-5-(4-octyloxy-phenyl)-[1,3,4]oxadiazole (Example 6) gives 2-[3-(9,9-dioctyl-9H-fluoren-2-ylethynyl)-5-phenylethynyl-phenyl]-5-(4-octyloxy-phenyl)-[1,3,4]oxadiazole.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]Cl)[CH2:10][CH:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CC(C)=O>[Cl:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])[CH2:10][CH:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1
Reactant: CCNCC
Reactant: ClCCN1CCN(Cc2ccc(Cl)cc2)C(c2ccccc2)C1
Agent: Cl
Solvent: CC(C)=O
Product: CCN(CC)CCN1CCN(Cc2ccc(Cl)cc2)C(c2ccccc2)C1

Procedure:
20 g. of 1-(4'-chloro benzyl)-2-phenyl-4-(β-chloro ethyl) piperazine hydrochloride, 14 g. of diethylamine and 200 cc. of acetone are boiled under reflux for 12 hours. After cooling, the precipitated diethylamine hydrochloride is filtered off with suction and the solvent of the filtrate is evaporated in a vacuum. The residue is distilled in a vacuum. 15 g. of a light yellow oil having a boiling point of 190° C./0.06 mm. Hg are obtained. This product is identical with the product as obtained according to Example 2 B).
Reaction SMILES: O[CH:2]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1.C(N(S(F)(F)[F:31])CC)C>C(Cl)Cl>[F:31][CH:2]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1cccc(C#CC(O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: ClCCl
Product: Cc1cccc(C#CC(F)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
Into a solution of the Compound of Example 39 (300 mg, 0.91 mmol) in anhydrous CH2Cl2 (10 mL) cooled at −78° C. was dropped diethylaminosulfur trifluoride (144 μL, 1.01 mmol). The reaction mixture was kept at the same temperature for 2 h, then warmed up to r.t., quenched with water and extracted with CH2Cl2. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc 7:3, affording the title product (140 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[H-].[Na+].[Cl:25][C:26]1[N:31]=[C:30](Cl)[CH:29]=[CH:28][N:27]=1>CN(C)C=O>[Cl:25][C:26]1[N:31]=[C:30]([O:18][CH2:17][C:14]2[CH:15]=[CH:16][C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:19]([F:20])([F:21])[F:22])[CH:4]=3)=[C:10]([CH:13]=2)[C:11]#[N:12])[CH:29]=[CH:28][N:27]=1
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(COc2ccnc(Cl)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a solution of 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-(hydroxymethyl)benzonitrile (2.50 g, 7.63 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (1.22 g, 30.5 mmol) at 0° C., then 2,4-dichloropyrimidine (1.25 g, 8.39 mmol) was added at 0° C. after 10 min. The reaction mixture was stirred for 30 min, and poured into ice-water (100 mL), extracted with ethyl acetate (50 mL) twice. Combined organic parts were washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification via ISCO system afforded the title product (2.31 g). LC-MS (ESI): m/z 440 [M+H]+; 3.95 min (ret time).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9]1)C1C=CC=CC=1>CO.[Pd].[OH-].[Pd+2].[OH-]>[N:13]1([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: c1ccc(CN2CCC(N3CCCC3)C2)cc1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Product: C1CCN(C2CCNC2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
180 mg 10% Pd/C are added to a solution of 1.80 g (7.42 mmol) 1′-benzyl-[1,3′]bipyrrolidinyl in 80 mL MeOH. The reaction solution is stirred for 5 h at RT and at 3 bar H2. Another 180 mg 10% Pd/C are added and after 4 h 100 mg palladium hydroxide are added. The reaction is stirred for a further 6 h at RT and at 3 bar H2. The catalyst is suction filtered and the solvent is eliminated i.vac.
Reaction SMILES: Br.Cl[C:3]1[C:12]2[N:13]=[C:14]([NH2:24])[N:15]([C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[NH3:25]>CO>[C:18]1([C@H:16]([N:15]2[C:11]3[C:10]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]=[C:3]([NH2:25])[C:12]=3[N:13]=[C:14]2[NH2:24])[CH3:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@H](c1ccccc1)n1c(N)nc2c(Cl)nc3ccccc3c21
Reactant: N
Agent: Br
Solvent: CO
Product: C[C@H](c1ccccc1)n1c(N)nc2c(N)nc3ccccc3c21
Temperature: 135 °C

Procedure:
4-Chloro-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-amine hydrobromide (4.2 g, 13 mmol) and ammonia (65 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 135° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.4:7.6:92). The chromatographed product was washed with diethyl ether to provide 362 mg of 1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinoline-2,4-diamine as brown needles, mp 156-160° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([O:23]C)=[O:22])=[CH:11][CH:10]=2)[C:6]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[Cl:29].[OH-].[K+].Cl>O.CO>[NH2:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([OH:23])=[O:22])=[CH:13][CH:14]=2)[C:6]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[Cl:29]
Reactant: CCCCc1nc(Cl)c(CN)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1nc(Cl)c(CN)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 111.1 %

Procedure:
5-Aminomethyl-2-butyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloroimidazole (1.64 g. 3.98 mmol, 1 eq), 0.5N KOH in methanol (11.96 mL, 5.98 mmol, 1.5 eq), water (1.0 mL) and methanol (20 mL) were mixed and refluxed under N2 overnight. The solution was then brought to neutrality with 1N HCl and the solvents removed in vacuo. The residue was taken up in DMF and the salts filtered off. The DMF was then removed in vacuo to yield 1.76 g of a glass. NMR (200 MHz, DMSO-d6) δ7.50 (d, 1H, J=7 Hz); 7.40-7.18 (m, 5H); 6.92 (d, 2H, J=8 Hz); 6.50 (bm, 3H); 5.26 (s, 2H); 3.60 (s, 2H); 2.55 (t, 2H, J=7 Hz); 1.51 (t of t, 2H, J=7,7 Hz); 1.27 (t of q, 2H, J=7,7 Hz); 0.81 (t, 3H, J=7 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]([NH:20][CH2:21][CH2:22][CH3:23])=[O:19])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][CH:13]=2)=[CH:6][C:5]([C:18]([NH:20][CH2:21][CH2:22][CH3:23])=[O:19])=[CH:4][CH:3]=1
Reactant: CCCNC(=O)c1ccc(C)c(-c2ccc(C(=O)OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCNC(=O)c1ccc(C)c(-c2ccc(C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
Methyl 6′-methyl-3′-[(propylamino)carbonyl]-1,1′-biphenyl-4-carboxylate (216 mg, 0.7 mmol) in methanol (4 ml) was mixed with aqueous sodium hydroxide (2N, 1 ml) and stirred at room temperature for 2 h. The methanol was evaporated, the reaction diluted with water (4 ml) and extracted with chloroform (2×5 ml). The aqueous was acidified with hydrochloric acid (2N, 2 ml) and extracted with chloroform (2×6 ml). Both sets of organic extracts were combined in methanol (4 ml) and stirred with aqueous sodium hydroxide (2N, 2 ml) for 3 h. The methanol was evaporated, the reaction diluted with water (4 ml) and washed with chloroform (2×5 ml). The aqueous was acidified with hydrochloric acid (2N, 2 ml) and extracted with chloroform (2×6 ml). The solvent was evaporated from the organic extracts to give 6′-methyl-3′-[(propylamino)carbonyl]-1,1′-biphenyl-4-carboxylic acid (121 mg). NMR: ∂H CDCl3 8.13,(2H, d), 7.69,(1H, dd), 7.62,(1H, d), 7.41,(2H, d), 7.35,(1H, d), 3.42,(2H, t), 2.30,(3H, s), 1.64,(2H, m), 0.99,(3H, t).
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10]C(C)(C)C)=[CH:6][CH:5]=1.C(O)C.S(=O)(=O)(O)O>O>[F:1][CH:2]([F:15])[O:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CC(C)(C)Oc1ccc(OC(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: Oc1ccc(OC(F)F)cc1
Yield: 72 %

Procedure:
30 g of 1-(difluoromethoxy)-4-(tert.-butoxy)benzene from Example 4a), 200 ml of ethanol, 50 ml of water and 10 ml of concentrated sulfuric acid were stirred at 80° C. for 2 hours. The reaction mixture was extracted with ether, the organic phase was dried and filtered, and the filtrate was concentrated to give 16 g of 4-difluoromethoxyphenol.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:9][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])=[N:3][CH:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1cc(F)cnc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ncc(F)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
To a mixture of 2-bromo-5-fluoropyridin-3-amine (3.3 g, 17.3 mmol), TEA (7.3 mL, 51.9 mmol), PdCl2(PPh3)2 (1.2 g, 1.73 mmol), and Cu(I)I (0.33 g, 1.73 mmol) in THF (50 mL) at 0° C. under nitrogen was added a solution of (trimethylsilyl)acetylene (3.39 mL, 34.6 mmol). The mixture was stirred at RT for 2 h and then concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (5:1) to afford 2.0 g (915) of 5-fluoro-2-((trimethylsilyl)ethynyl)pyridin-3-amine as a yellow solid. MS (ESI): m/z=209.1 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[C:8]([NH:22][CH2:23][CH2:24][CH3:25])=[N:9][C:10]([NH:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[N:11][CH:12]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[O:1]=[CH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[C:8]([NH:22][CH2:23][CH2:24][CH3:25])=[N:9][C:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[CH:20][CH:21]=2)=[N:11][CH:12]=1
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C#CCCCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C#CCCC=O
Reaction time: 3 h
Yield: 243.4 %

Procedure:
To a solution of 4-((5-(5-hydroxy-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile (G11, 124 mg) in methylene chloride (4 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H)-one (313 mg) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture, ethyl acetate and 10% aqueous sodium thiosulfate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 4-((5-(5-oxo-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile (G12, 300 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=3)[N:15]=[C:14]([CH3:25])[N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:26]I.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=3)[N:15]=[C:14]([CH3:25])[N:13]=2)[CH3:26])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(C)nc3ccc([N+](=O)[O-])cc23)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2nc(C)nc3ccc([N+](=O)[O-])cc23)cc1OC

Procedure:
The title compound was prepared from (3,4-dimethoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-amine (105 mg, 0.31 mmol), methyl iodide (0.029 ml, 0.46 mmol), sodium hydride (19 mg, 0.46 mmol, 60% oil dispersion) in DMF similar to example 21 to give 10.1 mg (9.2%) of yellow solids. 1H NMR (CDCl3): 8.30-8.62 (m, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.76 (d, J=9.3 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.86-6.82 (m, 1H), 6.74 (d, J=2.7 Hz, 1H), 3.95 (s, 3H)), 3.81 (s, 3H), 3.66 (s, 3H), 2.73 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([Cl:13])[C:4]=1[C:5](Cl)=[O:6].[CH3:14][NH2:15]>CCOCC>[CH3:14][NH:15][C:5](=[O:6])[C:4]1[C:8]([Cl:13])=[CH:9][CH:10]=[C:11]([Cl:12])[C:3]=1[O:2][CH3:1]
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)Cl
Reactant: CN
Solvent: CCOCC
Product: CNC(=O)c1c(Cl)ccc(Cl)c1OC
Temperature: 4 °C

Procedure:
Methylamine (146.1 grams; 4.70 moles) contained in 40% aqueous methyl amine solution (365.4 grams) was placed in a 3-liter, 3-necked glass reaction flask equipped with addition funnel, stirrer, thermometer and reflux condenser and containing ether (1200 ml) cooled to 4° C. 2-methoxy-3,6-dichlorobenzoic acid chloride (375 grams; 1.56 moles) in ether (50 ml) was added dropwise with stirring maintaining the temperature below 8° C. After the completion of the addition the reaction mixture was stirred for an additional two hours at a temperature of between 2° and 5° C. The insoluble white solid was filtered with suction, washed with water, transferred to a 3-liter beaker and stirred fifteen (15) minutes with 10% sodium carbonate (2 liters). The insoluble white solid was filtered with suction, washed with water and dried. The product weighed 352 grams and had a melting point of 172.5°-175° C.