Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12]1[O:13][C:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][N:16]=1.O.O.[Sn](Cl)Cl>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:11][C:12]1[O:13][C:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][N:16]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1ncc(-c2cccnc2)o1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(N)cc1Nc1ncc(-c2cccnc2)o1
Yield: 65.1 %

Procedure:
To a solution of (2-methyl-5-nitro-phenyl)-(5-pyridin-3-yl-oxazol-2-yl)-amine (600 mg, 2.02 mmol) in ethanol (20 mL) was added tin(II) chloride dihydrate (2.50 g, 10 mmol). The reaction mixture was heated under reflux for 6 h. The mixture was then concentrated, saturated aqueous NaHCO3 was added and the resultant suspension was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous MgSO4 and concentrated. The residue was silica gel column chromatographed (dichloromethane/ethanol:97/3). 350 mg (65%) of (2-methyl-5-amino-phenyl)-(5-pyridin-3-yl-oxazol-2-yl)-amine was obtained as pale yellow powder.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[CH2:5]([C@@H:7]1[CH2:12][O:11][CH2:10][CH2:9][N:8]1[C:13]1[N:18]=[C:17]([NH:19][CH3:20])[N:16]=[C:15]([C:21]2[CH:28]=[C:27](F)[C:24]([C:25]#[N:26])=[C:23]([F:30])[CH:22]=2)[CH:14]=1)[CH3:6].C[O-].[Na+]>CCOC(C)=O.CN(C=O)C>[CH2:5]([C@@H:7]1[CH2:12][O:11][CH2:10][CH2:9][N:8]1[C:13]1[N:18]=[C:17]([NH:19][CH3:20])[N:16]=[C:15]([C:21]2[CH:28]=[C:27]([O:2][CH3:1])[C:24]([C:25]#[N:26])=[C:23]([F:30])[CH:22]=2)[CH:14]=1)[CH3:6]
Reactant: CC[C@@H]1COCCN1c1cc(-c2cc(F)c(C#N)c(F)c2)nc(NC)n1
Reactant: CO
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@@H]1COCCN1c1cc(-c2cc(F)c(C#N)c(OC)c2)nc(NC)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
CH3OH (10 mL) was added dropwise to a 100 mL RBF at 0° C. charged with sodium hydride (66.8 mg, 2.78 mmol). The mixture was stirred for 10 minutes and then allowed to warm to room temperature for 10 minutes. To a 4 mL vial were added 4-[6-[(3R)-3-ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2,6-difluorobenzonitrile (100 mg, 0.278 mmol), DMF (1 mL) and 1.2 mL of sodium methoxide solution (1.2 eq). The reaction was stirred at room temperature overnight. An extra 0.5 eq of sodium methoxide was added to the reaction and it was heated to 40° C. for 3 hours. The reaction mixture was then poured into EtOAc (10 mL). The organics were washed with H2O (2×) and then dried over Na2SO4 and concentrated to afford 4-[6-[(3R)-3-ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2-fluoro-6-(methyloxy)benzonitrile. This material was taken up in CH3CN (1 mL) and added to a 5 mL microwave vial followed by the addition of hydrazine (0.035 mL, 1.113 mmol) and Hunig's base (0.39 mL, 2.23 mmol). The reaction was irradiated at 150° C. for 90 minutes. The reaction mixture was then concentrated and purified via reverse phase HPLC (10-30% CH3CN/H2O, 0.1% TFA). Fractions were combined and diluted with EtOAc. The organics were washed with saturated NaHCO3 solution that was back extracted with EtOAc (×1). The organics were combined and dried over Na2SO4. The product was taken up in 2 mL H2O and lyophilized to afford the title compound (34.8 mg) as a white fluffy powder. LC-MS (ES) m/z=384 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.88 (t, 3H), 1.59-1.82 (m, 2H), 2.82 (d, J=3.8 Hz, 3H), 3.07-3.18 (m, 1H), 3.39-3.49 (m, 1H), 3.50-3.56 (m, 1H), 3.82-3.87 (m, 1H), 3.87-3.92 (m, 1H), 3.94 (s, 3H), 4.10-4.23 (m, 1H), 4.27-4.39 (m, 1H), 5.02 (s, 2H), 6.45-6.57 (m, 1H), 6.94 (bs, 1H), 7.52 (bs, 1H), 8.30-8.34 (bs, 1H), 11.53 (bs, 1H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:28][C:29]1[C:34](=[O:35])[C:33]([CH3:36])=[C:32]([CH3:37])[C:31](=[O:38])[C:30]=1[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=1)[C:45](O)=[O:46]>C(Cl)Cl>[CH3:28][C:29]1[C:34](=[O:35])[C:33]([CH3:36])=[C:32]([CH3:37])[C:31](=[O:38])[C:30]=1[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=1)[C:45]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1)=[O:46]
Reactant: CC(=O)Oc1ccc(CC2=C(C)C(=O)C(C)=C(C)C2=O)cc1C(=O)O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(CC2=C(C)C(=O)C(C)=C(C)C2=O)cc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.1 %

Procedure:
4-Trifluoromethylaniline (0.176 g, 1.096 mmol), triethylamine (0.111 g, 1.096 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.185 g, 1.096 mmol) were added to a methylene chloride solution (100 ml) of 5-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.730 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from a mixed solvent of ethyl acetate and hexane (1:2) to obtain the titled compound (0.220 g, 0.453 mmol, 62%).
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:21][O:22][C:23](=[O:25])[N:24]=2)[CH:15]=1.[CH2:28]([N:30]([CH2:34][CH3:35])[C:31](Cl)=[O:32])[CH3:29]>N1C=CC=CC=1>[F:27][C:13]([F:12])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[N:24]([C:31]([N:30]([CH2:34][CH3:35])[CH2:28][CH3:29])=[O:32])[C:23](=[O:25])[O:22][N:21]=2)[CH:15]=1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: CCN(CC)C(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CCN(CC)C(=O)n1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Reaction time: 18 h
Yield: 31.5 %

Procedure:
To 1 ml of pyridine were added 0.2 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.18 g of N,N-diethylcarbamoyl chloride was added at room temperature. After stirring for 18 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.09 g of 3-(4-trifluoromethylpyridin-2-yl)-N,N-diethyl-1,2,4-oxadiazol-5-one-4-carboxamide (present compound (16)).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[Br:1][C:2]1[C:3]([NH:8][C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncccc1Br
Product: CC(=O)Nc1ncccc1Br
Temperature: 100 °C

Procedure:
3-Bromo-pyridin-2-ylamine (1.00 g, 5.78 mmol) was dissolved in acetic anhydride (12.4 mL). This solution was heated at 100° C. for 16 h and cooled to room temperature. The mixture was concentrated in vacuo, diluted with EtOAc (100 mL) and poured into a mixture of ice and saturated NaHCO3 solution (150 mL). This mixture was then saturated with solid NaHCO3 and extracted with EtOAc (3×150 mL). The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo to give 1.49 g of N-(3-Bromo-pyridin-2-yl)-acetamide in a quantitative yield. HPLC Rt=1.79 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) LC/MS: M+H+=215.
Reaction SMILES: [B-](F)(F)(F)F.[CH3:6][CH2:7][O+](CC)CC.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][CH2:24][CH2:25][CH3:26])=[C:18]([CH:22]=1)[C:19]([NH2:21])=[O:20]>C(Cl)Cl>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][CH2:24][CH2:25][CH3:26])=[C:18]([CH:22]=1)[C:19](=[NH:21])[O:20][CH2:6][CH3:7]
Reactant: CC[O+](CC)CC
Reactant: CCCOc1ccc(C)cc1C(N)=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCCOc1ccc(C)cc1C(=N)OCC
Reaction time: 8 h

Procedure:
A solution of triethyloxonium borofluoride (34 g.) in anhydrous methylene chloride (90 ml.) was added during 5 minutes to a solution of crude 5-methyl-2-propoxybenzamide (34.5 g.) in anhydrous methylene chloride (300 ml.), and the solution was left to stand at room temperature overnight. The solution was concentrated to about 150 ml. and then diluted with anhydrous diethyl ether (500 ml.). The precipitated solid was filtered off and washed with anhydrous diethyl ether to give crude ethyl 5-methyl-2-propoxybenzimidate borofluoride (47 g.), m.p. 148°-150° C.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH2:8][N:9]([CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[O:23][CH3:24])[CH2:14]1)[CH2:10][CH2:11][CH3:12]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][CH2:8][N:9]([CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[O:23][CH3:24])[CH2:14]1)[CH2:10][CH2:11][CH3:12]
Reactant: O=S(Cl)Cl
Reactant: CCCN(CCCO)C1CCc2c(cccc2OC)C1
Solvent: ClC(Cl)Cl
Product: CCCN(CCCCl)C1CCc2c(cccc2OC)C1

Procedure:
185.8 g thionylchloride are added to 190 g 1,2,3,4-tetrahydro-2-[N-(3-hydroxypropyl)-N-propylamino]-5-methoxy-naphthalene (free base) in 1.5 liters chloroform. The resultant warm reaction mixture is refluxed for 1 hour, and after concentration partitioned between methylene chloride and 2 N sodium hydroxide. The organic phase is washed with water, dried over sodium sulphate, filtered and concentrated. The crude heading compound so obtained is converted into the bis[base]naphthalene-1,5-disulphonate. M.pt. 239°-242° (decomp).
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:19]([OH:21])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[Cl:14])=[O:9].[NH2:29][C@H:30]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[NH:40])[NH:36][N+:37]([O-:39])=[O:38].ON1C2C=CC=CC=2N=N1.C1(N=C=N)CCCCC1>C(Cl)Cl.C(N(CC)CC)C>[NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:19]([NH:29][C@H:30]([C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[NH:40])[NH:36][N+:37]([O-:39])=[O:38])=[O:21])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[Cl:14])=[O:9]
Reactant: N=C(NCCC[C@H](N)C(=O)OCc1ccccc1)N[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)O
Agent: N=C=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Boc-Lys(Cl-Z)-OH (4.15 g), H-Arg(NO2)OBzl.2TsOH (6.54 g) and 1-hydroxybenzotriazole (1.35 g) were dissolved in methylene chloride (70 ml) and then triethylamine (2.02 g) was added, followed by addition of cyclohexylcarbodiimide (2.06 g) under ice-cooling. The temperature was raised to room temperature. The mixture was stirred for 4 hours and then filtered. The filtrate was concentrated and extracted with ethyl acetate. The extract was washed with water, dilute sodium hydrogen carbonate, water and sodium chloride in that order, dried over magnesium sulfate, and concentrated to give Boc-Lys(Cl-Z)-Arg(NO2)-OBzl (7.29 g) as an amorphous solid.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[C:7]([Br:15])=[CH:6][C:5]=1[Cl:16].O.[OH-].[Li+]>CO>[Br:15][C:7]1[C:8]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:9][C:4]([C:3]([OH:17])=[O:2])=[C:5]([Cl:16])[CH:6]=1
Reactant: COC(=O)c1cc(OC(F)(F)F)c(Br)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(OC(F)(F)F)c(Br)cc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
To a mixture of 4-bromo-2-chloro-5-trifluoromethoxy-benzoic acid methyl ester (1.0 g, 3.0 mmol, Preparation 48) dissolved in methanol (4 mL) and water (4 mL) was added lithium hydroxide (360 mg, 15 mmol). The reaction mixture was stirred at 60° C. for 1 h and concentrated. The reaction mixture was adjusted to acidic pH with 1 N HCl, dissolved in EtOAc (60 mL) and washed with water (60 mL). The aqueous layer was extracted with EtOAc (60 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to produce the title intermediate (966 mg, 100% yield) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][O:12][C:13]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:14]=1[CH2:15][C:16]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:17]=1[O:18][CH:19]([CH3:23])[C:20]([OH:22])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34]1[CH:35]=CC2N(O)N=[N:40][C:38]=2[CH:39]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.N1CCCC1>C(#N)C>[CH2:1]([O:8][C:9](=[O:10])[CH2:11][O:12][C:13]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:14]=1[CH2:15][C:16]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:17]=1[O:18][CH:19]([CH3:23])[C:20](=[O:22])[N:40]1[CH2:35][CH2:34][CH2:39][CH2:38]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CC(Oc1ccc(Cl)cc1Cc1cc(Cl)ccc1OCC(=O)OCc1ccccc1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCNC1
Solvent: CC#N
Product: CC(Oc1ccc(Cl)cc1Cc1cc(Cl)ccc1OCC(=O)OCc1ccccc1)C(=O)N1CCCC1

Procedure:
To a suspension of 2-[2-(2-benzyloxycarbonylmethoxy-5-chloro-benzyl)-4-chloro-phenoxy]-propionic acid (Intermediate A) (100 mg, 0.204 mmol), HOBt (27.6 mg, 0.204 mmol) and PS-CDI (326.4 mg, 1.25 mmol/g, 0.408 mmol) in acetonitrile (15 mL) is added pyrrolidine (17.1 μL, 0.204 mmol). The reaction mixture is heated using microwave radiation in a Personal Chemistry Emrys™ Optimizer microwave reactor at 100° C. for 5 minutes. The PS-CDI resin is removed by filtration, rinsing with DCM and MeOH and the filtrate is concentrated in vacuo. The crude product is dissolved in EtOAc (50 mL) and washed with water (50 mL), aqueous sodium carbonate solution (30 mL), brine (50 mL) and then dried (MgSO4). The solvent is removed in vacuo and purification of the crude product by chromatography on silica eluting with EtOAc/iso-hexane (1:4) affords the titled product as a racemic mixture; MH+=542.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:18]([S:25][CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: SCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CSCc1ccccc1
Reaction time: 8 h

Procedure:
2-bromo-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanone and benzyl mercaptan were dissolved in DMF. Cesium carbonate was added and the reaction stirred overnight. Standard aqueous workup afforded provided the product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19]>>[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:17]=[CH:16][CH:15]=[C:4]([CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=2)=[CH:22][CH:21]=1)=[O:19]
Reactant: CN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(B(O)O)cc1
Product: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)OC(C)(C)C

Procedure:
In a manner similar to that of Example 1(e) by reacting 13.7 g (45 mmol) of tert-butyl (3-bromo benzyl)-N-methylcarbamate (prepared in Example 1(b)) with 10 g (67 mmol) of 4-formylbenzene-boronic acid, 11 g (76%) of the expected are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][C:6]([C:12]([OH:14])=[O:13])=[CH:5]2>CO.[Pd]>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH:6]([C:12]([OH:14])=[O:13])[CH2:5]2
Reactant: O=C(O)C1=Cc2cc(O)ccc2OC1
Agent: [Pd]
Solvent: CO
Product: O=C(O)C1COc2ccc(O)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A solution of 6-hydroxy-2H-chromene-3-carboxylic acid (2.00 g, 10.4 mmol) in MeOH (100 mL) was degassed. To this solution was added Pd/C (5 wt %, 1.32 g). The reaction mixture was allowed to stir at rt under an atmosphere of hydrogen for 3 h and then filtered through Celite. Concentration of the filtrate gave 6-hydroxychromane-3-carboxylic acid (1.52 g, 75%). LCMS: ES− 193.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COC(=O)c1ccc(C)cc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1OC

Procedure:
A mixture of methyl 2-methoxy-4-methylbenzoate (5.0 g), N-bromosuccinimide (4.94 g), 2,2′-azobis(isobutyronitrile) (0.23 g) and carbon tetrachloride (50 ml) was heated for 40 minutes under reflux. The mixture was cooled and the precipitate was filtered off. The filtrate was concentrated to give methyl 4-bromomethyl-2-methoxybenzoate as an oil.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].C1(CN)CCCCC1.[O:14]=[C:15]1[C:23]2([CH2:27][O:26][C:25]3[CH:28]=[C:29]4[C:33](=[CH:34][C:24]2=3)[CH2:32][CH2:31][O:30]4)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]1[CH2:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](O)=[O:39].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH2:1]([NH:5][C:38](=[O:39])[C:37]1[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=1[CH2:35][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2([CH2:27][O:26][C:25]3[CH:28]=[C:29]4[C:33](=[CH:34][C:24]2=3)[CH2:32][CH2:31][O:30]4)[C:15]1=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: CCCCN
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: CCCCNC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using butylamine to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-butyl-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (77%) as a colorless solid: mp 176-178° C.; 1H NMR (300 MHz, CDCl3) δ7.48-7.41 (m, 1H), 7.37-7.14 (m, 6H), 7.09-6.99 (m, 3H), 6.55-6.37 (m, 3H), 5.25-5.07 (m, 2H), 4.94 (d, J=9.0 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.52 (t, J=8.2 Hz, 2H), 3.47 (q, J=6.6 Hz, 2H), 2.98 (t, J=8.7 Hz, 2H), 1.67-1.55 (m, 2H), 1.50-1.35 (m, 2H), 0.95 (t, J=6.6 Hz, 1H); MS (ES+) m/z 491.1 (M+23).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.[C:20](O)(=[O:23])[CH:21]=[CH2:22].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:20](=[O:23])[CH:21]=[CH2:22])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C=CC(=O)O
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
To a solution of 6-amino-4-[(3-bromophenyl)amino]-quinazoline (2.0 g, 6.35 mmol) in dry DMF (20 mL) under N2 was added acrylic acid (12.7 mmol, 0.87 mL). The resulting solution was cooled to 0° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI·HCl) (7.62 mmol, 1.46 g) was added. The reaction was stirred at 0° C. for 15 minutes and then allowed to warm to room temperature and stirred for a further 2 hours, after which additional acrylic acid (0.30 mL) and EDCI·HCL (0.30 g) were added. After a further 2 hours, the reaction was complete by tlc, solvent was removed under reduced pressure, and the resulting residue diluted with saturated NaHCO3 and repeatedly extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Column chromatography on grade III alumina eluting with EtOAc/MeOH (95:5) followed by recrystallization from EtOAc/hexane gave a spongy white solid, which upon several hours under high vacuum gave N-[4-[(3-bromophenyl)amino]quinazolin-6-yl]acrylamide (1.06 g, 45%) as a cream powder, mp 258-261° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][N:26]=[N:25][CH:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:21][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])=[N:7][C:2]([NH:22][C:23]2[CH:28]=[CH:27][N:26]=[N:25][CH:24]=2)=[N:3][CH:4]=1
Reactant: Nc1ccnnc1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Cl)ncc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccnnc2)ncc1Cl
Temperature: 120 °C
Yield: 21 %

Procedure:
A mixture of 2-(2-(2-(2,5-Dichloropyrimidin-4-yl)ethyl)phenyl)propanamide (A30) 2-(2-(2-(2,5-Dichloropyrimidin-4-yl)ethyl)phenyl)propanamide (A30 (0.080 g, 0.25 mmol), 4-aminopyridazine (0.046 g, 0.49 mmol), Xantphos (0.0057 g, 0.010 mmol) and Cs2CO3 (0.24 g, 0.74 mmol) in 1,4-dioxane (3 mL) was bubbled with nitrogen for 10 minutes. Palladium (II) acetate (0.0011 g, 0.0049 mmol) was added and the mixture was heated at 120° C. under microwave irradiation for 28 minutes. The volatiles were removed in vacuo and the residue was purified by silica gel column chromatography (Combiflash Rf, 0-15% MeOH in DCM) to give the title compound 42 as a light yellow solid (0.020 g, 21%). LCMS-C: rt 4.23 min; m/z 383 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27](Cl)[C:26]=1[N+:32]([O-:34])=[O:33].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)[C:26]=1[N+:32]([O-:34])=[O:33]
Reactant: CN1CCNCC1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(Cl)c1[N+](=O)[O-]
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(N2CCN(C)CC2)c1[N+](=O)[O-]

Procedure:
In an analogous procedure to that described in Example 15, N-[2-methyl-5-(2-morpholinopyrid-4ylcarbonylamino)phenyl]-3-chloro-2-nitrobenzamide was reacted with 1-methylpiperazine to give the title compound; NMR Spectrum: (DMSOd6) 2.84-2.89 (m, 4H), 2.92-3.08 (m, 4H), 3.58-3.61 (m, 4H), 3.81-3.84 (m, 4H), 6.95 (d, 1H), 7.09 (s, 1H), 7.10 (d, 1H), 7.41-7.44 (m, 2H), 7.53 (d, 1H), 7.76 (d, 1H), 7.96 (s, 1H), 8.04 (s, 1H), 8.3 (d, 1H); Mass Spectrum: M+H+ 560.