Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH:23]=[C:22]([S:24](Cl)(=[O:26])=[O:25])[N:21]=[CH:20]1.N1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([NH:15][S:24]([C:22]2[N:21]=[CH:20][N:19]([CH3:18])[CH:23]=2)(=[O:26])=[O:25])[C:9]=1[F:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1c(F)ccc(N)c1F
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)Nc2ccc(F)c(NC(=O)OC(C)(C)C)c2F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
The tert-butyl-3-amino-2,6-difluorophenylcarbamate (50 mg, 0.20 mmol) prepared at Step 3 was added and dissolved into dichloromethane solvent. 1-methyl-1H-imidazole-4-sulfonyl chloride (44 uL, 0.25 mmol) and pyridine (50 uL, 0.61 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 74 mg of the target compound, tert-butyl-2,6-difluoro-3-(1-methyl-1H-imidazole-4-sulfonamido)phenylcarbamate (percentage yield: 95%), was obtained.
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[N:6]=[C:7]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4].[OH-:26].[K+]>CCO>[C:14]1([C:7]2[N:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]3=[C:5]([C:3]([OH:26])=[O:4])[N:6]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(c1nc(-c2cccc3ccccc23)n2ccccc12)C(F)(F)F
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1nc(-c2cccc3ccccc23)n2ccccc12
Yield: 54.8 %

Procedure:
To a solution of 2,2,2-trifluoro-1-(3-naphthalen-1-yl-imidazo[1,5-a]pyridin-1-yl)-ethanone (260 mg, 0.76 mmol) in EtOH (10 mL) was added KOH (582 mg, 10.4 mmol) and the mixture was heated to reflux for 30 min. The mixture was allowed to cool and concentrated. The residue was dissolved in water (25 mL) and acidified to pH 3 with 2N HCl. The precipitate was filtered, dried and recrystallized from ethyl acetate to yield the title compound (120 mg, 55%). 8.30 (1H), 8.10 (2H), 7.78 (2H), 7.70 (1H), 7.59 (2H), 7.52 (1H), 7.02 (1H), 6.70 (1H); m/z (M+H)=289.24.
Reaction SMILES: Cl.[F:2][C:3]([F:15])([F:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH2:13])=[NH2+:12].CC(C)([O-])C.[K+].[F:22][C:23]([F:31])([F:30])[C:24]([CH2:26][C:27](=O)[CH3:28])=O>O1CCCC1>[CH3:28][C:27]1[CH:26]=[C:24]([C:23]([F:31])([F:30])[F:22])[N:13]=[C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([F:14])([F:15])[F:2])[N:12]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: NC(=[NH2+])Nc1ccccc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)nc(Nc2ccccc2C(F)(F)F)n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A suspension of 24 g (0.1 mole) of 2-trifluoromethylphenyl-guanidinium hydrochloride in 80 ml of tetrahydrofuran is added to a solution of 12 g (0.1 mole) of potassium tert.-butoxide in 100 ml of tetrahydrofuran. When the exothermic reaction has subsided, 15.4 g (0.1 mole) of α,α,α-trifluoroacetylacetone in 20 ml of tetrahydrofuran are added. The reaction mixture is stirred for 2 hours at 60° C., then concentrated by evaporation in a rotary evaporator. The residue is chromatographed on silica gel with a mixture of ethyl acetate and hexane (ratio 1:2). 18.7 g (58 2% of the theoretical amount) of the title compound of formula ##STR16## are obtained in the form of crystals having a melting point of 65°-66° C. (Comp. No. 2.020).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.Br[CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>>[Cl:9][C:5]1[C:6]([O:8][CH:12]([CH3:14])[CH3:13])=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[CH:4]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Oc1cc(N)c(F)cc1Cl
Yield: 62 %

Procedure:
A stirring mixture of 5-amino-2-chloro-4-fluorophenol (22.0 g, 136.19 mmol), 2-bromopropane (38.4 mL, 50.25 g, 408.57 mmol) and potassium carbonate (37.6 g, 273.0 mmol) was heated at reflux for 17 h. The reaction mixture was cooled and filtered. The filtrate was evaporated to dryness under reduced pressure. Flash chromatography yielded the title compound of Step A as a brown oil (17.2 g). 1H NMR (CDCl3): δ7.02 (d, 1H), 6.44 (d, 1H) 4.38 (q, 1H), 3.81 (br s,2H), 1.33 (d,6H). IR (cm-1): 3378.4, 3475.6.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>N1C=CC=CC=1.N1CCCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:13][C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1O
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(C=CC(=O)O)cc1O
Temperature: 120 °C
Yield: 104.5 %

Procedure:
The mixture of 3-hydroxy-4-methoxy-benzaldehyde (30 g) and malonic acid (42 g) in pyridine (80 ml) and piperidine (4 ml) was heated at 120° C. for 6 hours. The solution was cooled to room temperature and concentrated to 20 ml. The residue was dissolved in 500 ml of water and the solution was acidified with concentrated HCl until PH=3. The solid was collected to give 3-(3-Hydroxy-4-methoxy-phenyl)-acrylic acid (40 g). LC-MS: m/e 195 (MH+).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]=2[C:4](O)=[N:3][CH:2]=1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[Cl:15][C:4]1[C:5]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: Oc1ncnc2cccnc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1ncnc2cccnc12
Temperature: 25 °C

Procedure:
To a stirred solution pyrido[3,2-d]pyrimidin-4-ol (B-2) (16 g, 109 mmol, 1.0 eq) in DCM (200 mL) and DMF (0.4 mL) at RT, oxalyl chloride (23.2 mL, 272 mmol, 2.5 eq) is added dropwise (over 5 min) and the resulting mixture is stirred at reflux overnight. The mixture is allowed to cool to RT and concentrated in vacuo. The residue is diluted with water (200 mL), neutralized with saturated aqueous NaHCO3 solution below 10° C. to adjust the pH to 8-9 and then extracted with ethyl acetate (4×100 mL). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (16-50% ethyl acetate-petroleum ether) to afford the product, 4-chloropyrido[3,2-d]pyrimidine (B-3).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][CH:13]=[CH:14][N:15]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]2[O:12][CH:13]=[CH:14][N:15]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)c(-c2ncco2)c1
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2-c2ncco2)CC1
Yield: 70 %

Procedure:
2-(2-Chloro-5-nitrophenyl)-oxazole (0.366 g, 1.63 mmol) was heated in N-methylpiperazine (15 mL) at reflux for 5 hrs. The mixture was allowed to cool and excess N-methylpiperazine was distilled under high vacuum. The residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with water then brine, dried over sodium sulfate, filtered and concentrated. Drying under high vacuum gave 1-methyl-4-(4-nitro-2-oxazol-2-yl-phenyl)-piperazine (0.328 g, 70%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][C:5]([CH:6]=[CH:7][C:8]([NH:10][CH2:11][C:12]([N:14]([C:16]2[C:17]([Cl:36])=[C:18]([C:32]([Cl:35])=[CH:33][CH:34]=2)[CH2:19][O:20][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]3)[CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=1[CH3:39].C(N(CC)CC)C.[CH3:47][N:48]=[C:49]=[O:50]>ClCCl>[Cl:36][C:17]1[C:16]([N:14]([CH3:15])[C:12](=[O:13])[CH2:11][NH:10][C:8](=[O:9])[CH:7]=[CH:6][C:5]2[CH:37]=[CH:38][C:2]([NH:1][C:49]([NH:48][CH3:47])=[O:50])=[C:3]([CH3:39])[CH:4]=2)=[CH:34][CH:33]=[C:32]([Cl:35])[C:18]=1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N)c(C)c4)c3Cl)c2n1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)Nc1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 8-[3-[N-(4-amino-3-methylcinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (200 mg) and triethylamine (35.9 mg) in dichloromethane was dropwise added methyl isocyanate (0.023 ml) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 1 hour at the same temperature and for 2 hours at ambient temperature. Methyl isocyanate (0.03 ml) was further added thereto, and the mixture was stirred overnight at ambient temperature. The mixture was partitioned between dichloromethane and water, the organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=15:1, V/V) to give 8-[2,6-dichloro-3-[N-methyl-N-[3-methyl-4-(N'-methylureido)cinnamoylglycyl]amino]benzyloxy]-2-methylquinoline (150 mg) as an amorphous powder.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.O>[CH2:30]([N:24]1[C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][CH:13]=3)=[CH:29][C:19]=2[CH:20]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH2:22][CH2:23]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
In 1,2-dichloroethane (7 ml) were dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.4 g) and benzaldehyde (0.43 g). To the solution was added sodium triacetoxyborohydride (0.43 g), and the mixture was stirred under nitrogen atmosphere at room temperature overnight, poured into water, neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 1-benzyl-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.49 g) as oil.
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[O:7])=[CH:4][CH:3]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27](=[O:35])[C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:25][CH2:26]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:16])([F:17])[F:18])=[O:7])=[CH:36][CH:37]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2C(F)(F)F)cc1
Product: CC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2C(F)(F)F)cc1

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2-trifluoromethylphenyl)benzamide (243.0 mg, 0.474 mmol) and acetic anhydride (0.13 ml, 1.40 mmol), the procedure of Inventive Example 94 was repeated to obtain 265.0 mg quantitative) of the title compound in a colorless amorphous form.
Reaction SMILES: [CH2:1](O)[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:36])C(=O)C1>CN(C=O)C>[Br:36][CH2:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCC/C=C\CCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCC/C=C\CCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of cis-oct-3-en-1-ol (1.00 g, 7.81 mmol) in DMF (18 mL) was added triphenylphosphine (2.28 g, 8.69 mmol). The solution was cooled to 0° C. and NBS (1.50 g, 8.43 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (1 mL). The solution was diluted with ether (100 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford cis-1-bromo-oct-3-ene (1.36 g, 91%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.53 (1H, m), 5.35 (1H, m), 3.36 (2H, t, J=7.2 Hz), 2.60 (2H, m), 2.04 (2H, m), 1.33 (4H, m), 0.89 (3H, t, J=7.2 Hz); 3C NMR (75 MHz, CDCl3) δ 133.27, 125.84, 32.93, 31.97, 31.12, 27.43, 22.64, 14.30.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH2:34]=[O:35]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:34][OH:35])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=O
Reactant: COc1cc(-c2nnc3n2CCCC3c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc3n2CCCC3(CO)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Reaction time: 1 h
Yield: 13.3 %

Procedure:
To a mixture of 8-(3,4-dichlorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (300 mg) in DMF (5 mL) was added sodium hydride (60%, 31.6 mg) under ice-cooling, and the mixture was stirred for 1 hr under a nitrogen atmosphere. Paraformaldehyde (39.6 mg) was added to the reaction mixture, and the mixture was stirred for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (42.5 mg).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][NH2:23].CCCCCC>CS(C)=O>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:23][CH2:22][CH:21]([O:24][CH3:25])[O:20][CH3:19])[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Reactant: COC(CN)OC
Solvent: CS(C)=O
Solvent: CCCCCC
Product: COC(CNc1nc(-c2ccccc2)c2cc(Cl)ccc2n1)OC
Temperature: 0 °C
Yield: 100.4 %

Procedure:
The starting material may be prepared as follows: To a suspension of 5.5 g of 2,6-dichloro-4-phenylquinazoline in 70 ml of dimethylsulfoxide was added 4.2 g of 2,2-dimethoxyethylamine. The mixture was heated at 90°-100° C. for 1.5 hours with stirring. After cooling, the mixture was poured into 400 ml of ice-water. The resulting mixture was stirred with a small quantity of n-hexane, and the precipitate that formed was collected by filtration, washed with water and dried to give 6.9 g of 6-chloro-2-(2,2-dimethoxyethylamino)-4-phenylquinazoline. Recrystallization from ethanol gave yellow needles, m.p. 122.5°-123° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH2:37][CH3:38])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=O)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)C(C)C)(C)C.[C:54]([C:58]1[CH:59]=[C:60]([NH2:65])[C:61]([NH2:64])=[CH:62][CH:63]=1)([CH3:57])([CH3:56])[CH3:55]>CN(C)C=O>[NH2:65][C:60]1[CH:59]=[C:58]([C:54]([CH3:56])([CH3:55])[CH3:57])[CH:63]=[CH:62][C:61]=1[NH:64][C:34](=[O:36])[CH2:33][CH2:32][CH:30]1[CH2:29][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:39]=[CH:40][C:41]([O:43][CH3:44])=[CH:42][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH2:37][CH3:38])[CH2:31]1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: CCN(C[C@H]1C[C@@H](n2ccc3c(NCc4ccc(OC)cc4OC)ncnc32)[C@@H]2OC(C)(C)O[C@H]12)C1CC(CCC(=O)O)C1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C[C@H]1C[C@@H](n2ccc3c(NCc4ccc(OC)cc4OC)ncnc32)[C@@H]2OC(C)(C)O[C@H]12)C1CC(CCC(=O)Nc2ccc(C(C)(C)C)cc2N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.84 g, 2.2 mmol) added to a solution 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(ethyl)amino)cyclobutyl)propanoic acid (0.89 g, 1.5 mmol) and N,N-Diisopropylethylamine (0.84 ml, 4.8 mmol) and 4-tert-butylbenzene-1,2-diamine (0.29 g, 1.8 mmol) in N,N-Dimethylformamide (9 ml). The reaction was stirred overnight at RT, partially concentrated to ca. 2 ml and then NaHCO3 (saturated) was added. The mixture was extracted with EtOAc (3×) and the combined organics were dried with MgSO4, filtered and concentrated. The residue was purified by flash chromatography (DCM I 7N NH3 in MeOH 94:6) to give the desired compound (0.88 g) as a colorless solid. Retention time C, 3.363 minutes.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH2:21][CH:22]([CH3:42])[CH:23]([C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[F:41])[S:24]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([CH:23]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[F:41])[CH:22]([CH3:42])[CH2:21][CH2:20][CH2:19][OH:18])(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: CC(CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(CCCO)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 101.4 %

Procedure:
The 2-[5-(t-butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-2-methylpentyl]-1,4-difluorobenzene (isomer mixture) (1.40 g, 2.23 mmol) obtained in Example 38 was dissolved in tetrahydrofuran (30 ml), followed by the addition of a tetrahydrofuran solution (1.0M, 5.0 ml, 5.0 mmol) of tetrabutylammonium fluoride under ice cooling. The resulting mixture was stirred at room temperature for 14 hours. After addition of water (3 ml), the residue obtained by concentrating the resulting mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure, whereby 5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-4-methyl-1-pentanol (isomer mixture) (879 mg, quant.) was obtained as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].CI.[C:16](OCC)(=O)C>CN(C=O)C>[CH3:16][N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc2cc(C=O)ccc21
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of indole-5-carbaldehyde (1.0 g, 6.9 mmol) in DMF (15 mL) was added sodium hydride (303 mg of 60% dispersion in oil, 7.59 mmol) in 3 portions. The mixture was stirred for 30 mins. Methyl iodide (1.96 g, 13.8 mmol) was then added and the mixture was stirred overnight. Ethyl acetate (200 mL) was added and solution was washed with H2O (3×20 mL) and brine (25 mL) dried over MgSO4 and concentrated to afford N-methylindole-5-carboxaldehyde as an orange oil (1.0 g, 91%). 1H NMR (200 MHz, CDCl3) δ 10.05 (s, 1H), 8.09 (s, 1H), 7.90-7.80 (m, 1H), 7.35-7.15 (m, 2H), 6.85-6.80 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][C@H:14]3[CH2:18][O:17][C:16](=[O:19])[NH:15]3)[CH:11]=2)[NH:6][CH:5]=1)#N.[CH3:20][NH:21][CH3:22]>[Pd]>[CH3:20][N:21]([CH2:1][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][C@H:14]3[CH2:18][O:17][C:16](=[O:19])[NH:15]3)[CH:11]=2)[NH:6][CH:5]=1)[CH3:22]
Reactant: CNC
Reactant: N#CCc1c[nH]c2ccc(C[C@H]3COC(=O)N3)cc12
Agent: [Pd]
Product: CN(C)CCc1c[nH]c2ccc(C[C@H]3COC(=O)N3)cc12
Reaction time: 24 h

Procedure:
A suspension of the product from step (c) (1.3 g) and 10% w/w Pd/C (1.0 g) in 30% w/w ethanolic dimethylamine (25 ml) was hydrogenated for 24 hours and filtered through Hyflo. Fresh Pd/C (0.7 g) and ethanolic dimethylamine (5 ml) were added to the filtrate and hydrogenation continued for a further 16 hours. The mixture was filtered through a silica column using DCM/EtOH/NH4OH (40:8:1) as eluant to give the desired product as a colourless foam (0.3 g). Elemental analysis and 1H NMR were consistent with the proposed structure.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH2:14]Cl)[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[NH:16]1[CH:20]=[CH:19][CH:18]=[N:17]1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:5]([CH2:14][N:16]1[CH:20]=[CH:19][CH:18]=[N:17]1)[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4]
Reactant: Cc1cccc(C)c1N(CCl)C(=O)CCl
Reactant: c1cn[nH]c1
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1N(Cn1cccn1)C(=O)CCl

Procedure:
43.9 parts by weight of 2-chloro-2',6'-dimethyl-N-chloromethyl acetanilide and 25.8 parts by weight of pyrazole are stirred for 7 hours at 90° C. in 120 parts by volume of toluene. After the mixture has cooled it is filtered, and the filtrate is washed 3 times with water, each time with 50 parts by volume, and dried over sodium sulfate. The solvent is evaporated and the residue pasted with 50 parts by volume of petroleum ether to give 39.1 parts by weight of 2-chloro-2',6'-dimethyl-N-(pyrazol-1-yl-methyl)-acetanilide, m.p.: 81° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[C:12]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:12])[N:9]=2)[CH:5]=[CH:4][C:3]=1[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2cn[nH]c2c1Br
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: Cc1ccc2cn(C)nc2c1Br
Temperature: 80 °C

Procedure:
To a solution of 7-bromo-6-methyl-1H-indazole (1 equiv.) in acetonitrile, Cs2CO3 (1.3 equiv.) and MeI (3 eq.) was added and reaction was heated at 80° C. for 1.5 h. On completion, it was cooled and quenched by addition of water. Extraction was carried out using ethyl acetate. Organic layer was dried over Na2SO4 and crude compound was column purified to afford the title compound. (Polar isomer confirmed as N-2-Methyl and non-polar isomer confirmed as N-1-Methyl by NOE experimentation).