Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:14](O)=[N:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11][C:10]=3[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(Cl)([Cl:31])=O)C=CC=CC=1.C(=O)(O)[O-].[Na+].C>CCCCCC.C(OCC)(=O)C>[Cl:31][C:14]1[C:15]2[CH2:16][CH2:17][N:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9][C:10]=2[N:11]=[C:12]([C:19]([F:22])([F:21])[F:20])[N:13]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: Oc1nc(C(F)(F)F)nc2c1CCN(Cc1ccccc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: FC(F)(F)c1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Temperature: 150 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A mixture of 29.6-g (95.7 mmol) of 7-(phenylmethyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (prepared essentially as described in Example 1, Step A) and 53 mL of phenylphosphonic dichloride in a 250-mL round bottom flask was heated at 150° C. After 2 h, the reaction was judged to be complete by TLC analysis. The mixture was cooled to ambient temperature and poured onto 400 g of ice, transferring with ˜500 mL of ethyl acetate. The aqueous layer was neutralized with solid sodium bicarbonate and the layers separated. The aqueous layer was extracted with two portions of ethyl acetate. The combined organics were washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated to give a brown solid. The solid was boiled in 2 L of hexane with charcoal, filtered, and concentrated in vacuo to give 23.9 g (76%) of the title compound as a yellow solid. LC-MS 328.3 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[N:19][C:20]([Cl:26])=[CH:21][CH:22]=2)[N:17]=1>O>[Cl:26][C:20]1[N:19]=[C:18]2[C:23]([CH:24]=[CH:25][C:16]([NH:15][C:10](=[O:12])[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][CH:13]=3)=[N:17]2)=[CH:22][CH:21]=1
Reactant: CCCCOc1ccc(C(=O)O)cc1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: O
Product: CCCCOc1ccc(C(=O)Nc2ccc3ccc(Cl)nc3n2)cc1
Yield: 35.2 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-butoxybenzoic acid (15.5 g), N,N'-carbonyldiimidazole (12.9 g) and 2-amino-7-chloro-1,8-naphthyridine (8.9 g). The product produced by precipitation in water (approximately 18 g; m.p. 140° C.) is purified by chromatography on a column 40 mm in diameter charged with silica (200 g; 0.063-0.2 mm), using methylene chloride as eluant and collecting 60-cc fractions. After concentration to dryness of fractions 8 to 12 at 40° C. under reduced pressure (4 kPa), N-(7-chloro-1,8-naphthyridin-2-yl)-4-butoxybenzamide (6.2 g) is produced, m.p. 197° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([SH:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)#[N:14]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[S:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:14][C:6](=[O:8])[C:5]=2[CH:9]=[CH:10][CH:11]=1
Reactant: N#Cc1ccccn1
Reactant: COc1cccc(C(=O)O)c1S
Solvent: c1ccncc1
Product: COc1cccc2c(=O)nc(-c3ccccn3)sc12
Temperature: 135 °C
Yield: 27.7 %

Procedure:
A mixture of 3-methoxy-2-mercaptobenzoic acid (1.84 g, 10.0 mmol), 2-cyanopyridine (1.05 g, 10.2 mmol) and pyridine (30.0 ml) was refluxed at 135° C. for 18 hrs as described in Example 9. The mixture was concentrated. The obtained crystals were recrystallized from ethanol to give the titled compound (0.75 g, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl[CH2:31][C:32]1[O:36][C:35]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:33]=1>>[CH3:40][O:39][C:37]([C:35]1[O:36][C:32]([CH2:31][N:19]2[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)/[S:21][C:20]2=[O:22])=[CH:33][CH:34]=1)=[O:38]
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: COC(=O)c1ccc(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)o1

Procedure:
5-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}furan-2-carboxylic acid methyl ester was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and methyl 5-chloromethylfuroate following General Procedure S (reaction time of 16 h).
Reaction SMILES: C([N:4]([CH2:8][CH3:9])[CH:5](C)C)(C)C.[F:10][C:11]1[CH:27]=[C:26]([C:28]2[CH:29]=[N:30][C:31]3[N:32]([C:34]([C:37]4([C:40]5[CH:41]=[C:42]6[C:47](=[CH:48][CH:49]=5)[N:46]=[CH:45][CH:44]=[CH:43]6)[CH2:39][CH2:38]4)=[CH:35][N:36]=3)[CH:33]=2)[CH:25]=[CH:24][C:12]=1[C:13]([NH:15][C@@H:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:17]([OH:19])=O)=[O:14].Cl.N1CCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[N:4]1([C:17]([C@@H:16]([NH:15][C:13](=[O:14])[C:12]2[CH:24]=[CH:25][C:26]([C:28]3[CH:29]=[N:30][C:31]4[N:32]([C:34]([C:37]5([C:40]6[CH:41]=[C:42]7[C:47](=[CH:48][CH:49]=6)[N:46]=[CH:45][CH:44]=[CH:43]7)[CH2:38][CH2:39]5)=[CH:35][N:36]=4)[CH:33]=3)=[CH:27][C:11]=2[F:10])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH2:5][CH2:9][CH2:8]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)[C@H](NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)O
Agent: C1CNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)[C@H](NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)N1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (14 μL, 0.084 mmol) was added to a mixture of (2S)-2-(2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoylamino)-3,3-dimethylbutanoic acid (15 mg, 0.028 mmol), azetidine hydrochloride (3.9 mg 0.042 mmol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (18 mg, 0.042 mmol) in N,N-dimethylformamide (0.5 mL). After stirring at RT overnight, the reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=577.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[O:32][CH3:33])=[CH:20][CH:19]=1)[NH:5][C:6](=[O:16])[C:7]1[C:12]([Cl:13])=[CH:11][C:10](Br)=[CH:9][C:8]=1[Cl:15].[CH3:35][Si:36]([CH3:50])([CH3:49])[CH2:37][CH2:38][O:39][CH2:40][N:41]1[C:45](B(O)O)=[CH:44][CH:43]=[N:42]1>C1COCC1>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[O:32][CH3:33])=[CH:20][CH:19]=1)[NH:5][C:6](=[O:16])[C:7]1[C:12]([Cl:13])=[CH:11][C:10]([C:45]2[N:41]([CH2:40][O:39][CH2:38][CH2:37][Si:36]([CH3:50])([CH3:49])[CH3:35])[N:42]=[CH:43][CH:44]=2)=[CH:9][C:8]=1[Cl:15]
Reactant: C[Si](C)(C)CCOCn1nccc1B(O)O
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cc(Br)cc1Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cc(-c2ccnn2COCC[Si](C)(C)C)cc1Cl
Yield: 95.6 %

Procedure:
N-(4-Bromo-2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (0.240 g) was coupled with 1-[[2-(trimethylsilyl)ethoxy]methyl]-5-pyrazoleboronic acid (0.343 g) in THF (10 mL) as described in Example 7-2) to give N-[4-[1-[[2-(trimethylsilyl)ethoxy]methyl]-5-pyrazolyl]-2,6-dichlorobenzoyl]-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (0.277 g). ESMS: m/z 684 (MH+) and 682 (M−H)−.
Reaction SMILES: C1COCC1.[Br:6][C:7]1[CH:8]=[C:9]([Mg]Br)[CH:10]=[CH:11][CH:12]=1.[CH2:15]([N:22]1[CH2:27][CH:26]=[C:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH3:31])=[O:29])[CH:24]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Br:6])[CH:8]=2)[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Br[Mg]c1cccc(Br)c1
Reactant: COC(=O)C1=CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C1CCN(Cc2ccccc2)CC1c1cccc(Br)c1
Temperature: 20 °C
Yield: 60.5 %

Procedure:
A 0.5 M THF solution of (3-bromophenyl)magnesium bromide (20 mL, 10 mmol) was cooled to −15° C., and methyl 1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate (1.05 g, 4.3 mmol) in toluene (3.0 mL) was slowly added for 3 h at −15° C. The reaction mixture was warmed to 20° C. and quenched by addition of saturated NH4Cl aqueous solution followed by extraction with EtOAc. The combined organic solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed in silica gel column (Hex/EtOAc 9/1) to give methyl 1-benzyl-3-(3-bromophenyl)piperidine-4-carboxylate (1.0 g, 2.6 mmol).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:12]=3)=[N:9][N:10]=2)[CH:7]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:46][C:47]([O:50][C:51]([NH:53][CH:54]1[CH2:59][CH2:58][CH:57]([OH:60])[CH2:56][CH2:55]1)=[O:52])([CH3:49])[CH3:48]>C1(C)C=CC=CC=1.CCOC(C)=O.[Cu]I>[C:47]([O:50][C:51](=[O:52])[NH:53][C@H:54]1[CH2:55][CH2:56][C@H:57]([O:60][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)[CH:12]=4)=[N:9][N:10]=3)[CH:7]=2)[CH2:58][CH2:59]1)([CH3:49])([CH3:46])[CH3:48]
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Reactant: Ic1ccc2nnc(-c3cccc(OCCN4CCOCC4)c3)n2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccc3nnc(-c4cccc(OCCN5CCOCC5)c4)n3c2)CC1
Temperature: 25 °C

Procedure:
A mixture of Example 1 step b (234 mg, 0.52 mmol), copper (I) iodide (9 mg, 0.052 mmol), 1,10-phenanthroline (19 mg, 0.104 mmol), cesium carbonate (335 mg, 1.04 mmol) and trans-4-boc-aminocyclohexanol (560 mg, 2.6 mmol) in toluene (3 mL) was heated at 110° C. for 72 h under an argon atmosphere. The suspension was cooled to RT, diluted with EtOAc (10 mL) and filtered through HiFlo. The filtrate was concentrated in vacuo and the residue purified by reverse phase preparative HPLC (Method 3) to afford the title compound (205 mg, 39%) as an off-white solid. LCMS (Method 2): Rt 2.53 min, m/z 538 [MH+].
Reaction SMILES: [H-].[Na+].[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13].Cl.Cl[CH2:16][C:17]1[C:21]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[S:28][C:29]4[C:30]([N:35]=3)=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][C:20]=2[O:19][CH:18]=1>CN(C=O)C>[S:28]1[C:29]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[N:35]=[C:27]1[O:26][C:24]1[CH:23]=[CH:22][C:21]2[C:17]([CH2:16][N:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:6][CH2:5][C:4]3=[O:13])=[CH:18][O:19][C:20]=2[CH:25]=1
Reactant: O=C1CCc2ccccc2N1
Reactant: ClCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2ccccc2N1Cc1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
To a solution of 60% NaH (68 mg, 1.7 mmol) in DMF (2.5 mL) at 0° C. was added a solution of 3,4-dihydro-1H-quinolin-2-one (208 mg, 1.4 mmol) in DMF (2.0 mL). The reaction mixture was stirred (0° C., 30 min) before the addition of 2-(3-chloromethyl-benzofuran-6-yloxy)-thiazolo[4,5-b]pyridine hydrochloride (50 mg, 0.14 mmol). The reaction mixture was stirred (rt, 30 min), washed with water, extracted with ethyl acetate, dried, filtered and concentrated. The residue was purified by reverse phase HPLC to provide the title compound (22 mg, 36%). MS (ESI): mass calcd. for C24H17N3O3S, 427.10; m/z found, 428.0 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.54-8.48 (m, 1H), 8.43-8.36 (m, 1H), 7.88-7.81 (m, 1H), 7.78 (d, J=8.5, 1H), 7.64 (d, J=2.1, 1H), 7.44-7.38 (m, 2H), 7.36-7.30 (m, 1H), 7.30-7.16 (m, 2H), 7.05-6.98 (m, 1H), 5.38 (s, 2H), 2.98-2.85 (m, 2H), 2.79-2.70 (m, 2H).
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].CCOCC>[OH-].[Na+]>[CH2:13]([O:12][C:10]([NH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(N)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 45.3 %

Procedure:
3-Amino-3-methylbutyric acid (2.40 g, 20.49 mmol) was dissolved in NaOH (2 M aq, 35 mL), the resulting mixture cooled to 0° C., and benzyl chloroformate (5.77 mL, 40.97 mmol) added. The reaction mixture was stirred vigorously at 0° C. for 1 h and at RT for 3 h. Et2O (50 mL) was then added, and the layers separated. The organic layer was discarded. The aqueous layer was acidified to pH 2, brine added, and the resulting mixture extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give 3-benzyloxycarbonylamino-3-methyl-butyric acid (2.33 g, 46% yield) without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[CH:27]=[C:26]([C:28]([O:30]CC)=[O:29])[O:25][N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[O:25][N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2OCc2ccccc2)no1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2OCc2ccccc2)no1
Reaction time: 0.25 h
Yield: 48.6 %

Procedure:
A solution of ethyl 3-(2,4-dibenzyloxyphenyl)isoxazole-5-carboxylate (2.2 g) in hot methanol (100 mL) is treated with 10% aqueous potassium hydroxide solution (10 mL w/v) and the mixture is heated to reflux for 2 hours. The reaction mixture is evaporated to low bulk, stirred with 1 N hydrochloric acid (50 mL) for 15 minutes and filtered. The resulting solid is washed with water, dried and crystallised from ethyl acetate to give 3-(2,4-dibenzyloxyphenyl)isoxazole-5-carboxylic acid (1 g), in the form of a white solid, m.p. 192-193° C. [Elemental analysis:- C,71.7; H,4.67; N,3.34%. Calculated:- C,71.8; H,4.77; N,3.49%].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:19][C:18]2[C:13](=[N:14][CH:15]=[N:16][CH:17]=2)[N:12]=1.[OH:20]O>FC(F)(F)C(O)=O.O.C(=O)([O-])[O-].[K+].[K+]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:10])=[O:20])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:19][C:18]2[C:13](=[N:14][CH:15]=[N:16][CH:17]=2)[N:12]=1
Reactant: COc1cc(SC)ccc1-c1nc2ncncc2[nH]1
Reactant: OO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(S(C)=O)ccc1-c1nc2ncncc2[nH]1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
An amount of 2.27 g of 8-(2-methoxy-4-methylmercaptophenyl)-purine was dissolved in 20 ml of trifluoro acetic acid, and 1.2 ml of 30% hydrogen peroxide were added under cooling to 5° C. After stirring for 3 hours at room temperature and for 0.5 hours at 30° C., the reaction mixture was diluted with water and neutralized with potassium carbonate, and the residue obtained after evaporation was extracted with hot ethanol. The product obtained was purified over silicagel (eluate: methylene chloride/ethanol in a volume ratio of 19:1).
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.[CH3:19]C(C)([O-])C.[K+].CI>C1COCC1>[CH3:19][O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COC1CN(C(=O)OC(C)(C)C)CCC1(OC)OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1,1-dimethylethyl 3-hydroxy-4,4-bis(methyloxy)-1-piperidinecarboxylate D16 (11 g) in THF (150 ml) was added Potassium t-Butoxide (23.5 g, 210 mmol) at 0° C. The reaction mixture was stirred for 20 mins and the methyliodide (5.2 ml, 84 mmol) was added. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The resulting mixture was concentrated and dissolved in EtOAc and washed with water. The organic layer was concentrated in vacuo to obtain crude product. Product was purified on silica gel eluting with DCM/MeOH 50/1 to obtain the desired product D17 as a yellow oil in 5 g. LCMS [MH+] 298@1.385 min (5 min run)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH3:16][NH2:17]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][CH3:16])(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Product: CNS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Yield: 90 %

Procedure:
In an analogous manner to General Procedure A, 4-Bromo-2-trifluoromethylbenzenesulfonyl chloride (0.50 g, 1.54 mmol) and methylamine (10 mL, 33% in ethanol) were stirred in sealed tube for 16 hours. 4-bromo-N-methyl-2 (trifluoromethyl)benzenesulfonamide (0.44 g, 90%) was provided after purification. MS (ESI) m/z 318. HPLC purity 100.0% at 210-370 nm, 8.5 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[CH3:18][S:19][C:20]1[N:25]=[C:24]([C:26]2[S:30][C:29]([S:31](Cl)(=[O:33])=[O:32])=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1.S1C(S(Cl)(=O)=O)=CC2C=CC=CC1=2>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:31]([C:29]2[S:30][C:26]([C:24]3[CH:23]=[CH:22][N:21]=[C:20]([S:19][CH3:18])[N:25]=3)=[CH:27][CH:28]=2)(=[O:32])=[O:33])[C:4]1=[O:17])#[N:13]
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: CSc1nccc(-c2ccc(S(=O)(=O)Cl)s2)n1
Agent: Cl
Agent: O=S(=O)(Cl)c1cc2ccccc2s1
Product: CSc1nccc(-c2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)s2)n1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-benzonitrile hydrochloride as described in EXAMPLE 1, Part E using 5-[2-(methylthio)-pyrimidin-4-yl]thiophene-2-sulfonyl chloride in a place of benzo[b]thiophene-2-sulfonyl chloride. The crude product is obtained as a white solid and is of sufficient purity to be used in the subsequent step.
Reaction SMILES: [N:1]1([C:5](=[O:23])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13]CC3C=CC=CC=3)=[CH:9][C:8]=2[O:21][CH3:22])[CH2:4][CH2:3][CH2:2]1>C(O)C.[OH-].[OH-].[Pd+2]>[N:1]1([C:5](=[O:23])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[O:21][CH3:22])[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(OCc2ccccc2)ccc1CC(=O)N1CCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(O)ccc1CC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(azetidin-1-yl)-2-[4-(benzyloxy)-2-methoxyphenyl]ethanone (1.26 g, 4.05 mmol) was dissolved in ethanol (10 ml) and palladium hydroxide on carbon (20%) (284 mg, 0.405 mmol) added. The mixture was stirred under an atmosphere of hydrogen gas at RT overnight. The mixture was filtered and the filtrate concentrated under reduced pressure. The reside was purified by column chromatography using a Biotage RP C18 cartridge (30 g) using a gradient eluant of 0-30% water: acetonitrile+0.05% formic acid to afford the title compound. LC/MS (m/z): 222 (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].CCN(CC)CC.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27]>C(Cl)Cl>[CH2:1]([N:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([F:15])([F:16])[F:17])=[CH:8][CH:7]=1)[C:25](=[O:28])[CH:26]=[CH2:27])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CC(=O)Cl
Reactant: C=CCCNc1ccc(OCC(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCN(C(=O)C=C)c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To the mixture of but-3-enyl-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-amine (1.56 g, 6 mmol) and NEt3 (1.7 g, 17 mmol) in 30 mL of DCM, acryloyl chloride (0.65 g, 7 mmol) was added slowly into at 0° C. The mixture was stirred at ambient temperature overnight. And then the solution was washed with water (2×15 mL) and brine (2×20 mL), dried with anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica-gel column chromatography (eluting with petroleum ether/ethyl acetate=20:1) to obtain the title compound (1.6 g, 89%) as colorless oil. LC-MS: 300.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][NH:9][C:10](=O)[C@H:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[C:18]=2[CH3:26])[C:12]([OH:15])([CH3:14])[CH3:13])=[O:7])=[CH:4][CH:3]=1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[Cl:25][C:19]1[C:18]([CH3:26])=[C:17]([NH:16][C@@H:11]([C:10]2[O:7][C:6]([C:5]3[CH:28]=[CH:29][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)[C:12]([OH:15])([CH3:14])[CH3:13])[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Cl)cc2)C(C)(C)O)ccc(C#N)c1Cl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(Cl)cc3)o2)C(C)(C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 334.6 %

Procedure:
The crude material of (R)-4-chloro-N′-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoyl)benzohydrazide (intermediate 15a) (230 mg, 0.53 mmol) was added to THF (50 mL) stirred at room temperature. PS-BEMP (721 mg, 1.59 mmol base) was added to the solution followed by slow addition of p-TSCl (111 mg, 0.58 mmol). The reaction mixture was stirred for 1 h and the progress of the reaction was monitored by TLC. After the completion of the reaction the BEMP reagent was filtered off and the solution concentrated to get the crude material. The crude material was chromatographed with hexanes:EtOAc (6:4) to provide the product (740 mg): 1H NMR (500 MHz; CDCl3, δ in ppm) 7.95 (d, J=9 Hz, 2H), 7.50 (d, J=9 Hz, 2H), 7.39 (d, J=9 Hz, 1H), 6.63 (d, J=9 Hz, 1H), 5.37 (d, J=9 Hz, 1H), 4.74 (d, J=9 Hz, 1H), 2.36 (s, 3H), 1.52 (s, 3H), 1.36 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](Cl)[C:5]2=[CH:9][CH:10]=[CH:11][N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[C:4]2=[N:3]1.[C:21]1([CH3:31])[CH:26]=CC(S(O)(=O)=O)=CC=1>C(NCCC)CC>[CH3:1][N:2]1[CH:7]=[C:6]([N:2]([CH2:26][CH2:21][CH3:31])[CH2:7][CH2:6][CH3:5])[C:5]2=[CH:9][CH:10]=[CH:11][N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[C:4]2=[N:3]1
Reactant: CN1C=C(Cl)C2=CC=CN(c3ccc(Cl)c(Cl)c3)C2=N1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCNCCC
Product: CCCN(CCC)C1=CN(C)N=C2C1=CC=CN2c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
Heat a mixture of 2-methyl-4-chloro-8-(3,4-dichlorophenyl)pyrido[2,3-c]pyridazine (4) (1.0 g, 3.1 mmol) and p-toluenesulfonic acid (1.6 g) in 5 mL of di-n-propylamine in a sealed tube at 180° C. for 48 hours. Cool the reaction mixture to ambient temperature and partition between ethyl acetate and water. Wash the organic layer with water and dry over MgSO4. Evaporate the dried solution and purify the desired product 5 by flash chromatography.