Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[F:2][C:3]1([F:16])[C:7]([F:9])([F:8])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([Mg]Cl)[C:5]=2[O:4]1.C[CH:18](OC(C)=O)[O:19]C(C)=O.Cl.CCCCCCCC>C1(C)C=CC=CC=1>[F:2][C:3]1([F:16])[C:7]([F:9])([F:8])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:18][OH:19])[C:5]=2[O:4]1
Reactant: CC(=O)OC(C)OC(C)=O
Reactant: FC1(F)Oc2c([Mg]Cl)cccc2C1(F)F
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCCCCCCC
Product: OCc1cccc2c1OC(F)(F)C2(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, the reaction mixture from above is decanted into a clean, dry reaction vessel, leaving the unreacted magnesium turnings in the first vessel. This solution containing 2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmagnesium chloride is heated at reflux, and 16.5 grams (0.55 mole based on formaldehyde) of polyoxymethylene diacetate (avg. mol. wgt. approx. 50,000, commercially available from E. I. du Pont De Nemours & Co., Inc. Wilmington Del., under the trade name Delrin 500 acetal homopolymer resin), milled to about 80 mesh, is added with stirring during about a three hour period. Upon completion of addition, the reaction mixture is heated at reflux for an additional four hours and then is allowed to cool to ambient temperature as it stood for about 18 hours. The reaction mixture is warmed to about 53° C. and then is poured into 100 grams of ice, 52 grams of concentrated hydrochloric acid, and 200 grams of a mixture of 95% n-octane and 5% toluene (wt/wt). This mixture is filtered, and the organic layer is separated. The organic layer is concentrated under reduced pressure, yielding 2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethanol.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9](Cl)[C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([NH2:6])=O.[O:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1.[B:20]1([OH:30])[C:24]2[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=2[CH2:22][O:21]1>>[Cl:12][C:8]1[C:9]([O:29][C:27]2[CH:26]=[CH:25][C:24]3[B:20]([OH:30])[O:21][CH2:22][C:23]=3[CH:28]=2)=[N:10][C:2]([O:19][CH:16]2[CH2:17][CH2:18][O:13][CH2:14][CH2:15]2)=[C:3]([CH:7]=1)[C:4]#[N:6]
Reactant: OC1CCOCC1
Reactant: OB1OCc2cc(O)ccc21
Reactant: NC(=O)c1cc(Cl)c(Cl)nc1Cl
Product: N#Cc1cc(Cl)c(Oc2ccc3c(c2)COB3O)nc1OC1CCOCC1

Procedure:
This compound was prepared from 2,5,6-trichloronicotinamide, tetrahydro-2H-pyran-4-ol, and benzo[c][1,2]oxaborole-1,5(3H)-diol in a similar manner to that of D230. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 2.49-2.5 (m, 2H), 3.06-3.12 (m, 2H), 3.06-3.2 (m, 2H), 3.68-3.73 (m, 2H), 4.51-4.54 (m, 1H), 5.0 (s, 2H), 7.23 (dd, J=6.0, 1.7 Hz, 1H), 7.32 (s, 1H), 7.8 (d, J=6.0 Hz, 1H), 8.57 (s, 1H), 9.25 (s, 1H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].NC1N=CN=C([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)C=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:1][CH2:2][C:3]([N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)ncn2)CC1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CBr)CC1

Procedure:
A solution of bromoacetyl bromide (0.59 g, 2.95 mmol) in methylene chloride (3 mL) was added drop wise via addition funnel to a stirred solution of tert-butyl piperazine-1-carboxylate 12-1 (0.50 g, 2.68 mmol) and aqueous sodium carbonate (0.34 g, 3.22 mmol) in methylene chloride (15 mL) at 0° C. After a 10 minute reaction time the methylene chloride layer was drawn off, dried and evaporated to an oil. This was purified this on a silica column to afford 42-1. Hi-Res MS (M+Na): calc: 329.0471 found: 329.0462. 1H-NMR(CDCl3): 3.87(s, 2H); 3.61(m, 2H); 3.52(m, 2H); 3.50(m, 2H); 3.44(m, 2H); 1.47(s, 9H).
Reaction SMILES: Br[C:2](=[CH:5]OC(C)C)[CH:3]=[O:4].[NH2:10][C:11]1[CH2:16][N:15]([CH3:17])[C:14](=[O:18])[CH2:13][N:12]=1.C(N(CC)CC)C>C(#N)C>[CH3:17][N:15]1[C:14](=[O:18])[CH2:13][N:12]2[CH:5]=[C:2]([CH:3]=[O:4])[N:10]=[C:11]2[CH2:16]1.[CH3:17][N:15]1[C:14](=[O:18])[CH2:13][N:12]2[C:2]([CH:3]=[O:4])=[CH:5][N:10]=[C:11]2[CH2:16]1
Reactant: CN1CC(N)=NCC1=O
Reactant: CC(C)OC=C(Br)C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1Cc2nc(C=O)cn2CC1=O
Product: CN1Cc2ncc(C=O)n2CC1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 11.6 %
Yield: 49.1 %

Procedure:
The solution of 2-bromo-3-isopropoxy-propenal (1.3 g) in dry acetonitrile (60 mL) was added to the solution of 5-amino-1-methyl-3,6-dihydro-1H-pyrazin-2-one (782 mg) in dry acetonitrile (60 mL) at room temperature. The reaction mixture was stirred at room temperature for 20 h, added triethylamine (0.95 mL) and then refluxed for 2 h. The reaction mixture was cooled to room temperature and then evaporated under reduce pressure. The residue was dissolved in chloroform (10 mL) and washed with 50% K2CO3 aqueous solution (10 mL). The aqueous layer was extracted with chloroform. The organic layer was dried (MgSO4) and filtered. The filtrate was evaporated under reduce pressure. The residue was applied to silica gel column chromatography and eluted with CHCl3-MeOH (95:5) to obtain the title compound 7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazine-2-carbaldehyde as a pale yellow solid (541 mg, 49.1%) and its regio isomer 7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazine-3-carbaldehyde as a pale yellow solid (128 mg, 11.6%).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH:15](F)F)[N:8]=[C:7]([C:18]([F:21])([F:20])[F:19])[C:6]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl.[Zn]>[CH:1]1([NH:4][C:5]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH3:15])[N:8]=[C:7]([C:18]([F:20])([F:21])[F:19])[C:6]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1NC1CC1
Agent: [Zn]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(C(F)(F)F)nc(C)c(C(=O)OC)c1NC1CC1
Yield: 58.7 %

Procedure:
This compound was prepared as described in Example 85: 17 g (0.264 mol) of zinc dust, 4.76 g (0.012 mol) of product of Example 56 and 17 ml of trifluoroacetic acid in 100 ml of CH2Cl2 were reacted affording 2.44 g (59%) of product after kugelrohr distillation at 100°-140° C./53 Pa as a light yellow oil, nD25 1.5032.
Reaction SMILES: ClC(OCC(C)C)=O.[CH3:9][N:10]([CH3:17])[CH2:11][C:12]#[C:13][C:14](O)=[O:15].CN1CCOCC1.[NH2:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]=[CH:31][C:30]([C:36]#[N:37])=[C:29]2[NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Br:45])[CH:40]=1>N1C=CC=CC=1>[Br:45][C:41]1[CH:40]=[C:39]([NH:38][C:29]2[C:28]3[C:33](=[CH:34][CH:35]=[C:26]([NH:25][C:14](=[O:15])[C:13]#[C:12][CH2:11][N:10]([CH3:17])[CH3:9])[CH:27]=3)[N:32]=[CH:31][C:30]=2[C:36]#[N:37])[CH:44]=[CH:43][CH:42]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: CN(C)CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: CN(C)CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16.9 %

Procedure:
Isobutyl chloroformate (0.342 g, 2.5 mmol) was dropwise added into an ice cold solution of 4-dimethylamino-2-butynoic acid (0.9 g, 3.8 mmol) and N-methyl-morpholine (0.384 g, 3.8mmol) in 50 mL of tetrahydrofaan under N2. After stirring for 30 min, a solution of 0.644 g (1.9 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 10 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2.5 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 15% methanol in ethyl acetate. The product was collected, and dried in vacuo to give 0.144 g (21%) of yellow solid; mass spectrum (electrospray, m/e,): 447.9, 450.2 (M+H+); mp 180° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[F:11].[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[Br:1][C:2]1[C:3]([F:11])=[C:4]2[C:5]([CH:12]=[CH:13][NH:8]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: Fc1c(Br)ccc2cc[nH]c12
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-2-fluoro-3-nitrobenzene (2.5 g, 11.3 mmol) in THF (25 mL) at −50° C. was added vinyl magnesium bromide (34 mL, 34 mmol) and the mixture was stirred at −40° C. for 1 h. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to yield a gum, which was purified by column chromatography over silica gel eluting with EtOAc/hexane to afford pure 6-bromo-7-fluoro-1H-indole. 1H NMR (400 MHz, CDCl3) δ=6.53-6.62 (m, 1H), 7.16-7.25 (m, 2H), 7.29 (d, J=8.34 Hz, 1H) and 8.36 (br. s., 1H); MS (ES+): m/z 214.08 [MH+].
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)C>C(O)C>[N+:1]([C:4]1[C:9]([CH:10]=[N:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: NC1CCCCC1
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(C=NC2CCCCC2)c([N+](=O)[O-])cc1OC
Yield: 80.4 %

Procedure:
A suspension of 42.2 g (0.2 mole) of 6-nitroveratraldehyde, 19.8 g (0.2 mole) cyclohexylamine, 1.0 ml. glacial acetic acid, and 1.25 l. ethanol was stirred and refluxed for five min., cooled, and filtered. The solid was washed with 100 ml. cold ethanol and air dried to give 47.0 g (80%) of the product, m.p. 160°-161°.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[CH:34]=[CH:33][C:32]([S:35][CH3:36])=[C:31]([CH3:37])[CH:30]=1)[CH:7]=[CH:6]2.Cl.B(Br)(Br)Br.O>C(OCC)(=O)C.C(OCC)C>[CH3:37][C:31]1[CH:30]=[C:29]([C:8]2[C:9]([O:13][C:14]3[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]3)[CH:34]=[CH:33][C:32]=1[S:35][CH3:36]
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(SC)c(C)c3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Dissolve the product of Example 47 in ethyl acetate (10 mL) and diethyl ether (5 mL). Add 2M HCl in diethyl ether (5 mL, 10.0 mmol). Concentrate the slurry and dry in vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool the solution to 0° C. with external ice bath and add BBr3 (0.3 mL, 3.2 mmol). After 1 hour, add water (1.0 mL) and ethyl acetate (10 mL). Separate the layers, wash the organic layer with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). Dry with MgSO4, filter, and concentrate in vacuo. Chromatograph the residue on a column eluting the material with a step gradient of methanol in dichloromethane (0 to 0.5%) to give 330 mg of the title compound (92%): mass spectrum (ion spray): m/z=500.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][CH3:15])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[O:8][CH:7]2[OH:12].C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH3:24].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][CH3:15])[CH:5]=[C:6]([CH:7]=[O:12])[C:10]=1[C:9]([O:8][CH2:23][CH3:24])=[O:11]
Reactant: CCI
Reactant: CCCc1cc(Cl)c2c(c1)C(O)OC2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(Cl)c(C(=O)OCC)c(C=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.1 %

Procedure:
To a solution of (±)-7-chloro-3-hydroxy-5-propylisobenzofuran-1 (3H)-one (0.66 g, 2.91 mmol) in 10 mL of DMF was added potassium carbonate (0.80 g, 5.82 mmol) followed by iodoethane (0.26 mL, 3.20 mmol). The resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was cooled to 0° C. and carefully acidified with 6N HCl, diluted with water and extracted with EtOAc. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 0.69 g (93%) of the title compound which was used without purification. 1H NMR (CDCl3): δ 9.88 (s, 1H), 7.52 (d, 1H, J=1.4 Hz), 7.40 (d, 1H, J=1.6 Hz), 4.42 (q, 2H, J=7.1 Hz), 2.60 (t, 2H, J=7.7 Hz), 1.64-1.55 (m, 2H), 1.34 (t, 3H, J=7.1 Hz), 0.89 (t, 3H, J=7.1 Hz).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH:17]3[CH2:18][CH2:19][N:20]([C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:21][CH2:22]3)=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Clc1ncccn1
Reactant: O=C(c1ccc(-c2cccc(Cl)c2)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(c1ccc(-c2cccc(Cl)c2)cc1)C1CCN(c2ncccn2)CC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
(3′-Chloro-biphenyl-4-yl)-piperidine-4-yl-methanone hydrochloride (2, 23.4 kg, 69.6 mol), 2-chloropyrimidine (8.9 kg, 1.3 equiv), and 325-mesh potassium carbonate (25 kg, 3 equiv) were mixed in acetonitrile (211 L) in a 100-gallon reactor. The batch was heated with agitation at 55-65° C. for 16 h. The batch was then cooled to 20-30° C., followed by the addition of water (70 L) and further stirred for 15 min. The batch was transferred to a 300-gallon reactor and rinsed with water (360 L) to afford a thick white suspension. After stirring for 2 h, the batch was filtered and washed with water (2×70 L) and dried to constant weight at 45-55° C. to afford crude compound 3 (23.5 kg, 89.5% yield, >99% purity) as a white crystalline solid.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH3:8]CCCCC.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.CO>C1C=CC=CC=1>[CH3:8][O:23][C:22](=[O:24])[CH:21]([C:18]1[CH:17]=[CH:16][C:15]([Br:14])=[CH:20][CH:19]=1)[OH:25]
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Reactant: CCCCCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
A solution of trimethylsilyldiazomethane in hexane (2 M, 1.4 mL, 2.8 mmol) was added to a solution of 4-bromo-phenyl-hydroxy-acetic acid (506 mg, 2.19 mmol) in benzene (2.1 mL)-methanol (1.0 mL) under cooling with ice, and the mixture was stirred at room temperature for five minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (500 mg, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]2[CH2:12]1>O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:8]2[C:11](=[O:17])[CH2:12][C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: O
Product: COc1ccc(CN2C(=O)Cc3ccccc3C2=O)cc1
Temperature: 180 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
4-Methoxybenzylamine (8.3 g) was added to homophthalic anhydride (8.1 g). The mixture was stirred at 180° C. overnight. Water was added to the reaction solution. The mixture was then extracted with ethyl acetate. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=8:2) to give 2-(4-methoxybenzyl)-4H-isoquinoline-1,3-dione (11.8 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH3:19])[CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1.[C:22]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH3:19])[CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:22])[C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)cccc1-n1c(=O)[nH]c2c(C)cccc2c1=O
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: Cc1c(Br)cccc1-n1c(=O)c2cccc(C)c2n(C)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 104.4 %

Procedure:
A mixture of 3-(3-bromo-2-methylphenyl)-8-methylquinazoline-2,4(1H,3H)-dione (470 mg, 1.36 mmol) and Cs2CO3 (1.33 g, 4.08 mmol) in DMF (8 mL) was treated with iodomethane (0.85 mL, 13.6 mmol) and stirred at room temperature for 1.5 h. The mixture was diluted with EtOAc, washed sequentially with water and two portions of 10% aqueous LiCl. The combined aqueous phases were extracted with EtOAc. The combined organic phases were washed sequentially with 10% aqueous LiCl and water, dried and concentrated to give impure 3-(3-bromo-2-methylphenyl)-1,8-dimethylquinazoline-2,4(1H,3H)-dione as a white solid (510 mg), used without further purification. Mass spectrum m/z 359, 361 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][NH2:32])[CH3:28]>CC#N>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][NH:32][CH2:31][CH2:30][N:29]([CH2:33][CH3:34])[CH2:27][CH3:28])=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: Cc1nc(NC(=O)CCBr)sc1-c1ccnc(Nc2ccc(Cl)cc2)n1
Reactant: CCN(CC)CCN
Solvent: CC#N
Product: CCN(CC)CCNCCC(=O)Nc1nc(C)c(-c2ccnc(Nc3ccc(Cl)cc3)n2)s1

Procedure:
By treatment of 3-bromo-N-{5-[2-(4-chloro-phenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide with N1,N1-diethyl-ethane-1,2-diamine. Anal. RP-HPLC: tR=11.8 min (10-70% MeCN, purity >97%). 1H-NMR (DMSO-D6) δ: 1.20 (t, 6H, J=7.0 Hz, CH3), 1.53 (d, 2H, J=6.5 Hz, CH2), 2.52 (s, 6H, CH3), 3.18 (m, 4H, CH2), 3.28 (m, 4H, CH2), 7.13 (d, 1H, J=5.0 Hz, pyrimidinyl-H), 7.30 (m, 2H, Ph-H), 7.81 (m, 2H, Ph-H), 8.51 (d, 1H, J=5.0 Hz, pyrimidinyl-H), 9.82 (brs, 1H, NH).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:12][C:13](N)=[O:14]>>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4]([OH:5])=[N:12][C:13]([OH:14])=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC(N)=O
Reactant: Nc1cc(F)ccc1C(=O)O
Product: Oc1nc(O)c2ccc(F)cc2n1
Temperature: 160 °C
Yield: 89.5 %

Procedure:
A mixture of 2-amino-4-fluorobenzoic acid (25.3 g) and urea (48.9 g) was gradually added to a flask heated at 160° C. and then heated to 245° C. over 30 min. Light yellow solids were precipitated. The reaction mixture was cooled to room temperature, then methanol (250 mL) was added to the reaction mixture, the mixture was heated to reflux for 30 min, the solids were washed and cooled to room temperature, and then the precipitated solids were collected by filtration. The resulting solids were washed again with methanol (300 mL) to obtain 7-fluoroquinazoline-2,4-diol (26.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH3:24])[CH:11]3[C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[CH3:32])[C:5]2=[CH:4][CH:3]=1.C[O:35][CH:36]([Si](C)(C)C)[CH3:37].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH2:37][CH2:36][OH:35])[C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH3:24])[CH:11]3[C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[CH3:32])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(C)[Si](C)(C)C
Reactant: Cc1ccc(F)cc1C1N(C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)cc1C1N(C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)N(CCO)c1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-methyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.16 g, 0.26 mmol) prepared in example 56a in dichloromethane (10 mL) was added trifluoroacetic acid (20 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated. The residue was neutralized with saturated NaHCO3 aqueous solution, then extracted with ethyl acetate. The organic layer was separated, dried over MgSO4 and concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-methyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-ethanol (Yield 90 mg, 67.7%).
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[Br:11]N1C(=O)CCC1=O>>[Br:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:2])[O:3]1
Reactant: O=C1OCc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Product: O=C1OC(Br)c2ccccc21

Procedure:
A benzoic acid derivative of formula 1 is reacted with formaldehyde under acidic conditions to yield a phthalide derivative of formula 2. ##STR4## The phthalide derivative is then brominated with any suitable brominating agent, e.g. N-bromosuccinimide to yield an unstable bromophthalide derivative, 3, which is readily reacted with water to a phthalaldehydic acid derivative, 4. ##STR5## The phthalaldehydic acid derivative may then be oxidized to the desired phthalic anhydride derivative, 5, in good yield using a suitable oxidizing agent such as manganese dioxide. ##STR6##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][C:3]=1[O:10][CH3:11].[CH3:12][O:13][C:14]1[CH:40]=[CH:39][C:17]([CH2:18][O:19][C:20](=[O:38])[C:21]2[CH:26]=[C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[CH:24]=[CH:23][C:22]=2I)=[CH:16][CH:15]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][O:19][C:20](=[O:38])[C:21]2[CH:26]=[C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[CH:24]=[CH:23][C:22]=2/[CH:9]=[CH:8]/[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:10][CH3:11])[CH:4]=2)=[CH:39][CH:40]=1
Reactant: COc1ccc(COC(=O)c2cc(OCc3ccc(OC)cc3)ccc2I)cc1
Reactant: C=Cc1ccc(F)c(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)c2cc(OCc3ccc(OC)cc3)ccc2/C=C/c2ccc(F)c(OC)c2)cc1

Procedure:
To a stirred solution of 1-fluoro-2-methoxy-4-vinylbenzene (INTERMEDIATE I.1) (4.49 g, 29.53 mmol) and 2-iodo-5-(4-methoxybenzyloxy)benzoic acid 4-methoxybenzyl ester (14.89 g, 29.53 mmol) in anhydrous acetonitrile (75 mL) was added triethylamine (8.2 mL, 59.06 mmol) and tri(o-tolyl)phosphine (1.17 g, 3.84 mmol). The mixture was sparged for 5 min with argon, and palladium(II) acetate (662 mg, 2.95 mmol) was added. The mixture was heated at reflux for 13 h and concentrated to give the crude product (E)-2-[2-(4-fluoro-3-methoxyphenyl)vinyl]-5-(4-methoxybenzyloxy)benzoic acid 4-methoxybenzyl ester as a dark brown residue, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[PH2:11]([O-:13])=[O:12].[NH4+:14].O>C1(C)C(C)=CC=CC=1>[NH2:14][C:6]1([CH2:9][P:11]([OH:13])[OH:12])[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH2:7]1
Reactant: O=[PH2][O-]
Reactant: [NH4+]
Reactant: COc1ccc(C=O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COC1=CCC(N)(CP(O)O)C=C1

Procedure:
A mixture of 13.6 parts anisaldehyde and 8.3 parts ammonium hypophosphite in 100 parts xylene was refluxed with water separation. The xylene was cooled, decanted and the residue boiled with ethanol to give a white solid. Filtration gave DL-1-amino-p-methoxyphenylmethanephosphonous acid, melting point 239°-241° (dec.).