Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[N:25]([CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:26]=[O:27].Cl>[OH-].[Na+].O.O1CCOCC1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([C:26](=[O:27])[NH:25][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COC(=O)CCCN=C=O
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)CCCNC(=O)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Reaction time: 2 h
Yield: 63.2 %

Procedure:
6.6 g (0.02 mol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazin-1-yl)-quinoline-3-carboxylic acid are dissolved in a solution of 0.4 g of sodium hydroxide in 40 ml of water, and a solution of 3.2 g (0.022 mol) of methyl 4-isocyanato-butyrate in 12 ml of dioxane is added, while cooling with ice. Thereafter, stirring is continued for 2 hours at room temperature, the pH is adjusted to 5 with 2N hydrochloric acid and the precipitate is filtered off under suction and recrystallised from methanol. 6 g (63% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-{4-[(3-methoxycarbonylpropyl)-carbamoyl]-piperazin-1-yl}-quinoline-3-carboxylic acid of melting point 198°-200° C. are obtained.
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[CH:10][C:11]=2[CH3:13])[S:6][CH2:5][CH2:4]1)[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20].Cl>ClCCl>[C:19]([C:10]1[C:11]([CH3:13])=[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=1)[S:6][CH2:5][CH2:4][CH:3]2[CH2:1][CH3:2])(=[O:21])[CH3:20]
Reactant: CCC1CCSc2c(C)ccc(C)c21
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC1CCSc2c(C)cc(C(C)=O)c(C)c21
Yield: 72.2 %

Procedure:
A mixed solution containing. 1.91 g (9.26 mmol) of the 4-ethyl-5,8-dimethylthiochroman and dichloromethane was dropwise added to a mixed solution containing 1.49 g (11.1 mmol) of aluminum chloride, 0.82 ml (11.6 mmol) of acetyl chloride and 6 ml of dichloromethane at 0° C., and the mixture was stirred for 1.5,hours. The reaction mixture was poured into ice and a solution containing 5% hydrochloric acid and extracted with dichloromethane. The extract was washed with a saturated sodium hydrogencarbonate, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to give 1.66 g (yield 72%) of 6-acetyl-4-ethyl-5,8-dimethylthiochroman.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:52]1([CH:58]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH2:59][CH2:60][NH2:61])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CN(C=O)C.C(OCC)C>[C:62]1([CH:58]([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:59][CH2:60][NH:61][C:12]([C@@H:11]([NH:10][C:8]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)NCCC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.51 g, 2.0 mmol, Example 1, Step B) was dissolved in dry DMF (5 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.68 mL, 3.9 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.74 g, 2.0 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; 3,3-diphenylpropylamine (0.41 g, 1.9 mmol, Aldrich, Milwaukee, Wis.) was then added. After additional 30 minutes stirring at 0° C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with 5% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. The solution was concentrated in vacuo, a white solid was obtained. Recrystallization from EtOAc-hexanes afforded 0.63 g (72%) of the pure titled compound as a white solid; mp 144-145° C. APCI-MS m/z 450.3 (MH+).
Reaction SMILES: CC1(C)C2C=C(C#C[C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)C=CC=2C(=O)CC1.[CH3:25][C:26]1([CH3:50])[C:35]2[CH:34]=[CH:33][C:32]([C:36]#[C:37]C3C=CC(C(OCC)=O)=CC=3)=[CH:31][C:30]=2[C:29](=[O:49])[CH2:28][CH2:27]1>>[CH3:25][C:26]1([CH3:50])[C:35]2[CH:34]=[CH:33][C:32]([C:36]#[C:37][C:16]3[CH:15]=[CH:14][CH:22]=[CH:21][C:17]=3[C:18]([OH:20])=[O:19])=[CH:31][C:30]=2[C:29](=[O:49])[CH2:28][CH2:27]1
Reactant: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Product: CC1(C)CCC(=O)c2cc(C#Cc3ccccc3C(=O)O)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4- [(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl ) ethynyl]benzoic acid (Compound 7 ) , 500 mg (1.45 mmol) of ethyl 4-[(5,6,7,8 -tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl) ethynyl]benzoate (Compound 2 ) was converted into the title compound using 4 ml (4 mmol) of LiOH (1N aqueous solution).
Reaction SMILES: Br[C:2]1[C:6]([CH:7]=[O:8])=[CH:5][S:4][CH:3]=1.[CH2:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)[CH3:10].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:6]([CH:7]=[O:8])=[CH:5][S:4][CH:3]=2)=[CH:13][CH:12]=1)[CH3:10]
Reactant: O=Cc1cscc1Br
Reactant: CCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1ccc(-c2cscc2C=O)cc1
Temperature: 128 °C
Reaction time: 5 h

Procedure:
A mixture of 3-bromo-4-formylthiophene (0.62 g, 3.18 mmol) and 4-ethylphenylboronic acid (0.95 g, 6.36 mmol) in toluene (12 mL), EtOH (12 mL) and aqueous Na2CO3 solution (2 M, 3.18 mL, 6.36 mmol) in a seal tube was deoxygenated under reduced pressure and flushed with argon for 3 times, followed by addition of Pd(PPh3)4 (184 mg, 0.16 mmol) and deoxygenated again. The resulting solution was stirred at 128° C. in an oil bath for 5 hour. The reaction progress was monitored by TLC/LCMS (ethyl acetate/petroleum ether=1:6). The reaction was partitioned between ethyl acetate and water. Collected the organic phases and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 440 mg (64%) of 4-(4-ethylphenyl)thiophene-3-carbaldehyde as light yellow oil.
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]2[C:20](=[CH:21][C:22]=1[F:23])[C:12]1[N:13]([CH2:16][C@H:17](O)[CH3:18])[CH:14]=[CH:15][C:11]=1[CH2:10]2.C(N(CC)CC)C.[N-:31]=[N+:32]=[N-:33].[Na+]>ClCCl.CN(C)C=O.O>[N:31]([C@@H:17]([CH3:18])[CH2:16][N:13]1[CH:14]=[CH:15][C:11]2[CH2:10][C:9]3[C:20]([C:12]1=2)=[CH:21][C:22]([F:23])=[C:7]([F:6])[CH:8]=3)=[N+:32]=[N-:33]
Reactant: C[C@@H](O)Cn1ccc2c1-c1cc(F)c(F)cc1C2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H](Cn1ccc2c1-c1cc(F)c(F)cc1C2)N=[N+]=[N-]
Yield: 78 %

Procedure:
0.7 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.13 g of (R)-1-(6,7-difluoro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 2.48 ml of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 70 ml of dichloromethane, washed twice with 60 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 60 ml of dichloromethane. The combined organic phases were washed with 90 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.58 g of sodium azide and the reaction mixture was heated to 60° for 17 hours while stirring. After cooling, the solution was poured into 70 ml of water and extracted three times with 70 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (hexane/ethyl acetate 4:1). 0.97 g (79%) of (S)-1-(2-azido-propyl)-6,7-difluoro-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=O)=[C:6]([NH:11][C@@H:12]2[CH2:16][C@H:15]([CH2:17][OH:18])[CH:14]=[CH:13]2)[N:5]=[C:4]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[N:3]=1.C(O)(C)C.Cl.C(OCC)(OCC)OCC.C([O-])(O)=O.[Na+].[CH:45]1([NH2:48])[CH2:47][CH2:46]1>>[CH:45]1([NH:48][C:2]2[N:3]=[C:4]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[N:5]=[C:6]3[C:7]=2[N:8]=[CH:9][N:11]3[C@@H:12]2[CH2:16][C@H:15]([CH2:17][OH:18])[CH:14]=[CH:13]2)[CH2:47][CH2:46]1
Reactant: CC(C)C(=O)Nc1nc(Cl)c(NC=O)c(N[C@H]2C=C[C@@H](CO)C2)n1
Reactant: NC1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Solvent: CC(C)O
Product: CC(C)C(=O)Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 41 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
Under nitrogen atmosphere, N-{4-chloro-5-formamido-6-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enylamino]pyrimidin-2-yl}isobutyramide (15 mg, 42.4 mmol) was dissolved in an anhydrous solution of isopropanol/HCl 1 N (254 ml, 254.4 mmol) and heated to 40-42° C. for 3.5 h. The solution was cooled to 5/10° C. and triethyl orthoformate (21 ml, 127.2 mmol) was added. The resulting mixture was stirred for 2 h at 5-10° C. NaHCO3 (21.37 g, 254.4 mmol) was added slowly, stirred 30 min and the salts were filtered off. To the resulting clear solution, NaHCO3 (3.56 g, 42.4 mmol) and cyclopropylamine (14.7 ml, 212 mmol) were added, the mixture was refluxed for 1 h and the salts were filtered off. The solution was evaporated and the syrup was dissolved in hot isopropanol (120 ml). This mixture was cooled to 0-2° C. and the resulting slurry filtered off. The solid was dried under vacuum at 30° C. There was obtained 10.97 g (73%) of (−)-N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purin-2-yl}isobutyramide as a white powder. HPLC analysis: 95.0%+3.8% Abacavir.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:22]([CH3:24])[CH3:23])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: CC(C)I
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(C(C)C)c3c(Cl)cccc23)cc1
Yield: 28.6 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxyphenyl)-1H-indazole (0.129 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 2-iodopropane (0.10 mL, 1.0 mmol) to give the title compound (0.043 g) as a white solid.
Reaction SMILES: NC[C@@H]1[C@H](C)CCCN1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[CH3:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:46])[C:33]2[C:38]([C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)=[CH:37][CH:36]=[C:35]([CH3:45])[N:34]=2)[C@@H:27]1[CH2:47][N:48]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:48][CH2:47][C@@H:27]1[C@H:26]([CH3:25])[CH2:31][CH2:30][CH2:29][N:28]1[C:32]([C:33]1[C:38]([C:39]2[N:44]=[CH:43][CH:42]=[CH:41][N:40]=2)=[CH:37][CH:36]=[C:35]([CH3:45])[N:34]=1)=[O:46]
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)n1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using 2-(((2S,3R)-3-methyl-1-(6-methyl-3-(pyrimidin-2-yl)picolinoyl)piperidin-2-yl)methyl)isoindoline-1,3-dione. ESI-MS (m/z): 326 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:9][CH:8]=1)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]([NH2:46])=[NH:45])[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]2[N:45]=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH:17]=[CH:16][CH:15]=[N:14]4)=[CH:9][CH:8]=3)[CH:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[N:46]=2)[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(-n2cccn2)cc1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2nc(-c3ccc(-n4cccn4)cc3)cc(C(F)(F)F)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 4,4,4-trifluoro-1-(4-pyrazol-1-yl-phenyl)-butane-1,3-dione (137 mg, 0.0.49 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (180 mg, 0.49 mmol) using in analogous manner the procedure described in example 29). Obtained as a pale-yellow solid (25 mg, 10%). Mp 252-254° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][N:26]1[CH:30]=[CH:29][N:28]=[C:27]1[SH:31]>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:31][C:27]3[N:26]([CH3:25])[CH:30]=[CH:29][N:28]=3)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: Cn1ccnc1S
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3nccn3C)s2)c(C(=O)C2CCCC2)c1
Yield: 31.9 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(1-methyl-1H-imidazol-2-ylsulfanyl)-thiazol-2-yl]-urea (141 mg, 32%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 1-methyl-1H-imidazole-2-thiol (228 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[C:12]1([C:18]2[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:19][CH:20]=2)[N:3]=1
Reactant: NCc1ccc(-c2ccccc2)cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Clc1nc(NCc2ccc(-c3ccccc3)cc2)c2[nH]cnc2n1
Temperature: 120 °C
Yield: 99 %

Procedure:
The 2,6-dichloropurine (5.0 g, 26.45 mmol) was suspended in n-butanol (50 ml) and the 4-phenylbenzylamine (6.61 g, 29.1 mmol) and triethylamine (4.1 ml, 29.1 mmol) were added. The solution was heated at 120° C. overnight then cooled. Filtered off product using excess n-butanol and washed precipitate with 100 ml 1M HCl and 200 ml water. The solid was dried in vaccum over overnight at 70° C. to give the desired product as a pale yellow solid. Yield=99%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+]>>[N+:1]([C:4]1[CH:5]=[N:6][C:7]([C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccccc1-c1ccc([N+](=O)[O-])cn1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccccc1-c1ccc([N+](=O)[O-])cn1
Yield: 71.8 %

Procedure:
In a similar manner to that described in Example 2, a reaction was carried out using methyl 3-nitropyridine-6-ylbenzoate (545 mg), which is the product of Reference example 32(a), and aqueous sodium hydroxide solution (1N, 3.16 ml) at 90° C. and the reaction mixture was treated to afford the title compound (370 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:32](O)[C:33]([F:36])([F:35])[F:34])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.[Cl:49]CCl.C(N(CC)CC)C.CS(Cl)(=O)=O>>[Cl:49][CH:32]([C:18]1[CH:17]=[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:48][CH:47]=3)[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[N:10]=2)[C:21]([NH:22][C:23]2[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=2)=[N:20][CH:19]=1)[C:33]([F:35])([F:34])[F:36]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)C(F)(F)F)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(Cl)C(F)(F)F)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-2,2,2-trifluoroethanol (1.03 g, 1.547 mmol) in dichloromethane (20 mL, 1.547 mmol) was added triethylamine (0.539 mL, 3.87 mmol) and methanesulfonyl chloride (0.244 mL, 3.09 mmol) at 0° C. and the mixture was stirred at the same temperature for 3 h, and warmed up to room temperature and stirred for another 2 h. The reaction was quenched with saturated aqueous NH4Cl solution and water at room temperature, and the separated aqueous layer was extracted with DCM (2×50 mL) and the combined organic layers were dried over Na2SO4 and concentrated and dried under vacuum to give the crude product. m/z (ESI, +ve ion) 684 (M+H)+. The material was used directly without further purification.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=2)=[C:20]([CH:24]=1)[C:21](O)=[O:22]>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=2)=[C:20]([CH:24]=1)[C:21]([NH:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4])=[O:22]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Oc1cc(F)cc(F)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2cc(F)cc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5) and 5-chloro-2-(3,5-difluorophenoxy)benzoic acid (step 2): 1H-NMR (CDCl3) δ 8.14 (1H, d, J=2.8 Hz), 7.94 (2H, d, J=8.4 Hz), 7.45 (1H, dd, J=8.8, 2.8 Hz), 7.37 (1H, d, J=7.9 Hz), 7.28 (2H, d, J=8.4 Hz), 6.95 (1H, d, J=8.8 Hz), 6.58–6.68 (1H, m), 6.48–6.38 (2H, m), 5.31 (1H, dq, J=7.9, 7.0 Hz), 3.91 (3H, s), 1.49 (3H, d, J=7.0 Hz); MS (ESI) m/z 446 (M+H)+, 444 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[C:9](/[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=2)=[C:10](/[NH:12][C:13](=[O:28])[C:14]([CH3:27])([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)[CH3:15])\[CH3:11])=[CH:4][CH:3]=1.C([O-])([O-])=[O:38].[K+].[K+].OO.CCCCCCC>C(OC(C)C)(=O)C.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[C:9](/[C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[C:35]([NH2:36])=[O:38])=[C:10](/[NH:12][C:13](=[O:28])[C:14]([CH3:15])([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][N:18]=2)[CH3:27])\[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: C/C(NC(=O)C(C)(C)Oc1ccc(C(F)(F)F)cn1)=C(\Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Agent: OO
Agent: [K+]
Solvent: CCCCCCC
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)C
Product: C/C(NC(=O)C(C)(C)Oc1ccc(C(F)(F)F)cn1)=C(\Cc1ccc(Cl)cc1)c1cccc(C(N)=O)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 0.02 %

Procedure:
To a 5 L, 3-necked round bottom flask equipped with overhead stirrer, thermocouple, and nitrogen inlet was added 524 g of the cyano enamide product of Example 14, N-[(1Z)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylprop-1-en-1-yl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide, and 112 g K2CO3. DMSO (2.7 L) was charged and the vessel was submerged in a RT water bath. Hydrogen peroxide solution (165 mol of a 30% aqueous solution) was slowly added to the reactor such that the temperature never rose above 25° C. After the addition was complete, the reaction was aged for 1 hour. The batch was diluted with 1 L of isopropyl acetate and filtered over a bed of SOLKA FLOC. The bed was washed with 4.5 L of isopropyl acetate and the resulting solution was transferred to a 50 L extractor containing 5.5 L of water. The layers were separated and the organic layer was washed twice with 3.1 L of water, concentrated to 5 L, and solvent switched to 5 L toluene at −60° C. Upon completion of the solvent switch, 500 mol of heptane was added and the mixture was cooled to 20° C. The batch was aged for 30 minutes at 20° C., then filtered and washed with 1 L of toluene. The resulting solid was dried overnight under a stream of nitrogen to afford 522 g of the title compound (99.4 LCAP, 98.0 wt %, 0.02% dppb-oxide, 512 g assay).
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].C1CCC(N=C=NC2CCCCC2)CC1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)[N:29]=[CH:28][C:27]([C:40]#[N:41])=[C:26]2[NH:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[C:45]([Cl:50])[CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Cl:50][C:45]1[CH:44]=[C:43]([CH:48]=[CH:47][C:46]=1[F:49])[NH:42][C:26]1[C:25]2[C:30](=[CH:31][C:32]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:24]=2)[N:29]=[CH:28][C:27]=1[C:40]#[N:41]
Reactant: CC#CC(=O)O
Reactant: CN1CCN(c2cc3ncc(C#N)c(Nc4ccc(F)c(Cl)c4)c3cc2N)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC#CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cc1N1CCN(C)CC1
Reaction time: 18 h
Yield: 69.2 %

Procedure:
To a stirred solution of 2-butynoic acid (0.25 g, 3.0 mmol) in 1.5 ml of DCM at 0° was added DCC (0.21 g, 1.0 mmol). After 15 m the mixture was warmed to 25°, recooled to 0°, and treated with 6-amino-4-(3-chloro-4-fluroanilino)-7-(4-methyl-1-piperazinyl)-3-quinolinecarbonitrile (0.21 g, 0.50 mmol) followed by 0.5 ml DCM rinse. The resulting mixture was stirred at 25° for 18 h and filtered to remove dicyclohexyl urea. The filtrate was partitioned with water which contained potassium carbonate (0.4 g, 3 mmol). The organic layer was washed with water, dried, and concentrated. The residue was passed as a solution in DCM onto a pad of silica gel. The product was eluted with 50:2:1 acetone-MeOH-TEA and concentrated to give 0.165 g amorphous solid; ms 477.2 (M+H)+, 239.1 (M+2H)+2.