Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([CH:4](O)[C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH2:3].[ClH:12]>>[Cl:12][CH2:3][C:2]([F:1])=[CH:4][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: C=C(F)C(O)C#CC(C)(C)C
Reactant: Cl
Product: CC(C)(C)C#CC=C(F)CCl
Reaction time: 5 h

Procedure:
Ten grams (0.064 mole) of 2-fluoro-3-hydroxy-6,6-dimethylhept-1-ene-4-yne was added 200 ml of concentrated hydrochloric acid, and the mixture was aged for 5 hours at room temperature with stirring. The reaction mixture was extracted with three 100 ml portions of diethylether. The organic layers were combined, washed once with 100 ml of a saturated aqueous sodium chloride solution and concentrated under reduced pressure. The resulting oily product was distilled under reduced pressure to obtain 5 g of 1-chloro-2-fluoro-6,6-dimethylhept-2-ene-4-yne.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[OH-].[Na+].CN(C)C=O.Br[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]>O>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:1][CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: CC(C)=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCOc1ccc(C)cc1

Procedure:
A mixture of p-cresol and sodium hydroxide was stirred with dimethylformamide and water while 1-bromo-3-methylbut-2-ene (VII; R1 =R2 =CH3, Hal=Br) was added dropwise. The 1-(p-methylphenoxy-3-methylbut-2-ene was isolated as described under Example B(i).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([C@@H:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([C@@H:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:30][CH:31]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Yield: 67.5 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (760 mg, 2.4 mmol) was reacted with (S)-tert-butyl 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethylcarbamate (1.3 g, 3.7 mmol) to afford the desired product (730 mg, 66%) as a light yellow solid: ESI MS m/z 451 [C25H26N2O4S+H]+.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:6]=[C:7]([C:11](OC)=[O:12])[CH:8]=[N:9][CH:10]=1)([CH3:4])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.ClCCl>[OH:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[O:12])[CH:8]=[N:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: COC(=O)c1cncc(C(C)(C)O)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(O)c1cncc(C=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of the title compound from Step B (0.50 g, 2.6 mmol) in toluene (15 mL) and dichloromethane (15 mL) was added a solution of diisobutyl aluminum hydride in toluene (1.0 M, 6.0 mL, 6.0 mmol). After 10 min, the reaction was quenched with water (5 mL), allowed to warm to room temperature and dried with magnesium sulfate. Concentration of the filtrate under reduced pressure provided the title compound: 1H NMR (500 MHz, CDCl3) δ 10.10 (s, 1 H), 8.99 (d, J=2.3 Hz, 1 H), 8.93 (s, 1 H), 8.30 (s, 1 H), 2.22 (br s, 1 H), 1.67 (s, 6 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[N:18]3[N:19]=[C:20](S(C)(=O)=O)[N:21]=[C:17]3[N:16]=[C:15]([CH3:26])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[O-:27][CH2:28][CH3:29].[Na+]>C(O)C>[CH2:28]([O:27][C:20]1[N:21]=[C:17]2[N:16]=[C:15]([CH3:26])[CH:14]=[C:13]([NH:12][C:4]3[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([F:1])[CH:3]=3)[N:18]2[N:19]=1)[CH3:29]
Reactant: CC[O-]
Reactant: Cc1cc(Nc2ccc(C(F)(F)F)c(F)c2)n2nc(S(C)(=O)=O)nc2n1
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc2nc(C)cc(Nc3ccc(C(F)(F)F)c(F)c3)n2n1
Temperature: 120 °C

Procedure:
Intermediate 14 (0.19 g, 0.488 mmol) was added to sodium ethoxide (ALDRICH, 0.1 g, 1.464 mmol) in ethanol (4 mL). The mixture was heated under microwave irradiation at 120° C. for 30 minutes and solvent was removed under vacuum to yield a yellowish residue. The crude mixture was purified by flash chromatography (Si, eluting with Hexane/EtOAc mixtures from 90:10 to 0:100%) to yield the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18](Cl)=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A mixture of 38 g of p-hydroxyphenylacetic acid, 39.4 g of 4-nitrochlorobenzene and 69 g of anhydrous potassium carbonate in 275 ml of N,N-dimethylacetamide is heated to 155°-160° C. over 2 hours, and maintained at that temperature, under Argon atmosphere for 4 hours with vigorous stirring. On cooling, an orange solid separated. A 1000 g solution of 5% NaHCO3 is added, resulting in a red brown solution. The solution is extracted with 4×100 ml of ether. The aqueous layer is acidified by the dropwise addition of 150 ml of concentrated HCl. A light yellow solid precipitates and is filtered and washed with 1500 ml of H2O to give the product, mp 132°-136° C. A sample is recrystallized from 19:1 methanol-water, to give the product, mp 135°-137° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:31][C@@H:32]1[CH2:37][CH2:36][O:35][C:33]1=[O:34]>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][CH2:3][CH2:2][NH:1][C:33](=[O:34])[C@H:32]([OH:31])[CH2:37][CH2:36][OH:35])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: O=C1OCC[C@H]1O
Reactant: NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: O=C(NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)[C@H](O)CCO
Yield: 55 %

Procedure:
The procedure described in Example 63 was repeated using 5-(2-aminoethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 2.6, preparation of starting materials) and (R)-(+)-α-hydroxy-γ-butyrolactone to give the title compound in 55% yield; NMR spectrum (DMSO-d6) 1.38-1.55 (m, 1H), 1.69-1.85 (m, 1H), 3.37-3.50 (m, 2H), 3.61-3.77 (m, 2H), 3.89-4.00 (m, 1H), 4.28-4.45 (m, 3H), 5.29 (s, 2H), 5.51 (d, 1H), 7.13 (d, 1H), 7.22 (d, 1H), 7.28-7.41 (m, 2H), 7.49-7.62 (m, 2H), 7.71 (t, 1H), 8.01 (d, 1H), 8.14-8.25 (m, 1H), 8.45 (s, 1H), 8.59 (d, 1H), 9.82 (s, 1H); Mass spectrum MH+ 523.9.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([C:16]2[N:20]([CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[N:19]=[CH:18][CH:17]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.Cl>CO>[F:26][C:23]([F:24])([F:25])[CH2:22][CH2:21][N:20]1[C:16]([C:11]2[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:17][CH:18]=[N:19]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccnc1-c1ccnn1CCC(F)(F)F
Agent: Cl
Solvent: CO
Product: OCc1cccnc1-c1ccnn1CCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To 3-((tert-butyldimethylsilyloxy)methyl)-2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridine (1.58 g, 4.1 mmol) in MeOH (20 mL) was added HCl (4 N, 4.0 mL). The mixture was stirred at rt for 1 h, concentrated, and diluted with EtOAc (50 mL) and NaHCO3(sat) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, and concentrated to give (2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methanol (1.1 g, 99%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.64 (dd, J=4.7, 1.7 Hz, 1H), 8.00 (dd, J=7.9, 1.7 Hz, 1H), 7.57 (d, J=1.9 Hz, 1H), 7.38 (dd, J=7.9, 4.8 Hz, 1H), 6.48 (d, J=1.9 Hz, 1H), 4.69 (s, 2H), 4.51-4.43 (m, 2H), 2.85-2.72 (m, 2H), 2.70 (s, 1H). LRMS (M+H+) m/z 272.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][NH:15][C:16]([CH:18]3[O:23][CH2:22][CH2:21][NH:20][CH2:19]3)=[O:17])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]([C:28]1[CH:29]=[C:30](OB(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH2:14][NH:15][C:16]([CH:18]3[O:23][CH2:22][CH2:21][N:20]([C:32]4[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=4)[C:26]([O:25][CH3:24])=[O:27])[CH2:19]3)=[O:17])=[C:11]([CH3:13])[N:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CNC(=O)C1CNCCO1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Product: COC(=O)c1cccc(N2CCOC(C(=O)NCc3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 71 %

Procedure:
Using N-[[2-(4-chlorophenyl)-4-methylthiazol-5-yl]methyl]morpholine-2-carboxamide (29.5 mg, 0.0838 mmol) and 3-(methoxycarbonyl)phenylboric acid (30.2 mg, 0.168 mmol), the same procedure was followed as in Example 2 to give 28.9 mg (71%) of the desired compound as a colorless oil.
Reaction SMILES: [CH2:1]([CH:8]([C:16]([OH:18])=[O:17])[C:9]([CH2:14][CH3:15])(O)[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C>[CH2:1]([C:8]1[C:16]([O:18][C:10](=[O:12])[C:9]=1[CH2:14][CH3:15])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)(C(=O)O)C(Cc1ccccc1)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCC1=C(Cc2ccccc2)C(=O)OC1=O
Temperature: 110 °C
Reaction time: 15 h
Yield: 79 %

Procedure:
The 3-Benzyl-2-ethyl-2-hydroxysuccinic acid obtained was dissolved in acetic anhydride (35 mL) and stirred at 110° C. for 15 h. The residue obtained by evaporating the acetic anhydride of the reaction mixture under reduced pressure was subjected to silica gel column chromatography (hexane-toluene-ethyl acetate 8:3:1) to give 619 mg of the title compound as oil (yield: 79%).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[CH:12]=[C:11]4[CH:15]=[CH:16][CH:17]=[CH:18][C:10]4=[CH:9][C:8]=3[N:7]=[C:6](Cl)[C:5]=2[N:4]=[CH:3]1.[CH3:20][NH2:21]>CCOC(C)=O>[CH3:1][N:2]1[C:14]2[C:13]3[CH:12]=[C:11]4[CH:15]=[CH:16][CH:17]=[CH:18][C:10]4=[CH:9][C:8]=3[N:7]=[C:6]([NH:21][CH3:20])[C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2c(Cl)nc3cc4ccccc4cc3c21
Reactant: CN
Solvent: CCOC(C)=O
Product: CNc1nc2cc3ccccc3cc2c2c1ncn2C
Temperature: 80 °C
Yield: 4 %

Procedure:
A mixture of 1-methyl-4-chlorobenzo(g)imidazo(4,5-c)quinoline (Preparation 19) (130 mg, 0.49 mmol) and MeNH2 (2.0M/THF, 1.5 mL, 2.92 mmol) was heated in a pressure tube at 80° C. for 18 hours. After the reaction mixture was cooled to RT, it was diluted with EtOAc (100 mL), washed with sat'd NaCO3 (50 mL), and brine. The organic layer was dried over MgSO4, filtered and evaporated in vacuo. The crude material was submitted to flash chromatography (5% MeOH/EtOAc) affording the title compound as a pale white solid (5.2 mg, 4%). 1H NMR(CDCl3): 8.44(s, 1H), 8.35(s, 1H), 7.94(d, J=8.3, 1H), 7.90(d, J=8.3, 1H), 7.72(s, 1H), 7.46(m, 1H), 7.40(m, 1H), 5.95(b, 1H), 4.28(s, 3H), 3.31(s, 3H). (ESI) m/z (M+H)+=263.14.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:18]([O:20][C:21](=[O:47])[CH2:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:47])[CH2:22][C:23]1([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:2]4[S:3][CH:4]=[CH:5][C:6]=4[CH:7]([OH:17])[CH2:8][CH2:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:34][CH:33]=3)=[CH:30][CH:31]=2)[CH2:24][CH2:25]1)[CH3:19]
Reactant: OC(CCCc1ccccc1)c1ccsc1Br
Reactant: CCOC(=O)CC1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4sccc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: 1-(2-bromo-thiophen-3-yl)-4-phenyl-butan-1-ol and {1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=2)[C:28](O)=[O:29])[N:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=[N:25][CH:26]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1coc(-c2ccc(F)cc2)n1
Product: O=C(NCCc1coc(-c2ccc(F)cc2)n1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Yield: 46 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)ethanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (55 mg, yield 46%). 1H NMR (400 MHz, MeOD) δ 9.39 (d, J=2.0 Hz, 1H), 9.19 (d, J=2.0 Hz, 1H), 8.89 (t, J=2.0 Hz, 1H), 8.07-8.03 (m, 2H), 7.81 (s, 1H), 7.26-7.22 (m, 2H), 3.78-3.75 (t, J=6.9 Hz, 2H), 2.97-2.94 (t, J=6.9 Hz, 2H). MS (ESI) m/z: Calculated for C20H13F4N5O3: 447.10. found: 448.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:21](=O)[CH3:22])[C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16].[NH2:24][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][C:27]#[N:28].CC(C)([O-])C.[K+]>CC(O)C>[C:27]([C:26]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:14]([C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])=[C:21]([CH3:22])[NH:24][C:25]=1[C:29]([F:32])([F:31])[F:30])#[N:28]
Reactant: CCCOC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Reactant: N#CC=C(N)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCCOC(=O)C1=C(C)NC(C(F)(F)F)=C(C#N)C1c1cccc2c(=O)cc(C)oc12

Procedure:
A solution of 295 mg (0.94 mmol) of propyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate in 20 ml of 2-propanol is mixed with 127.71 mg (0.94 mmol) of 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation in analogy to K. Krespan, J. Org. Chem. 34, 4245 (1969)] and 15.8 mg (0.14 mmol) of potassium tert-butoxide and stirred under reflux for 12 h. After cooling, the mixture is concentrated. The residue is purified on an Analogix cartridge (F12M) (mobile phase: cyclohexane/ethyl acetate 2:1). After concentration of the product fractions, the residue is crystallized from diethyl ether. 88.4 mg (20.7% of theory) of the title compound are obtained as white crystals.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([O:15][CH2:14][CH2:13][CH2:12][NH:11][C:8]2[C:9](=[O:10])[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:6](=[O:22])(=[O:23])[C:7]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)N1C(=O)C(NCCCO)=C(c2ccccc2)S1(=O)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A mixture of 2-tert-butyl-4-[(3-hydroxypropyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide (Example 49) (2.75 g, 8.12 mmol), 4-methylbenzenesulfonyl chloride (1.86 g, 9.74 mmol), DMAP (0.99 g, 8.12 mmol) and Na2CO3 (2.58 g, 24.35 mmol) in DCM (50 ml) was stirred at rt. After 2 h the mixture was filtered, evaporated and the residue purified by silica gel column chromatography (Horizons Biotage) using 5:1 DCM/petroleum ether 40-60° C. as eluent to give the title compound (2.34 g, 58%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.74 (d, 2H), 7.50-7.39 (m, 3H), 7.36 (d, 2H), 5.30 (t, 1H), 3.85 (t, 2H), 2.98 (q, 2H), 2.48 (s, 3H), 1.73 (s, 9H), 1.62 (qt, 2H); 13C NMR (125 MHz, CDCl3): δ 159.8, 145.4, 134.9, 132.9, 131.8, 130.2, 130.1, 129.0, 128.1, 124.9, 107.9, 67.2, 61.6, 40.3, 28.8, 27.8, 21.9; Mass Spectrum M+H+ 493.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].COC[C:21]([Cl:23])=O>[N+](C)([O-])=O>[Cl:23][CH2:21][C:13]1[CH:12]=[C:9]([CH:8]=[CH:7][C:6]=1[O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH:10]=[O:11]
Reactant: CC(C)COc1ccc(C=O)cc1
Reactant: COCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC(C)COc1ccc(C=O)cc1CCl
Temperature: 0 °C
Yield: 59.5 %

Procedure:
To a mixture of 4-isobutoxybenzaldehyde (6.9 g, 38.7 mmol), aluminum chloride (12.9 g, 96.8 mmol) and nitromethane (39 mL) was added methoxyacetyl chloride (4.1 mL, 44.5 mmol) under stirring at 0° C., and the mixture was stirred at the same temperature for 3 hr. After completion of the reaction, the reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-4/1) to give the title compound (5.22 g, yield 60%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:26])[N:14]([C:19]4[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1.C1COCC1.[CH3:32][C:33]1[CH:37]=[CH:36][O:35][C:34]=1[C:38](Cl)=[O:39]>CCN(CC)CC>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:26])[N:14]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:38]([C:34]5[O:35][CH:36]=[CH:37][C:33]=5[CH3:32])=[O:39])=[CH:23][CH:24]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Cc1ccoc1C(=O)Cl
Reactant: Cc1ccn(-c2ccc(N)cc2)c(=O)c1N1CCc2nc(N)ncc2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1ccc(-n2ccc(C)c(N3CCc4nc(N)ncc4C3)c2=O)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-1-(4-aminophenyl)-4-methylpyridin-2(1H)-one (25 mg, 0.075 mmol) in2 mL of THF under N2(g) containing 3 mL of NEt3 was treated with 3-methylfuran-2-carbonyl chloride (13 mg, 0.090 mmol). The reaction mixture was heated to 40° C. and allowed to stir for 3 h. The reaction was cooled and then extracted with EtOAc (3×˜10 mL) and water (˜10 mL). The combined organic layers were then washed with ˜20 mL of NaHCO3 (aq). The organic layers were then dried over anhydrous Na2SO4, filtered and then concentrated in vacuo. The crude mixture was purified over silica (EtOAc/Hexanes gradient). Following concentration of the appropriate fractions the title compound was collected as a grey solid (25 mg, 76%). 1H NMR (DMSO) δ: 9.52 (s, 1H), 7.92 (s, 1H), 7.81 (d, J=5.6 Hz, 1H), 7.45-7.52 (m, 2H), 7.41 (d, J=6.7 Hz, 1H), 7.24-7.31 (m, 2H), 6.65 (d, J=5.6 Hz, 1H), 6.28 (s, 2H), 6.17 (d, J=7.0 Hz, 1H), 3.96 (br. S, H), 3.29 (s, 2H), 2.66(t, j=5.3 Hz, 2H), 2.35 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C:3]2([CH2:10][CH:9]3[CH2:11][N:6]2[CH2:7][CH2:8]3)[CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].Br[C:65]1[CH:66]=[C:67]([O:71][CH2:72][CH3:73])[CH:68]=[N:69][CH:70]=1>C1(C)C=CC=CC=1>[CH2:72]([O:71][C:67]1[CH:66]=[C:65]([N:1]2[CH2:5][CH2:4][C:3]3([CH2:10][CH:9]4[CH2:11][N:6]3[CH2:7][CH2:8]4)[CH2:2]2)[CH:70]=[N:69][CH:68]=1)[CH3:73]
Reactant: C1CC2(CN1)CC1CCN2C1
Reactant: CCOc1cncc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCOc1cncc(N2CCC3(CC4CCN3C4)C2)c1
Temperature: 160 °C
Yield: 34.1 %

Procedure:
A mixture of spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] (50 mg, 0.3 mmol) tris(dibenzylideneacetone)dipalladium(0) (9 mg, 0.009 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (12 mg, 0.018 mmol), potassium tert-butoxide (147 mg, 1.2 mmol), and 5-bromo-3-ethoxypyridine (73 mg, 0.36 mmol) in dry toluene (5 mL) was placed in a sealed tube under argon and heated at 160° C. for 17 h. The reaction was cooled to 0° C. and the contents transferred to a 100 mL round bottom flask. The solvent was removed by rotary evaporation and the residue was dissolved in a saturated solution of NaHCO3 (10 mL) and extracted with chloroform (4×15 mL). The combined chloroform extracts were dried (K2CO3), filtered and concentrated by rotary evaporation to give a dark colored syrup. This was purified by column chromatography, using MeOH:CHCl3:NH4OH (8:2:0.01, v/v) as the eluent, to give 28 mg (27%) of 1′-(5-ethoxy-3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] as a viscous brown oil.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:21][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[CH:19]2
Reactant: BrBr
Reactant: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After 6.0 g (23.7 mmol) of 9-phenylanthracene was dissolved in 80 mL of carbon tetrachloride, a solution of 3.80 g (21.1 mmol) of bromine dissolved in 10 mL of carbon tetrachloride was dripped through a dropping funnel into the reaction solution. After the dripping, the solution was stirred at room temperature for one hour. After the reaction, a sodium thiosulfate aqueous solution was added to stop the reaction. An organic layer was washed with a sodium hydroxide (NaOH) aqueous solution and a saturated saline solution and dried with magnesium sulfate. After the solution was filtered naturally, the filtrate was concentrated, dissolved in toluene, and filtered through Florisil, Celite, and alumina. When the filtrate was concentrated and recrystallized with dichloromethane and hexane, 7.0 g of a light yellow solid of 10-bromo-9-phenylanthracene that was an object was obtained (yield: 89%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[N:4][C:5]([C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][O:11][CH2:10]1.Cl[CH2:28][CH:29]1[CH2:31][O:30]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][C:2]1[C:7]([NH:8][C@@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)=[N:6][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:28][CH:29]3[CH2:31][O:30]3)[CH:15]=2)=[N:4][C:3]=1[N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: Cc1c(N[C@@H]2CCOC2)nc(-c2cccc(O)c2)nc1N1CCOCC1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(N[C@@H]2CCOC2)nc(-c2cccc(OCC3CO3)c2)nc1N1CCOCC1
Yield: 34.6 %

Procedure:
A mixture of (R)-3-(5-methyl-4-morpholino-6-(tetrahydrofuran-3-ylamino)pyrimidin-2-yl)phenol (50 mg, 0.14 mmol); 2-(chloromethyl)oxirane (16 mg, 0.17 mmol) and K2CO3 (39 mg, 0.28 mmol) in MeCN (10 mL) was heated at 80° C. in a sealed vial for 14 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by chromatographic column on silica gel (EtOAc/petroleum ether, gradient elution, from 1/5 to 4:1) to give the 5-methyl-6-morpholino-2-(3-(oxiran-2-ylmethoxy)phenyl)-N—((R)-tetrahydrofuran-3-yl)pyrimidin-4-amine (20 mg, 34% yield) as a light yellow solid. ESI-LCMS (m/z): 413.2 [M+1]+.