Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11]O)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1C=CC(OP(OC2C=CC=CC=2)([N:22]=[N+:23]=[N-:24])=O)=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.C(Cl)Cl>[N:22]([CH2:11][C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][CH:2]=[N:1]2)=[CH:6][CH:7]=1)=[N+:23]=[N-:24]
Reactant: OCc1ccc2cccnc2c1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1ccc2cccnc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of quinolin-7-ylmethanol (1.2 g, 7.2 mmol) and diphenylphosphonic azide (3.8 mL, 17 mmol) was dissolved in toluene (20 mL) and methylene chloride (6 mL). The mixture was cooled to 0° C. and neat 1,8-diazabicyclo[5.4.0]undec-7-ene (2.6 mL, 17 mmol) was added. The reaction was stirred for 30 minutes at 0° C. and then reacted at room temperature for 2 h. The mixture was diluted with CH2Cl2 (100 mL) and washed with water (100 mL×2). The organic layer was concentrated in vacuo and purified by silica gel chromatography (0-100% EtOAc/hexane) to afford a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:37]5[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=5)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)c4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccnc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(3-bromo-phenylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and pyridine-3-boronic acid.
Reaction SMILES: [CH3:1]/[C:2](/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:27])/[CH:11]=[CH:12]/[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][C:21]([F:24])([F:23])[F:22])=[C:15]([CH3:25])[C:14]=1[CH3:26])=[CH:3]\[C:4]([OH:6])=O.C(N1C=CN=C1)([N:30]1[CH:34]=[CH:33]N=C1)=O.C(N)C>C1COCC1.CCCCCC>[CH2:34]([NH:30][C:4](=[O:6])/[CH:3]=[C:2](\[CH3:1])/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:27])/[CH:11]=[CH:12]/[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][C:21]([F:22])([F:23])[F:24])=[C:15]([CH3:25])[C:14]=1[CH3:26])[CH3:33]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(/C=C/c1c(C)cc(OC(F)(F)F)c(C)c1C)=C\C=C\C(C)=C\C(=O)O
Agent: CCN
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCNC(=O)/C=C(C)/C=C/C=C(C)/C=C/c1c(C)cc(OC(F)(F)F)c(C)c1C
Temperature: -10 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
A solution of 2.0 g (5.3 mmol) of (2E,4E,6E,8E)-3,7-dimethyl-9-[2,3,6-trimethyl-4-(trifluoromethoxy)phenyl]-nonatetraenoic acid in 60 ml of dry THF and 1.6 g of (10 mmol) of carbonyldiimidazole was heated to 35°-40° C. for 0.5 hour. The reaction mixture was cooled to -10° C. and excess gaseous ethyl amine was introduced. The resulting mixture was stirred for 1 hour at 23° C., diluted with 100 ml of hexane, and filtered through silica gel (200 g, 1:1 ethyl acetate-hexane as elutant). Further chromatographic purification (silicia gel, 5 to 10% ethyl acetate in methylene chloride) gave a yellow solid which, after recrystallization (ethyl acetate-hexane), yielded 1.4 g of N-ethyl(2E,4E,6E,8E)-3,7-dimethyl-9-[2,3,6-trimethyl-4-(trifluoromethoxy)phenyl]-nonatetraenamide; mp 198°-200° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=[N:18][C:14]=3[CH:13]=[C:12]([C:25]([F:28])([F:27])[F:26])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:29][Mg]Br>O1CCCC1>[OH:3][C:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=[N:18][C:14]=3[CH:13]=[C:12]([C:25]([F:27])([F:28])[F:26])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:29])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(=O)c1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1
Solvent: C1CCOC1
Product: CC(C)(O)c1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an ice-cooled solution of 7-(3-acetylphenyl)-1-phenyl-5-trifluoromethylbenzimidazole ((0.76 g, 2.0 mmol) in anhydrous tetrahydrofurane (5 ml) was added a solution of methylmagnesium bromide (1.0 ml, 3M) dropwise over 5 min. The ice-bath was removed and the mixture was stirred at ambient temperature for 4 hours. Aqueous ammonium chloride, and subsequently ethyl acetate, was added.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])=[O:5].[CH2:24]([N:26]([CH2:38][CH3:39])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:28]=1)[CH3:25].C(OC(=O)C)(=O)C>CO>[CH2:34]([N:33]([CH2:36][CH3:37])[C:29]1[CH:28]=[C:27]([N:26]([CH2:24][CH3:25])[CH2:38][CH3:39])[CH:32]=[CH:31][C:30]=1[C:4]1([C:3]2[CH:15]=[CH:16][C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:18][C:2]=2[Cl:1])[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:5]1)[CH3:35]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(Cl)c1
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3ccccc32)c(Cl)c1
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A mixture of 2-(2-chloro-4-(diethylamino)benzoyl)benzoic acid (6.61 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (4.30 g.) and acetic anhydride (5 ml.) was allowed to stand overnight at room temperature, then diluted with methanol (10 ml.), affording 3-(2,4-bis(diethylamino)phenyl)-3-(2-chloro-4-(diethylamino)phenyl)phthalide (I: X=Y4 =(CH3CH2)2N, Y2 =Cl, Z4 =Z5 =Z6 =Z7 =H) (3.94 g., m.p. 141°-143° C.).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8][CH3:9])[CH3:2].[CH2:10]([O:12][P:13](Cl)(Cl)=[O:14])[CH3:11]>>[CH2:1]([N:3]1[CH2:4][CH2:5][CH2:6][N:7]([CH2:8][CH3:9])[P:13]1([O:12][CH2:10][CH3:11])=[O:14])[CH3:2]
Reactant: CCOP(=O)(Cl)Cl
Reactant: CCNCCCNCC
Product: CCOP1(=O)N(CC)CCCN1CC
Yield: 24.7 %

Procedure:
Substantially the same procedure was followed as in Example 1, with 4.00 grams (30.7 mmol) N,N'-diethyl-1,3-diaminopropane and 5.0 grams (30.7 mmol) ethyldichlorophosphate, to produce 1.67 grams of 1,3-diethyl-2-ethoxy-2-oxo-1,3-diaza-2-phosphacyclohexane, ##STR24## as a phosphorus amide catalyst.
Reaction SMILES: [H-].[Na+].[CH2:3]=[CH:4][CH2:5][CH:6]([OH:10])[CH2:7][CH:8]=[CH2:9].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>C1COCC1>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:10][CH:6]([CH2:7][CH:8]=[CH2:9])[CH2:5][CH:4]=[CH2:3]
Reactant: BrCCCCCCCCCCBr
Reactant: C=CCC(O)CC=C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(CC=C)OCCCCCCCCCCBr
Reaction time: 13 h
Yield: 25.7 %

Procedure:
8.9 g of 60% sodium hydride was suspended in 100 ml of THF, and 25 g of 1,6-heptadien-4-ol dissolved in 50 ml of THF was dropped therein in an atmosphere of argon. 94 g of 1,10-dibromodecane dissolved in 50 ml of THF was further dropped therein, and reflux was carried out for 13 hours in an atmosphere of argon. After the generated precipitate was filtered off, the solvent was evaporated, and the residue was purified by silica gel column chromatography, to obtain 19 g of the compound (4). (Yield: 26%)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C@@H:12]([NH2:14])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([CH:12]([NH:14][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](N)c1ccccc1
Product: CC(NS(C)(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
TEA (2.90 mL, 20.9 mmol) and methanesulfonylchloride (2.0 g, 17.46 mmol). were added to a solution of (S)-1-phenyl-ethylamine Compound 3h1 (2.13 g, 17.46 mmol) at 0° C., under a N2 atmosphere. The mixture was stirred for 3 hrs, while warming to r.t. The reaction was quenched with water (20 mL) and the organic layer was diluted with CH2Cl2 (100 mL), washed with water and brine, separated and dried with anhydrous sodium sulfate, then filtered and concentrated in vacuo to yield N-(1-phenyl-ethyl)-methanesulfonamide Compound 3h2 as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][C:42]=1[N+:43]([O-])=O)[O:5][CH2:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:39])([CH3:38])[O:11][Si:12]([CH3:37])([CH3:36])[O:13][Si:14]([CH3:35])([CH3:34])[O:15][Si:16]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[C:26]([F:33])[CH:25]=1)([CH3:18])[CH3:17].[H][H]>[Pd]>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][Si:16]([CH3:17])([CH3:18])[O:15][Si:14]([CH3:35])([CH3:34])[O:13][Si:12]([CH3:37])([CH3:36])[O:11][Si:10]([CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]2[CH:40]=[CH:41][C:42]([NH2:43])=[C:2]([F:1])[CH:3]=2)([CH3:38])[CH3:39])=[CH:25][C:26]=1[F:33]
Reactant: [H][H]
Reactant: C[Si](C)(CCCCOc1ccc([N+](=O)[O-])c(F)c1)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Product: C[Si](C)(CCCCOc1ccc(N)c(F)c1)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc(N)c(F)c1
Yield: 99.6 %

Procedure:
1.66 g of the above (2g) (2.35 mmol) and 10 mL of a 10 wt % Pd/C (0.0275 g) ethyl acetate solution were mixed, and stirred for 2 days in a hydrogen atmosphere at room temperature. The solution was filtrated by Celite and then concentrated to obtain a colorless oily material of 1,7-bis[4-(4-amino-3-fluorophenoxy)butyl]-1,1,3,3,5,5,7,7-octamethyltetrasiloxane (3g) (1.51 g, 99% of yield) represented by the following formula. Various measurements were carried out with regard to the obtained (3 g), and results are shown below.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:17](=[O:25])[NH:18][C:19]2[CH:23]=[CH:22][N:21]([CH3:24])[N:20]=2)=[N:10][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].O>C(Cl)Cl>[CH3:24][N:21]1[CH:22]=[CH:23][C:19]([NH:18][C:17]([C:9]2[C:8]([NH2:7])=[CH:13][CH:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[N:10]=2)=[O:25])=[N:20]1
Reactant: Cn1ccc(NC(=O)c2nc(C3CC3)ccc2NC(=O)OC(C)(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cn1ccc(NC(=O)c2nc(C3CC3)ccc2N)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83.3 %

Procedure:
A solution of 70 mg (0.228 mmol) of [6-Cyclopropyl-2-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-pyridin-3-yl]-carbamic acid tert-butyl ester in 3 ml of methylene chloride was treated with 0.26 ml (0.39 g, 3.42 mmol, 15 equiv.) of trifluoroacetic acid. After stirring for 2.5 h at room temperature, the mixture was worked up with Ethyl acetate/Sodium bicarbonate/water to yield 49 mg (0.19 mmol, 83%) of crude title compound as a light yellow solid, MS (ISP): m/e=258.1 (M+H+); which was sufficiently pure to be used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:3]2[S:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[C:25]1([C@H:31]([CH2:33][OH:34])[NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C.O>O1CCOCC1.CS(C)=O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:7]=[C:2]([NH:32][C@H:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:33][OH:34])[C:3]4[S:23](=[O:24])[CH2:22][CH2:21][C:4]=4[N:5]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Reactant: N[C@@H](CO)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(N[C@@H](CO)c3ccccc3)c21
Temperature: 120 °C

Procedure:
220 mg 4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine 5-oxide (cf Example 124), 157.48 mg (R)-(−)-2-phenylglycinol and 197.52 μl diisopropylethylamine are placed in 4 ml dioxane, heated to 120° C. in the microwave for 0.3 hours. Then the reaction mixture is mixed with water, the precipitate formed is suction filtered, washed and dried. The diastereomers are separated by preparative HPLC (method B). 52.8 mg of Diastereomer 1 (Example 49) and 42.0 mg of Diastereomer 2 (Example 56) are obtained as a powder. 1H NMR (400 MHz, DMSO): Diastereomer 1: 7.41-7.35 (m, 2H), 7.35-7.28 (m, 2H), 7.28-7.19 (m, 3H), 6.99-6.92 (m, 2H); Diastereomer 2: 7.42-7.35 (m, 2H), 7.33-7.15 (m, 5H), 6.99-6.92 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[N:4]([CH2:10][CH2:11][CH2:12][C:13](=[O:15])[CH3:14])[C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1)#[N:2].CC(C)([O-])C.[K+]>O1CCCC1>[C:13]([C:12]1[CH2:11][CH2:10][N:4]2[C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=[C:3]2[C:1]=1[NH2:2])(=[O:15])[CH3:14]
Reactant: CC(=O)CCCn1c(C#N)nc(C)c1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)C1=C(N)c2nc(C)c(C)n2CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
102 g of 2-cyano-4,5-dimethyl-1-N-(pentan-2-on-5-yl)imidazole from Example 5 are dissolved in tetrahydrofuran (1.2 l) under a dry N2 atmosphere and cooled in an ice bath to T=0° C. Potassium tert-butoxide solution (1.0 M in THF, 640 ml) is then added dropwise over a period of about 15 min. After a further 15 min, the ice bath is removed so that the beige reaction suspension slowly warms to RT. It is then stirred vigorously for 2 h. After completion of the reaction (TLC toluene/acetone=4:1 and CH2Cl2/MeOH=9:1), saturated NH4Cl solution (about 140 ml) is added until the cessation of the reaction and tetrahydrofuran is distilled off. The residue is then dissolved in dichloromethane and extracted twice with saturated NH4Cl solution and once with saturated NaCl solution. The organic phase is dried (MgSO4), filtered off with suction and concentrated to dryness in a high vacuum. The title compound is obtained here as a crude product in the form of an amorphous solid (86 g). The crude product is dissolved in ethanol (90 ml) at a temperature of about 85° C. The solution is then cooled in an ice bath and diethyl ether (180 ml) is added. The product phase is allowed to stand overnight at T=4° C. The precipitate of product is filtered off with suction, washed with a little cold diethyl ether and the filtercake is dried in a high vacuum. The mother liquor is concentrated to dryness, then taken up in the solvent mixture toluene/acetone=5:1 and treated with 5 times the amount of flash silica gel (Mallinckrodt-Baker, 30-60 μm). After filtration and removal of the solvent by distillation, precipitation is carried out again as described above. The title compound (55 g) is obtained as a pure substance in the form of a yellow-orange, amorphous solid, which is sensitive to photooxidation and is stored under N2. TLC (CH2Cl2/MeOH=9:1), Rf=0.59; m.p.: 204° C. (decomposition).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[NH2:15][CH2:16][C:17]([N:19]([CH3:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18].ClC1C(C)=C(C)N=C(C2C=CC=CC=2)N=1.NCC(N(CCC)CCC)=O>>[CH3:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([NH:15][CH2:16][C:17]([N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[CH:7]=1
Reactant: CN(C(=O)CN)c1ccccc1
Reactant: Cc1cc(Cl)nc(-c2ccccc2)n1
Agent: CCCN(CCC)C(=O)CN
Agent: Cc1nc(-c2ccccc2)nc(Cl)c1C
Product: Cc1cc(NCC(=O)N(C)c2ccccc2)nc(-c2ccccc2)n1

Procedure:
The same procedures as Example 1 are repeated except that 4-chloro-6-methyl-2-phenylpyrimidine and 2-amino-N-methyl-N-phenylacetamide are used instead of 4-chloro-5,6-dimethyl-2-phenylpyrimidine and 2-amino-N,N-dipropylacetamide, respectively. The product thus obtained is recrystallized from isopropanol to give the desired compound, m.p. 134-136° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].[C:11]([O:15][C:16](=[O:24])[NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[C:11]([O:15][C:16]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:2][CH2:3][O:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:19]1)=[O:24])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: CC(C)(C)C(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.3 %

Procedure:
A mixture of 2,2-dimethylpropionic acid 2-bromoethyl ester (2.3 g, 11 mmol), (5)-piperidin-3-ylcarbamic acid tert-butyl ester (2 g, 10.0 mmol), potassium carbonate (4.15 g, 30 mmol) and sodium iodide (0.15 g, 1 mmol) in DMF (20 mL) was stirred at RT for 3 days. The reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane) affording the title compound as a colourless oil (3.23 g, 98%). 1H NMR (CDCl3, 300 MHz): 5.08 (1H, bs), 4.27-4.07 (2H, m), 3.73 (1H, bs), 2.65-2.50 (3H, m), 2.48 (1H, bs), 2.30-2.24 (1H, m), 1.74-1.61 (1H, m), 1.58-1.47 (3H, m), 1.44 (9H, s), 1.21 (9H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a 100 mL roundbottom flask was charged 4-bromopyrazole (13.6 mmol, 2.00 g), K2CO3 (20.4 mmol, 2.82 g), and DMF (20 mL). To this suspension was added 2-(trimethylsilyl)ethoxymethyl chloride (15.0 mmol, 2.64 mL). This suspension was allowed to stir at room temperature 18 hours. The reaction mixture was then concentrated in vacuo, dissolved in 20 mL DCM, and filtered through celite. The crude mixture was purified via silica gel chromatography (0% to 80% ethyl acetate in hexanes gradient) to yield 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.53 g, 9.12 mmol, 67% yield) as clear oil.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][CH3:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: CC#Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Yield: 98 %

Procedure:
tert-butyldimethyl((4-(prop-1-yn-1-yl)benzyl)oxy)silane (252 mg, 0.968 mmol) was dissolved in 20 mL of ethyl acetate, and then passed through H-Cube apparatus equipped with 10% Pd/C catridge under 20 bar of hydrogen pressure at a speed of 0.5 mL/min. The solution thus passed was concentrated by distillation under reduced pressure to obtain 251 mg (0.949 mmol, 98%) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.[C:24](=O)([O-])[OH:25].[Na+].[OH-].[Na+]>ClCCl.C(O)=O>[CH:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)=[O:25]
Reactant: O=C([O-])O
Reactant: COC(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Solvent: ClCCl
Product: COC(=O)c1ccc(NC=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Formic acid (90.0 mL) was added to a dichloromethane solution (900 mL) of methyl 4-aminobenzoate (90.0 g) and to the mixture was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (114 g) at 5° C. over thirty minutes, and then the mixture was stirred at room temperature for three hours. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution (1.2 L) and the pH was adjusted to 10 with 1N sodium hydroxide, and the residue was separated. The aqueous layer was extracted with dichloromethane, and the organic layer was combined and washed with 1N hydrochloric acid, water and brine successively. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue obtained was washed with ethyl acetate to obtain the titled compound (88.7 g) as crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:35]=[CH:34][C:6]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[C:15]([O:18][CH3:19])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[C:5]([F:36])[CH:4]=1>O1CCOCC1.C(#N)C>[ClH:2].[Cl:2][C:3]1[CH:35]=[CH:34][C:6]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[C:15]([O:18][CH3:19])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[C:5]([F:36])[CH:4]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OC1CCNCC1
Temperature: 70 °C
Yield: 139.7 %

Procedure:
A solution of 4M hydrogen chloride in dioxane (100 ml) was added to a stirred solution of tert-butyl 4-({4-[4-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidine-1-carboxylate (7.23 g, 14.4 mmol) in acetonitrile (100 ml). The reaction mixture was heated at 70° C. for 1 hour then concentrated to ½ volume. The resulting precipitate was collected by filtration, washed with acetonitrile and dried under vacuum to give N-(4-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride as a white solid (4.42 g, 76.3%); 1H NMR Spectrum: (DMSO-d6): 1.90-2.10 (m, 2H), 2.10-2.32 (m, 2H), 3.00-3.35 (m, 4H), 4.02 (s, 3H), 4.90 (m, 1H), 7.36-7.50 (m, 1H), 7.50-7.70 (m, 3H), 8.48 (s, 1H), 8.80(s, 1H), 9.30(bs, 2H), 11.90 (bs, 1H); Mass Spectrum: (M+H)+ 403.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:24])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][CH2:33][N:34]1[CH:38]=[CH:37][CH:36]=[CH:35]1.[Cl-].[Na+]>O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][O:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:18])([OH:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:32][CH2:33][N:34]3[CH:38]=[CH:37][CH:36]=[CH:35]3)=[CH:5][C:4]=2[N:3]=1
Reactant: BrCCn1cccc1
Reactant: COCCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Product: COCCc1nc2c(N)nc3cc(OCCn4cccc4)ccc3c2n1CC(C)(C)O
Temperature: 50 °C

Procedure:
4-Amino-1-(2-hydroxy-2-methylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ol was alkylated as described in the general procedure for Examples 7-20, using 2 equivalents of cesium carbonate and 1.1 equivalents of 1-(2-bromoethyl)pyrrole. The reaction was heated overnight at 50° C. and then heated to 80° C. for an additional four hours. The reaction was cooled and poured into water containing 20 g of sodium chloride. The resulting precipitate was filtered and purified using column chromatography eluting with a gradient of 0-8% methanol in dichloromethane. The clean fractions were combined, concentrated, and recrystallized from acetonitrile to give 160 mg of 1-[4-amino-2-(2-methoxyethyl)-7-[2-(pyrrol-1-yl)ethoxy]-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as an off-white solid, mp 168.0-169.0° C.