Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([NH:6][C:7]3[C:12]([C:13](O)=[O:14])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.C1C=CC2N(O)N=[N:24]C=2C=1.C(Cl)CCl.[OH-].[NH4+]>C1COCC1.C(#N)C>[C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:24])=[O:14])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2
Reactant: CSc1ncc(C(=O)O)c(NC23CC(C2)C3)n1
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CSc1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a stirring solution of 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (108 g, 0.43 mol) and HOBt (67 g, 0.49 mol) in anhydrous THF (4 L) was added drop-wise a mixture of EDC (94 g, 0.49 mol) in acetonitrile (2 L) at room temperature. After the reaction mixture was stirred for 1 hr at room temperature, aqueous ammonium hydroxide (600 mL, 28-30% concentrated, 10 eq) was added drop-wise over 30 min and then the mixture was heated to gentle reflux for 3 h (60±5° C.). After that all solvents were removed under reduced pressure, the residual paste/solid was diluted with saturated aqueous sodium bicarbonate solution (2 L) and the resulting suspension was filtered to afford the desired compound (100 g, 0.4 mol, 93% yield) as an off-white fluffy solid; MS (ESI): m/z 251.1 [M+1]+.
Reaction SMILES: [CH2:1]1[C:4]2([O:9][CH2:8][CH:7]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:17]O)[C:12]=3[CH3:19])[CH2:6][O:5]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])O.[Na+].[SH:37][C:38]1[NH:39][C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1>CO.O1CCCC1>[CH2:1]1[C:4]2([O:9][CH2:8][CH:7]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:37][C:38]4[NH:42][C:41]5[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=5[N:39]=4)[C:12]=3[CH3:19])[CH2:6][O:5]2)[CH2:3][CH2:2]1
Reactant: Cc1c(OC2COC3(CCC3)OC2)ccnc1CO
Reactant: Sc1nc2ccccc2[nH]1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(OC2COC3(CCC3)OC2)ccnc1CSc1nc2ccccc2[nH]1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
A tetrahydrofuran (20 ml) solution of the (4-(5,9-dioxaspiro[3.5]non-7-yloxy)-3-methylpyridin-2-yl)methanol (630 mg, 2.37 mmol) obtained in the step (9g) and triethylamine (0.66 ml, 4.74 mmol) was stirred at −10° C. After 10 minutes, methanesulfonyl chloride (275 μl, 3.56 mmol) was added at the same temperature and the resultant mixture was stirred in the same conditions for 30 minutes. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was poured. The reaction mixture was extracted with ethyl acetate twice and organic layers were combined, washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. Dichloromethane (30 ml) was added to the residue to make a solution, and thereafter, 2-mercaptobenzimidazole (354 mg, 2.36 mmol) was added at room temperature. Furthermore, triethylamine (0.493 ml, 3.54 mmol) was added, and additionally, methanol was added until 2-mercaptobenzimidazole was dissolved. After the reaction mixture was stirred at room temperature for 2 hours, NH silica gel was added to the reaction mixture, which was then concentrated. The residue was subjected to silica gel column chromatography (elution solvent: heptane/ethyl acetate=1/1, ethyl acetate) to obtain the title compound (690 mg, yield: 73.6%) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(O)C>[N+:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1COCCN1
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1N1CCOCC1
Yield: 98.9 %

Procedure:
4-Fluoronitrobenzene (5 g) and morpholine (7.2 g) were dissolved in ethanol (50 ml) and refluxed for 2 hr, before the ethanol was removed in vacuo. The resulting slurry was dissolved in ethyl acetate (30 ml) and washed with water (20 ml), dried over magnesium sulphate (2 g), and the solvent removed in vacuo to yield the title compound as an orange solid (7.3 g).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[CH3:22][C:23]1[N:24]=[C:25]([CH2:28]O)[S:26][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:28][C:25]5[S:26][CH:27]=[C:23]([CH3:22])[N:24]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: Cc1csc(CO)n1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1csc(COc2ccn(-c3ccc4nc(C5CC5)n(C)c4c3)c(=O)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.2 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (4-methyl-1,3-thiazol-2-yl)methanol (45.9 mg) and triphenylphosphine (140 mg) in THF (5 ml) was added bis(2-methoxyethyl) azodicarboxylate (125 mg), and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-water to give the title compound (11.3 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:14]([O-])=O)=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7].[H][H]>C(O)C.[Pd]>[NH2:14][C:4]1[C:3]([O:2][CH3:1])=[C:12]([CH3:13])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(C)c(OC)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(C)c(OC)c1N
Yield: 94 %

Procedure:
To a solution of methyl 3-methoxy-4-methyl-2-nitrobenzoate (395 g, 1.75 mol) in ethanol (6700 mL) was added Pd/C (39.5 g) in one portion. The reaction mixture was stirred at room temperature under 50 psi of hydrogen overnight. TLC (petroleum ether/ethyl acetate=3:1) indicated the reaction was complete. The mixture was filtered and the filtrate was evaporated in vacuo to give the crude product, which was re-crystallized from ethanol (1.6 L) to give the title compound (321 g, 93.8%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:11])[NH:8][C:9]=1[CH:10]=[CH:14][N:15]([CH3:17])[CH3:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(=O)[nH]c1C
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(=O)[nH]c1C=CN(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture containing 15.1 g of 5-acetyl-6-methyl-2(1H)-pyridinone, 200 ml of dimethylformamide and 15 ml of dimethylformamide dimethyl acetal was stirred at room temperature for 30 minutes, heated gently with stirring on a steam bath for 2 hours, then allowed to cool and stirred at room temperature overnight. The golden yellow needles that separated were collected, washed with methanol and dried in a vacuum oven at 80° C. to yield 10.7 g of 5-acetyl-6-(2-dimethylaminoethenyl)-2(1H)-pyridinone, m.p. 238°-240° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10]([O:12][C:13]3[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=3)=[CH:11][C:6]=2[C:5](=[O:20])[N:4]([CH2:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:3]1=[O:31].[Li+].CC([N-]C(C)C)C.[CH3:40][CH:41]([CH3:45])[CH2:42][CH:43]=[O:44]>C1COCC1.C(Cl)Cl.O>[OH:44][CH:43]([C:11]1[C:6]2[C:5](=[O:20])[N:4]([CH2:21][CH2:22][CH2:23][O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[C:3](=[O:31])[N:2]([CH3:1])[C:7]=2[N:8]=[CH:9][C:10]=1[O:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1)[CH2:42][CH:41]([CH3:45])[CH3:40]
Reactant: Cc1cncc(Oc2cnc3c(c2)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)c1
Reactant: CC(C)CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cncc(Oc2cnc3c(c2C(O)CC(C)C)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a solution of 1-methyl-6-(5-methylpyridin-3-yloxy)-3-(3-(tetrahydro-2H-pyran-2-yloxy) propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 27, step 1, 100 mg, 0.23 mmol) in THF (5 mL) at −78° C. was added LDA (2M in THF, 0.48 mL, 0.940 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 3-methylbutanal (40 mg, 0.470 mmol) in THF (1 mL) was added. The reaction was stirred at −78° C. for 45 min then diluted with DCM (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to give 5-(1-hydroxy-3-methylbutyl)-1-methyl-6-(5-methylpyridin-3-yloxy)-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (120 mg, 90% yield) as a solid. LCMS: [M+-THP] 429 and TR=1.769 min. Used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32].C(=O)(O)[O-].[Na+]>ClCCl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:31]([CH:30]=[CH2:29])(=[O:33])=[O:32])=[CH:3][CH:4]=3)[C:16]=12
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)n1nc(-c2ccc(N)cc2)c2c(N)ncnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)Nc1ccc(-c2nn(C(C)C)c3ncnc(N)c23)cc1
Reaction time: 1 h
Yield: 16 %

Procedure:
A solution of dichloromethane (5 mL), compound 23 (45 mg, 0.168 mmol) and triethylamine (71 μL, 0.509 mmol) was cooled to 0° C. 2-chloro-1-ethane sulfonyl chloride (16 μL, 0.148 mmol) was added and the reaction was allowed to proceed for 1 hour prior to addition of saturated sodium bicarbonate (10 mL) and extraction with dichloromethane (2×10 mL). The combined organic layers were dried with MgSO4, filtered and concentrated in vacuo. The product was purified by preparative RP-HPLC and lyophilized (8.7 mg, 16% yield): 1H NMR (400 MHz, DMSO) δ 10.30 (s, 1H), 8.36 (s, 1H), 7.60 (d, J=8.5, 2H), 7.31 (d, J=8.6, 2H), 6.86 (dd, J=16.4, 9.9, 1H), 6.21 (d, J=16.4, 1H), 6.09 (d, J=9.9, 1H), 5.08 (hept, J=6.7, 2H), 1.49 (d, J=6.7, 6H); 13C NMR (100 MHz, DMSO) δ 155.44, 152.03, 151.64, 144.22, 138.54, 136.17, 129.25, 127.98, 127.41, 119.52, 96.95, 48.66, 21.75; [M+H]+ calculated for C16H18N6O2S 359.1, found 359.5.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:5]2=[N:6][CH:7]=[CH:8][N:9]=[C:4]2[CH:3]=1.[CH3:12][C:13]1([CH3:37])[CH2:22][CH2:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]([N:23]3[CH2:29][C:28]4[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:27]=4[O:26][CH2:25][CH2:24]3)[C:15]=2[CH2:14]1>>[CH3:12][C:13]1([CH3:37])[CH2:22][CH2:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]([N:23]3[CH2:29][C:28]4[CH:30]=[C:31]([C:2]5[CH:11]=[N:10][C:5]6=[N:6][CH:7]=[CH:8][N:9]=[C:4]6[CH:3]=5)[CH:32]=[CH:33][C:27]=4[O:26][CH2:25][CH2:24]3)[C:15]=2[CH2:14]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: Brc1cnc2nccnc2c1
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc6nccnc6c5)cc4C3)c2C1

Procedure:
Prepared according to the method of example 5 by using 7-bromopyrido[2,3-b]pyrazine and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, DMSO-d6): 9.56 (s, 1H), 9.13 (s, 1H), 9.10 (s, 1H), 8.78 (s, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 7.88 (d, 1H), 7.14 (d, 1H), 4.71 (s, 2H), 4.41 (m, 2H), 3.85 (m, 2H), 2.71 (t, 2H), 2.49 (s, 2H), 1.62 (t, 2H), 0.84 (s, 6H); MS (EI) for C26H26N6O: 439 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH:11][C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=2[C:31]([F:32])([F:34])[F:33])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2]
Reactant: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c(Br)c1
Product: CCOC(Cn1nc(-c2cccnc2)cc1Nc1cc([N+](=O)[O-])ccc1C(F)(F)F)OCC

Procedure:
Analogously to Example 13A/Step 1, 1.50 g (5.43 mmol) of the compound of Example 4A and 1.47 g (5.43 mmol) of 2-bromo-4-nitro-1-(trifluoromethyl)benzene gave 2.03 g (75% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[N:10]([CH2:11][CH3:12])[C:9]([C:13]3[C:14]([NH2:18])=[N:15][O:16][N:17]=3)=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.C([Li])CCC.CN(C)[CH:26]=[O:27]>O1CCCC1>[NH2:18][C:14]1[C:13]([C:9]2[N:10]([CH2:11][CH3:12])[C:3]3[C:2]([CH:26]=[O:27])=[CH:7][N:6]=[CH:5][C:4]=3[N:8]=2)=[N:17][O:16][N:15]=1
Reactant: CN(C)C=O
Reactant: CCn1c(-c2nonc2N)nc2cncc(Br)c21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1c(-c2nonc2N)nc2cncc(C=O)c21

Procedure:
A solution of the product from Example 100 (0.1 g, 0.324 mmol) in tetrahydrofuran (4 ml) at −78° C. was treated with a i 0.6M solution of n-butyllithium (0.6 ml, 0.97 mmol) in hexanes. After 5 minutes the mixture was treated with dimethylformamide (0.3 ml) and allowed to reach room temperature. After 30 minutes at room temperature the reaction was carefully quenched with water and extracted into dichloromethane (×2). The organic layer was then washed with brine, dried (Na2SO4) and reduced in vacuo. The residue was purified by silica gel chromatography eluting with ethyl acetate, to afford the title compound, (0.0349, 41%); MS (ES+) m/e 259 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=3)=[C:16]([F:28])[CH:15]=2)=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1.[OH-].[Na+]>CN(C)C=O.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:40]([CH:37]4[CH2:39][CH2:38]4)=[O:41])[CH:22]=3)=[C:16]([F:28])[CH:15]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)cc2F)ccn1
Reactant: O=C(Cl)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CC(=O)Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)c(F)c1)Nc1ccc(F)cc1
Reaction time: 1 h
Yield: 53 %

Procedure:
N-(4-Fluorophenyl)-N′-[4-(2-aminopyridin-4-yloxy)-3-fluorophenyl]malonamide (34 mg) was dissolved in N,N-dimethylformamide (0.5 ml), and then triethylamine (0.047 ml) and cyclopropanecarbonyl chloride (0.016 ml) were added dropwise thereto under a nitrogen atmosphere at room temperature, followed by stirring for 1 hr. To the reaction mixture were added a 1 N aqueous solution of sodium hydroxide (1.5 ml) and methanol (1.0 ml), followed by stirring and extracting with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, which was then dried in vacuum to provide the titled compound (21.1 mg, 53%) as white powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([CH2:26][CH2:27]C=C)[CH2:23][CH:24]=[CH2:25])[N:16]=3)=[C:9]([F:36])[CH:8]=1.O>C(Cl)Cl.CC1C=C(C)C(N2[CH-]N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]2([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:26][CH2:27][CH:25]=[CH:24][CH2:23]2)[N:16]=3)=[C:9]([F:36])[CH:8]=1
Reactant: C=CCCC(CC=C)(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1cc(C)c(N2[CH-]N(c3c(C)cc(C)cc3C)CC2)c(C)c1
Solvent: O
Solvent: ClCCl
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccccc4)CC=CCC3)nc2s1
Reaction time: 4 h

Procedure:
To a solution of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(4-phenylocta-1,7-dien-4-yl)thiazolo[5,4-b]pyridine (0.580 g, 1.16 mmol) in 22 mL DCM under argon was added tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidene]ruthenium(IV) dichloride (0.0492 g, 0.0579 mmol). The flask was fitted with a water-cooled reflux condenser and heated to reflux. The reaction was checked after 4 h and judged complete. Silica gel (4 g) was added and the reaction mixture was dried, purified by ISCO, gradient, 0-100% EA/hexanes, to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylcyclohex-3-enyl)thiazolo[5,4-b]pyridine as a foam/oil which solidified to an off-white solid. MS (ESI) m/z: Calculated: 472.2; Observed: 473.2 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[N+:14]([O-])=O)[N:10]([C:17](=[O:22])[CH2:18][N:19]([CH3:21])[CH3:20])[CH2:9][CH2:8][CH2:7]2)[CH3:2].[H][H]>CO.[Pd]>[CH3:21][N:19]([CH2:18][C:17]([N:10]1[C:11]2[C:6](=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[C:13]([NH2:14])[CH:12]=2)[CH2:7][CH2:8][CH2:9]1)=[O:22])[CH3:20]
Reactant: CCOc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOc1cc2c(cc1N)N(C(=O)CN(C)C)CCC2
Reaction time: 16 h
Yield: 54.5 %

Procedure:
A solution of {2-[6-(ethyloxy)-7-nitro-3,4-dihydro-1(2H)-quinolinyl]-2-oxoethyl}dimethylamine (5.8 g, 18.87 mmol) in degassed methanol (50.0 mL) was added to a suspension of 10% Pd/C (3.0 g, 16.36 mmol) in degassed methanol (5 mL) and maintained under a 50 psi hydrogen gas with rapid stirring for 16 hours. The suspension was purged with nitrogen, filtered through celite, all volatiles removed, and the resulting residue was purified by flash column chromatography to afford 1-[(dimethylamino)acetyl]-6-(ethyloxy)-1,2,3,4-tetrahydro-7-quinolinamine (2.85 g, 63%) as a viscous yellow liquid which solidified upon standing for 10 hours. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.80 (s, 1 H), 6.55 (s, 1 H), 4.52 (s, 2 H), 3.95 (q, J=6.89 Hz, 2 H), 3.61 (t, J=6.02 Hz, 2 H), 3.15 (s, 2 H), 2.55 (t, J=6.52 Hz 2 H), 2.20 (s, 6 H), 1.73-1.86 (m, 2 H), 1.32 (t, J=7.02 Hz, 3 H).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[N:16]1([C:22]2[N:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:25]2[CH:26]=[N:27][C:22]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)=[CH:23][CH:24]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CC1(C)OB(c2ccc(N3CCCCC3)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N3CCCCC3)nc2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 6-(piperidin-1-yl)pyridine-3-boronic acid pinacol ester (0.581 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 18 h to give 4-chloro-5,7-difluoro-3-methyl-2-(6-(piperidin-1-yl)pyridin-3-yl)quinoline as a yellow solid. Mass Spectrum (ESI) m/e=374.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:9][CH2:10][C:11]([N:13]2[CH2:26][CH2:25][C:16]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17]3)[CH2:15][CH2:14]2)=[O:12])=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[CH2:9][CH2:10][C:11]([N:13]2[CH2:26][CH2:25][C:16]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(CC=C(c1ccc(F)cc1)c1ccc(F)cc1)N1CCC2(C=Cc3ccccc32)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(CCC(c1ccc(F)cc1)c1ccc(F)cc1)N1CCC2(CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.3 %

Procedure:
0.50 g (1.13 mmol) of 1-[4,4-bis(4-fluorophenyl)but-3-enoyl]-spiro[piperidine-4,1′-indene] (33) was dissolved in 20 mL of methanol under nitrogen atmosphere and then 200 mg of palladium/Charcoal (5%, Aldrich) was added. The nitrogen atmosphere was replaced with hydrogen gas. The resulting mixture was stirred at room temperature for 6 hours and filtered through a pad of celite. The methanol solution (200 mL) was concentrated and the resulting residue purified by column chromatography using a gradient of ethyl acetate/hexane as eluent to give 0.5 g of the title compound 35. MS: m/z 445. 1H NMR (CDCl3): δ 7.24-7.17 (m, 7H), 7.10-7.07 (m, 1H), 7.02-6.95 (m, 4H), 4.67-4.57 (m, 1H), 4.04-3.93 (m, 1H), 3.68-3.58 (m, 1H), 3.18-3.06 (m, 1H), 2.98-2.85 (m, 2H), 2.82-2.71 (m, 1H), 2.44-2.33 (m, 2H), 2.33-2.24 (m, 2H), 2.14-1.99 (m, 2H), 1.82-1.61 (m, 2H), 1.61-1.48 (m, 3H).
Reaction SMILES: C([O:4][C:5](=[O:76])[CH2:6][C@H:7]([OH:75])[C@H:8]([NH:12][C:13](=[O:74])[C@H:14]([NH:36][C:37](=[O:73])[C@H:38]([NH:43][C:44](=[O:72])[CH2:45][C@@H:46]([OH:71])/[CH:47]=[CH:48]/[CH2:49][CH2:50][S:51][C:52]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:15][S:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]([CH3:11])[CH3:10])C=C.N1CCOCC1>CO.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>[OH:75][C@H:7]([C@H:8]([NH:12][C:13](=[O:74])[C@H:14]([NH:36][C:37](=[O:73])[C@H:38]([NH:43][C:44](=[O:72])[CH2:45][C@@H:46]([OH:71])/[CH:47]=[CH:48]/[CH2:49][CH2:50][S:51][C:52]([C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH2:39][CH:40]([CH3:41])[CH3:42])[CH2:15][S:16][C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH:9]([CH3:11])[CH3:10])[CH2:6][C:5]([OH:76])=[O:4]
Reactant: C=CCOC(=O)C[C@H](O)[C@H](NC(=O)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@@H](CC(C)C)NC(=O)C[C@@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: CO
Product: CC(C)C[C@@H](NC(=O)C[C@@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](C(C)C)[C@@H](O)CC(=O)O
Reaction time: 2 h
Yield: 63.3 %

Procedure:
To a solution of 4C (168 mg, 0.158 mmol) in dry CH3OH (5 mL) at rt was added morpholine (27.6 μl, 0.48 mmol) followed by Pd(PPh3)4 (18.3 mg, 0.016 mmol). After stirring for 2 h the solvent was evaporated, the product rinsed with CH2Cl2 and washed with 1 M HCl (10 mL), sat NaHCO3 (10 mL) and sat. NaCl (10 mL) solutions. The organic layer was then dried with MgSO4 and filtered, the solvent was removed in vacuo and the crude product was washed with hexane (3×20 mL) and purified by flash chromatography (1-20% CH3OH/CHCl3) to give 5C (101 mg, 0.1 mmol, 63%).