Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=2[C:30]([NH:32][CH2:33][CH3:34])=[O:31])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=2[C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[N:26][C:21]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:22][CH:23]=1
Reactant: CCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Product: CCNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(C)(F)F)CC3)ncc1Cl

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-benzamide in an analogous manner to Example 61e. Product isolated as a white solid (0.011 g, 11%). MP: 165-167° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 10.94 (s, 1H), 8.65 (d, 1H, J=8.6 Hz), 8.10 (d, 1H, J=1.5 Hz), 8.09-8.07 (m, 1H), 7.53-7.39 (m, 3H), 7.12-7.06 (m, 1H), 6.64 (s, 1H), 6.13 (br s, 1H), 3.86 (s, 3H), 3.57-3.48 (m, 2H), 2.90-2.73 (m, 10H), 1.69 (t, 3H, J=18.6 Hz), 1.30-1.24 (m, 3H). MS: 545.21 (MH)+.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[N:10]=[C:11]([CH:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[S:12][CH:13]=1)=[O:8])C>C1COCC1.O>[C:19]([O:18][C:17](=[O:23])[NH:16][CH:14]([C:11]1[S:12][CH:13]=[C:9]([C:7]([OH:8])=[O:6])[N:10]=1)[CH3:15])([CH3:20])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1csc(C(C)NC(=O)OC(C)(C)C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
Lithium hydroxide monohydrate (165 mg, 3.9 mmol) was added to a solution of tert-butyl (1-(4-(ethyloxycarbonyl)thiazol-2-yl)ethyl)carbamate (1.4 g crude material) in THF (25 ml) and water (20 ml) and stirred at room temperature for 18 h. A further amount of lithium hydroxide monohydrate was added (165 mg) and stirring continued for 4 h. The THF was removed in vacuo, the aqueous residue acidified with 1N hydrochloric acid and extracted twice with chloroform. The combined organic layers were washed with brine, dried and reduced. Chromatography (50:2:1 chloroform, methanol, acetic acid) and recrystallisation (EtOAc/hexanes) afforded tert-butyl(1-(4-carboxythiazol-2-yl)ethyl)carbamate (686 mg, 64% over two steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](O)[CH:6]=[CH:5]2.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc2cc(Cl)ccc2n1
Product: Clc1ccc2nc(Cl)ccc2c1
Temperature: 25 °C
Yield: 90 %

Procedure:
180 mg 6-chloro-2-hydroxy quinoline was treated by 3 ml POCl3, the mixture was refluxed for 3 hours, the remaining POCl3 was evaporated out. After cooling to room temperature, the residue was treated by cold water, the solid was filtered out and dried as green powder, yield: 90%. Following the general procedure in claim 5, the listed compounds were achieved. Mass calculated for C9H5Cl2N: 198; LCMS: 200.1 (M+2)+; 1HNMR (400 MHZ), DMSO-d6) δ ppm 8.04 (1H, d, J=7.8 Hz), 7.97 (1H, d, J=8.8 Hz), 7.81 (1H, d, J=1.9 Hz), 7.68 (1H, dd, J=9.8 Hz, J=2.9 Hz), 7.42 (1H, d, J=8.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([OH:34])[C:19]2[O:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[H-].[Na+].I[CH3:38]>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([O:34][CH3:38])[C:19]2[O:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: CI
Reactant: CC(C)(Oc1ccc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)o2)c(Cl)c1Cl)C(=O)O
Agent: [H-]
Agent: [Na+]
Product: COC(CCc1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)o1

Procedure:
2-(2,3-Dichloro-4-(3-methoxy-3-(5-(4-(trifluoromethyl)phenyl)fur-2-yl)propyl)-phenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)fur-2-yl)propyl)phenoxy)-2-methyl propanoic acid using 2.1 equivalents of sodium hydride and 2.1 equivalents of iodomethane according to general procedure H.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([N+:19]([O-])=O)=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=1.C(O)(=O)C>[Zn].O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH2:19])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=1
Reactant: COCCOc1cc(Oc2cccnc2)cnc1[N+](=O)[O-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COCCOc1cc(Oc2cccnc2)cnc1N
Temperature: 105 °C
Yield: 93 %

Procedure:
3-(2-Methoxy-ethoxy)-2-nitro-5-(pyridine-3-yloxy)-pyridine (0.52 mmol) is dissolved in acetic acid (50 eq.). After addition of water (1.5 ml), zinc powder (6.3 eq.) is added and the reaction suspension is heated to 105° C. for 90 minutes. The reaction suspension is cooled to room temperature and filtrated. The filtrate is pored into 3.5% NaOH (30 ml) and extracted with dichloromethane. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-(2-Methoxy-ethoxy)-5-(pyridine-3-yloxy)-pyridine-2-ylamine is obtained as yellow oil in a yield of 93%. HPLC (method C): 0.44 min, LC-MS (method A): 0.46 min, 262.15 (MH+),
Reaction SMILES: Cl.[O:2]1[CH2:8][CH2:7][C:6]([NH2:9])=[N:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[N:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])=[N:18][CH:17]=1>C(O)C>[N:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:9]=[C:6]3[CH2:7][CH2:8][O:2][CH2:3][CH2:4][N:5]3[C:24](=[O:25])[CH:23]=2)=[N:18][CH:17]=1
Reactant: NC1=NCCOCC1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncn2)nc2n1CCOCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.5 %

Procedure:
To a suspension of 25.00 g (165.99 mmol) of 2,3,6,7-tetrahydro-[1,4]oxazepin-5-ylamine monohydrochloride (synthesis as described in WO97/16430 and Bioorganic & Medicinal Chemistry Letters (2004), 14(23), 5907-5911) in 550 mL of ethanol was added 25.23 g (182.59 mmol) of potassium carbonate. The reaction mixture was stirred at room temperature for 10 min, 35.45 g (182.59 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate was added and the resulting mixture was stirred under reflux for 4 hours. The cooled solution was evaporated to remove solvent. The mixture was dissolved with water and diethyl ether. After stirring, the resulting solid was filtered, washed with water and diethyl ether to afford 21.7 g (53%) of the desired compound as a powder.
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)[Cl:41].CO>Cl.O1CCOCC1>[ClH:41].[ClH:41].[ClH:41].[O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: c1ccc(Oc2cc(Sc3ccccn3)cnc2Nc2nc(C3CCNCC3)ns2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Tert-butyl 4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (0.587 g, 1.04 mmol) was dissolved in 1:1 CH2Cl2/methanol and 4N HCl in dioxane added. The reaction was stirred at ambient temperature for 1 hour. The reaction was concentrated and dried in a vacuum oven to provide the title compound (0.473 g, 98.0% yield). 1H NMR (d6-DMSO) δ 12.39 (s, 1H), 8.95 (bs, 1H), 8.80 (bs, 1H), 8.39 (d, 1H), 8.37 (m, 1H), 7.67 (dt, 1H), 7.47 (d, 1H), 7.43 (t, 2H), 7.22-7.12 (m, 5H), 3.30 (d, 2H), 3.16-2.99 (m, 3H), 2.17 (d, 2H), 1.98 (m, 2H).
Reaction SMILES: CS(C[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1NC1C=CC(OC)=CC=1)=O)=O.CS([CH2:25][C:26]([C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[NH:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:39][CH:38]=1)=[O:27])=O>>[CH2:44]([O:43][C:40]1[CH:41]=[CH:42][C:37]([N:36]2[C:29]3[C:28](=[CH:33][C:32]([O:34][CH3:35])=[CH:31][CH:30]=3)[C:26](=[O:27])[CH:25]=[C:5]2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:38][CH:39]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COc1ccc(Nc2ccccc2C(=O)CS(C)=O)cc1
Reactant: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(=O)CS(C)=O)c1
Product: COc1ccc2c(c1)c(=O)cc(-c1ccccc1)n2-c1ccc(OCc2ccccc2)cc1

Procedure:
Following a procedure similar to that described in Example 12, Procedure 3, but substituting for 2-(methylsulfinyl)-2'-(4-methoxyanilino)acetophenone an equivalent amount of 2-(methylsulfinyl)-2'-(4-benzyloxyanilino)-5'-methoxyacetophenone there can be obtained 1-(4-benzyloxyphenyl)-2-phenyl-6-methoxy-4(1H)-quinolone.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[CH3:26][C:27]1([C:51]([NH2:53])=[O:52])[C:32]([CH3:34])([CH3:33])[S:31][CH2:30][CH2:29][N:28]1[S:35]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]#[C:47][CH2:48][CH2:49]O)=[CH:40][CH:39]=1)(=[O:37])=[O:36].C(Br)(Br)(Br)[Br:55]>C1COCC1>[CH3:26][C:27]1([C:51]([NH2:53])=[O:52])[C:32]([CH3:34])([CH3:33])[S:31][CH2:30][CH2:29][N:28]1[S:35]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]#[C:47][CH2:48][CH2:49][Br:55])=[CH:40][CH:39]=1)(=[O:37])=[O:36]
Reactant: BrC(Br)(Br)Br
Reactant: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCO)cc2)C1(C)C(N)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCBr)cc2)C1(C)C(N)=O
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a solution of 2.123 g (8.093 mmol) of triphenylphosphine and 0.373 mL (4.61 mmol) of pyridine in 40 mL of dry THF under nitrogen was added 1.73 g (4.046 mmol) of methyl 4-({4-[(5-hydroxy-2-pentynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxamide. The solution was cooled in a water bath and 1.34 g (4.046 mmol) of carbon tetrabromide was added and the resulting mixture was stirred for 3 h. The resulting suspension was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate:hexanes (1:8) to provide 1.726 g (87%) of methyl 4-({4-[(5-bromo-2-pentynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxamide as a pale yellow oil. Electrospray Mass Spec: 492.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[CH:5]=[C:4]([CH3:12])[N:3]=1>C(O)C.[Ni]>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH3:12])=[CH:5][C:6]=1[Cl:11]
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: [Ni]
Solvent: CCO
Product: Cc1cc(Cl)c(N)c(Cl)n1
Temperature: 60 °C
Reaction time: 7 h
Yield: 96 %

Procedure:
2,4-Dichloro-6-methyl-3-nitropyridine (30 g, 144.9 mmol) was dissolved in ethanol (300 mL), and Raney nickel (1.50 g, 25.6 mmol) was added to the solution, followed by stirring for 7 hours at 60° C. under hydrogen atmosphere(0.15 MPa). Raney nickel was removed through filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform (60 mL), and the solution was left to stand for one hour. Subsequently, the formed insoluble substance was removed through filtration, and the filtrate was concentrated under reduced pressure, to thereby yield 24.62 g of 3-amino-2,4-dichloro-6-methylpyridine (yield: 96%) as a colorless solid. The product was recrystallized from hexane, to thereby yield colorless crystals.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[CH:8][C:9]([OH:15])=[C:10]([C:12](=[O:14])[CH3:13])[CH:11]=1>C(O)(=O)C>[F:5][C:6]1[CH:7]=[C:8]([N+:1]([O-:4])=[O:2])[C:9]([OH:15])=[C:10]([C:12](=[O:14])[CH3:13])[CH:11]=1
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Reaction time: 3 h
Yield: 98.48 %

Procedure:
Conc. HNO3 (22.49 g, 357 mmol) was added to a solution 1-(5-fluoro-2-hydroxyphenyl)ethanone (50 g, 325 mmol) in acetic acid (300 mL) at 0° C. and stirring was continued at 20° C. for 3 h. The reaction mixture was quenched with ice cold water. The separated solid was filtered and washed with cold water and dried to afford 1-(5-fluoro-2-hydroxy-3-nitrophenyl)ethanone (Int-19) (65 g, 98.48% yield) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.6 (1H, s), 8.3-8.2 (1H, dd), 8.2-8.1 (1H, dd), 2.7 (3H, s) ppm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[C:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)#[N:8].C(N(CC)CC)C>ClCCl>[C:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])=[O:14])=[CH:11][CH:10]=1)#[N:8]
Reactant: NCCCCO
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)NCCCCO)cc1
Temperature: 5 °C
Reaction time: 15 h

Procedure:
100 mmol (9.2 ml) of 4-aminobutanol are slowly added, at a temperature of 5° C., to 100 mmol (16.56 g) of 4-cyanobenzoyl chloride in 400 ml of dichloromethane. While maintaining the temperature at 5° C., 100 mmol (13.9 ml) of triethylamine are added. The reaction mixture is stirred for 15 hours at room temperature before being hydrolysed. The organic phase is then decanted off and washed with a 1N hydrochloric acid solution. After evaporating off the solvent, the residue obtained is purified by chromatography on silica gel using a 97/3 dichloromethane/methanol mixture as eluant to yield the expected product.
Reaction SMILES: C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[I:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([OH:40])=O)=[CH:33][CH:32]=1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CN(C=O)C>[I:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][C:38]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:40])=[CH:35][CH:36]=1
Reactant: C1COCCN1
Reactant: O=C(O)Cc1ccc(I)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(I)cc1)N1CCOCC1
Temperature: 0 °C
Yield: 62.3 %

Procedure:
Triethylamine (5.30 mL, 38.0 mmol), HOBt (3.96 g, 28.5 mmol) and EDC.HCl (5.47 g, 28.5 mmol) were added to a solution of (4-iodo-phenyl)-acetic acid (5.0 g, 19.0 mmol) in DMF (100 mL) and stirred. After 5 min morpholine (2.0 mL, 22.9 mmol) was added at RT. The reaction mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water (50 mL) and obtained solid was filtered, dried to get 3.92 g (Yield: 62.1%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([O:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[CH:3][CH:2]=1.[CH2:21](O)[CH3:22]>>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([O:14][C:15]([CH3:20])([CH3:19])[C:16]([O:18][CH2:21][CH3:22])=[O:17])=[CH:3][CH:2]=1
Reactant: CCO
Reactant: CC(C)(Oc1cccc2c1sc1ccccc12)C(=O)O
Product: CCOC(=O)C(C)(C)Oc1cccc2c1sc1ccccc12

Procedure:
2-(4-Dibenzothiophenoxy)-2-methylpropionic acid (9.5 g) was dissolved in 500 ml absolute ethanol. Dry hydrogen chloride was bubbled through for 3 hours, and the mixture was stored over night. After evaporation of the solvent, the residue was dissolved in 250 ml ether, washed with sodium bicarbonate solution, dried and evaporated to give 8.5 g of a brown liquid, b.p. 155-170/0.001 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[F:36][C:37]1[CH:38]=[C:39]([C:43]2[NH:44][C:45](=[O:53])[C:46]3[CH:52]=[CH:51][CH:50]=[N:49][C:47]=3[N:48]=2)[CH:40]=[CH:41][CH:42]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:51]4[CH:50]=[N:49][C:47]5[N:48]=[C:43]([C:39]6[CH:40]=[CH:41][CH:42]=[C:37]([F:36])[CH:38]=6)[NH:44][C:45](=[O:53])[C:46]=5[CH:52]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(-c2cccc(F)c2)nc2ncccc12
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc4nc(-c5cccc(F)c5)[nH]c(=O)c4c3)cc12
Temperature: 80 °C
Reaction time: 5 h
Yield: 13.5 %

Procedure:
To a mixture of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (90 mg, 0.18 mmol), 2-(3-fluorophenyl)pyrido[2,3-d]pyrimidin-4(3H)-one (63 mg, 0.19 mmol) and K3PO4.3H2O (143 mg, 0.54 mmol) in 1,4-dioxane/H2O (3 mL/0.3 mL), Pd2(dba)3 and X-Phos (10 mg/10 mg) were added under N2 protection. After being stirred at 80° C. for 5 h, the reaction mixture was concentrated in vacuo, suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC give the product of 2-(4-fluorophenyl)-5-(2-(3-fluorophenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (15 mg, yield: 13%). 1H-NMR (DMSO-d6, 400 MHz) δ 12.97 (br s, 1H), 9.03 (d, J=2.4 Hz, 1H), 8.50˜8.60 (m, 2H), 8.16 (s, 1H), 8.12 (d, J=7.6 Hz, 1H), 8.00˜8.09 (m, 3H), 7.79 (s, 1H), 7.65 (dd, J=14.0, 8.0 Hz, 1H), 7.46˜7.52 (m, 1H), 7.43 (t, J=8.8 Hz, 2H), 3.26 (s, 3H), 3.02 (s, 3H), 2.85 (d, J=4.8 Hz, 3H). MS (M+H)+: 616.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]=C.CSC.C[OH:19]>>[CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]=[O:19]
Reactant: CO
Reactant: C=CCc1ccc2c(c1C)COC2=O
Solvent: CSC
Product: Cc1c(CC=O)ccc2c1COC2=O
Temperature: 25 °C

Procedure:
A solution of 4-methyl-5-prop-2-en-1-yl-2-benzofuran-1(3H)-one (220 mg, 1.2 mmol) in MeOH (20 mL) was cooled to −78° C. To this solution was bubbled ozone until the reaction turned blue. Nitrogen was bubbled through the reaction to drive off excess ozone, followed by addition of DMS (0.870 mL, 11.7 mmol). The reaction was allowed to warm up to RT. The solvents were removed under reduced pressure. The crude product was purified by flash chromatography to afford (4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde. 1H-NMR (500 MHz, CDCl3) δ ppm 9.78 (s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.34 (d, J=7.5 Hz, 1H), 5.27 (s, 2H), 3.90 (s, 2H), 2.23 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12](=[O:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1.[C:16]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].CC(CC(C)C)=O>[C:16]1([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([C:10]4[NH:11][C:12](=[O:15])[S:13][CH:14]=4)=[CH:6][CH:5]=3)[CH2:28][CH2:27]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: O=c1[nH]c(-c2ccc(CCCl)cc2)cs1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: CCN(CC)CC
Product: O=c1[nH]c(-c2ccc(CCN3CCN(c4cccc5ccccc45)CC3)cc2)cs1
Yield: 21.6 %

Procedure:
To a 35 ml round-bottomed flask equipped with condenser and N2 inlet were added 1.40 g (5.84 mmol) of 4-(4-(2-chloroethyl)phenyl)thiazol-2-one, 1.24 g (5.84 mmol) of N-(1-naphthyl)piperazine, 0.81 ml (5.84 mmol) of triethylamine, 0.62 g (5.84 mmol) of sodium carbonate, 2 mg of sodium iodide, and 12 ml of methylisobutylketone. The reaction was heated at reflux for 5 days, cooled, and evaporated. The residue was taken up in ethyl acetate/water, the layers separated, and the ethyl acetate layer washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using ethyl acetate/methylene chloride as eluent. The product fractions were evaporated, and the residue taken up in hot methylene chloride/methanol, treated with ethyl acetate saturated with hydrochloride, precipitated with ether, filtered, washed with ether, and dried to give 0.523 g (18%) of a white solid, m.p. 307°-309° C.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[C:7]([C:10]1[O:14][C:13]([CH3:15])=[N:12][C:11]=1[CH3:16])(=[O:9])[CH3:8]>>[CH3:15][C:13]1[O:14][C:10]([C:7]([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)([OH:9])[CH3:8])=[C:11]([CH3:16])[N:12]=1
Reactant: Brc1ccsc1
Reactant: CC(=O)c1oc(C)nc1C
Product: Cc1nc(C)c(C(C)(O)c2ccsc2)o1

Procedure:
Starting with 3-bromothiophene and 5-acetyl-2,4-dimethyloxazole and following the general method of Example 4 the title compound was prepared. M.p. 132°-133° C.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:18]([CH:33]3[CH2:35][CH2:34]3)=[N:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:21][CH:22]=2)=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[Li+].[OH-]>O1CCCC1.CCOCC>[CH:33]1([C:18]2[C:17]([CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:36])=[O:3])=[CH:10][CH:11]=3)=[CH:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=3)[N:19]=2)[CH2:35][CH2:34]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1)C(=O)O
Yield: 93.6 %

Procedure:
445 mg (0.889 mmol) of 2-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester and 2.7 ml 1N LiOH in 5 ml tetrahydrofurane were stirred at 50° C. over night. The reaction mixture was taken up in ether and washed with 1N HCl and water. The crude product was suspended with AcOEt/heptane 1:19. The resulting crystals were filtered off providing 393 mg pure 2-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-propionic acid.