Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[NH:15]1[C:19]([CH2:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)=[N:18][N:17]=[N:16]1.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[NH:18]1[C:19]([CH2:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]3[NH:6][C:4](=[O:5])[C:3]4[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=4[O:13][CH3:14])[N:1]=3)=[CH:23][CH:22]=2)=[N:15][N:16]=[N:17]1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1ccc(Cc2nnn[nH]2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(Cc4nnn[nH]4)cc3)nc2c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
IBX (0.437 g, 1.562 mmol) was dissolved in anhydrous DMSO (5 mL) and [4-(1H-tetrazol-5-ylmethyl)-phenyl]-methanol (0.270 g, 1.562 mmol) was added. The reaction mixture was stirred at room temperature under nitrogen for 4 hours. Water (20 mL) was added. The white precipitate was filtered off, washed with water, and dried under vacuum. The crude compound was mixed with methanol (20 mL) and stirred for 30 minutes, before being filtered. The filtrate was concentrated to give 4-(1H-tetrazol-5-ylmethyl)-benzaldehyde as a white solid. Yield: 0.267 g (99%). To a solution of 2-amino-4,6-dimethoxybenzamide (0.157 g, 0.8 mmol) in N,N-dimethyl acetamide (5 mL) were added 4-(1H-tetrazol-5-ylmethyl)-benzaldehyde (0.260 g, 1.4 mmol), sodium hydrogen sulfite (58.5%, 0.159 g, 0.88 mmol) and p-toluenesulfonic acid (19 mg, 0.08 mmol). The reaction mixture was stirred at 150° C. for 3 h, then cooled to room temperature. Water (40 mL) was then added. A yellow precipitate was formed and filtered off, washed with water, and small amount of methanol. It was triturated with 10% methanol in ether to give 0.107 g of solid, which was further purified by preparative HPLC, to give the title compound (0.082 g, 28%) as a white solid. MS (ES) m/z: 365.1 (M+1). MP 295-296° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23].C1C=C(Cl)C=C(C(OO)=[O:34])C=1>>[CH3:25][CH:2]([CH3:1])[CH2:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:13]([O-:34])=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)CC(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCC(=O)CC(C)C

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 6-methyl-1-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)heptan-4-one (2.40 g, 7.10 mmol) by reaction with m-CPBA (3.9 g) to provide 6-methyl-1-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)heptan-4-one followed by reaction with p-toluenesulfonyl chloride (2.0 g, 10.5 mmol) and ammonium hydroxide solution (75 mL) to provide 1-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-6-methylheptan-4-one as tan crystals after recrystallization from aqueous methanol, mp 136-138° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([Li])[CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-:17].[Cl-].[Cl-].[Cl-].[Zr+4:21]>O1CCCC1.C1(C)C=CC=CC=1.ClCCl>[Cl-:17].[Cl-:17].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([Zr+2:21][C:11]3([C:8]4[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=4)[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]C1(c2ccc(C(C)(C)C)cc2)C=CC=C1
Reactant: [Zr+4]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C2([Zr+2]C3(c4ccc(C(C)(C)C)cc4)C=CC=C3)C=CC=C2)cc1
Reaction time: 2 h

Procedure:
A solution of 1.2 g of 4-t-butylphenylcyclopentadienyllithium (0.0059 mole) in 20 ml tetrahydrofuran was slowly added at room temperature to a solution of 0.685 g of zirconium tetrachloride (0.0029 mole) in 50 ml tetrahydrofuran. After stirring the solution for 2 hours, the tetrahydrofuran was removed by evaporation leaving a residue. The resulting residue was taken up in hot toluene. Any undissolved material was removed by filtration and a resultant clear solution was evaporated to dryness. The solid residue obtained from the evaporation to dryness was taken up in dichloromethane. Undissolved, off-white solids were removed by centrifugation and decantation. The clear solution was once again evaporated to dryness yielding bis[(4-t-butylphenyl)cyclopentadienyl]zirconium dichloride as a yellow solid material. Spectral data from a proton-NMR is consistent with the product obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1CN.[CH:20]([N:23](CC)C(C)C)(C)C.CS(C)=O>O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:23][CH2:20][CH:15]2[CH2:14][CH2:13][O:12][CH2:17][CH2:16]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: NCC1CCCCO1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1NCC1CCOCC1
Temperature: 25 °C

Procedure:
2-Fluoro-5-chloronitrobenzene (0.762 g; 4.341 mmol), tetrahydropyran methyl amine (0.5 g; 4.341 mmol), N,N-diisopropylethylamine (0.756 mL; 4.341 mmol) and dimethylsulfoxide (2 mL) are heated at 80° C. in an oil bath for 4 days. After this time the reaction is cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organics are washed with water and brine and concentrated in vacuo to afford title compound as an orange oil which solidified upon standing and was used crude in subsequent reactions. ESI m/z 271 [M+H]+
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH:10]2[O:19][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[O:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:20]1[CH2:22][CH:21]1[CH2:23][N:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30]>CO>[O:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[O:19][CH:10]([CH2:9][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:22][CH:21]([OH:20])[CH2:23][N:24]2[CH2:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])[CH2:11]1
Reactant: c1ccc(CNCC2COc3cccnc3O2)cc1
Reactant: O=C1CN(CC2CO2)C(=O)N1
Solvent: CO
Product: O=C1CN(CC(O)CN(Cc2ccccc2)CC2COc3cccnc3O2)C(=O)N1
Yield: 62.9 %

Procedure:
A mixture of 2,3-dihydro-N-(phenylmethyl)-1,4-dioxino[2,3-b]pyridine-3-methanamine (0.0059 mol) and intermediate (18) (0.00497 mol) in methanol (30 ml) was stirred and refluxed overnight. The solvent was evaporated. The residue was purified by short open column chromatography over silica gel (eluent: CH2Cl2/2-propanone 96/4, 90/10 and 80/20), then CH2Cl2/CH3OH 96/4 and 90/10). The product fractions were collected and the solvent was evaporated, yielding 1.29 g of (±)-1-[3-[[(2,3-dihydro-1,4-dioxino-[2,3-b]pyridin-3-yl)methyl](phenylmethyl)amino]-2-hydroxypropyl]-2,4-imidazolidine-dione (compound 12).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][CH:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13].C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C.O1C2C=CC=CC=2C=CN1>O>[Cl:1][C:2]1[C:3]([F:13])=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:24]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17](=[O:16])[C:11]([CH:12]=1)=[C:5]23
Reactant: CC1COc2c(ccc(Cl)c2F)N1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: C1=Cc2ccccc2ON1
Solvent: O
Product: CCOC(=O)c1cn2c3c(c(F)c(Cl)cc3c1=O)OCC2C
Reaction time: 2 h
Yield: 67 %

Procedure:
A mixture of 1.11 g (5.5 mmols) of 7-chloro-8-fluoro-3-methyl-2,3-dihydro-4H-1,4-benzoxazine and 1.4 g (6.2 mmols) of diethyl ethoxymethylenemalonate was stirred for 2 hours while heating at 130°-140° C. (bath temperature). After confirming disappearance of the starting benzoxazine compound by thin-layer chromatography, 5 g of ethyl polyphosphate was added to the reaction mixture and the mixture was again allowed to react for 1 hour at 140° C. (bath temperature). After cooling, 20 ml of water was added to the mixture and the precipitate formed was extracted with 150 ml of chloroform. The chloroform extract was dried with sodium sulfate and chloroform was then distilled off. The resulting residue was purified by silica gel (20 g) column chromatography using methanol-chloroform (5:95 by volume) as an eluant to provide 1.2 g (67.0% yield) of ethyl 9-chloro-10-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate with m.p. 263°-264° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[C:12](NC1C=CC(C(O)=O)=CC=1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:12]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Product: Cc1cc(C(=O)O)ccc1NC(=O)OC(C)(C)C

Procedure:
4-amino-3-methylbenzoic acid (5 g, 33.1 mmol) was reacted according to the same procedure as N-BOC-4-aminobenzoic acid. The orange-brown solid was recrystallized from ethyl acetate and hexanes to yield 4.99 g (60%) of tan prismatic crystals. mp 180-182° C.; 1H NMR (CD3OD) 1.51 (9 H, s), 2.27 (3 H, s), 7.66 (1 H, d, J=8.1 Hz), 7.79-7.82 (2 H, m), 8.32 (1 H, s); 13C NMR (CD3OD) 17.98, 28.62, 81.47, 123.12, 127.05, 129.14, 130.65, 132.99, 142.45, 155.33, 168.70; anal calc for C13 H17NO4, C: 62.15, H: 6.82, N: 5.58; found C: 62.07, H: 6.86, N: 5.46; m/ z (EI) 251; HRMS calc. for C13H17NO4, 251.1158; found, 251.1153.
Reaction SMILES: C([O:8][C:9](=[O:47])[CH2:10][N:11]([C:18](=[O:46])[C@H:19]([CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:45])[NH2:44])[N:20]([N+:36]([O-])=O)[S:21]([C:24]1[C:33]2[C:28](=[CH:29][C:30]([CH3:35])=[C:31]([CH3:34])[CH:32]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH2:12][CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1)C1C=CC=CC=1.[H][H]>C(O)(C)(C)C.C(O)(=O)C.[Pd]>[N:20]#[N:36].[CH3:35][C:30]1[CH:29]=[C:28]2[C:33](=[CH:32][C:31]=1[CH3:34])[C:24]([S:21]([NH:20][C@H:19]([C:18]([N:11]([CH2:12][CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1)[CH2:10][C:9]([OH:47])=[O:8])=[O:46])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:44])[NH2:45])(=[O:23])=[O:22])=[CH:25][CH:26]=[CH:27]2
Reactant: Cc1cc2cccc(S(=O)(=O)N([C@@H](CCCNC(=N)N)C(=O)N(CC(=O)OCc3ccccc3)CC3CCCO3)[N+](=O)[O-])c2cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: Cc1cc2cccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N(CC(=O)O)CC3CCCO3)c2cc1C
Product: N#N

Procedure:
To a solution of 1.2 g of NG -nitro-N2 -(6,7-dimethyl-1-naphthalenesulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine benzyl ester in 20 ml of tert-butanol and 5 ml of acetic acid, was added 0.2 g of palladium black and then the mixture was shaken in a hydrogen atmosphere for 20 hours at room temperature. The solution was filtered to remove the catalyst and evaporated to give an oily product. Reprecipitation with ethanol-diethyl ether gave 0.8 g of N2 -(6,7-dimethyl-1-naphthalenesulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine.
Reaction SMILES: [Cl:1][C:2]1[N:3](/[N:13]=C/C2C=CC(Cl)=CC=2)[CH:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1.O.NN>COCCO>[Cl:1][C:2]1[N:3]([NH2:13])[CH:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1
Reactant: Clc1ccc(/C=N/n2cc(-c3cccnc3)nc2Cl)cc1
Agent: NN
Solvent: O
Solvent: COCCO
Product: Nn1cc(-c2cccnc2)nc1Cl
Temperature: 130 °C
Yield: 77.9 %

Procedure:
To a solution of E-2-Chloro-N-(4-chlorobenzylidene)-4-(pyridin-3-yl)-1H-imidazol-1-amine (210 mg, 0.66 mmol) in 2-methoxyethanol (5 mL) was added 80% hydrazine hydrate (0.5 mL). The reaction mixture was heated to 130° C. for 1 hour and then the reaction mixture was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give the title compound (100 mg, 78%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 8.50-8.49 (m, 1H), 8.06-8.03 (m, 1H), 7.43 (s, 1H), 7.34-7.30 (m, 1H), 4.87 (br, 2H); ESIMS m/z 195 [(M+H)]+.
Reaction SMILES: C(N(CC)C(CCCC(NF)C)CC)C.CCN([C:21]1[CH:26]=[CH:25][C:24]2[C:27]3([C:37]4[CH:43]=[C:42](Cl)[CH:41]=[CH:40][C:38]=4[O:39][C:23]=2[CH:22]=1)OC(=O)C1C3=CC=CC=1)CC>>[CH:43]1[C:37]2[CH2:27][C:24]3[C:23](=[CH:22][CH:21]=[CH:26][CH:25]=3)[O:39][C:38]=2[CH:40]=[CH:41][CH:42]=1
Reactant: CCN(CC)c1ccc2c(c1)Oc1ccc(Cl)cc1C21OC(=O)c2ccccc21
Agent: CCC(CCCC(C)NF)N(CC)CC
Product: c1ccc2c(c1)Cc1ccccc1O2

Procedure:
Rhodamin B anilinolactam, Rhodamin B-p-chloroanilinolactam, 3-diethylamino-7-dibenzylaminofluoran, 3-diethylamino-7-octylaminofluoran, 3-diethylamino-7-phenylfluoran, 3-diethylamino-7-phenoxyfluoran, 3-diethylamino-7-chlorofluoran, 3-diethylamino-6-chloro-7-methylfluoran, 3-diethylamino-7-(3,4-dichloroanilino)fluoran, 3-diethylamino-7-(2-chloroanilino)fluoran, 3-diethylamino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-tolyl)amino-6-methyl-7-phenethylfluoran, 3-diethylamino-7-(4-nitroanilino)fluoran, 3-dibutylamino-6-methyl-7-anilinofluoran, 3-(N-methyl-N-propyl)amino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-isoamyl)amino-6-methyl-7-anilinofluoran, 3-(N-methyl-N-cyclohexyl)amino-6-methyl-7-anilinofluoran, 3-(N-ethyl-N-tetrahydrofuryl)amino-6-methyl-7-anilinofluoran, etc.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:22]2[CH2:24][CH2:23]2)=[N:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:7][C:8]=1[CH2:9][O:10][CH3:11].[CH2:25]([O:27][C:28](=[O:41])[C:29]([O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][C:34]=1[CH3:40])([CH3:31])[CH3:30])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:25]([O:27][C:28](=[O:41])[C:29]([O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:2][C:3]2[C:4]([CH:22]3[CH2:24][CH2:23]3)=[N:5][C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:7][C:8]=2[CH2:9][O:10][CH3:11])=[CH:35][C:34]=1[CH3:40])([CH3:30])[CH3:31])[CH3:26]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C2CC2)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(COC)nc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C

Procedure:
A solution of 200 mg (0.56 mmol) 5-chloromethyl-4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 113H]), 134 mg (0.56 mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 237 mg (0.73 mmol) cesium carbonate in 3 ml DMF was stirred for 3 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. After purification of the crude product by chromatography over silica gel with AcOEt/heptane 1:3, 257 mg of pure 2-{4-[4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy-2-methyl-propionic acid ethyl ester could be isolated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[CH:10]([CH2:23]C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C1C[O:34]CC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[CH:10]([CH2:23][OH:34])[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCC1CN(C(=O)OC(C)(C)C)CCC1n1ccc2ccccc21
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CCC(n2ccc3ccccc32)C(CO)C1
Temperature: 25 °C
Yield: 45.2 %

Procedure:
Dissolve 1-(1-tert-Butoxycarbonyl-3-ethyl-piperidin-4-yl)-1H-indole (2.86 g, 7.7 mmol) in TIP (25 ml) and stir at ambient temperature. Add a 1M solution of lithium aluminum hydride in THF (8.5 ml, 8.5 mmol) dropwise via syringe. Stir for two hours, then quench with 0.34 ml water, 0.26 ml 5N sodium hydroxide, and 1.2 ml water. Filter through a pad of Celite®, concentrate to an oil. Purify by flash chromatography to yield the title compound (1.15 g, 45%). ES (M++1): 275.1
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[I:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:15])=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: COc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)c2ccc(I)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
To commercially available nitromethane (10 ml) were added commercially available anisole (1.08 g), commercially available 4-iodobenzoyl chloride (2.67 g) and commercially available ytterbium(III) trifluoromethanesulfonate (620 mg), and the admixture was stirred at 60° C. overnight. The reaction mixture was partitioned between water and chloroform, and the chloroform layer was then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate to obtain 722 mg of the title compound (yield: 21%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:16]1[N:17]([CH3:30])[C:18](=[O:29])[CH:19]=[C:20]([C:22]2[C:27]([F:28])=[CH:26][N:25]=[CH:24][N:23]=2)[N:21]=1.C(N(CC)CC)C.Cl>O1CCCC1>[F:28][C:27]1[C:22]([C:20]2[N:21]=[C:16]([N:11]3[CH2:12][CH2:13][O:14][C@@H:9]([C:6]4[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=4)[CH2:10]3)[N:17]([CH3:30])[C:18](=[O:29])[CH:19]=2)=[N:23][CH:24]=[N:25][CH:26]=1
Reactant: Cn1c(Cl)nc(-c2ncncc2F)cc1=O
Reactant: Fc1ccc([C@H]2CNCCO2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCO[C@@H](c3ccc(F)cc3)C2)nc(-c2ncncc2F)cc1=O
Reaction time: 8 h
Yield: 78 %

Procedure:
To a mixture of (S)-2-(4-fluorophenyl)-morpholine hydrochloride (0.19 g, 0.87 mmol; This compound was synthesized according to WO2007/011065) and 2-chloro-5′-fluoro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (intermediate 1, 0.20 g, 0.83 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.35 mL, 2.5 mmol) at room temperature. The reaction mixture was stirred for 8 hours and poured into 1N hydrochloric acid. Extraction with chloroform was performed and the organic phase was dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure and the residue was crystallized from ethanol to afford (S)-5′-fluoro-2-[2-(4-fluoro-phenyl)-morpholin-4-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (0.25 g, 0.65 mmol, 78%) as colorless crystalline.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][C:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[C:30]([O:32]CC)=[O:31])=[O:22])[CH2:13][CH2:12]1.[OH-].[Na+].Cl>CC(O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][C:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[C:30]([OH:32])=[O:31])=[O:22])[CH2:13][CH2:12]1
Reactant: CCOC(=O)C1=C(NC(=O)CCCCN2CCN(c3ccc4ccccc4n3)CC2)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(CCCCN1CCN(c2ccc3ccccc3n2)CC1)NC1=C(C(=O)O)CCCC1
Yield: 83.5 %

Procedure:
In 725 ml of 2-propanol and 365 ml of distilled water, 168.0 g of ethyl 2-[5-(4-quinolin-2-ylpiperazin-1-yl)pentanoylamino]cyclohex-1-enecarboxylate as synthesized in above Step 7-1-D was suspended. To the suspension 580 ml of 1N-aqueous sodium hydroxide was added and heated under reflux for 1.5 hours. After cooling, the reaction mixture was neutralized with 2N-hydrochloric acid. Whereupon precipitated crystals were recovered by filtration and dried to provide 131.8 g (83.4%) of 2-[5-(4-quinolin-2-ylpiperazin-1-yl)pentanoylamino]cyclohex-1-enecarboxylic acid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.N1(C/C=C/CO)CCCC1.[Cl:23]N([C:32]1[C:41]2[C:36](=[CH:37][C:38](O)=[C:39](OC)[CH:40]=2)[N:35]=[CH:34][N:33]=1)C1C=CC=CC=1F.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[ClH:23].[N:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[N:33][CH:34]=1
Reactant: COc1cc2c(N(Cl)c3ccccc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: OC/C=C/CN1CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cl
Product: c1ccc2ncncc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 108 %

Procedure:
Diethyl azodicarboxylate (5.91 ml, 37 mmol) was added dropwise to a stirred mixture of (E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (3.97 g, 28 mmol), 4-(chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (3.0 g, 9 mmol), (prepared as described for the starting material in Example 2), and triphenylphosphine (9.84 g, 38 mmol) in methylene chloride (300 ml). The reaction mixture was stirred for 18 hours at ambient temperature. The volatiles were removed by evaporation and the residue was purified by column chromatography eluting with methylene chloride/methanol (a gradient from 80120 to 70/30). The purified product was dissolved in methylene chloride/methanol and 1M ethereal hydrogen chloride (25 ml) was added. The precipitated product was collected by filtration, washed with ether and dried to give (E)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-pyrrolidin-1-yl)but-2-en-1-yloxy)quinazoline hydrochloride (1.62 g, 33%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[C:5]([O:11][CH3:12])[CH:4]=1)=C.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:22].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[O:22])=[CH:4][C:5]=1[O:11][CH3:12])#[N:10]
Reactant: C=Cc1ccc(C#N)c(OC)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C=O)ccc1C#N
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a solution of 1-vinyl-4-cyano-3-methoxybenzene (0.343 g, 2.16 mmol, 1.0 eq) in dioxane (7 mL) was added 2,6-lutidine (0.461 g, 0.50 mL, 4.31 mmol, 2.0 eq) followed by osmium tetroxide (1.37 g, 1.32 mL of a 4% solution in water, 0.22 mmol, 0.1 eq). A brown/black solution resulted after 1→2 minutes. Sodium periodate (1.847 g, 8.63 mmol as a solution in 7 mL of water, 4.0 eq) was added forming a white precipitate. The mixture was stirred at room temperature for 35 minutes before partitioning between EtOAc (100 mL) and HCl (1M, 100 mL). The organics were washed with brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (10→50% EtOAc-hexane) yielded the title compound as a white solid; 1H nmr (CDCl3) d 9.89 (1H, s, CHO), 8.09 (2H, m, ArH-2, H-6), 7.12 (1H, d, J 9.5 Hz, ArH-3), 4.04 (3H, s, OCH3); m/z 162 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([O:16]C)=O.[F:18][C:19]1([F:36])[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][O:26][C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=2[O:34][CH3:35])[CH2:20]1.[CH2:37](O)C>>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:14](=[O:16])[N:31]([C:30]4[CH:32]=[CH:33][C:27]([O:26][CH2:25][CH2:24][N:21]5[CH2:22][CH2:23][C:19]([F:18])([F:36])[CH2:20]5)=[C:28]([O:34][CH3:35])[CH:29]=4)[CH:37]=[N:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: COc1cc(N)ccc1OCCN1CCC(F)(F)C1
Reactant: CCO
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN1CCC(F)(F)C1
Temperature: 110 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
Methyl 3-amino-5-(4-chlorophenyl)thiophene-2-carboxylate (0.1367 g, 0.5107 mmol) was taken up in dimethylformamdide dimethyl acetal (3 mL) and heated to 110° C. The reaction was stirred for 3 h and then concentrated. 4-[2-(3,3-Difluoropyrrolidin-1-yl)ethoxy]-3-methoxyaniline (0.1389 g, 0.5107 mmol) in absolute ethanol (3 mL) was added to the residue and concentrated. Fresh absolute ethanol (1 mL) was added and the reaction heated to reflux. The reaction was stirred for 18 h and then cooled to RT and the precipitate was collected to give 0.058 g (0.1120 mmol, 22%) of the product as a white solid. 1H NMR (D6-DMSO) δ 8.38 (s, 1H), 7.96 (s, 1H, 7.91 (d, 2H, J=8.4 Hz), 7.56 (d, 2H, J=8.4 Hz), 7.18 (s, 1H), 7.11 (d, 1H, J=8.5 Hz), 7.04 (d, 1H, J=8.6 Hz), 4.12 (t, 2H, J=5.5 Hz), 3.77 (s, 3H), 3.00 (t, 2H, J=13.6 Hz), 2.85 (t, 2H, J=5.5 Hz), 2.81 (t, 2H, J=7.0 Hz), 2.22 (m, 2H). LRMS M+H