Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:14]1([C:20]([C:22]2[CH:23]=[C:24]([CH2:28]O)[CH:25]=[CH:26][CH:27]=2)=[CH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[C:14]1([C:20]([C:22]2[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=2)[CH2:28][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)=[CH2:21])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: C=C(c1ccccc1)c1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C=C(c1ccccc1)c1cccc(COc2ccc(CCC(=O)OC)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
A solution of methyl 3-(4-hydroxyphenyl)propanoate (0.360 g, 2.00 mmol), [3-(1-phenylvinyl)phenyl]methanol (0.421 g, 2.00 mmol) and tributylphosphine (0.747 mL, 3.00 mmol) in toluene (30 mL) was stirred under ice-cooling, 1,1′-(azodicarbonyl)dipiperidine (0.757 g, 3.00 mmol) was added by small portions under a nitrogen atmosphere, and the mixture was stirred at room temperature for 18 hrs. Hexane (15 mL) was added to the reaction mixture, the precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-20% ethyl acetate/hexane) to give the title compound as a colorless oil (0.641 g, yield 86%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(OCC)(=O)C>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1ccccc1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
5.08 g (30 mmol) of 2-aminobiphenyl, 50 ml of ethyl acetate, and 3.1 g (30 mmol) of triethylamine were placed in a flask, to which 4.1 g (30 mmol) of ethyl chloroglyoxylate was added dropwise under ice cooling. The reaction mixture was stirred at room temperature for three hours, and then 50 ml of ethyl acetate was added thereto. The organic layer was washed with 30 ml of 1N hydrochloric acid and 30 ml of brine one by one, and then was dried with anhydrous sodium sulfate. The solvent was removed by evaporation to obtain 6.8 g (24 mmol, yield 85%) of ethyl N-biphenyl-2-yloxamate as colorless crystals.
Reaction SMILES: [NH2:1][C@H:2]([C@H:10]([OH:22])[C@H:11]([OH:21])[C@@H:12]([NH2:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:23]([O:27][C:28](O[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:29])([CH3:26])([CH3:25])[CH3:24]>ClCCl>[NH2:1][C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C@@H:10]([OH:22])[C@@H:11]([OH:21])[C@@H:12]([NH:20][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:23]([O:27][C:28]([NH:1][C@H:2]([C@@H:10]([OH:22])[C@@H:11]([OH:21])[C@@H:12]([NH:20][C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@@H](N)Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@@H](N)Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %
Yield: 20 %

Procedure:
A solution of 200 mg (0.67 mmol) of (2S,3S,4R,5S)-2,5-diamino-3,4-dihydroxy-1,6-diphenylhexane in 10 ml of dichloromethane was treated with 174 mg (0.8 mmol) of di-t-butyldicarbonate. After being allowed to stir overnight at ambient temperature, the solution was concentrated, and the residue was purified by silica gel chromatography using 10% methanol in chloroform to provide 180 mg (56%) of the desired compound along with 80 mg (20%) of the resultant compound of Example 206.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:20])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH:5]=O.[CH3:21]/[C:22](/[NH2:26])=[CH:23]\[C:24]#[N:25].[CH2:27]([CH:30]1[CH2:35][C:34](=[O:36])[CH2:33][C:32](=O)[CH2:31]1)[CH2:28][CH3:29]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:33]3[C:34](=[O:36])[CH2:35][CH:30]([CH2:27][CH2:28][CH3:29])[CH2:31][C:32]=3[NH:26][C:22]([CH3:21])=[C:23]2[C:24]#[N:25])[CH:7]=[C:8]([OH:20])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: COc1cccc(COc2c(O)cc(C=O)cc2Br)c1
Reactant: CCCC1CC(=O)CC(=O)C1
Reactant: C/C(N)=C\C#N
Solvent: CCO
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(O)c(OCc2cccc(OC)c2)c(Br)c1
Temperature: 80 °C

Procedure:
A mixture of 3-bromo-5-hydroxy-4-(3-methoxy-benzyloxy)-benzaldehyde (1.43 g), 3-aminocrotonitrile (350 mg) and 5-propylcyclohexane-1,3-dione (654 mg) in ethanol (100 ml) was heated at 80° C. for 17 h. The mixture was concentrated in vacuo and then purified by chromatography on silicagel in heptane/ethyl acetate 1/0→0/1 (v/v) as eluent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9](C(C1C=CC=CC=1)C1C=CC=CC=1)[C:8](=[O:24])[CH:7]2[C:25]1[C:26]([OH:34])=[CH:27][C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:24])[C:7]12[CH2:35][O:34][C:26]2[CH:27]=[C:28]3[C:29](=[CH:33][C:25]1=2)[CH2:30][CH2:31][O:32]3
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2cccc(F)c2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1Nc2c(F)cccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 7-fluoro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 7′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (97%) as a colorless solid: mp>250° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ11.01 (s, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.70 (d, J=7.1 Hz, 1H), 7.00-6.94 (m, 1H), 6.56 (s, 1H), 6.40 (s 1H), 4.80 (d, J=9.4 Hz, 1H), 4.68 (d, J=9.4 Hz, 1H), 4.49 (m, 2H), 2.95 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ178.5, 161.0, 160.5, 139.4, 134.7, 128.4, 123.4, 122.3, 120.1, 119.8, 118.9, 113.8, 92.3, 79.8, 72.0, 58.0, 28.2; MS (ES+) m/z 298.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6](=[O:17])[N:5]([CH3:18])[C:4](=[O:19])[CH:3]=1.CCOCC.[NH2:25][NH2:26]>CCO.CO>[NH:25]([C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6](=[O:17])[N:5]([CH3:18])[C:4](=[O:19])[CH:3]=1)[NH2:26]
Reactant: NN
Reactant: COc1ccc(Cn2c(Cl)cc(=O)n(C)c2=O)cc1
Solvent: CO
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(Cn2c(NN)cc(=O)n(C)c2=O)cc1
Yield: 84 %

Procedure:
To a solution of 6-chloro-1-(4-methoxybenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione (2.4 g 8.6 mmol) in EtOH (25 mL) and MeOH (50 mL), anhydrous hydrazine (1.2 mL) is added slowly. The reaction mixture is refluxed for three hours, and then cooled. A large amount of ether is added into the reaction mixture, and then filtered to give 2.0 g of product as crystalline solids (Yield: 84%). 1H NMR (DMSO-d6) δ 3.13 (s, 3H), 3.73 (s, 3H), 4.42 (br, 1H), 5.03 (s, 2H), 5.15 (s, 1H), 6.88 and 7.15 (AB, 4H, J=6.4 Hz), 8.08 (br, 1H). MS (FAB) m/z 277.28 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1.[CH:12]([S:14]([CH:17]=[CH2:18])(=[O:16])=[O:15])=[CH2:13].[F:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:21]=1[NH2:22]>C(OCC)(=O)C>[F:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:21]=1[N:22]1[CH2:18][CH2:17][S:14](=[O:16])(=[O:15])[CH2:12][CH2:13]1
Reactant: C=CS(=O)(=O)C=C
Reactant: Nc1c(F)cccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: O=S1(=O)CCN(c2c(F)cccc2F)CC1
Temperature: 110 °C
Yield: 55.2 %

Procedure:
Aluminum chloride (310 g, 2.3 mol) is added to chlorobenzene (2.5 L) to give a cloudy green suspension. Vinyl sulfone (230 mL, 2.3 mol) is added via a funnel. 2,6-Difluoroaniline (250 mL, 2.3 mol) is added a via funnel. The light brown solution is heated to 110° C. Upon completion, the heat is removed and the black solution is self-cooled to 70° C. The reaction mixture is quenched in methylene chloride (4 L) and ice water (5 L). The aqueous phase is extracted with methylene chloride. The combined organic layers are concentrated and added branched octane (3 L), and then cooled to 0° C. for 30 minutes. The solids are filtered and washed with branched octane (2×500 mL). The crude black solids are dissolved into methylene chloride (3 L) and then loaded onto a SiO2 plug (1.8 kg). The column is eluted with dichloromethane (16 L) until clear. The methylene chloride solution is concentrated to give light brown solids (387 g or 68% yield). The solids are dissolved in hot ethyl acetate (3 L) followed by the addition of hexanes (900 mL). The black solution is self-cooled to room temperature overnight. The light amber crystal needles are filtered and washed with hexanes (4×250 mL). The solids are dried in vacuo at 50° C. overnight to give 314 g of the title compound (55% recystallized yield 1st crop).
Reaction SMILES: C[O:2]C(OC)(C)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11](S(O)(=O)=O)=[CH:10][CH:9]=1.[O:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CC(C)=O.CCOCC>[CH2:18]([O:19][CH2:24][CH:23]1[O:22][CH:21]1[CH2:20][OH:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1COCCO1
Reactant: COC(C)(C)OC
Solvent: CCOCC
Solvent: CC(C)=O
Product: OCC1OC1COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2-Dimethoxypropane (12 mL, 97 mmol) was added with stirring to a solution of crude diols A and B, catalytic p-toluenesulfonic acid in acetone (50 mL). The mixture was stirred at room temperature overnight, diluted with ether and washed with aqueous sodium bicarbonate solution (twice). The organic extract was dried (magnesium sulfate), filtered and concentrated. The crude oil was chromatographed on a silica gel column and eluted with 2-10% ethyl acetate in hexanes to obtain dioxane C (5.85 g, 65% overall yield from 4-benzyloxy-2,3-epoxy-1-butanol) as a colorless oil.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([Si:13]([CH2:25][CH3:26])([CH2:23][CH3:24])[C:14]1[O:15][CH:16]=[C:17]([CH2:19][CH2:20][CH2:21][OH:22])[CH:18]=1)[CH3:12].C(N(CC)CC)C>ClCCl>[CH2:25]([Si:13]([CH2:11][CH3:12])([CH2:23][CH3:24])[C:14]1[O:15][CH:16]=[C:17]([CH2:19][CH2:20][CH:21]=[O:22])[CH:18]=1)[CH3:26]
Reactant: CC[Si](CC)(CC)c1cc(CCCO)co1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC[Si](CC)(CC)c1cc(CCC=O)co1
Reaction time: 0.08 h

Procedure:
A mixture of dimethyl sulfoxide (0.9 ml) and dichloromethane (9 ml) was added to a solution of oxalyl chloride (0.64 ml, 7.39 mmol) at -78 degrees under argon. After 5 minutes, a solution of 3-(2-triethylsilyl-4-furyl)propan-1-ol (1.27 g, 5.28 mmol) in dichloromethane (9.0 ml) was added dropwise and after 20 minutes, triethylamine (2.9 ml, 21.1 mmol) was added. Stirring was continued at -78 degrees C. for 40 minutes and at room temperature for 3 hours. The mixture was quenched with water and was extracted thoroughly with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by a silica column to give the titled aldehyde.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([F:7])[CH2:5][N:4]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH:17]([CH3:19])[CH3:18])=[C:10]([NH:20][C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[N:9]=2)[CH2:3]1.C([O-])(O)=O.[Na+].[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>C(Cl)Cl>[F:7][C@@H:6]1[CH2:5][N:4]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH:17]([CH3:19])[CH3:18])=[C:10]([NH:20][C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[N:9]=2)[CH2:3][C@H:2]1[NH:1][C:32](=[O:35])[CH:33]=[CH2:34]
Reactant: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(N3C[C@@H](N)[C@H](F)C3)nc21
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CC(=O)N[C@@H]1CN(c2nc(Nc3cnn(C)c3)c3ncn(C(C)C)c3n2)C[C@H]1F

Procedure:
Crude 2-((trans)-3-amino-4-fluoropyrrolidin-1-yl)-9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine (assumed 1 mmol ca.) was partitioned between DCM (30 mL) and sat. aq. NaHCO3 (10 mL) and stirred vigorously. Acryloyl chloride (121 μL, 1.5 mmol) was added in one portion and the mixture stirred for 30 min. The mixture was then diluted with DCM (50 mL) and the organic layer was separated, dried over Na2SO4 and evaporated to give a dark residue that was subjected to chiral SFC purification to separate the two trans enantiomers (Chiralpak AD-H 21.2×250 mm 5μ column. Eluted with 30% EtOH (200 proof) in CO2 held 38° C. at 100 bar, ˜60.0 mL/min, UV detection at λ=260 nm. Peak 1(−) elutes 3.99-4.68 min. Peak 2(+) elutes 5.80-6.38 min). Yielded:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]=[C:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([C:9]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10][CH2:11][CH2:12][C:8]1=[O:7])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(Cc2ccccc2)CCCC1=O
Temperature: 25 °C
Yield: 66.9 %

Procedure:
38.7 grams of anhydrous potassium carbonate and 90 ml of acetone were mixed, then with stirring, to the resulting mixture was dropwise added a solution of 10.4 ml of ethyl 2-oxocyclopentane carboxylate in 45 ml of acetone. After stirring at room temperature for 35 minutes, 16.7 ml of benzyl bromide was dropwise added thereto, and the reaction was allowed to continue under reflux for 3 hours. Then the reaction mixture was cooled to room temperature, filtered, concentrated, and distilled under reduced pressure. 11.54 g of colorless liquid as the second distillate cut was collected. Yield: 66.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].N1C=CC=CC=1.FC(F)(F)C(O[C:32]1[C:37]([F:38])=[C:36]([F:39])[C:35]([F:40])=[C:34]([F:41])[C:33]=1[F:42])=O>CN(C)C=O.C(OCC)(=O)C>[F:38][C:37]1[C:32]([O:13][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][C:17]([F:20])=[C:18]([F:19])[C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[Cl:1])=[C:33]([F:42])[C:34]([F:41])=[C:35]([F:40])[C:36]=1[F:39]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(F)c(F)c1Nc1ccc(I)cc1Cl
Yield: 91.1 %

Procedure:
To a solution of the product of Example 2, Step A, 2-(2-chloro-4-iodophenylamino)-3,4-difluorobenzoic acid (10.0 g, 24.4 mmol), and pyridine (2.16 mL, 26.8 mmol) in anhydrous dimethylformamide (49 mL) was added pentafluorophenyl trifluoroacetate (5.35 mL, 30.5 mmol). The resultant solution was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (600 mL) and washed with 0.1 M aqueous hydrochloric acid (2×240 mL), 25% saturated aqueous sodium bicarbonate (2×240 mL), and saturated brine (240 mL). The organics were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford an oil that was purified on silica gel. Elution with hexanes-ethyl acetate (19:1) afforded 2-(2-chloro-4-iodophenylamino)-3,4-difluorobenzoic acid pentafluorophenyl ester (12.8 g, 91%) as a pale-yellow powder: m.p. 108.5-110.0° C.; 1H-NMR (400 MHz, CDCl3) δ 8.77 (br s, 1H), 8.07 (br s, 1 H), 7.69 (br s, 1H), 7.48 (br d, J=7.0 Hz, 1H), 6.91 (br d, J=7.2 Hz, 1 H), 6.67 (br s, 1H); 19F-NMR (376 MHz, CDCl3) δ −123.74 (s, 1F), −139.17 (d, J=16.8 Hz, 1F), −152.35 (d, J=21.4 Hz, 2F), −156.96 (t, J=21.4 Hz, 1F), −161.81 (t, J=21.4 Hz, 2F). Anal. Calcd/found for C19H6NO2F7ClI: C, 39.65/39.32; H, 1.05/0.91; N, 2.43/2.35; F, 23.10/22.85; Cl, 6.16/6.92; I, 22.05/22.50. Step C: Preparation of 2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[N:12]=[C:13]([CH3:19])[N:14]([CH:16]([F:18])[F:17])[CH:15]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:15]1[N:14]([CH:16]([F:17])[F:18])[C:13]([CH3:19])=[N:12][C:11]=1[C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[Cl:3]
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)cn1C(F)F
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(-c2ccc(Cl)cc2Cl)c(Br)n1C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
Bromine (0.54 g, 3.1 mmol), in 7 ml of methylene chloride, was added dropwise to a solution of 0.9 g (3.2 mmol) of 4-(2,4-dichlorophenyl)-1-difluoromethyl-2-methylimidazole stirring in 35 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight. Another 0.3 g of bromine, in 5 ml of methylene chloride, were added and the reaction stirred overnight. Methylene chloride (250 ml) and saturated sodium bicarbonate (200 ml) were added and the organic layer separated and washed with saturated sodium bicarbonate and brine followed by drying over magnesium sulfate. Evaporating in vacuo gave a red oil residue. Flash chromatography on silica gel (20:1-10:1-5:1-3:1 hexane/ethyl acetate) afforded 0.7 g of 5-bromo-4-(2,4-dichlorophenyl)-1-difluoromethyl-2-methylimidazole as a white solid (m.p. 81-83° C.). NMR (CDCl3, 200 MHz) δ 2.65 (s, 3H), 7.20 (t, 1H), 7.27-7.40 (m, 2H), 7.52 (s, 1H)
Reaction SMILES: [OH-:1].[Na+].CN(C(N=NC(N(C)C)=O)=O)C.Cl.[NH2:16]O.[C:18]1([P:24](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.O1CCOCC1>[NH2:16][O:25][P:24](=[O:1])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NO
Reactant: [OH-]
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: NOP(=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
A 5 L 4-neck round bottom flask (rbf) fitted with an overhead stirrer & a thermocouple was charged with; (1) a solution of NaOH (60.85 g, 1.52 mol, 2.4 eq) in 180 mL water, (2) a solution of hydroxylamine-HCl (110.12 g, 1.58 mol, 2.5 eq) in 180 mL water and (3) 180 mL dioxane. The mixture was cooled in an ice/acetone bath to 0° C. 150 g of ice was added, followed by a precooled (to about 10° C.) solution of diphenylphosphinic chloride (150.0 g, 0.634 mol, 1 eq) in 180 mL dioxane (added all at once). The reaction became very thick with a white precipitate, requiring vigorous stirring. The internal temperature rose to 22° C. After 5 additional minutes stirring (10 minutes maximum), the reaction mixture was diluted with 2.5 L of ice cold water and filtered thru a large fritted funnel (15 cm diameter). The crude material was left on the frit to drain for one hour, then transferred back into the 5 L rbf. The solid was suspended in 500 mL ice cold 0.25N NaOH solution and vigorously stirred for five minutes (no more than 10 min), then filtered again, washing 2× with ice cold water and left to dry overnight on the fritted filter. The partially dried material was dried for 12 h in a vacuum oven (50° C., 0.1 torr) and then well crushed with a mortar & pestle. An additional 16 h of drying in the vacuum oven afforded 122 g (82%) the above compound as a white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[N:25]=1.[NH2:26][C:27]1[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[O:32])=[CH:29][C:28]=1[O:43][CH3:44].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)(C)C>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[N:25]=[C:2]([NH:26][C:27]3[CH:42]=[CH:41][C:30]([C:31]([NH:33][CH:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)=[O:32])=[CH:29][C:28]=3[O:43][CH3:44])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: CN1C(=O)C(F)(F)CN(CCOc2ccccc2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(CCOc1ccccc1)CC(F)(F)C(=O)N2C
Yield: 0 %

Procedure:
The mixture of 0.08 g (0.22 mole) of 2-chloro-7,7-difluoro-5-methyl-9-(2-phenoxy-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-304), 0.070 g (0.26 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.062 g (0.33 mole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in a pressure tube at 140 degrees overnight. After cooling, dichloromethane and saturated sodium carbonate were added. The mixture was extracted twice with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-20:80) gave 0.051 g of give 4-[7,7-difluoro-5-methyl-6-oxo-9-(2-phenoxy-ethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide as a white solid (I-304).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]2[C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][C:19]=3[O:21][CH3:22])[N:14]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]2=[O:32])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[C:33]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:22][O:21][C:19]1[CH:18]=[CH:17][C:16]([O:23][CH3:24])=[C:15]2[C:20]=1[C:12]1([C:3]3[C:2](=[CH:11][C:6]4[O:7][CH2:8][CH2:9][O:10][C:5]=4[CH:4]=3)[O:1][CH2:33]1)[C:13](=[O:32])[N:14]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31]
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: COCCOCCN1C(=O)C(c2cc3c(cc2O)OCCO3)c2c(OC)ccc(OC)c21
Product: COCCOCCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(OC)ccc(OC)c21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,7-dimethoxy-1-[2-(2-methoxyethoxy)ethyl]-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 4′,7′-dimethoxy-1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (24%): mp 109-110° C.; 1H NMR (300 MHz, CDCl3) δ6.80 (d, J=9.0 Hz, 1H), 6.47 (d, J=9.0 Hz, 1H), 6.39 (s, 1H), 6.24 (s, 1H), 4.76 (ABq, 2H), 4.26-4.03 (m, 6H), 3.81 (s, 3H), 3.77-3.69 (m, 2H), 3.64-3.59 (m, 2H), 3.59 (s, 3H), 3.49-3.43 (m, 2H), 3.31 (s, 3H); 13C NMR (75 MHz, CDCl3) δ178.4, 155.6, 150.4, 144.1, 139.7, 137.6, 131.0, 120.2, 119.5, 113.4, 111.1, 106.1, 98.7, 71.9, 69.8, 68.8, 64.5, 63.8, 59.0, 57.5, 56.4, 56.0, 41.2; MS (ES+) m/z 457.9 (M+1).