Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])(C)C.[CH:17](=[O:19])[CH3:18]>S(=O)(=O)(O)O>[CH3:11][C:9]1[CH:8]=[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]([OH:16])=[C:5]([CH:1]([C:18]2[CH:1]=[C:5]([CH3:10])[CH:6]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:17]=2[OH:19])[CH3:4])[CH:10]=1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC=O
Agent: O=S(=O)(O)O
Product: Cc1cc(C(C)c2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reaction time: 1 h
Yield: 70.4 %

Procedure:
Into the reactor described in the foregoing Example 1 there are charged 220 g (1.0 g-mol) of 2,6-ditert.butyl-4-methylphenol, 2.2 g of sulfuric acid and 44 g (1 g-mol) of acetaldehyde are fed into the reactor for one hour at the temperature of 125° C. On completion of the reaction, the reaction mass is treated following the procedure described in the foregoing Example 1 to give 124.6 g of 1,1,-bis-(5-methyl-3-tert.butyl-2-hydroxyphenyl)ethane which constitutes 96.4% of theory, as calculated for the reacted 2,6-ditert.butyl-4-methylphenol (conversion of the latter is 73%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[Br:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][N:26]([CH2:30][CH2:31]Cl)[CH2:27][CH2:28]Cl)=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:28][CH2:27][N:26]([CH2:25][C:24]2[CH:33]=[CH:34][C:21]([Br:20])=[CH:22][CH:23]=2)[CH2:30][CH2:31]1)=[O:19])[CH3:2]
Reactant: C#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Reactant: ClCCN(CCCl)Cc1ccc(Br)cc1
Product: C#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Br)cc3)CC2)cc1

Procedure:
1-(4-Bromo-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 6). Starting from (4-prop-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (21.62 g, 76.7 mmol) and (4-bromo-benzyl)-bis-(2-chloro-ethyl)-amine (31.9 g, 92 mmol), 23 g of the ester derivative was isolated. Yiel: (58%); yellow oil; MS: 521.9 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][CH2:5][C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][CH:7]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([CH3:23])=[CH:18][C:17]=1[S:24](Cl)(=[O:26])=[O:25]>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([CH3:23])=[CH:18][C:17]=1[S:24]([NH:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:5][O:4][CH2:3][C:2]([F:1])([F:13])[F:14])[N:11]=1)(=[O:26])=[O:25]
Reactant: Nc1cccc(COCC(F)(F)F)n1
Reactant: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Product: Cc1cc(S(=O)(=O)Nc2cccc(COCC(F)(F)F)n2)c(Cl)cc1Cl

Procedure:
This material was prepared in analogy to example 1 from 6-(2,2,2-Trifluoro-ethoxymethyl)-pyridin-2-ylamine (0.08 g) and 2,4-dichloro-5-methyl-benzenesulfonyl chloride (0.11 g) as a light yellow gum (0.095 g). MS (ESI−): 427.1 ([M−H]−).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OC(C)C)=O.C1(C)C=CC=CC=1.[NH2:35][CH2:36][CH:37]([OH:39])[CH3:38]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:11](=[O:13])[NH:35][CH2:36][CH:37]([OH:39])[CH3:38])[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(O)CN
Agent: CC(C)OC(=O)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(O)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
N-(tert-Butoxycarbonyl)-L-alanine (10.0 g, 52.8 mmol) is dissolved in 150 mL of THF. Once the triethylamine (11.0 ml, 79.2 mmol) is added, the solution is cooled to 0° C. Isopropyl chloroformate in toluene (1M) (52.8 ml, 52.8 mmol) is added slowly followed by the addition of (2RS) 1-amino-2-propanol (6.1 ml, 79.2 mmol). After stirring overnight, the mixture is washed with 1N sodium hydroxide and 1N hydrochloric acid. Concentration of the organic solvent afforded (2RS, 1S)-[1-(2-hydroxy-propylcarbamyl)-ethyl]-carbamic acid tert-butyl ester (9.92 g, 76% yield) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.C[O:9][C:10]([C:12]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[CH:25]=2)[C:15]2[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=2[CH:13]=1)=O>>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([NH:1][C:10]([C:12]2[CH:22]=[C:21]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[CH:25]=3)[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=2)=[O:9])=[N:3]1
Reactant: Cn1ccc(N)n1
Reactant: COC(=O)c1cc(Oc2ccc(C#N)c(Cl)c2)c2c(c1)OC(C)(C)C2
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C#N)c(Cl)c3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 3-amino-1-methyl-pyrazole (157 mg, 1.62 mmol) and 4-(3-chloro-4-cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (189a) (58 mg, 0.16 mmol) to give a white solid (53 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1 H) 7.91 (d, J=8.34 Hz, 2 H) 7.07 (dd, J=16.67, 8.34 Hz, 4 H) 6.78 (s, 1 H) 3.78 (s, 3 H) 2.90 (s, 2 H) 1.50 (s, 6 H); LCMS for C22H19ClN4O3 m/z 423.00 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13]C)=O)[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23].[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]3[N:10]([C:6]=2[CH:5]=[CH:4][N:3]=1)[CH2:23][CH:22]([C:21]([O:25][CH3:26])=[O:24])[C:11]3=[O:13]
Reactant: C=CC(=O)OC
Reactant: COC(=O)c1cc2c(Cl)nccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C1Cn2c(cc3c(Cl)nccc32)C1=O
Temperature: 100 °C

Procedure:
To a suspension of methyl 4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (12.5 g, 59 mmol) in THF (116 mL)-toluene (460 mL) were added a 1.0 M TBF solution of potassium tert-butoxide (64 mL, 64 mmol) and methyl acrylate (55 mL, 611 mmol). The resulting mixture was heated at 100° C. for 18 h. After this time, the suspension was cooled to room temperature and it was poured into a mixture of saturated aqueous NH4Cl (400 mL) and hexanes (400 mL). The solids were decanted, filtered and washed with H2O and hexanes to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:26](=O)[CH2:27][C:28]2[C:29]([C:34]([F:37])([F:36])[F:35])=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([O:43][CH2:44][CH3:45])(=[O:42])[NH:40][NH2:41].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[C:26](=[N:41]\[NH:40][C:39]([O:43][CH2:44][CH3:45])=[O:42])/[CH2:27][C:28]2[C:29]([C:34]([F:36])([F:35])[F:37])=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)NN
Reactant: O=C(Cc1cccnc1C(F)(F)F)c1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N/N=C(/Cc1cccnc1C(F)(F)F)c1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 1-(3,4-bis(benzyloxy)-5-nitrophenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)ethanone (0.485 g, 0.93 mmol), ethyl carbazate (0.11 g, 1.06 mmol) and p-toluene sulfonic acid (4 mg) in toluene (10 mL) was refluxed until distillation of water ceased. The reaction mixture was cooled to room temperature, the solvents were evaporated to dryness, and the crude solid was triturated with diethyl ether (15 mL), filtered and dried yielding (Z)-ethyl 2-(1-(3,4-bis(benzyloxy)-5-nitrophenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)ethylidene)hydrazinecarboxylate, 0.475 g (84%).
Reaction SMILES: Cl.C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:20])[CH2:13][NH:14][C:15]([CH2:18][CH3:19])([CH3:17])[CH3:16])=[CH:8][C:7]=1[F:21])(=O)C>>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:20])[CH2:13][NH:14][C:15]([CH2:18][CH3:19])([CH3:16])[CH3:17])=[CH:8][C:7]=1[F:21]
Reactant: CCC(C)(C)NCC(O)c1ccc(NC(C)=O)c(F)c1
Agent: Cl
Product: CCC(C)(C)NCC(O)c1ccc(N)c(F)c1

Procedure:
m.p. of the hydrochloride: 153°-155° C. (decomp.), was prepared from 1-(4'-acetylamino-3'-fluoro-phenyl)-2-tert.pentylaminoethanol analogous to Example 4.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2[CH2:16][C:17]([OH:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:23])(=O)=O>C1C=CC=CC=1>[Cl:23][C:8]1([CH2:16][C:17]([OH:19])=[O:18])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[C:11]2[CH:12]=[CH:13][CH:14]=[C:10]2[O:9]1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(O)Cc1oc2cccc-2cc1-c1ccccc1
Solvent: c1ccccc1
Product: O=C(O)CC1(Cl)OC2=CC=CC2=CC1c1ccccc1

Procedure:
3-Phenyl-7-benzofuranacetic acid, 6.0 g., is heated for 15 minutes with 3.4 g. of sulfuryl chloride in 50 ml. of benzene then left at room temperature overnight to give 2-chloro-3-phenyl-7-benzofuranacetic acid which precipitates from the reaction mixture. Recrystallization from benzene-hexane gives material of m.p. 150.5°-152° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[C:15](=[O:18])[NH:16][N:17]=[C:13]3[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11]([CH3:29])=[C:10]2[C:30]([OH:32])=[O:31])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][N:58]([CH2:60][CH2:61][CH2:62]O)[CH3:59]>CN(C=O)C>[CH3:57][N:58]([CH3:59])[CH2:60][CH2:61][CH2:62][O:31][C:30]([C:10]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[N:14]2[C:15](=[O:18])[NH:16][N:17]=[C:13]2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=2)[C:11]=1[CH3:29])=[O:32]
Reactant: CN(C)CCCO
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)n2c(n[nH]c2=O)N1c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC1=C(C(=O)OCCCN(C)C)C(c2ccc(C#N)cc2)n2c(n[nH]c2=O)N1c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of Example 9 (42 mg, 0.095 mmol) in DMF (1 mL), was added diiosopropylethylamine (33 μL, 0.19 mmol) followed by HATU (72 mg, 0.19 mmol). After 1 hour, N, N-dimethylpropanolamine (67 μL, 0.57 mmol) was added, and the reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was allowed to cool to RT then partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-6% (2 M NH3 in MeOH) in DCM to give the title compound as a white solid (15 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].Cl.[N:11]([O-])=[O:12].[Na+]>O>[N:11]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8])=[O:12]
Reactant: O=N[O-]
Reactant: O=C(O)C1COCCN1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CCOCC1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 142.6 %

Procedure:
To a solution of morpholine-3-carboxylic acid (6.96 g, 52 mmol) in water (20 ml), at 0° C. under nitrogen, was added concentrated hydrochloric acid (4 ml), followed by sodium nitrite (5.0 g, 72 mmol) in small portions. The mixture was stirred at 0° C. for 1 hr, and then concentrated under vacuum at 30 to 35° C. The residue was stirred with 200 ml of acetone and filtered. The filtrate was evaporated and the residue treated with 50 ml of THF and concentrated. The process was repeated with 2×50 ml of THF to give 11.87 g of light yellow foam; MS (ESI) m/z 159.2 (M−H).
Reaction SMILES: Br[CH2:2][CH:3]1[O:5][CH2:4]1.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=2)=[CH:9][C:8]=1[NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>O>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:16]=2)=[CH:9][C:8]=1[NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:2][CH:3]2[O:5][CH2:4]2)[CH:31]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(O)c1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OCC2CO2)c1

Procedure:
1-Bromo-2,3-epoxypropane (1.5 ml) was added to a stirred mixture of N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-hydroxybenzamide (1.5 g), caesium carbonate (2.84 g) and DMA (100 ml) and the resultant solution was stirred at ambient temperature for 18 hours. The mixture was poured into water (750 ml). The precipitate was isolated, washed with water and dried under vacuum at 60° C. There was thus obtained the title compound (1.3 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.73 (m, 1H), 2.85 (m, 1H), 3.2 (t, 4H), 3.75 (t, 4H), 3.91 (m, 1H), 4.43 (m, 1H), 7.2 (m, 3H), 7.37 (m, 4H), 7.66 (m, 3H), 7.56 (m, 3H), 7.8 (s, 1H), 9.9 (s, 1H), 10.14 (s, 1H); Mass Spectrum: M−H− 486.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12](/[C:15](/[CH3:19])=[CH:16]/[CH2:17][OH:18])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:20]([O:22][C@@H:23]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]>>[CH2:20]([O:22][C@@H:23]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:18][CH2:17]/[CH:16]=[C:15](/[C:12]2[CH:13]=[CH:14][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:10][CH:11]=2)\[CH3:19])=[CH:34][CH:35]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]
Reactant: COc1cccc(-c2ccc(/C(C)=C/CO)cc2)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(OC)c3)cc2)cc1)OCC
Yield: 59 %

Procedure:
The title compound (280 mg, 59%) was prepared as a colourless solid from (E)-3-(3′-methoxy-biphenyl-4-yl)-but-2-en-1-ol (254 mg, 1.00 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (250 mg, 1.05 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([C:15]2[CH:20]=[CH:19][C:18](Br)=[C:17]([CH2:22][C:23]3[CH:32]=[CH:31][C:26]4[O:27][CH2:28][CH2:29][O:30][C:25]=4[CH:24]=3)[CH:16]=2)[O:8][CH:7]([O:33][CH3:34])[C@H:6]1[O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[CH:39]1(P(C2CCCCC2)C2CCCCC2)CCCC[CH2:40]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(B(O)O)C>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([C:15]2[CH:20]=[CH:19][C:18]([CH2:39][CH3:40])=[C:17]([CH2:22][C:23]3[CH:32]=[CH:31][C:26]4[O:27][CH2:28][CH2:29][O:30][C:25]=4[CH:24]=3)[CH:16]=2)[O:8][CH:7]([O:33][CH3:34])[C@H:6]1[O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: COC1O[C@@H](c2ccc(Br)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCB(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc([C@@H]2OC(OC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1Cc1ccc2c(c1)OCCO2
Temperature: 90 °C
Reaction time: 8 h
Yield: 125.5 %

Procedure:
Step-III: To a stirred solution of acetic acid (3S,4R,5S,6S)-4,5-diacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-2-methoxy-tetrahydro-pyran-3-yl ester (700 mg, 1.18 mmol) in toluene (11 ml) was added tricyclohexylphosphine (132 mg, 0.47 mmol), a solution of potassium phosphate tribasic (1.0 g, 4.72 mmol) in water (1 ml), ethylboronic acid (262 mg, 3.54 mmol). The reaction mixture was degassed for 40 min then added palladium (II) acetate (39 mg, 0.18 mmol). Reaction mixture was stirred at 90° C. for overnight. Reaction mixture was cooled to room temperature and was filtered through celite bed, washed with ethyl acetate (10 ml). Organic layer was washed with water (15 ml) followed by brine (15 ml), dried over sodium sulfate, concentrated and purified by column chromatography to give 320 mg of acetic acid (3S,4R,5S,6S)-4,5-diacetoxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-2-methoxy-tetrahydro-pyran-3-yl ester as white solid.
Reaction SMILES: S(=O)(=O)(O)O.C(Cl)(Cl)Cl.[N+:10]([O-:13])(O)=[O:11].C(=O)([O-])[O-].[K+].[K+].[CH:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[N+:10]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O-:13])=[O:11]
Reactant: c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccccc1

Procedure:
Sulfuric acid was added to a chloroform solution containing the benzene. To the solution was then added nitric acid, and the mixture was heated at a temperature of 50° C. for five hours. After completion of the reaction, the organic layer was neutralized with a 5% aqueous potassium carbonate solution, washed with water, and dried on magnesium sulfate. The solvent was evaporated to give a white solid. The white solid was recrystallized in petroleum-derived ethanol to give nitrobenzene. The obtained nitrobenzene was allowed to react with hydrogen gas at a temperature of 200° C. in the presence of a nickel catalyst so that aniline was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)=[O:49])=[CH:44][C:43]=1[CH3:56]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([C:48]([N:50]6[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]6)=[O:49])=[CH:44][C:43]=5[CH3:56])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1cc(C(=O)N2CCCCC2)ccc1Br
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCCCC4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (50 mg) and (4-bromo-3-methyl-phenyl)-piperidin-1-yl-methanone (40 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-phenyl]-piperidin-1-yl-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-268) as a pale brown powder (14 mg, 30%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].C1C=CC=CC=1>O1CCCC1>[CH2:1]([NH:8][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[I:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1I
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: O=C(NCc1ccccc1)c1ccccc1I

Procedure:
A solution of 15 ml of benzylamine in 20 ml of tetrahydrofuran was reacted with a solution of 8.0 g of o-iodobenzoyl chloride in 20 ml of tetrahydrofuran in accordance with the procedure of Example 3. There was obtained by recrystallization from benzene 9.1 g of N-benzyl-o-iodobenzamide, m.p. 122°-123°, Rf 0.78.
Reaction SMILES: [OH-].[K+].[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]([N:17]([CH:21]([CH:27]2[CH2:29][CH2:28]2)[C:22]2[N:23]=[CH:24][NH:25][CH:26]=2)[CH2:18][CH2:19][CH3:20])[S:14][C:15]=1[CH3:16].[CH3:30]I>CC(C)=O.ClCCl>[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]([N:17]([CH:21]([CH:27]2[CH2:29][CH2:28]2)[C:22]2[N:23]=[CH:24][N:25]([CH3:30])[CH:26]=2)[CH2:18][CH2:19][CH3:20])[S:14][C:15]=1[CH3:16]
Reactant: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1c[nH]cn1)C1CC1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1cn(C)cn1)C1CC1
Reaction time: 0.08 h

Procedure:
Add 570 mg of powdered potassium hydroxide to 856 mg of the compound of Example 42 dissolved in 10 ml of acetone. Stir for 5 minutes and then add 0.14 ml of methyl iodide. After 15 minutes at room temperature, dilute the reaction mixture in 100 ml of dichloromethane, and then wash with water and with water saturated with sodium chloride. Dry the organic phase over sodium sulphate, evaporate to dryness and then subject the residue to chromatography on a silica column, using a mixture of cyclohexane and ethyl acetate (1:1 V/V) as eluent.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][C:5]1[N:10]=[C:9](Cl)[C:8]([F:12])=[C:7]([Cl:13])[N:6]=1>C1COCC1>[Cl:13][C:7]1[C:8]([F:12])=[C:9]([O:2][CH3:1])[N:10]=[C:5]([CH3:4])[N:6]=1
Reactant: C[O-]
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(C)nc(Cl)c1F
Temperature: 5 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
3.21 g of sodium methoxide are added to a solution of 9.8 g of 2-methyl-4,6-dichloro-5-fluoropyrimidine in 80 ml of THF cooled to 5° C. in an ice bath. The ice bath is removed. The suspension is stirred at ambient temperature for 3 hours. The reaction medium is cooled to 5° C. in an ice bath. 20 ml of water and 100 ml of ethyl acetate are added. After settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 9 g of 4-chloro-5-fluoro-6-methoxy-2-methylpyrimidine in the form of a colorless oil which crystallizes, the characteristics of which are the following:
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH2:11])=[CH:4][CH:3]=1.[Cl:12][C:13]([Cl:18])([Cl:17])[C:14](=[NH:16])[O-]>C(O)C>[I:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:11][CH:14]([C:13]([Cl:18])([Cl:17])[Cl:12])[NH:16][C:7]2=[O:9]
Reactant: N=C([O-])C(Cl)(Cl)Cl
Reactant: Nc1ccc(I)cc1C(=O)O
Solvent: CCO
Product: O=C1NC(C(Cl)(Cl)Cl)Nc2ccc(I)cc21
Temperature: 45 °C

Procedure:
To a solution of 5-iodoanthranilic acid (131.5 g, 500 mmol) in ethanol (700 mL), 2,2,2-trichloroacetimidate (88.2 g, 500 mmol) was added. The reaction mixture was heated at 45° C. for 3 days under stirring. The solid formed was filtered and washed with fresh ethanol and air-dried. Yield 129.51 g (66.4%). Mp 224°-225° C. 'H-NMR (DMSO) 7.59 (d, 1 h, J=8.6 Hz), 8.21 (dd, 1H, J=2 Hz, J=7.5 Hz), 8.44, 1H, J=1.9 Hz), 13.55 (bs, 1H).