Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]1([CH3:35])[CH2:6][O:5][N:4]([C:7]([C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH:21]([CH3:23])[CH3:22])[C:12]=3[S:11][C:10]=2[CH2:24][C:25]2[C:26]([C:31]([F:34])([F:33])[F:32])=[N:27][NH:28][C:29]=2[CH3:30])=[O:8])[CH2:3]1.Br[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu]I>[CH3:35][C@@:2]1([OH:1])[CH2:6][O:5][N:4]([C:7]([C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH:21]([CH3:22])[CH3:23])[C:12]=3[S:11][C:10]=2[CH2:24][C:25]2[C:26]([C:31]([F:32])([F:33])[F:34])=[N:27][N:28]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[C:29]=2[CH3:30])=[O:8])[CH2:3]1
Reactant: Brc1ncccn1
Reactant: Cc1[nH]nc(C(F)(F)F)c1Cc1sc2c(c1C(=O)N1C[C@](C)(O)CO1)c(=O)n(C)c(=O)n2C(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1c(Cc2sc3c(c2C(=O)N2C[C@](C)(O)CO2)c(=O)n(C)c(=O)n3C(C)C)c(C(F)(F)F)nn1-c1ncccn1
Temperature: 100 °C

Procedure:
A mixture of the product of example 10 part b) (279 mg), 2-bromopyrimidine (300 mg), copper(I) iodide (95 mg), trans-cyclohexanediamine (55 mg) and potassium carbonate (300 mg) in dioxane (2 ml) was heated at 100° C. for 16 hours under nitrogen. The reaction mixture was concentrated to dryness and purified by silica chromatography eluting with an ethyl acetate to 10% methanol/ethyl acetate gradient, followed by RPHPLC to give the title compound as a white solid (105 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:18]=CC=C[CH:14]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(O)(C)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH:13]([CH3:18])[CH3:14])[CH:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COC(=O)Cc1cccc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl(3-hydroxyphenyl)acetate (200 mg) in tetrahydrofuran (5 ml), 0.15 ml of isopropyl alcohol, 480 mg of triphenylphosphine, and 0.82 ml of diethyl azodicarboxylate (45% toluene solution) were added, and the reaction solution was stirred overnight at room temperature. The reaction solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-25:75-60/40)) to afford the title compound as a colorless oil.
Reaction SMILES: [CH:1]([O:4][CH:5]1[CH2:10][CH2:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]([O:18]CC)=[O:17])[C:12]=2[CH3:21])=[CH:7][CH2:6]1)([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>C1COCC1.C(O)C>[CH:1]([O:4][CH:5]1[CH2:10][CH2:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]([OH:18])=[O:17])[C:12]=2[CH3:21])=[CH:7][CH2:6]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1noc(C2=CCC(OC(C)C)CC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)noc1C1=CCC(OC(C)C)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of [ethyl 5-(4-isopropoxycyclohex-1-en-1-yl)-4-methylisoxazole-3-carboxylate] (393 mg, 1.340 mmol) in THF (3 mL) and Ethanol (3 mL), 2M NaOH (aq) (4.179 ml, 8.36 mmol) was added. The reaction mixture was stirred at room temperature. Upon completion the resulting mixture was poured into water (20 mL) and the pH adjusted to pH 6 with the addition of 1M HCl (aq). The aqueous was extracted with EtOAc (30 mL) and the organic extracts were washed with brine (20 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford the title compound;
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:11]=2)[CH:6]=[C:7]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]=1
Reactant: Clc1nccc2ccc(Br)cc12
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1nc(C=Cc2ccccc2)cc2ccccc12
Yield: 63.5 %

Procedure:
A solution of 7-bromo-1-chloroisoquinoline (200 mg, 0.80 mmol), styrene (94 mg, 0.90 mmol), tri-o-tolylphosphine (30 mg, 12 mol %), palladium (II) acetate (Pd(OAc)2) (10 mg, 5 mol %) and triethylamine (0.34 mL, 2.5 mmol) in DMF (0.75 mL) were placed in a MOS-2000™ (650 W) microwave and irradiated at full power for 7×40s (reaction monitored by TLC). The mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over MgSO4, evaporated in vacuo and the residue was purified by column chromatography upon silica gel using hexanes-EtOAc (100:0 to 95:5) as eluant to give 1-chloro-(2-phenylethen-1-yl)isoquinoline (135 mg, 0.508 mmol) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:12][C:11]=1[C:29]1[C:42](=[O:43])[N:41]([CH3:44])[C:32]2[N:33]=[C:34](S(C)(=O)=O)[N:35]=[CH:36][C:31]=2[CH:30]=1>CO>[NH2:1][C:2]1[CH:3]=[C:4]([NH:5][C:34]2[N:35]=[CH:36][C:31]3[CH:30]=[C:29]([C:11]4[CH:12]=[C:13]([NH:16][C:17](=[O:28])[C:18]5[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=5)[CH:14]=[CH:15][C:10]=4[Cl:9])[C:42](=[O:43])[N:41]([CH3:44])[C:32]=3[N:33]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(N)c1
Reactant: Cn1c(=O)c(-c2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: CO
Product: Cn1c(=O)c(-c2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2Cl)cc2cnc(Nc3cccc(N)c3)nc21
Temperature: 110 °C
Reaction time: 0.42 h

Procedure:
3-Aminoaniline (121.1 mg, 1.12 mmonl) is heated to 110° C. When melted, N-[4-chloro-3-(2-methanesulfonyl-8-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-phenyl]-3-trifluoromethyl-benzamide 34 (15 mg, 0.028 mmol) is added. The reaction is stirred at 110° C. for 25 minutes. The reaction is diluted with MeOH (1 mL) and purified by prep-HPLC to give the final product as a yellow solid: 1H NMR (CDCl3): δ3.64 (s, 3H), 6.66 (d, 1H), 7.17 (t, 1H), 7.28 (d, 1H), 7.42 (m, 2H), 7.48 (t, 1H), 7.50 (dd, 1H), 7.57 (s, 1H), 7.63 (m, 2H), 7.97 (d, 1H), 8.07 (s, 1H), 8.49 (s, 1H); MS m/z 565.0 (M+1).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5](O)=O)[CH2:3][CH2:2]1.[NH2:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18]>>[CH3:18][C:12]1[C:11]2[N:10]=[C:5]([CH:4]3[CH2:8][CH2:9][NH:1][CH2:2][CH2:3]3)[NH:17][C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)C1CCNCC1
Reactant: Cc1cccc(N)c1N
Product: Cc1cccc2[nH]c(C3CCNCC3)nc12

Procedure:
The title compound was prepared from isonipecotic acid and 2,3 diamino toluene using the method described in Description 14. MH+ 216.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30](Cl)=[CH:29][C:28]=2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36](S(=O)(=O)N)[CH:35]=2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.BrC1C=CC=CC=1C(=O)C(F)(F)F>>[C:28]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C@@H:22]([O:21][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=1)[C:23]([F:24])([F:25])[F:26]
Reactant: Nc1nc(O[C@H](c2ccc(Cl)cc2-c2cccc(S(N)(=O)=O)c2)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1
Agent: O=C(c1ccccc1Br)C(F)(F)F
Product: Nc1nc(O[C@H](c2ccccc2-c2ccccc2)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(5-chloro-3′-sulfamoyl-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 34u) starting with 1-(2-bromophenyl)-2,2,2-trifluoroethanone.
Reaction SMILES: [C:1]1(=[O:14])[N:9]2[CH:4]([CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[CH2:3][NH:2]1.[H-].[Na+].Cl[CH2:18][C:19]1[N:20]=[CH:21][N:22]([C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]=1[CH3:24].O>CN(C)C=O>[CH3:24][C:23]1[N:22]([C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:21]=[N:20][C:19]=1[CH2:18][N:2]1[CH2:3][CH:4]2[CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]2[C:1]1=[O:14]
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1NCC2COc3ccccc3N12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CN2CC3COc4ccccc4N3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2,3,3a,4-tetrahydro-1H-imidazo [5,1-c][1,4]benzoxazin-1-one (0.89 g; 0.0047 moles) in 20 ml of anhydrous dimethylformamide kept under nitrogen atmosphere, 50% NaH (0.22 g; 0.0047 moles) is added. The solution is stirred for 1 hour at 60° C.; then, at room temperature, 4-chloromethyl-5-methyl-1-triphenylmethyl-1H-imidazole (1.75 g; 0.0047 moles) is added. The mixture is stirred for 6 hours at 70° C., then cooled, poured into water and extracted with methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH:5]=O.[CH2:23]1[S:29][C:27](=[O:28])[NH:26][C:24]1=[O:25].C([O-])(=O)C.[NH2+]1CCCCC1.N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH:5]=[C:23]1[S:29][C:27](=[O:28])[NH:26][C:24]1=[O:25]
Reactant: COc1ccc(Oc2c(Cl)cc(C=O)cc2Cl)cc1C(C)C
Reactant: O=C1CSC(=O)N1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(Oc2c(Cl)cc(C=C3SC(=O)NC3=O)cc2Cl)cc1C(C)C
Yield: 33.1 %

Procedure:
To a suspension of the title compound from Step B (60 mg, 0.18 mmol) and thiazolidinedione (21 mg, 0.18 mmol) in dry toluene (2 ml) was added a catalytic amount of piperidinium acetate which was generated by the addition of piperidine (1.5 mg, 0.018 mmol) and acetic acid (1.1 mg, 0.018 mmol). The mixture was heated to reflux under nitrogen for two hours. The solution was cooled, diluted with ethyl acetate (15 ml), washed with 1 N HCl (3×10 ml) and brine (10 ml), dried, filtered, and concentrated. The residue was purified by preparative TLC (5% methanol in dichloromethane) to give the title compound (26.1 mg) as a yellow solid. MS (APCl−) Calc.: 437.0, Found: 436.1 (M−1).
Reaction SMILES: BrCCCCCC(C1C=CC2C(=CC(OC)=C(OC)C=2)C=1)=O.[C:23]1([CH2:29][O:30][C:31](=[O:43])[C:32]2[CH:37]=[CH:36][C:35](O)=[C:34]([CH2:39][CH2:40][CH3:41])[C:33]=2O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O.CN(C)C=O>[C:23]1([CH2:29][O:30][C:31](=[O:43])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:39][CH2:40][CH3:41])[CH:33]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCCc1c(O)ccc(C(=O)OCc2ccccc2)c1O
Agent: COc1cc2ccc(C(=O)CCCCCBr)cc2cc1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cccc(C(=O)OCc2ccccc2)c1

Procedure:
A mixture of 7.60 g (0.021 mole) of 6-bromo-(6,7-dimethoxy-2-naphthalenyl)-1-hexanone, 5.96 g (0.021 mole) of 2,4-dihydroxy-3-propylbenzoic acid phenylmethyl ester, 5.75 g (0.042 mole) of potassium carbonate and 3.20 g (0.021 mole) of sodium iodide in 100 mL of acetone and 25 mL of dimethylformamide was stirred at reflux for 26 hours. The solvents were removed under reduced pressure and the crude product was purified by HPLC using 2% ethyl acetate-toluene, to give 8.14 g (69% yield) of 2-hydroxy-4-[[6,7-dimethoxy-2-naphthalenyl)-6-oxohexyl]oxy]-3-propylbenzoic acid phenylmethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1.S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>>[Br:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1
Reactant: Cc1ccc(Br)c[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Temperature: 0 °C
Yield: 90.3 %

Procedure:
5-bromo-2-methylpyridine 1-oxide (2.269 g, 12.07 mmol, 1 eq) was dissolved in sulfuric acid (4 mL, 80 mmol, 6 eq) and cooled at 0° C. Fuming nitric acid (3 mL, 60 mmol, 5 eq) was added dropwise. After addition of the nitric acid was complete, the reaction mixture was first warmed to room temperature and then heated to 90° C. After 2 hours the reaction was cooled in an ice bath and slowly adjusted to pH 10 with 2 M aqueous sodium carbonate. This solution was extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated to yield 2.54 g (90%) of 5-bromo-2-methyl-4-nitropyridine 1-oxide. LMCS (ESI) m+H=233.0.
Reaction SMILES: [C:1]1([C:7](O)([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([O:13][C:14](=[O:22])[C:15]([O:17][Si](C)(C)C)=[CH2:16])[CH3:12].[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH2:11]([O:13][C:14](=[O:22])[C:15](=[O:16])[CH2:17][C:7]([CH3:9])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])[CH3:12]
Reactant: C=C(O[Si](C)(C)C)C(=O)OCC
Reactant: CC(C)(O)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C(=O)CC(C)(C)c1ccccc1
Reaction time: 0.25 h
Yield: 27 %

Procedure:
10.0 g of 2-phenyl-2-propanol and 30.4 g of 2-(trimethylsilyloxy)acrylic acid-ethyl ester (Bull. Chem. Soc. Jpn. 1992, 65, 3209) are introduced into 386 ml of CH2Cl2 and treated at −70° C. with 11.5 ml of tin tetrachloride. After 15 minutes at −70° C., the batch is introduced into semiconcentrated potassium carbonate solution, extracted with CH2Cl2, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with ethyl acetate-cyclohexane yields 4.64 g of the product as a colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[NH2:36][C:37]1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.C(C1C=CC(N=C=O)=CC=1)#N>>[C:37]([C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=[CH:6][CH:7]=1)#[N:36]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Agent: N#Cc1ccc(N=C=O)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(C#N)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 252 was prepared analogous to compound of example 224 by reaction of compound of example 223 with 4-cyanophenyl isocyanate. The compound of example 252 was used directly without isolation for the preparation of compound of example 253.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:20])[CH:12]=[CH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:9].CC([O-])=O.[Na+]>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:2]1(/[C:13](/[CH2:12][C:11]([O:10][CH2:8][CH3:9])=[O:20])=[CH:14]\[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: CCOC(=O)C=CCC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)/C=C(/CC(=O)OCC)c1ccccc1
Temperature: 130 °C
Yield: 28 %

Procedure:
A solution of iodobenzene (1.08 ml, 9.67 mmol) in DMA (5 ml) was added dropwise to a solution of diethylglutaconate (2 g, 10.74 mmol), Pd(OAc)2 (250 mg, 1.07 mmol), NaOAc (880 mg, 10.74 mmol) in DMA (5 ml) at 115° C. under argon. After heating for 8 hours at 130° C., the reaction was cooled, diluted with CH2CI2 (60 ml), and washed with water (4×10 ml). The organic layer was washed with sat. aq. NaHCO3 (20 ml), brine (20 ml), dried with Na2SO4, filtered, and concentrated under reduced pressure. The dark oil was purified by column chromatography using CH2Cl2 as the eluent. The product oil was dried overnight in vacuo giving diethyl (2Z)-3-phenylpent-2-ene-1,5-dioate in 28% yield.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2ON=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:5][C:6]1[C:2]([CH3:1])=[CH:10][C:9]2[O:11][CH2:12][C:13]3([C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[C:14]3=[O:22])[C:8]=2[CH:7]=1
Reactant: BrCc1ccccn1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: Cc1cc2c(cc1C)C1(CO2)C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dimethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 5,6-dimethyl-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (76%) as a colorless solid: mp 165-168° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ8.67 (d, J=6.0 Hz, 1H), 8.12-8.06 (m, 1H), 7.59-7.55 (m, 2H), 7.26-7.23 (m, 1H), 7.21-7.20 (m, 1H), 7.03-6.98 (m, 2H), 6.76 (s, 1H), 6.55 (s, 1H), 5.18 (s, 2H), 4.74 (ABq, 2H), 2.13 (s, 3H), 2.01 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.5, 159.1, 154.0, 146.7, 142.6, 141.5, 138.3, 132.6, 129.1, 126.7, 124.5, 124.4, 124.1, 123.7, 123.5, 111.3, 109.7, 79.5, 57.8, 43.7, 20.2, 19.2; MS (ES+) m/z 357.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[N:11]1([C:2]2[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: c1nc[nH]n1
Reactant: O=C(O)c1cnc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(-n2cncn2)nc1
Temperature: 25 °C

Procedure:
2-Chloropyrimidine-5-carboxylic acid (0.75 g), 1,2,4-1H-triazole (0.98 g) and potassium carbonate (1.96 g) in 3.75 mL of N,N-dimethylformamide are heated in microwave at 50° C. for 30 min, then cooled to room temperature and acidified with 3 mL of 1N HCl, followed by addition of conc. HCl to pH 2. The precipitate is filtered, washed with minimum amount of water, diethyl ether and dried in vacuo to afford the title compound. LC (method 20): tR=0.82 min; Mass spectrum (APCI): m/z=192 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2].[H-].[Na+].I[CH:21]([CH3:23])[CH3:22].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C@H:3]1[C:8](=[O:9])[N:7]([CH:21]([CH3:23])[CH3:22])[C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2]
Reactant: CC(C)I
Reactant: CC[C@@H]1Oc2cc(C(=O)OC)ccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC[C@@H]1Oc2cc(C(=O)OC)ccc2N(C(C)C)C1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
A solution of (S)-2-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.60 g) in dimethylformamide (50 ml) were added 60% sodium hydride (in oil) (0.27 g) and 2-iodopropane (1.38 g) and the mixture was stirred at 60° C. overnight. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v) ] to give (S)-2-ethyl-7-methoxycarbonyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (0.85 g) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:34])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[C:27]([CH3:32])[C:26]=4[F:33])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:35][C:36]1[CH:37]=[C:38]([O:42][CH2:43][CH2:44][N:45]([CH3:47])[CH3:46])[CH:39]=[CH:40][CH:41]=1>CC(O)C.Cl.C(Cl)Cl>[CH3:46][N:45]([CH3:47])[CH2:44][CH2:43][O:42][C:38]1[CH:37]=[C:36]([NH:35][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:34])[C:25]5[C:30]([F:31])=[CH:29][CH:28]=[C:27]([CH3:32])[C:26]=5[F:33])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: Cc1ccc(F)c(C(=O)Nc2cccc(-c3nn4ccccc4c3-c3ccnc(Cl)n3)c2)c1F
Reactant: CN(C)CCOc1cccc(N)c1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: Cc1ccc(F)c(C(=O)Nc2cccc(-c3nn4ccccc4c3-c3ccnc(Nc4cccc(OCCN(C)C)c4)n3)c2)c1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a suspension of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluoro-3-methylbenzamide (100 mg, 0.21 mmol) (prepared in a manner similar to that described in Example 186) and {2-[(3-aminophenyl)oxy]ethyl}dimethylamine (47 mg, 0.26 mmol) in 2-propanol (3 mL) was added 2 drops of concentrated HCl. The reaction was stirred at 80° C. overnight. After 16 h, the mixture was diluted with DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and adsorbed onto silica. The crude product was purified by column chromatography to generate the title compound in 86% yield (112 mg, 0.18 mmol). 1H NMR (400 MHz, d6-DMSO) δ 10.90 (s, 1H), 9.55 (s, 1H), 8.86 (d, J=6.7 Hz, 1H), 8.51 (d, J=8.6 Hz, 1H), 8.28 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.45-7.52 (m, 4H), 7.36 (d, J=7.3 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 7.12-7.16 (m, 3H), 6.53 (d, J=5.1 Hz, 1H), 3.97 (t, J=5.6 Hz, 2H), 2.58 (t, J=5.8 Hz, 2H), 2.26 (s, 3H), 2.17 (s, 6H). MS (ESI) m/z=620 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)(CC(C)C)C)=[CH:4][CH:3]=1.[OH:21]C1C=CC(C(CC2C=CC=CC=2)=O)=CC=1>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: CC(C)CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Product: O=C(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
2,2-bis(4-hydroxyphenyl)-4-methylpentane; benzyl 4-hydroxy- phenyl ketone;
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[C:15]([OH:17])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C(ON1N=NC2[CH:29]=[CH:30][CH:31]=[N:32]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>C(Cl)Cl>[CH:31]1([NH:32][C:15]([C@H:11]2[CH2:12][CH2:13][CH2:14][N:10]2[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:17])[CH2:29][CH2:30]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)[C@H]1CCCN1c1ccc([N+](=O)[O-])cc1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1CC1)[C@H]1CCCN1c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
To (R)-1-(4-nitro-phenyl)-pyrrolidine-2-carboxylic acid (Method 55; 1.8 g, 7.6 mmol) in DCM (50 ml) was added HATU (3.2 g, 8.4 mmol) and DIPEA (2.0 ml, 11.4 mmol). The reaction was stirred for 10 minutes before the addition of methylamine (0.84 g, 15 mmol); the reaction was stirred for 1 hour and then quenched with water (50 ml). The reaction was extracted with DCM (3×100 ml), dried and solvent removed in vacuo to yield a yellow gum. Purification was achieved via column chromatography eluting with 20% EtOAc/isohexane, 60% EtOAc/isohexane and finally 100% EtOAc. The title compound was obtained as a yellow solid (1.4 g, 74%). NMR (299.954 MHz, CDCl3) δ 8.13 (d, 2H), 6.55 (d, 2H), 6.06 (s, 1H), 4.14 (t, 1H), 3.70 (t, 1H), 3.38 (q, 1H), 2.75-2.66 (m, 1H), 2.36-2.29 (m, 2H), 2.17-1.95 (m, 2H), 0.82-0.73 (m, 2H), 0.46-0.35 (m, 2H); m/z 276.