Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:10]([C:19]([OH:21])=O)[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:10]([C:19]([NH:35][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)=[O:21])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(-c3cncc(C)c3)c(C(=O)O)c(-c3ccccc3)nc21
Reactant: COc1ccc(CN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncc2c(-c3cncc(C)c3)c(C(=O)NCc3ccc(OC)cc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.9 %

Procedure:
To a stirred solution of 1-ethyl-4-(5-methyl-3-pyridyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (18 mg) and 4-methoxybenzyl amine (10.3 mg) in DMF (1 ml) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (28.6 mg) and N,N-dimethylaminopyridine (9.2 mg). The reaction mixture was stirred at room temperature for 18 hours and at 50° for 5 hours. After cooling, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with diluted HCl, water, saturated aqueous NaHCO3, water, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crystalline residue was recrystallized from EtOAc and n-hexane to give 1-ethyl-N-(4-methoxybenzyl)-4-(5-methyl-3-pyridyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (15.8 mg) as a colorless crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([S:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH:20]=[C:9]1[CH2:8][S:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13])[CH3:19]
Reactant: CCOC(OCC)N(C)C
Reactant: COc1ccc2c(c1)C(=O)CCS2
Product: COc1ccc2c(c1)C(=O)C(=CN(C)C)CS2

Procedure:
The 3,4-dihydro-2-dimethylaminomethylene-7-methoxy-4-thia-1(2H)-naphthalenone starting material was prepared from 3,4-dihydro-7-methoxy-4-thia-1(2H)naphthalenone (1.0 g, 5.2 mmol [Degani, I. et al, Boll. Sci. Fac. Chim. Ind. Bologna (1966), 24(2-3) 75-91], and N,N-dimethyl-formamide diethyl acetal (2.7 ml, 15.6 mmol) to give the product as a mustard yellow solid (1.06 g). δH (CDCl3) 7.63 (1H, J 2.9 Hz), 7.60 (1H, s), 7.17 (1H, d, J 8. Hz), 6.90 (1H, dd, J 2.9, 8.4 Hz), 3.98 (2H, s), 3.83 (3H, s) and 3.15 (6H, s). MS(EI+) 249 (M+, 66%), 205 (13%), 177 (59%), 82 (100%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][C:22]([NH2:23])=[C:21]([CH3:28])[CH:20]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[C:21]([CH3:28])[CH:20]=1
Reactant: N#Cc1cnc2cc3ccccc3cc2c1Cl
Reactant: COc1cc(N)c(C)cc1Cl
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc(Nc2c(C#N)cnc3cc4ccccc4cc23)c(C)cc1Cl
Yield: 71 %

Procedure:
Following the procedure of Example 3, the reaction mixture of 141.8 mg (0.60 mmol) of 4-chlorobenzo[g]quinoline-3-carbonitrile, 102.9 mg (0.60 mmol) of 4-chloro-5-methoxy-2-methylaniline (can be prepared by the procedure disclosed in WO 85/01939, which is hereby incorporated by reference) and 57.8 mg (0.50 mmol) of pyridine hydrochloride in 8.0 mL of 2-ethoxyethanol is heated at 130–135° C. for 1.5 hours to yield the crude product. Purification of the crude product on preparative TLC (developing solvent: 95:5 methylene chloride/methanol) yields 159.3 mg (72.2%) of the pure product as a yellow solid, mp 195–197° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[CH2:13][S:14]([C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])(=[O:16])=[O:15].[N:27]1([CH2:32][C@@H:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)O)[CH:31]=[CH:30][N:29]=[CH:28]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[N:27]1([CH2:32][C@@H:33]([O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=3[C:3]=2[CH2:13][S:14]([C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])(=[O:16])=[O:15])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: COC(=O)c1cccc(S(=O)(=O)Cc2c(O)ccc3c2CCCC3=O)c1
Reactant: O[C@@H](Cn1ccnc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 96 %

Procedure:
Using the method in Example 154, this compound was prepared from methyl 3-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methylsulfonylbenzoate (1.98 g, 5.3 mmol), (R)-2-imidazol-1-yl-1-phenylethanol (1.00 g, 5.3 mmol), Ph3P (2.10 g, 8.0 mmol), and diethyl azodicarboxylate (1.39 g, 8.0 mmol) as a solid-foam, 2.80 g, 96% yield; mp 85° C. NMR spectrum was consistent with structure. Calcd. For C30H28N2O6S.0.5H2O:
Reaction SMILES: BrC[CH2:3][O:4][CH2:5]CBr.ClC1C=CC([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20](O)=[C:21](OC)[CH:22]=3)[N:17]=CN=2)=C(F)C=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:5][O:4][C:3]1[N:13]=[CH:14][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ncc2ccccc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 153.7 %

Procedure:
2-Bromoethyl ether (1.57 ml, 12 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1 g, 3.1 mmol), (prepared as described for the starting material in Example, 2), and potassium carbonate (1.73 g, 12 mmol) in DMF (10 ml). The mixture was stirred for 18 hours at ambient temperature and was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and then brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography on silica eluting with methylene chloride/acetonitrile/methanol (60/38/2). The purified product was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 7-(22-bromoethoxy)ethoxy)-4-(4-chloro-2-fuoroanilino) methoxyquinazoline (763 mg, 52%).
Reaction SMILES: Br[C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[Cl:20].BrC1N(COCC[Si](C)(C)C)C2C=NNC(=O)C=2C=1.[CH:40]1([O:44][C:45]2[CH:46]=[C:47](B3OC(C)(C)C(C)(C)O3)[CH:48]=[CH:49][C:50]=2[O:51][CH3:52])[CH2:43][CH2:42][CH2:41]1.C1(OC2C=C(B3OC(C)(C)C(C)(C)O3)C=CC=2OC(F)F)CC1>>[Cl:20][C:3]1[C:4]2[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:2]=1[C:47]1[CH:48]=[CH:49][C:50]([O:51][CH3:52])=[C:45]([O:44][CH:40]2[CH2:41][CH2:42][CH2:43]2)[CH:46]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC1CCC1
Reactant: C[Si](C)(C)CCOCn1c(Br)c(Cl)c2c(=O)[nH]ncc21
Agent: CC1(C)OB(c2ccc(OC(F)F)c(OC3CC3)c2)OC1(C)C
Agent: C[Si](C)(C)CCOCn1c(Br)cc2c(=O)[nH]ncc21
Product: COc1ccc(-c2c(Cl)c3c(=O)[nH]ncc3n2COCC[Si](C)(C)C)cc1OC1CCC1
Yield: 64.7 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 1-(a) except for using 0.40 g (1.1 mmol) of 2-bromo-3-chloro-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the following Reference example 16-(d) in place of 2-bromo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one, and using 0.49 g (1.6 mmol) of 2-(3-cyclobutoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in the following Reference example 1-(f) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, whereby 339 mg of the title compound was obtained as a pale yellowish solid. (Yield: 67%)
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:8][CH:9]=1)[OH:4].[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[N:20]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[O:8][CH:9]=[C:5]([CH:3]([OH:4])[CH2:2][NH:1][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([C:21]4[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=4)[CH:25]=3)[N:6]=2)=[CH:11][CH:12]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC(O)c1coc(-c2ccc(F)cc2)n1
Product: O=C(NCC(O)c1coc(-c2ccc(F)cc2)n1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 39 %

Procedure:
This compound was synthesized from 2-amino-1-(2-(4-fluorophenyl)oxazol-4-yl)ethanol and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (70 mg, yield 39%). 1H NMR (400 MHz, CDCl3) δ 8.51 (m, 1H), 8.28-8.26 (m, 1H), 8.08-8.01 (m, 3H), 7.73 (s, 1H), 7.66-7.62 (m, 1H), 7.17-7.08 (m, 3H), 5.05-5.03 (m, 1H), 4.12-4.06 (ddd, J=14.1 Hz, 6.3 Hz, 3.8 Hz, 1H), 3.91-3.85 (m, 1H), 3.77 (br s, 1H). MS (ESI) m/z: Calculated for C21H14F4N4O4: 462.10. found: 463.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([O:21][CH2:22][CH3:23])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH3:2]>CO.[Rh]>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1)OCC
Agent: [Rh]
Solvent: CO
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Yield: 10150156 %

Procedure:
3-(4-Benzyloxyphenyl)-2-ethoxyacrylic acid ethyl ester (0.5 g; 1.5 nmole) was hydrogenated at atmospheric pressure using rhodium on charcoal as catalyst (5%, 50 mg) in methanol (20 ml). The crude product was purified by chromatography using heptane:ethyl acetate (5:1) as eluant to give 50 mg (yield 10%) of 3-(4-benzyloxyphenyl)-2-ethoxypropanoic acid ethyl ester.
Reaction SMILES: B.C1COCC1.[N:7]([CH2:10][C:11]([C:13]1[CH:24]=[CH:23][C:16]2[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:15]=2[CH:14]=1)=[O:12])=[N+:8]=[N-:9].Cl>C1(C)C=CC=CC=1.C1COCC1>[N:7]([CH2:10][C@@H:11]([C:13]1[CH:24]=[CH:23][C:16]2[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:15]=2[CH:14]=1)[OH:12])=[N+:8]=[N-:9]
Reactant: CC1(C)OCc2cc(C(=O)CN=[N+]=[N-])ccc2O1
Agent: B
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CN=[N+]=[N-])ccc2O1
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
R-(+)-2-Methyl-CBS-oxazaborolidine solution in toluene (1M, 7.5 ml) was added to THF (75 ml) and the solution was diluted to 0° C. Borane-THF complex (1M solution in THF, 125 ml) was added and the mixture was stirred under nitrogen for 15 min. A solution of 2-azido-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (24.7 g) in THF (250 ml) was added dropwise over 1.5 h at 5° C. The mixture was stirred for a further 1 h and then cautiously treated with 2M HCl (100 ml). The reaction mixture was extracted with ether and the organic layer was washed with 2M HCl, NaHCO3, brine, dried (MgSO4). The solvent was removed by evaporation and the residue was chromatographed on a Biotage column eluting with diethyl ether-petrol (40-60° C.) (1:9; 1:1) to give the title compound (16.99 g). ES+ve 250 (MH)+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[C:38]([F:41])([F:40])[F:39].O>CN(C=O)C>[F:39][C:38]([F:40])([F:41])[C:29]1[CH:30]=[CH:31][C:32]([C:34]([F:37])([F:35])[F:36])=[CH:33][C:28]=1[CH2:27][N:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: FC(F)(F)c1ccc(C(F)(F)F)c(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2cc(C(F)(F)F)ccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) was added a solution of potassium carbonate (345 mg) and 2-(bromomethyl)-1,4-bis(trifluoromethyl)benzene (0.129 mL) in DMF (2 mL). The reaction mixture was stirred at room temperature overnight, water was added, 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 (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (156 mg).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].[S:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[S:25][CH:29]=[CH:28][N:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: c1cscn1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Product: O=C(c1cn(-c2cccc(-c3cccnc3F)c2)cn1)c1nccs1

Procedure:
This compound is prepared by method C using compound 12i and thiazole
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][N:3]=1.[C:10]([CH:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1)[CH3:14])([OH:12])=[O:11]>>[C:10]([CH:13]([N:15]1[CH2:16][CH2:17][CH:18]([N:21]=[CH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)[CH2:19][CH2:20]1)[CH3:14])([OH:12])=[O:11]
Reactant: CC(C(=O)O)N1CCC(N)CC1
Reactant: Nc1nccc(C=O)n1
Product: CC(C(=O)O)N1CCC(N=Cc2ccnc(N)n2)CC1

Procedure:
2-Aminopyrimidine-4-carboxaldehyde and 1-carboxyethyl-4-aminopiperidine were reacted by the procedure of example 1(c) to afford the title compound as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4([NH:31]C(=O)OC(C)(C)C)[CH2:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=3)=[N:19][C:10]3[CH2:11][CH2:12][C:13]4[CH:14]=[N:15][CH:16]=[N:17][C:18]=4[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O>[C:1]1([C:7]2[C:20]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4([NH2:31])[CH2:30][CH2:29][CH2:28]4)=[CH:25][CH:26]=3)=[N:19][C:10]3[CH2:11][CH2:12][C:13]4[CH:14]=[N:15][CH:16]=[N:17][C:18]=4[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3ncncc3CC4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3ncncc3CC4)cc2)CCC1
Reaction time: 0.01 h
Yield: 86 %

Procedure:
Tert-butyl (1-(4-(9-phenyl-5,6-dihydropyrido[2,3-h]quinazolin-8-yl)phenyl)cyclobutyl)carbamate (12 mg, 0.023 mmol) was dissolved in TFA (1 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (8 mg, 70% yield). 1H NMR (500 MHz, CH3OD) 9.09 (s, 1H), 8.74 (s, 1H), 8.67 (s, 1H), 7.52 (d, 2H), 7.43 (d, 2H), 7.32 (m, 3H), 7.26 (m, 2H), 3.22 (m, 2H), 2.75 (m, 2H), 2.59 (m, 2H), 2.23 (m, 1H), 1.98 (m, 1H). LCMS (Method A): RT=4.26 min, M+2H+=406.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH:13]([C:19]1([CH3:24])OCC[O:20]1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2=[O:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH:13]([C:19](=[O:20])[CH3:24])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2=[O:25]
Reactant: CCOC(=O)C(CN1C(=O)c2ccc(Cl)cc2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(CN1C(=O)c2ccc(Cl)cc2C1=O)C(C)=O

Procedure:
Ethyl 2-(5-chloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (171 mg, 34%) in the same manner as described in the above example 6 (20) from ethyl 3-(5-chloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.45 g, 1.22 mmol) and p-toluenesulfonic acid monohydrate (50 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH3:33])=[C:27](B(O)O)[CH:28]=1.C([O-])(O)=O.[Na+].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.O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:32][CH3:33])=[C:25]([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)[CH:24]=1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Reactant: COc1ccc(F)cc1B(O)O
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: CCO
Solvent: O
Product: COc1ccc(F)cc1-c1ccc(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)s1
Temperature: 80 °C
Yield: 19 %

Procedure:
A mixture of 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol), 5-fluoro-2-methoxyphenylboronic acid (10 mg, 0.06 mmol), Pd(PPh3)4 (3 mg, 0.0025 mmol), NaHCO3 (13 mg, 0.15 mmol), EtOH (750 μL) and water (250 μL) was heated in a sealed tube at 80° C. over night. The mixture was concentrated and purified by preparative HPLC (ACE C8 5 μm, 0.1% TFA in water/CH3CN) giving 4.1 mg (19%) of the title compound. MS (ESI+) calcd for C18H14FN5O3S2 431.052209, found 431.051439.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[F:17][C:18]1[C:23](B(O)O)=[CH:22][CH:21]=[CH:20][N:19]=1.C([O-])(=O)C.[K+].C(O)CCC>CCOC(C)=O.O>[F:17][C:18]1[C:23]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Reactant: OB(O)c1cccnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Fc1ncccc1-c1ncnc2c1ncn2C1CCCCO1

Procedure:
To a round bottom flask, under a reflux condenser, was added 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (1.0 g, 3.5 mmol), 2-fluoropyridin-3-ylboronic acid (0.75 g, 5.3 mmol), potassium acetate (1.0 g, 11 mmol), 1-butanol (50 mL) and DI water (10 mL). The mixture was purged with Ar (vacuum/purge three times) to remove oxygen, then PdCl2(P-tert-Bu2Ph)2 (0.026 g, 0.042 mmol) was added. The reaction mixture was stirred in a 100° C. oil bath for 45 min (complete by TLC, 80% EtOAc/hex).
Reaction SMILES: [CH2:1]([C:3]([C:21]1[S:25][C:24]([C:26]([OH:28])=O)=[C:23]([CH3:29])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].CCN(CC)CC.[NH2:37][CH2:38][CH2:39][S:40]([CH3:43])(=[O:42])=[O:41].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:43][S:40]([CH2:39][CH2:38][NH:37][C:26]([C:24]1[S:25][C:21]([C:3]([CH2:1][CH3:2])([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:17])([CH3:16])[CH3:18])=[C:8]([CH3:20])[CH:7]=2)[CH2:4][CH3:5])=[CH:22][C:23]=1[CH3:29])=[O:28])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)CCN
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)NCCS(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a mixture of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butyoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (0.6344 g, 1.52 mmol) and CH2Cl2 (10 mL) is added Et3N (0.85 mL, 6.07 mmol), followed by hydrochloride salt of 2-aminoethylmethylsulfone (0.2416 g, 1.52 mmol), EDCl (0.320 g, 1.67 mmol), and HOBT (0.226 g, 1.67 mmol). The resulting solution is stirred at RT overnight, diluted with CH2C2 (30 mL), washed with 1.0 M HCl (3×20 mL), brine (20 mL), dried over MgSO4, and concentrated. The resulting residue is purified by chromatography (50% EtOAc/Hex) to give the titled compound (0.4042 g, 0.77 mmol, 51%). 1H NMR (CDC3), δ 0.71 (t, J=7.3 Hz, 6H), 1.03 (s, 9H), 2.09 (q, J=7.3 Hz, 4H), 2.21 (s, 3H), 2.42 (d, J=3.0 Hz, 1H), 2.46 (s, 3H), 2.98 (s, 3H), 3.32 (t, J=6.4 Hz, 2H), 3.71 (dt, J=8.9, 2.9 Hz, 1H), 3.84-3.94 (m, 3H), 4.10 (dd, J=9.3, 2.5 Hz, 1H), 6.44 (t, J=5.8 Hz, 1H), 6.59 (s, 1H), 6.73 (d, J=8.4 Hz, 1H), 6.99 (d, J=1.7 Hz, 1H), 7.03 (dd, J=8.7, 2.5 Hz, 1H). LC/MS (m/z): calcd for C27H42NO5S2 (M+H)+:524.8; found: 524.2.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[CH:21][CH:22]=1>>[OH:1][C:2]1([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:16][CH3:15])[CH:22]=2)[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: COc1cccc([Mg]Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: COc1cccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 55 %

Procedure:
This compound was prepared from tert-Butyl 4-oxopiperidine-1-carboxylate and 3-methoxyphenylmagnesium bromide as described in Step 1 of Example 6 in 55% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1)#[N:23].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CO>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:16])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:27]3[CH:26]=[CH:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=3)[CH:3]=[C:4]([F:21])[C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: C[C@@]1(c2cc(N)cc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: N#Cc1ccc(C(=O)O)nc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(C#N)cn3)cc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
To a cooled (ice bath) solution of (4S,6S)-4-(5-amino-2,3-difluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.095 g, 0.307 mmol) and 5-cyano-2-pyridinecarboxylic acid (0.055 g, 0.369 mmol) in THF (2.5 mL) and MeOH (1.5 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (0.118 g, 0.399 mmol). After stirring for 30 min, the ice bath was removed. The reaction was stirred at ambient temperature for 15 h. The reaction was quenched with saturated sodium bicarbonate solution. MeOH was removed by rotary evaporation. The aqueous residue was extracted with EtOAc (2×). The organic extracts were combined, concentrated and purified by Shimadzu HPLC to afford N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4,5-difluorophenyl)-5-cyanopicolinamide (0.053 g, 0.121 mmol, 39.3% yield) as white solid. MS m/z=440.1 [M+H]+. Calculated for C19H14F5N5O2: 439.3