Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:33][CH:34]1[CH2:37][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:35]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][NH:33][CH:34]6[CH2:35][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37]6)=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC(NCc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C1

Procedure:
To a suspension of the aldehyde 47 (1.0 g, 2.25 mmol, scheme 15) in NMP (12 mL) were added 3-amino-1-N-Boc-azetidine (0.600 g, 3.38 mmol) and acetic acid (0.19 mL, 3.38 mmol) at RT and stirred for 30 mill. Then NaBH(OAc)3 (1.2 g, 5.63 mmol) was added and stirred for 3 days. The reaction mixture was poured into saturated aqueous solution of NaHCO3 to form a precipitate that was collected by filtration, rinsed with water and purified via Biotage [linear gradient 2-20%, (methanol/dichloromethane; SiliaFlash 25 g cartridge]. Title compound 430 was obtained as a beige solid (960 mg, 71% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H), 8.56 (d, J=1.2 Hz, 1H), 8.51 (d, J=5.2 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.89 (dd, J=8.0, 2.0 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.23-7.18 (m, 1H), 6.64 (dd, J=5.2, 1.2 Hz, 1H), 6.56 (bd, J=2.4 Hz, 1H), 3.98-3.83 (m, 2H), 3.69 (s, 2H), 3.62-3.47 (m, 3H), 2.58-2.51 (m, 1H), 1.36 (s, 9H), 0.68-0.62 (m, 2H), 0.45-0.40 (m, 2H), one NH is missing. MS (m/z): 605.46 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][C:20]([C:24]3[CH:25]=[CH:26][C:27]([N:30](C)[C:31](=O)OC(C)(C)C)=[N:28][CH:29]=3)=[CH:19][CH:18]=4)=[C:9]([O:39][CH3:40])[CH:8]=2)=[CH:5][N:4]=[C:3]1[CH3:41].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][C:20]([C:24]3[CH:29]=[N:28][C:27]([NH:30][CH3:31])=[CH:26][CH:25]=3)=[CH:19][CH:18]=4)=[C:9]([O:39][CH3:40])[CH:8]=2)=[CH:5][N:4]=[C:3]1[CH3:41]
Reactant: COc1cc(-c2cnc(C)n2C)ccc1Nc1cc2cc(-c3ccc(N(C)C(=O)OC(C)(C)C)nc3)ccc2cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1ccc(-c2ccc3cnc(Nc4ccc(-c5cnc(C)n5C)cc4OC)cc3c2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
To a solution of tert-butyl (5-(3-((4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-amino)isoquinolin-6-yl)pyridin-2-yl)(methyl)carbamate (Example 12, 10 mg, 0.018 mmol) in DCM (4 mL) at 0° C. was added TFA (0.6 mL). The reaction was stirred at room temperature for 16 hours. The solvents were removed in vacuo and the residue was purified by SCX-2 column eluting with 2M NH3/MeOH to afford the title compound as a yellow oil (8 mg, 98%).
Reaction SMILES: [Na].[N+]([O-])(O)=O.[NH2:6][C:7]([NH2:9])=[NH:8].N[C:11]1[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[N:14]([CH2:20][CH3:21])[C:13](=[O:22])[C:12]=1[CH:23]=O>C(O)C>[NH2:8][C:7]1[N:9]=[C:11]2[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[N:14]([CH2:20][CH3:21])[C:13](=[O:22])[C:12]2=[CH:23][N:6]=1
Reactant: CCn1c(N)c(C=O)c(=O)n(CC)c1=O
Reactant: N=C(N)N
Agent: [Na]
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: CCn1c(=O)c2cnc(N)nc2n(CC)c1=O
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
0.92 g of sodium was dissolved in 50 ml of absolute ethanol, and 6.40 g (53 mmol) of guanidine nitrate was added thereto. The solution was stirred for 10 minutes and filtered with Celite filter aid. 0.98 g (4.6 mmol) of 6-amino-1,3-diethyl-5-formyluracil was added to the filtrate and the reaction mixture was refluxed for 24 hours. After removal of the solvent under reduced pressure, 30 ml of water was added thereto. The crystalline precipitate was filtered off and recrystallized from ethanol to give 0.94 g of 7-amino-1,3-diethyl-pyrimido[4,5-d]pyrimidine-2,4-dione (compound 17) in a 87% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][C:25]([NH2:27])=[O:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][CH2:24][C:25]([NH2:27])=[O:26])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CCC(N)=O)(c4ccc(F)cc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamide and 6-methoxypyridine-3-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.254 min, m/z=477.21; 1H NMR (CDCl3) 1.55 (d, 3H), 2.01 (m, 1H), 2.15-2.34 (m, 5H), 2.46 (m, 1H), 2.96 (m, 1H), 4.00 (s, 3H), 5.66 (m, 1H), 5.80 (s, 1H), 6.19 (s, 1H), 6.86 (d, 1H), 7.03 (m, 4H), 7.23 (m, 2H), 7.79 (dd, 1H), 8.36 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][NH:13][CH2:14][C:15]#[CH:16]>ClCCl.C(N(CC)CC)C>[CH3:12][N:13]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:14][C:15]#[CH:16]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: C#CCNC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN(C)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
3.72 g (22.0 mmol) of p-nitrobenzyl chloride in 20 ml of dichloromethane is added, dropwise, at 0° C. to a solution of 1 g (1.45 mmol) of N-methylpropargylamine in 15 ml of dichloromethane and 3.1 ml of triethylamine. After stirring overnight, the reaction mixture is concentrated to dryness under vacuum, and the residue is diluted with dichloromethane and 40 ml of a saturated solution of NaCl. After stirring and decanting, the organic phase is separated and dried over magnesium sulphate, filtered and concentrated under vacuum. The expected product is obtained after chromatography on a silica column, eluent: (20% ethyl acetate in heptane), the pure fractions, after evaporation, produce a brown solid with a yield of 80%. Melting point 47-49° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C1(N=C=NC2CCCCC2)CCCCC1.O[NH:25][C:26](=[NH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1.O>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:8][N:33]=[C:26]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:25]=1
Reactant: N=C(NO)c1cccnc1
Reactant: O=C(O)c1ccco1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: O
Product: c1cncc(-c2noc(-c3ccco3)n2)c1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Furan-2-carboxylic acid (0.8 g; 7 mmol) in 15 ml of dichloromethane was cooled to 0° C., and 0.76 g of 1,3-dicyclohexylcarbodimide (4 mmol) was added slowly. The reaction mixture was stirred at 0-5° C. for 2 hours and filtered. The filtrate was evaporated, the residue was dissolved in 15 ml of pyridine and added 0.43 g of N-hydroxy-nicotinamidine (3.2 mmol). The reaction mixture was heated at reflux until the reaction was finished (measured by TLC), then cooled to room temperature and poured into 100 ml of water. The precipitate was isolated by filtration and dried under vacuum. The product was isolated by column chromatography. Yield 0.23 g (15%). Mp. 110-114° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([N:21]=[C:22]([N:25]([CH3:34])[N:26]=CC1C=CC=CC=1)SC)#[N:20].Cl>CC(C)=O>[CH3:34][N:25]1[C:22]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[N:21][C:19]([NH2:20])=[N:26]1
Reactant: CSC(=NC#N)N(C)N=Cc1ccccc1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: Cl
Solvent: CC(C)=O
Product: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCCC2)c1
Yield: 28.5 %

Procedure:
3-[3-[1-Piperidinylmethyl]phenoxy]propanamine (2.48 g) and N-cyano-1-methyl-2-(phenylmethylene)hydrazine carboximidothioic acid, methyl ester (2.32 g) were heated at 70° under water-pump vacuum for 4 hr. Acetone was added and the solution was treated with dilute hydrochloric acid for 1 hr, washed with ether, basified and extracted with ethyl acetate. Evaporation of the ethyl acetate extracts gave an oil which crystallised from toluene/ether to give the title compound as a white solid (0.98 g) m.p. 94°-5°. TLC silica, methanol/0.88 ammonia 80:1, Rf 0.5.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.S1(CCCC1)(=O)=O.[C:20]1([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F-].[K+]>>[C:20]1([C:26]2[CH:27]=[CH:28][C:29]([O:32][C:2]3[CH:3]=[C:4]4[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]4=[CH:11][CH:12]=3)=[CH:30][CH:31]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=C1OC(=O)c2cc(Oc3ccc(-c4ccccc4)cc3)ccc21
Reaction time: 5 h

Procedure:
To a solution of 0.66 parts (0.004 mole) of 4-fluorophthalic anhydride in 3 parts of sulfolane, was added 0.68 parts (0.004 mole) of p-phenylphenol and 0.23 parts (0.004 mole) of potassium fluoride. The mixture was heated and maintained at a temperature of about 175°-200°, with stirring for a period of about 5 hours.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:12][CH3:13])=[O:2].[C:14]1([N:20]=[C:21]=[S:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:21]([NH:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[S:22])=[CH:7][C:6]=1[O:12][CH3:13])=[O:2]
Reactant: S=C=Nc1ccccc1
Reactant: COc1cc(N)ccc1NNC=O
Product: COc1cc(NC(=S)Nc2ccccc2)ccc1NNC=O

Procedure:
Procedure (18.) was employed with 1-formyl-2-(4-amino-2-methoxyphenyl)hydrazine (1.0 g, 0.0056 mole) and phenyl isothiocyanate (0.75 g, 0.0056 mole). Yield 0.90 g (51%), m.p. 183°-184° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH2:11][CH2:12][CH:13]3OC=CO3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:19]([NH:22][CH2:23][CH2:24][NH2:25])(=[O:21])[CH3:20]>C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:25]([CH2:24][CH2:23][NH:22][C:19](=[O:21])[CH3:20])[CH:13]=[CH:12][CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(=O)NCCN
Reactant: O=C(CCC1OC=CO1)c1ccc2c(c1)OCO2
Solvent: CC(=O)O
Product: CC(=O)NCCn1cccc1-c1ccc2c(c1)OCO2
Yield: 91.2 %

Procedure:
1-(1,3-Benzodioxol-5-yl)-3-(1,3-dioxol-2-yl)-1-propanone (1.7 g) was added under argon and while stirring to a solution of 1.4 g of N-acetylethylenediamine in 20 ml of acetic acid. The reaction mixture was refluxed overnight, the acetic acid was subsequently removed in a vacuum. The residue was taken up in 80 ml of methylene chloride and washed with a mixture of 50 ml of saturated sodium hydrogen carbonate solution and 10 ml of 2N sodium hydroxide solution. The aqueous phase was back-extracted twice with 50 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 2.6 g of brown oil, was chromatographed on 50 g of silica gel with ethyl acetate/hexane (2:1) as the eluent. 1.7 g (95%) of N-[2-[2-(1,3-benzodioxol-5-yl)-pyrrol-1-yl]-ethyl]acetamide were isolated as a yellow oil. MS: m/e=272 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[NH:10]1[CH2:15][CH2:14][CH:13]([C:16](O)=O)[CH2:12][CH2:11]1.[OH-].[Na+].CCOC(C)=O.O>O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:16]([CH:13]3[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]3)=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: O=C(O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1ccc2oc(C3CCNCC3)nc2c1
Temperature: 190 °C
Yield: 49.1 %

Procedure:
2-amino-4-bromophenol (1.2 g, 5.8 mmol) and piperidine-4-carboxylic acid (0.74 g, 5.8 mmol) were dissolved in polyphosphoric acid (30 g). This mixture was heated at 190° C. for three and half hours. Reaction mixture cooled to rt and diluted with water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 9. Work up (AcOEt/H2O) followed removal of AcOEt afforded the titled compound (0.8 g) as a pale-yellow gummy solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[C@@H:10]([CH3:28])[CH2:9]1)=O)(C)(C)C.[NH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([CH3:39])[CH:33]=1>>[CH3:39][C:34]1[CH:33]=[C:32]([CH2:31][CH2:30][NH:29][C:23]2[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]4[CH3:28])[CH:16]=3)[CH:26]=[CH:25][N:24]=2)[CH:37]=[CH:36][C:35]=1[OH:38]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: Cc1cc(CCN)ccc1O
Product: Cc1cc(CCNc2nccc(-c3cccc(CN4CCNC[C@@H]4C)c3)n2)ccc1O

Procedure:
Intermediate 68 was coupled with 4-(2-amino-ethyl)-2-methyl-phenol following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 418. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.32 (s, 1H), 8.26 (d, 1H), 7.78 (d, 1H), 7.64 (t, 1H), 7.45 (d, 1H), 7.13 (d, 1H), 6.98 (s, 1H), 6.88 (d, 1H), 6.60 (d, 1H), 4.71 (d, 1H), 3.99 (d, 1H), 3.84 (s, 2H), 3.45 (m, 3H), 3.23 (m, 3H), 3.02 (t, 1H), 2.86 (t, 2H), 2.07 (s, 3H), 1.54 (d, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:17][C@H:11]2[CH2:12][N:13]([C:15]#[N:16])[CH2:14][C@@:10]2([C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][C:24]([C:30]([F:33])([F:32])[F:31])=[CH:25][CH:26]=3)[CH2:21]2)=[O:19])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=[O:36]>C(Cl)Cl>[NH2:7][C@@H:8]1[CH2:17][C@H:11]2[CH2:12][N:13]([C:15]([NH2:16])=[O:36])[CH2:14][C@@:10]2([C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][C:24]([C:30]([F:32])([F:31])[F:33])=[CH:25][CH:26]=3)[CH2:21]2)=[O:19])[CH2:9]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2CN(C#N)C[C@@]2(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)C1
Solvent: ClCCl
Product: NC(=O)N1C[C@@H]2C[C@@H](N)C[C@]2(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)C1

Procedure:
A solution of the product from Step A (0.03 g, 0.627 mmol) in TFA (1 mL) and DCM (1 mL) was stirred at rt for 1.5 h. The volatile organic compounds were removed by evaporation, and the residue was diluted with DCM and evaporated again to give the product as a TFA salt. LC/MS: C19H23F3N4O2: m/z 397.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11](C([Sn])=C(CCCC)CCCC)[CH2:12]CC.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:11]=[CH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=Cc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 90 %

Procedure:
To an ethanol solution (3 ml) containing 4-nitroiodobenzene (125 mg), tributylvinyltin (174 mg), and potassium carbonate (138 mg) the mesh catalyst precursor (12 mm by 14 mm, wire diameter of 0.1 mm, opening of 0.154 mm) prepared in Example 3 was added to be heated for 12 hours at 80° C. The reaction mixture was cooled to room temperature, and the mesh catalyst precursor was washed with ethanol to be taken off from the reaction mixture. The solvent was distilled from the reaction mixture under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give an intended product, 4-nitrostyrene with 90% yield. The mesh catalyst precursor taken off from the mixture was again used in the same reaction to again give the intended product, 4-nitrostyrene with 88% yield. The mesh catalyst precursor could be recycled at least ten times.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[CH:9]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:7]=2)[CH:3]=[N:2]1.[CH3:27]C1NN=CC=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[CH3:27][C:5]1[C:4]([C:6]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[CH:9]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:7]=2)=[CH:3][NH:2][N:1]=1
Reactant: c1cn2c(-c3cn[nH]c3)nc(-c3ccc(N4CCOCC4)cc3)cc2n1
Reactant: Cc1[nH]ncc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1n[nH]cc1-c1nc(-c2ccc(N3CCOCC3)cc2)cc2nccn12
Temperature: 100 °C
Yield: 48.1 %

Procedure:
4-(4-(5-Chloroimidazo[1,2-c]pyrimidin-7-yl)phenyl) morpholine (Example 113, Step D) (0.120 g, 0.381 mmol), 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.119 g, 0.572 mmol) and potassium carbonate (0.158 g, 1.144 mmol) were suspended in a mixture of DME (5 mL) and water (2 mL) and de-gassed with Ar(g). Tetrakis(triphenylphosphine)palladium (0) (0.0220 g, 0.0191 mmol) was added and the reaction sealed and heated at 100° C. for 4 hours. The reaction mixture was diluted with water and filtered. The solids were washed with acetone and dried under high vacuum to afford 4-(4-(5-(3-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-7-yl)phenyl)morpholine (0.0660 g, 0.1831 mmol, 48.0% yield). MS (apci) m/z=361.1 (M+H).
Reaction SMILES: [C:1]([C:4](=[C:9]([NH2:14])[C:10]([F:13])([F:12])[F:11])[C:5]([O:7][CH3:8])=[O:6])(=[O:3])[CH3:2].[C:15](OC(=O)C)(=O)C.C(OC)(OC)OC.[H-].[Na+]>COCCOC>[OH:3][C:1]1[CH:2]=[CH:15][N:14]=[C:9]([C:10]([F:12])([F:13])[F:11])[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C(C(C)=O)=C(N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: COC(OC)OC
Product: COC(=O)c1c(O)ccnc1C(F)(F)F
Temperature: 27.5 °C
Reaction time: 18 h
Yield: 18.5 %

Procedure:
A mixture of 105 g (0.5 mol) of methyl 2-acetyl-3-amino-4,4,4-trifluoro-2-butenoate (example 2 of U.S. Pat. No. 4,655,816), acetic anhydride (152 g), and trimethyl orthoformate (106 g) was held at reflux for 16 h then distilled to remove low boiling material (bp 65-90° C.). The remaining material was concentrated in vacuo and the residue was kugelrohr distilled at 2 torr (80-120° C.) to give 114 g of distillate. This distillate (44 g) was added dropwise to a mixture of 14.5 g of 60% sodium hydride oil dispersion in 100 ml of 1,2-dimethoxyethane (DME). The reaction mixture was maintained at 25-30° C. with an ice-water bath. The reaction mixture was stirred at room temperature for 18 h and poured into 300 ml of ice-water. The aqueous layer was extracted with ether and filtered. The aqueous layer was acidified with concentrated HCl. The oil precipitate was extracted into ether. The ether extract was extracted with 10% potassium carbonate. The potassium carbonate layer was acidified with concentrated HCl. The precipitate was filtered and air dried to give 20.4 g of the product, mp 78-82° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[N:21]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[N:25][C:20]2=[N:19][CH:18]=1)CCC>>[F:28][C:26]([F:27])([F:29])[C:24]1[CH:23]=[CH:22][N:21]2[C:17]([C:2]3[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][CH:3]=3)=[CH:18][N:19]=[C:20]2[N:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: CC(=O)Nc1cccc(Br)n1
Product: CC(=O)Nc1cccc(-c2cnc3nc(C(F)(F)F)ccn23)n1
Yield: 2.8 %

Procedure:
N-(6-Bromopyridin-2-yl)acetamide (0.33 g, 1.56 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.6 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with ethyl acetate on a gradient of methanol (0-5%) gave N-[6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]acetamide (14 mg) as an off-white solid: δH (400 MHz, DMSO) 2.19 (3H, s), 7.60 (1H, d, J 7), 7.85 (1H, d, J 7), 7.92 (1H, dd, J 8 and 8), 7.97 (1H, d, J 8), 8.90 (1H, s), 10.65 (1H, s), 10.75 (1H, d, J 7); m/z (ES+) 321 (M++H).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([Br:17])=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1.Br[CH2:19][CH2:20][CH2:21]Br>CS(C)=O.O>[Br:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([Br:17])=[CH:11][CH:12]=3)[C:7]3([CH2:21][CH2:20][CH2:19]3)[C:6]=2[CH:5]=1
Reactant: BrCCCBr
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Brc1ccc2c(c1)C1(CCC1)c1cc(Br)ccc1-2
Reaction time: 120 h

Procedure:
Powdered KOH (983 mg, 17.5 mmol) was added in batches over 1 minute to a heterogeneous mixture of 2,7-dibromo-9H-fluorene (1.31 g, 4.04 mmol) and 1,3-dibromopropane (837 mg, 4.15 mmol) in DMSO (20 mL), and stirred at ambient condition for ˜5 days. The mixture was diluted with water (200 mL) and extracted with 10% CH2Cl2/hexanes (100 mL, 2×). The combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resulting crude material was purified with a column chromatography (sample was loaded as a silica gel mesh; hexanes, with gravity elution) to afford 2′,7′-dibromospiro[cyclobutane-1,9′-fluorene] as a white fluffy solid (600 mg). 1H NMR (CDCl3, δ=7.24, 400 MHz): 7.86 (d, J=1.8, 2H), 7.48 (d, J=8.0, 2H), 7.44 (dd, J=8.1, 1.8, 2H), 2.61 (app t, J=8.1, 4H), 2.42-2.34 (m, 2H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:33])[C:13]([CH2:23][NH:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:14][N:15]3[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][C:9]=2[F:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>N1C=CC=CC=1>[C:35]([N:24]([CH2:23][C:13]1[C:12](=[O:33])[C:11]2[C:16](=[CH:17][C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:9]([F:34])[CH:10]=2)[N:15]([CH:18]([CH2:19][CH3:20])[CH2:21][CH3:22])[CH:14]=1)[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CCCNCc1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Solvent: c1ccncc1
Product: CCOC(=O)CCCN(Cc1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
170 mg of ethyl 4-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]methyl}amino)butanoate was dissolved in 2.0 ml of pyridine, and 0.040 ml of acetic anhydride was added, followed by overnight stirring at room temperature. After concentrating the reaction mixture under a reduced pressure, water was added to the resulting residue, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then filtered and concentrated under a reduced pressure. By purifying the resulting residue by silica gel column chromatography, 165 mg of ethyl 4-(acetyl{[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]methyl}amino)butanoate was obtained.