Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C@:4]1([CH3:23])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38].C(OCC)(=O)C>C(#N)C.O>[NH2:1][C:2]([C@:4]1([CH3:23])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[F:38])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3]
Reactant: Fc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@@]1(C)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3F)cc2)CC[C@@]1(C)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of 1,1-dimethylethyl(2S,5R)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-2-methyl-1-pyrrolidinecarboxylate (300 mg, 0.936 mmol) and potassium carbonate (194 mg, 1.4 mmol) in acetonitrile (4 ml) was added 1-(bromomethyl)-2-fluorobenzene (Sigma Aldrich Ltd.) (170 μl, 1.4 mmol) and the mixture was stirred overnight at room temperature. After the reaction was finished, as shown by TLC, ethyl acetate and water were added. The organic phase was then washed with brine, dried, filtered and evaporated. The crude material was purified by chromatography on silica gel using cyclohexane/ethyl acetate (8:2 to 7:3) to afford the title compound (306 mg, 72%); Rt (HPLC): 5.88 min; Rf (cyclohexane:ethyl acetate=1:1): 0.51; 1H NMR (300 MHz, DMSO-d6) δ(ppm): 7.60-7.49 (t, 2H); 7.46-7.32 (m, 2H); 7.29-7.15 (m, 3H); 7.13-7.02 (m, 1H); 6.98-6.88 (m, 2H); 5.11 (s, 2H); 4.87-4.62 (m, 1H); 2.41-2.16 (m, 2H); 1.78-1.64 (m, 1H); 1.64-1.56 (m, 1H); 1.52 (s, 3H); 1.32 and 1.03 (s, s, 9H).
Reaction SMILES: [C:1]([N-:5][CH:6]=[CH:7][N-:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[Li+].[Li+].[Li].Cl[SiH:17](Cl)Cl.[O-:20][C:21]#[N:22].[Na+]>CCCCCC.O1CCCC1>[C:9]([N:8]1[CH:7]=[CH:6][N:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[SiH:17]1[N:22]=[C:21]=[O:20])([CH3:12])([CH3:11])[CH3:10]
Reactant: N#C[O-]
Reactant: Cl[SiH](Cl)Cl
Reactant: CC(C)(C)[N-]C=C[N-]C(C)(C)C
Agent: [Li+]
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1N=C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
In an argon atmosphere, a dilithium(N,N′-di-tert-butyl-1,2-vinylenediaminide) solution prepared by using 32.16 g of tBuNCHCHNtBu, 250 mL of tetrahydrofuran and 2.67 g of lithium according to the procedure described in Reference Example-9 was added to a hexane (30 mL) solution containing 25.12 g (185.5 mmol) of trichlorosilane, and the mixture was stirred at room temperature for 3 hours. To this reaction mixture, 14.47 g (purity: 96%, 213.7 mmol) of sodium cyanate was added, and the mixture was stirred for 4 hours under heating an refluxing. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 85° C./3.3×102 Pa) to obtain 1,3-di-tert-butyl-2-isocyanato-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NCO) as a colorless liquid (yielded amount: 35.44 g, yield: 80%). The thus-obtained Si(tBuNCHCHNtBu)(H)NCO was measured for the 1H and 13C NMR spectra, as a result, these spectra agreed with spectra of those obtained in Example-29 and Example-30.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][CH2:12][CH:13]=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1CCC[C@H]1C(O)=O.Cl[N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30].C(Cl)(Cl)[Cl:32]>C(OCC)(=O)C>[Cl:32][CH:12]([CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)[CH:13]([N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30])[OH:14]
Reactant: ClC(Cl)Cl
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=CCCc1ccc2ncccc2c1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCOC(C)=O
Product: O=C1CCC(=O)N1C(O)C(Cl)Cc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
A solution of 3-(quinolin-6-yl)propanal (9, 407 g, 2.2 mol, 1.0 equiv) in chloroform (CHCl3, 1700 mL) was cooled to 0° C. before proline (52 g, 0.44 mol, 0.2 equiv) and N-chlorosuccinimide (NCS, 303 g, 2.31 mol, 1.05 equiv) were added. The resulting reaction mixture was allowed to slowly warm to room temperature (becomes homogeneous) and stirred at room temperature for overnight. The reaction was exothermal to around 40° C. when it reaches room temperature and a precipitate had formed at this point. Once TLC and LC/MS showed that the reaction was deemed complete, the reaction mixture was diluted with ethyl acetate (EtOAc, 1700 mL) and the resulting mixture was cooled to 0° C. The solid was collected by filtration and the collected wet solid cake was placed in a flask and triturated with water (750 mL). The resulting suspension was stirred at room temperature for 30 min before the solids were collected by filtration. The collected solids were washed with water (250 mL) and methyl tert-butyl ether (MTBE, 500 mL) and dried in a vacuum oven at 45° C. to constant weight to afford 1-(2-chloro-1-hydroxy-3-(quinolin-6-yl)propyl)pyrrolidine-2,5-dione (11, 378.7 g, 701.3 g theoretical, 54% yield) as off-white powder. For 11: 1HNMR (DMSO-d6, 400 MHz) δ ppm 8.86 (dd, 1H, J=4.15 Hz, 1.66 Hz), 8.33 (dd, 1H, J=8.51 Hz, 1.04 Hz), 7.98 (d, 1H, J=8.72 Hz), 7.85 (d, 1H, J=1.66 Hz), 7.68 (dd, 1H, J=8.51 Hz, 1.87 Hz), 7.51 (dd, 1H, J=8.29 Hz, 4.15 Hz), 7.36 (d, 1H, J=7.05 Hz), 5.28 (dd, 1H, J=9.54 Hz, 6.85 Hz), 5.07 (dt, 1H, J=9.75 Hz, 2.70 Hz), 3.65 (dd, 1H, J=14.52 Hz, 2.49 Hz), 3.09 (dd, 1H, J=14.52 Hz, 9.75 Hz), 2.64 (s, 4H); C16H15ClN2O3 (MW 318.75), LCMS (EI) m/e 319.2 (M++H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[CH:23]1([NH:26][CH2:27][C@@H:28]2[C@H:32]([F:33])[CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24]1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH2:31][C@@H:32]([F:33])[C@@H:28]([CH2:27][NH:26][CH:23]3[CH2:24][CH2:25]3)[CH2:29]2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:17][CH2:18]1
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1c(N2C[C@H](CNC3CC3)[C@H](F)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 100 °C
Reaction time: 9 h
Yield: 68.6 %

Procedure:
5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (250 mg), (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (190 mg), triethylamine (0.17 mL) and dimethylsulfoxide (4 mL) were mixed together. The mixture was stirred at 100° C. for 9 hours and was subsequently concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane: methanol=40:1). The eluted yellow solid was recrystallized from ethanol to give 5-amino-1-cyclopropyl-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid as yellow crystals (248 mg).
Reaction SMILES: [H-].[Na+].[CH3:3]C(N(C)C)=O.[F:9][C:10]1[CH:28]=[CH:27][C:13]([CH2:14][N:15]2[C:20]3[N:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18](=[O:25])[N:17]=[C:16]2[NH2:26])=[CH:12][CH:11]=1.CI>O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]2[C:20]3[N:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18](=[O:25])[N:17]([CH3:3])[C:16]2=[NH:26])=[CH:27][CH:28]=1
Reactant: CC(=O)N(C)C
Reactant: Nc1nc(=O)c2cccnc2n1Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1c(=O)c2cccnc2n(Cc2ccc(F)cc2)c1=N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.4 g. of sodium hydride in 60 ml. of dimethylacetamide is added 2.5 g. of 1-(4'-fluorobenzyl)-2-amino-pyrido[2,3-d]pyrimidin-4(1H)-one while maintaining the system under nitrogen. After stirring for one hour at room temperature, the mixture is treated by addition of 1.0 ml. of methyliodide. The resulting mixture is stirred at 20°C. for 15 hours. A small amount of water (ca 1.0 ml.) is then added and the mixture evaporated in vacuo. The residue is treated with ice/water and the resulting precipitate is recovered by filtering, washed with water and dried. The dried precipitate is then dissolved in methylene chloride, treated with charcoal and filtered through neutral alumina. The filtrate is concentrated in vacuo and ether added to obtain on crystallization 1-(4'-fluorobenzyl)-2,3-dihydro-2-imino-3-methyl-pyrido[2,3-d]pyrimidin-4(1H)-one
Reaction SMILES: N[C@H:2]([C:11]([O:13]CC=C)=[O:12])[CH2:3][CH2:4][C:5]([O:7]CC=C)=O.ClC(Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC.N[C@H:37]([C:45](O)=O)[CH2:38][C:39]1C=CC=CC=1>C(Cl)Cl>[CH:37]1[CH:45]=[C:4]2[C:5]([C:11]([OH:12])([OH:13])[C:2](=[O:20])[C:3]2=[CH:39][CH:38]=1)=[O:7]
Reactant: C=CCOC(=O)CC[C@H](N)C(=O)OCC=C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)C1(O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of diallyl glutamate (110 mg, 0.42 mmol) and triphosgene (43 mg, 0.14 mmol) in CH2Cl2(4 mL) at −78° C. was added Et3N (180 μL, 1.3 mmol) in CH2Cl2 (0.8 mL). The reaction mixture was allowed to warm to room temperature and stirred for 1.5 h. The phenylalanine derivative (140 mg, 0.251 mmol) in a solution of CH2Cl2 (1 mL) and Et3N (70 μL, 0.5 mmol) was then added at −78° C. and the reaction was stirred at room temperature for 12 h. The solution was diluted with CH2Cl2, washed twice with H2O, dried over MgSO4 (anh.) and purified by column chromatography (Hexane:AcOEt 3:1) to give 100 mg (57%) (TLC in CH2Cl2:MeOH 20:1 Rf=0.3, revealed with ninhydrin and uv light). 1H-NMR (CDCl3, 300 MHz) δ 7.80-6.95 (13H, aromatics, NHFmoc), 5.98-5.82 (m, 3H, 3-CH2CHCH2), 5.54 (bd, 1H, NHurea), 5.43-5.19 (m, 7H, 3-CH2CHCH2, NHurea), 4.85-4.78 (m, 1H, CH(pheala.)), 4.67-4.50 (m, 9H, 3-CH2CHCH2, CH2(Fmoc), CH(glu.)), 4.28 (t, 1H, CH(Fmoc)), 3.05 (d, 2H, CH2(pheala.)), 2.53-2.33 (m, 2H, CH2(glu.)), 2.25-2.11 and 1.98-1.80 (2m, 2H, CH2(glu.)).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[O:7]1[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]1>CS(O)(=O)=O>[C:1]([O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C1=COCCC1
Reactant: C=C(C)C(=O)O
Agent: CS(=O)(=O)O
Product: C=C(C)C(=O)OC1CCCCO1
Yield: 71.9 %

Procedure:
2-Tetrahydropyranyl methacrylate (THPMA) was prepared in an analogous manner to the THF-ester above using 24.5 g (0.29 mol) of methacrylic acid, 25.6 g (0.305 mol) of 4,5-dihydropyran and 0.05 g of methanesulfonic acid to yield 35.5 g (72%) of the desired product after distillation at reduced pressure.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Br:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[N:3]=1.C(OC([N:30]1[C:34]([CH3:35])=[CH:33][C:32]([NH2:36])=[N:31]1)=O)(C)(C)C.CC(O)=O>CC(N(C)C)=O>[Br:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[N:3]=[C:2]2[NH:36][C:32]1[CH:33]=[C:34]([CH3:35])[NH:30][N:31]=1
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3cccc(Br)c3n2)nc1
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(Br)cccc23)n[nH]1
Temperature: 100 °C
Yield: 21.8 %

Procedure:
To 4-chloro-2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-bromo-quinazoline (0.19 g, 0.49 mmol) in DMA (1.0 mL) were added 3-amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (0.30 g, 1.53 mmol) and HOAc (0.065 mL, 1.1 mmol) and the mixture was heated to 100° C. for 5 h. The mixture was allowed to cool to rt and purified by reverse phase HPLC (ammonium acetate modifier). Fraction 1 containing pure product was treated with saturated aq NaHCO3 (2-4 mL) and concentrated under reduced pressure. The aqueous residue was extracted with DCM (3×30 mL) and the combined extracts were washed with sat aqueous NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated to dryness under reduced pressure to afford 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (48 mg, 20%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.22 (br s, 1H), 10.87 (br s, 1H), 8.57-8.81 (m, 2H), 8.24 (d, J=7.5 Hz, 1H), 8.02 (d, J=5.3 Hz, 2H), 7.54 (t, J=7.9 Hz, 1H), 5.95 (s, 1H), 2.17 (s, 3H); LC-MS (ESI) m/z 449/451 (M+H+).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]3)[CH:9]=[N:10][CH:11]=1.[C:24](O)(=[O:27])[CH2:25][CH3:26]>>[CH3:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([C:8]3[CH:7]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:24](=[O:27])[CH2:25][CH3:26])[CH:11]=[N:10][CH:9]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:23]
Reactant: CCC(=O)O
Reactant: CN1C(=O)CCc2cc(-c3cncc(OCCN)c3)ccc21
Agent: Cl
Product: CCC(=O)NCCOc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1

Procedure:
In analogy to the procedure described for the preparation of example 37, 6-[5-(2-amino-ethoxy)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 42) has been reacted with propionic acid to give the title compound as a white solid. MS: 354.3 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([CH2:13][C:14]([CH3:22])([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][C:7]=1[Br:23].CN1CCOCC1.F[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>>[Br:23][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([CH3:22])([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]=[C:11]([F:12])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: Fc1ccccn1
Reactant: CCOC(=O)CC(C)(C)Cc1cc(F)c(OCCCN)c(Br)c1
Solvent: CN1CCOCC1
Product: CCOC(=O)CC(C)(C)Cc1cc(F)c(OCCCNc2ccccn2)c(Br)c1
Temperature: 115 °C

Procedure:
A mixture of the product of STEP 8 (0.725 g, 1.24 mmol), 4-methylmorpholine (1.01 g, 10 mmol), and 2-fluoropyridine (10 ml) was heated at 115° C. for 18 h under N2. The cooled reaction was concentrated. The residue was purified by chromatography (on silica gel, CH2Cl2/CH3OH/NH4OH=97/2/1) to give a brown oil in 0.251 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: C1([C@]2(O)[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])[CH3:10])CC1.[F:13][C:14]1[C:21]([CH3:22])=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].[C:24](=[O:27])([O-])[O-].[Li+].[Li+]>>[F:13][C:14]1[C:21]([CH3:22])=[C:20]([N:6]2[CH2:5][C:9]([CH3:11])([CH3:10])[C@H:24]([OH:27])[C@H:7]2[CH3:8])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: Cc1c(F)ccc(C#N)c1F
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: O=C([O-])[O-]
Agent: [Li+]
Product: Cc1c(N2CC(C)(C)[C@H](O)[C@H]2C)ccc(C#N)c1F

Procedure:
By an operation in the same manner as in Example 53 and using (2RS,3SR)-2,4,4-trimethylpyrrolidin-3-ol 0.5 oxalate (214 mg), 2,4-difluoro-3-methylbenzonitrile (240 mg) and lithium carbonate (246 mg), the title compound was obtained as a colorless solid (yield: 112 mg, yield: 35%).
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30].S.[OH-].[Na+]>C(O)C.C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[S:30][C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])=[CH:9][C:8]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)CC(C(=O)c2ccccc2)c2ccccc2)c(OC)c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)c(OC)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
In a 1-l stainless steel autoclave were placed 56.2 g (0.150 mole) of 1,2-diphenyl-4-(2,4-dimethoxyphenyl)butane-1,4-dione, 100 ml of xylene, 33.3 g (0.075 mole) of phosphorus pentasulfide and 120 g of hydrogen sulfide. The contents of the autoclave were stirred at 160°-162° C. (1040-1080 psig) for three hours. The autoclave was then cooled, and the remaining hydrogen sulfide was vented into a trap of aqueous sodium hydroxide. The residue was stirred with 150 ml of absolute ethanol to destroy excess phosphorus pentasulfide. Chilling to -78° C. and filtration gave 27.6 g (49.4%) of crude product, m.p. 107°-110° C. Recrystallization from 30 ml of dioxane and 60 mll of ethanol gave 17.3 g (31%) of pure 2,3-diphenyl-5-(2,4-dimethoxyphenyl)thiophene, m.p. 112°-114° C.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][C:14]=2[F:24])[N:5]=1)(=O)[CH3:2].[CH3:25]C(O)=O.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][NH2:37]>COC(OC)N(C)C>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[C:1]([C:4]2[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][C:14]=3[F:24])[N:5]=2)=[CH:2][CH:25]=[N:37]1
Reactant: NNc1ccccc1F
Reactant: CC(=O)O
Reactant: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(C)=O)c1=O
Agent: COC(OC)N(C)C
Product: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(-c2ccnn2-c2ccccc2F)c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A suspension of 3-acetyl-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxypyridazin-4(1H)-one (197 mg, 0.600 mmol) in N,N-dimethylformamide dimethyl acetal (2.0 mL) was stirred at 100° C. for 1 h. The reaction mixture was concentrated in vacuo. To the residue were added AcOH (2.0 mL) and 2-fluorophenylhydrazine (151 mg, 1.20 mmol). The mixture was stirred at 100° C. for 1 h. After solvent evaporated, the residue was diluted with saturated NaHCO3 aqueous solution (25 mL) and extracted with AcOEt (25 mL×3). The combined organic phase was washed with brine (40 mL), dried with MgSO4, and evaporated. The residue was crystallized from AcOEt to give a coarse solid, which was recrystallized from EtOH/hexane to give the title compound (125 mg, 47% yield) as a white solid: mp 202-206° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 3.79 (3H, s), 6.64 (1H, d, J=1.9 Hz), 6.96 (1H, t, J=8.5 Hz), 7.23-7.33 (3H, m), 7.41-7.53 (2H, m), 7.71 (1H, d, J=9.1 Hz), 7.84 (2H, dd, J=4.0, 1.7 Hz), 7.94 (1H, dd, J=12.3, 2.5 Hz), 8.48 (1H, d, J=1.9 Hz), 8.65 (1H, d, J=2.6 Hz). LC-MS (ESI) m/z 447 [M+H]+. Anal. Calcd for C23H16F2N6O2.0.4H2O: C, 60.90; H, 3.73; N, 18.53. Found: C, 60.68; H, 3.69; N, 18.39.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:11][CH2:10][CH2:9][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cccc(CCO)n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CCOS(=O)(=O)c2ccc(C)cc2)n1

Procedure:
A solution of 2-(6-methoxypyridin-2-yl)ethanol (0.23 g, 1.50 mmol), 4-dimethylaminopyridine (0.028 g, 0.23 mmol), triethylamine (0.63 mL, 4.50 mmol) and p-toluenesulfonyl chloride (0.34 g, 1.80 mmol) in dry dichloromethane (5 mL) was stirred at rt over night. The solvent was removed in vacuo. Ethyl acetate and water were added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (Na2SO4) and concentrated. The product was purified by flash chromatography (SiO2; heptane/EtOAc, gradient 0-100%). Yield: 0.18 g (38%).
Reaction SMILES: [OH:1][C:2]12[C:14](=[O:15])[C:10](=[CH:11][CH2:12][CH2:13]1)[CH:9]([OH:16])[C:8]#[C:7][CH:6]=[CH:5][C:4]#[C:3]2.CN(C1C=CC=CN=1)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:16][CH:9]1[C:10]2[C:14](=[O:15])[C:2]([OH:1])([CH2:13][CH2:12][CH:11]=2)[C:3]#[C:4][CH:5]=[CH:6][C:7]#[C:8]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C2=CCCC1(O)C#CC=CC#CC2O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CC(=O)OC1C#CC=CC#CC2(O)CCC=C1C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of 1,8-dihydroxy-bicyclo[7.3.1]-trideca-4,9-diene-2,6-diyn-13-one (product of Example 4, 32 mg, 0.149 mmol) in 1 ml of pyridine was added dimethylaminopyridine and 1 eq of acetic anhydride (14 ul, 0.149 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and then pyridine was stripped off on rotovap and on high vacuum. This residue was purified on a silica gel column using 10% and 20% ethyl acetate/hexane mixture as the solvent system. The title compound was obtained as light yellow foam in 85% yield (32.4 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[C:30]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]([NH2:36])=[CH:32][CH:33]=[CH:34][CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO.CN(C=O)C>[C:30]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:24]([C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][C:10]3[O:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[C:12]([C:13]([NH:14][CH3:15])=[O:16])[C:11]=3[CH:17]=2)[CH:29]=[CH:28][CH:27]=1)=[O:25]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: Nc1ccccc1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)Nc4ccccc4-c4ccccc4)c3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
In a 1 dram vial were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (30 mg, 0.077 mmol), biphenyl-2-amine (17 mg, 0.10 mmol), and HATU (40 mg, 0.105 mmol). DMF (0.4 mL) and DIPEA (50 μL, 0.29 mmol) were added, and the vial was capped and stirred at r.t. for overnight, then diluted with MeOH, filtered, and purified directly by prep HPLC. Concentration afforded the title compound (17 mg, 41% yield) as a fluffy white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.96 (s, 1H) 8.53 (q, J=4.58 Hz, 1H) 7.96-8.06 (m, 3H) 7.85-7.91 (m, 2H) 7.80 (d, J=8.55 Hz, 1H) 7.77 (d, J=7.32 Hz, 1H) 7.70 (dd, J=8.55, 1.83 Hz, 1H) 7.57-7.61 (m, 1H) 7.56 (d, J=6.10 Hz, 1H) 7.48 (d, J=7.32 Hz, 2H) 7.36-7.46 (m, 7H) 7.31 (t, J=7.48 Hz, 1H) 2.87 (d, J=4.88 Hz, 3H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10%
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[Br:12]Br.[BrH:14]>O>[BrH:12].[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:14])[CH:9]=2)[CH2:4]1
Reactant: BrBr
Reactant: NC1Cc2ccccc2C1
Agent: Br
Agent: Cl
Solvent: O
Product: NC1Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 2-amino-2,3-dihydro-1H-indene hydrochloride salt (10.0 g, 58.9 mmol) in water (50 mL) was warmed to 60° C. Next, bromine was added dropwise (3.50 mL, 67.9 mmol) over a 50 min period. Stirred for 1 hour, cooled to RT, stirred 1 hour, treated with 5 mL of 48% HBr (aq) and filtered. The residue was dried in a vacuum oven overnight (40° C.) to give 2-amino-5-bromo-2,3-dihydro-1H-indene hydrobromide salt (14.5 g, 84% yield) as a single isomer: 1H NMR (600 MHz, DMSO-d6) δ 8.08 (br s, 3H), 7.47 (s, 1H), 7.35 (dd, J=7.9, 0.9 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 3.97 (br s, 1H), 3.18-3.26 (m, 2H), 2.85-2.94 (m, 2H).