Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=O.[C:24]([O:28][C:29]([NH:31][C@@H:32]([C@@H:36]([CH3:39])[CH2:37][CH3:38])[C:33]([OH:35])=O)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH3:24][O:28][C:29]([CH:6]1[CH2:7][C@@H:8]2[C@@H:13]([CH2:12][CH2:11][CH2:10][C@@:9]2([O:23][C:33](=[O:35])[C@@H:32]([NH:31][C:29]([O:28][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:30])[C@@H:36]([CH3:39])[CH2:37][CH3:38])[C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[NH:5]1)=[O:30]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@H]2NC(C(=O)OC)C[C@H]21

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (2S,3S)-2-(tert-butoxycarbonylamino)-3-methylpentanoic acid to yield (3aR,4S,7aR)-4-((2S,3S)-2-tert-butoxycarbonylamino-3-methyl-pentanoyloxy)-4-m-tolylethynyl-octahydro-indole-carboxylic acid methyl ester. This NBoc-protected product was then stirred in hydrochloric acid dioxane solution (4M, 10 equiv.) at room temperature for 6 hrs. Subsequently the solvent was removed the residue dissolved in dichloromethane and washed with saturated sodium hydrogencarbonate solution. The organic layer was tried with sodium sulfate, filtrated and evaporated. The crude product was subjected to silica gel flash chromatography (ISCO CombiFlash; dichloromethane/methanol; 100/0 to 95/5) to yield (3aR,4S,7aR)-4-((2S,3S)-2-amino-3-methyl-pentanoyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT=5.703 min; HPLC Method I
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li]CCCC.CC(C)([O-])C.[K+].[F:22][C:23]([F:40])([F:39])[C:24](=[O:38])[CH2:25][C:26]1([CH3:37])[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=2)[O:29][CH2:28][CH2:27]1>C(OCC)C.C1COCC1>[F:40][C:23]([F:22])([F:39])[C:24]([CH2:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)([OH:38])[CH2:25][C:26]1([CH3:37])[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=2)[O:29][CH2:28][CH2:27]1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: CC1(CC(=O)C(F)(F)F)CCOc2ccc(F)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(CC(O)(Cc2cc3ccccc3[nH]2)C(F)(F)F)CCOc2ccc(F)cc21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a chilled (−78° C.) solution of 95.0 mg (0.72 mmol) of 2-methylindole in 10 mL of diethyl ether was added 710 μL (1.77 mmol) of a 2.5 M solution of n-BuLi in hexanes. After 5 minutes, 1.16 mL (1.16 mmol) of a 1 M solution of potassium tert-butoxide in THF was added and the mixture was warmed until a yellow precipitate formed. After 20 minutes, the reaction was cooled to −78° C. and 200 mg (0.72 mmol) of 1,1,1-trifluoro-3-(6-fluoro-4-methylchroman-4-yl)propan-2-one (Example 1) in 2 mL of diethyl ether was added. The reaction stirred at −78° C. for 30 minutes and was then warmed to room temperature, quenched with saturated aqueous ammonium chloride and extracted with diethyl ether. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified on a PLC plate with hexanes-EtOAc (8:2) to afford a mixture of two diastereomers. The diastereomers were separated on a PLC plate (hexanes-CH2Cl2 (1:1)) to give two diastereomer. One was purified again by PLC plate (hexanes-CH2Cl2 (1:1)) to afford 20 mg of the first diastereomer (M+1=408) and the second was triturated with hexanes and the solid collected by filtration to afford 15 mg of the other diastereomer (M+1=408) of the title compound.
Reaction SMILES: C(N1CCC(C)(O)CC1)C1C=CC=CC=1.[Cl-:16].[Cl-].[Cl-].[Al+3].[OH-].[Na+].[CH2:22]([N:29]1[CH2:34][CH2:33][C:32]([C:36]2[CH:41]=[CH:40][C:39](Cl)=[CH:38][CH:37]=2)([CH3:35])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClC1C=CC=CC=1>[CH2:22]([N:29]1[CH2:34][CH2:33][C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:16])([CH3:35])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: [Cl-]
Reactant: CC1(c2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Agent: CC1(O)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CC1(c2ccccc2Cl)CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-methyl-piperidin-4-ol (4.5 g) was dissolved in chlorobenzene (50 mL). Aluminium trichloride (15 g) was added portion wise and the mixture then heated at reflux for 0.5 hours. The mixture was then allowed to cool and poured over ice. The resulting solution was treated with sodium hydroxide until basic and the products extracted into ethyl acetate, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by silica chromatography eluting with a mixture of ethyl acetate and hexane. The fractions containing the desired products were combined and the solvent removed by evaporation to give a 4:1 mixture of the title compound and 1-benzyl-4-(4-chloro-phenyl)-4-methyl-piperidine which was used directly without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][C:3]=1[CH3:13].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:12][CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Br:1])=[C:3]([CH3:13])[CH:4]=1)(=[O:24])=[O:23]
Reactant: Cc1cc(CCCO)cc(C)c1Br
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(CCCOS(C)(=O)=O)cc(C)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a cooled (0° C.) solution of 3-(4-bromo-3,5-dimethylphenyl)propan-1-ol (250 mg) and triethylamine (160 μL) in dichloromethane (2 mL) is added methanesulfonyl chloride (850 μL). The mixture is stirred for 12 hours at room temperature. The mixture is partitioned between dichloromethane and saturated aqueous NaHCO3 solution and stirred vigorously for 30 minutes. The organic phase is separated, washed with brine and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→50:50) to give the title compound. Yield: 235 mg; LC (method 8): tR=0.44 min; Mass spectrum (ESI+): m/z=343 [M+Na]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C@:9]([NH2:16])([CH3:15])[C:10]([F:14])([F:13])[CH2:11][OH:12])=[O:5])[CH3:2].[N:17]#[C:18]Br>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C@:9]1([CH3:15])[C:10]([F:14])([F:13])[CH2:11][O:12][C:18]([NH2:17])=[N:16]1)=[O:5])[CH3:2]
Reactant: N#CBr
Reactant: CCOC(=O)[C@@H]1C[C@H]1[C@@](C)(N)C(F)(F)CO
Product: CCOC(=O)[C@@H]1C[C@H]1[C@@]1(C)N=C(N)OCC1(F)F
Yield: 88 %

Procedure:
Starting from (1R,2R)-2-((R)-1-amino-2,2-difluoro-3-hydroxy-1-methyl-propyl)-cyclopropane-carboxylic acid ethyl ester (intermediate J5.2) the cyclization with cyanogen bromide yielded the (1R,2R)-2-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-cyclopropanecarboxylic acid ethyl ester (88% yield) as a white solid. MS (ISP): m/z=263.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[C:26]([CH3:28])[C:5]([O:6][C:7]2[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([CH3:16])[N:10]=[C:9]([NH:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[N:8]=2)=[C:4]([CH3:29])[CH:3]=1.C(O[CH:35](N(C)C)[N:36]([CH3:38])[CH3:37])(C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:27]=[C:26]([CH3:28])[C:5]([O:6][C:7]2[C:12]([N+:13]([O-:15])=[O:14])=[C:11](/[CH:16]=[CH:35]/[N:36]([CH3:38])[CH3:37])[N:10]=[C:9]([NH:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[N:8]=2)=[C:4]([CH3:29])[CH:3]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1cc(Br)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(C)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(/C=C/N(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a homogenous mixture of 4-(4-(4-bromo-2,6-dimethylphenoxy)-6-methyl-5-nitropyrimidin-2-ylamino)benzonitrile (22.71 g, 50 mmol) in DMF (300 ml) was added tert-butoxybis (dimethylamino) methane (12.39 ml, 60 mmol) over 15 minutes. The mixture was stirred at room temperature overnight. DMF was partially removed. The residue was washed with water and extracted with ethyl acetate (×3). The organic layers were combined, washed with brine, dried (MgSO4) and concentrated to dryness yielding to the desired product as a yellow solid (23.41 g, 46.0 mmol, 92%) which was used in next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 2.14 (s, 6H), 2.98 (bs, 3H), 3.13 (bs, 3H), 5.54 (d, J=12.4 Hz, 1H), 7.03 (s, 1H), 7.27 (d, J=8.6, 2H), 7.28 (s, 2H), 7.40 (d, J=8.6, 2H), 8.03 (d, J=12.2 Hz, 1H).
Reaction SMILES: C[N:2](/[CH:4]=[C:5](/[C:11](=O)[C:12]([CH3:15])([CH3:14])[CH3:13])\[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25]N)=[CH:21][C:20]=1[C:27]([F:30])([F:29])[F:28].C(C1N(C2C=CC(Cl)=CC=2C)N=CC=1C(OCC)=O)(C)(C)C>>[C:12]([C:11]1[N:25]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[C:20]([C:27]([F:30])([F:28])[F:29])[CH:21]=2)[N:2]=[CH:4][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:15])([CH3:14])[CH3:13]
Reactant: NNc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)C(C)(C)C
Agent: CCOC(=O)c1cnn(-c2ccc(Cl)cc2C)c1C(C)(C)C
Agent: Cl
Product: CCOC(=O)c1cnn(-c2ccc(Cl)c(C(F)(F)F)c2)c1C(C)(C)C

Procedure:
Ethyl 5-tert-butyl-1-(4-chloro-3-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylate was prepared from (Z)-ethyl 2-((dimethylamino)methylene)-4,4-dimethyl-3-oxopentanoate (Intermediate #83) and (4-chloro-3-(trifluoromethyl)phenyl)hydrazine hydrochloride by the same process used for Intermediate #116.
Reaction SMILES: [CH:1]1([CH2:10][C:11]([OH:13])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.[CH2:26]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][S:33][CH2:32][NH:31]1)[CH3:27]>C(Cl)Cl>[CH2:26]([O:28][C:29](=[O:35])[C@@H:30]1[CH:34]([C:11](=[O:13])[CH2:10][CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)[S:33][CH2:32][NH:31]1)[CH3:27]
Reactant: O=C(O)CC1CCc2ccccc21
Reactant: CCOC(=O)[C@@H]1CSCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H]1NCSC1C(=O)CC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.1 %

Procedure:
1.4 g of 2-indanylacetic acid and 1.9 g of WSC.HCl were added to 15 ml of methylene chloride under ice-cooling. The mixture was stirred for 5 minutes at room temperature. After an addition of 1.3 g of L-thioproline ethyl ester dissolved in 10 ml of methylene chloride, the mixture was stirred for 5 hours. The reaction mixture was washed with water, diluted hydrochloric acid, and saturated sodium hydrogen carbonate in this order. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to produce 1.45 g of 3-(2-indanylacetyl)-L-thioproline ethyl ester as a colorless oil (yield: 57%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH3:22])=[CH:10][CH:9]=2.C(N(CC)CC)C.Cl[CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37]>ClCCl>[CH3:22][O:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:23])[N:6]([CH3:24])[C:5]([CH2:4][CH2:3][N:2]1[CH2:33][CH2:34][CH2:35][C:36]1=[O:37])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc2c(=O)n(C)c(CCN)c(-c3ccccc3)c2c1
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(=O)n(C)c(CCN3CCCC3=O)c(-c3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-(2-aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one hydrochloride (125 mg, 0.362 mmol) in 15 mL of dichloromethane was added triethylamine (0.202 mL, 1.45 mmol), followed by 4-chlorobutanoyl chloride (0.045 mL, 0.40 mmol). After 45 minutes, the mixture was concentrated in vacuo. Tetrahydrofuran was added (15 mL), and the solution was cooled to 0° C. Sodium hydride was added (58 mg, 60% dispersion in mineral oil, 1.45 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, at room temperature for 16 hours, then at 50° C. for 2 hours. The solution was partitioned between EtOAc and saturated NaHCO3 solution, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC to provide the titled product. Proton NMR for the product was consistent with the titled compound. ESI+MS: 377.27 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[S:19][C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:21][C:8]=2[C:7]=1[OH:28])=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32]>C[O-].[Na+].CO>[CH2:12]([C:10]1[C:9]2[S:19][C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:21][C:8]=2[C:7]([OH:28])=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[N:11]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1nc(Cc2ccccc2)c2sc(-c3ccccc3)nc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1nc(Cc2ccccc2)c2sc(-c3ccccc3)nc2c1O
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A mixture of 4-benzyl-7-hydroxy-2-phenyl-thiazolo[5,4-c]pyridine-6-carboxylic acid ethyl ester (48 mg, 0.12 mmole) and glycine (185 mg, 2.46 mmole) in 0.5 M sodium methoxide/methanol (4.7 ml) was refluxed for 45 h before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (15 ml) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (3.5 ml). The resulting precipitate was filtered, washed with water and dried in vacuo to give the title compound as a yellow solid (38 mg). 1H NMR (DMSO-d6, 200 MHz): δ=13.13 (br s, 1H), 9.34 (t, 1H, J=6.0 Hz), 8.08 (m, 2H), 7.58 (m, 3H), 7.33 (m, 5H), 4.36 (s, 2H), 4.06 (d, 2H, J=5.8 Hz); MS: (+) m/z 420.29 (M+1), MS: (−) m/z 418.29 (M−1).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]#[C:7][C:8]([OH:10])=O.ClC(OCC(C)C)=O.CN1CCOCC1.[Br:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([NH2:44])[CH:42]=3)[N:37]=[CH:36][N:35]=2)[CH:30]=[CH:31][CH:32]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([NH:44][C:8](=[O:10])[C:7]#[C:6][CH2:5][O:4][CH2:3][O:2][CH3:1])[CH:42]=3)[N:37]=[CH:36][N:35]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: COCOCC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COCOCC#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 0.66 g of 4-methoxymethoxy-but-2-ynoic acid and 0.60 mL of isobutyl chloroformate in 16 mL of tetrahydrofuran at 0° C. was added 0.5 mL of N-methylmorpholine followed by 1.2 g of solid N-(3-bromophenyl)-4,6-quinazolindiamine. Stirring was continued for 1 hr at 0° C. and 30 min at room temperature. Another equal amount of mixed anhydride as prepared above was added. The mixture was stirred an addition 30 min and stored at −10° C. over night. The mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic solution was dried over magnesium sulfate. The solvent was removed and the residue was chromatographed on silica gel eluting with ethyl acetate and choroform solvent mixtures to give 0.35 g of 4-Methoxymethoxy-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide as a tan solid: mass spectrum (m/e): M+H 441.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13](=[O:23])[N:14]([CH3:22])[C:15]2[C:20]([CH:21]=1)=[CH:19][N:18]=[CH:17][CH:16]=2>CCO.Cl.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>[NH2:8][C:7]1[C:2]([Cl:1])=[C:3]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]3[C:20]([CH:21]=2)=[CH:19][N:18]=[CH:17][CH:16]=3)[C:4]([Cl:11])=[CH:5][CH:6]=1
Reactant: Cn1c(=O)c(-c2c(Cl)ccc([N+](=O)[O-])c2Cl)cc2cnccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1c(=O)c(-c2c(Cl)ccc(N)c2Cl)cc2cnccc21
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a suspended solution of 3-(2,6-dichloro-3-nitro-phenyl)-1-methyl-1H-[1,6]naphthyridin-2-one (1.55 g, 4.427 mmol) in EtOH (12 mL) is added a solution of Sn(II)Cl2 (3.80 g, 19.92 mmol) in HCl (con. 16 mL) at 75° C. After stirring for 30 minutes at 75° C., the mixture is diluted with EtOAc and neutralized with K2CO3 to a pH of 8. The organic layer is washed with saturated K2CO3, brine and dried, filtered and concentrated to give crude product. The crude product is purified by recrystallization with CH2Cl2/EtOAc/Hexane to give the titled intermediate as a solid (1.32 g, 93.15%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH3:19].[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23]>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH3:19])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: CCCC(=O)Cl
Product: CCCC(=O)NCCCn1c(C)nc2c(N)nc3ccccc3c21
Yield: 42 %

Procedure:
Using the general method of Example 205, 1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 7.83 mmol) was reacted with butyryl chloride (835 mg, 7.83 mmol). The product was recrystallized from methanol to provide 1.07 g of N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]butanamide as a white powder, m.p. 221.8-223.3° C. Analysis: Calculated for C18H23N5O.0.25 CH4O: % C, 65.74; % H, 7.26; % N, 21.00. Found: % C, 65.79; % H, 7.14; % N, 21.25.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([CH3:11])=[C:6]([CH:9]=[O:10])[NH:7][CH:8]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.O>C1COCC1.C(OCC)(=O)C>[Br:3][C:4]1[C:5]([CH3:11])=[C:6]([CH:9]=[O:10])[N:7]([S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(Br)c[nH]c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c(C)c2C=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Following a general procedure,50 a stirred suspension of 60% NaH (2.5 g, 62 mmol) in dry THF (42 mL, distilled) was cooled to 0° C. under argon. The mixture was treated portionwise with 3 (7.78 g, 41.4 mmol). The mixture was stirred for 30 min at 0° C. before treating all at once with p-toluenesulfonyl chloride (8.00 g, 41.4 mmol). The reaction mixture was stirred at room temperature for 3 h, whereupon water (100 mL) was slowly added to quench the reaction. Ethyl acetate (100 mL) was added, and the organic layer was separated. The organic layer was washed with brine, dried (Na2SO4), and concentrated to a solid. The solid was dried under high vacuum for 2 h. The crude solid material was dissolved in 100 mL hexanes/ethyl acetate (5:1) by refluxing in a hot water bath. Upon allowing the solution to cool to room temperature the product crystallized. The mixture was cooled overnight at −10° C. to promote additional crystallization. The mixture was vacuum-filtered, and the resulting light brown crystals were dried under high vacuum (9.73 g, 69%): mp 152-155° C.; 1H NMR δ 2.29 (s, 3H), 2.43 (s, 3H), 7.34 (d, J=8.5 Hz, 2H), 7.55 (s, 1H), 7.76 (d, J=8.5 Hz, 2H), 10.14 (s, 1H); 13C NMR δ 2.1, 22.0, 106.2, 126.8, 127.6, 129.1, 130.6, 135.2, 136.4, 146.5, 180.1; Anal. Calcd for C13H12BrNO3S: C, 45.63; H, 3.53; N, 4.09. Found: C, 45.71; H, 3.44; N, 4.11.
Reaction SMILES: Cl.N1C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][C:25]=3[O:27]C)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]>N1C=CC=CC=1.N.CO>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:25]([OH:27])=[CH:24][C:23]([O:29][CH3:30])=[CH:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: COc1cc(OC)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Agent: Cl
Agent: N
Solvent: CO
Solvent: c1ccncc1
Product: COc1cc(O)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 115 °C
Reaction time: 23 h
Yield: 68.5 %

Procedure:
Pyridine hydrochloride (2.33 g) was added in one portion to a stirred mixture of N-(3-chloro-4-fluorophenyl)-5,7-dimethoxyquinazolin-4-amine (6.4 g) in pyridine (75 ml) at room temperature. The reaction mixture was stirred at 115° C. under a nitrogen atmosphere for 23 hours and then the brown solution was cooled to room temperature and the yellow precipitate was filtered and washed with ice cold water to leave a light yellow solid. The solid was taken up in 7N ammonia in methanol and stirred at room temperature for 10 minutes. The solution was filtered and the filtrate was concentrated in vacuo to leave 4-[(3-chloro-4-fluorophenyl)-amino]-7-methoxyquinazolin-5-ol as a light brown solid (4.2 g, 68%); Mass spectrum MH+ 320.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[CH:3]=1.N1C=CC=CC=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=2)(=[O:33])=[O:32])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[CH:3]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(Cl)cc1Cc1ccccc1Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)Nc2ccc(Cl)cc2Cc2ccccc2Cl)c1
Reaction time: 18 h
Yield: 56 %

Procedure:
Starting with 0.71 g of [4-chloro-2-(2-chlorobenzyl)phenyl]amine dissolved in 5 ml of THF are added 0.4 ml of pyridine and 0.8 g of 3-methoxybenzenesulfonyl chloride, and the mixture is left at room temperature for 18 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) cyclohexane/ethyl acetate solvent mixture to give 0.666 g of expected product.