Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Li+].C([N:6]1[C:14]2[C:9](=[CH:10][C:11](CC([O-])=O)=[CH:12][C:13]=2[CH3:15])[CH:8]=[N:7]1)(=O)C.[Cl-].[NH4+]>CO.O1CCCC1>[CH3:15][C:13]1[CH:12]=[C:11]([OH:1])[CH:10]=[C:9]2[C:14]=1[NH:6][N:7]=[CH:8]2
Reactant: CC(=O)n1ncc2cc(CC(=O)[O-])cc(C)c21
Reactant: [OH-]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(O)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A 2N-aqueous lithium hydroxide solution (3.7 ml, 7.4 mmol) was added to a solution of (1-acetyl-7-methyl-1H-indazol-5-yl)acetate (850 mg, 3.66 mmol) in methanol-tetrahydrofuran (1:1, 7.4 ml), and the resulting mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was poured into the reaction solution, followed by extraction with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then distilled under reduced pressure to remove the solvent. The residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=100:3) to obtain 7-methyl-1H-indazol-5-ol (505 mg, 93%).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])=[CH:11][CH:10]=1
Reactant: COc1ccc(CCCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(CCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 70.1 %

Procedure:
Pyridine (15 mL) was added drop wise to a cooled (0° C.) solution of 4-(4-methoxyphenyl)butanol (10.0 g, 0.055 mol) and p-toluenesulfonyl chloride (13.6 g, 0.072 mol) in dry chloroform (100 mL) under stirring. The reaction mixture was stirred overnight at room temperature. After this time, the reaction was quenched with 10% HCl (300 mL) and extracted with chloroform. The organic fraction was washed with saturated NaHCO3, water and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (eluent: hexane/ethyl acetate 15:1) to provide 12.9 g (66%) of 1 as clear oil. 1H NMR (360 MHz, CDCl3) δ 1.61 (m, 4H), 2.44 (s, 3H), 2.52 (m, 2H), 3.78 (s, 3H), 4.05 (m, 2), 6.77 (d, 2H), 7.05 (d, 2H), 7.34 (d, 2H), 7.78 (d, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([Cl:27])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[N:38]=[C:39]=[O:40]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH:24][C:39]([NH:38][C:32]4[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=4[F:30])=[O:40])=[C:22]([Cl:27])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OCc1ccccc1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2-chloroaniline (260 mg) was dissolved in chloroform (10 ml). 2,4-Difluorophenyl isocyanate (198 mg) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was purified by chromatography on silica gel by development with chloroform/acetone (10/1) to give 337 mg (yield 94%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]Cl)[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH2:28][C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: ClCc1cccnc1
Reactant: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-(4-(4-cyanophenyl)phenyl)-N-ethylsulfonylamine (200 mg, 0.7 mmol), 3-picolyl chloride hydrochloride (123 mg, 0.75 mmol), and cesium carbonate (2.3 g, 7.0 mmol) was dissolved in 10 ml DMF and stirred for 18 h at room temperature. The mixture was diluted with 80 ml ethyl acetate, 20 ml water. The organic phase was separated and washed twice with 25 ml of water. The organic phase was then dried over sodium sulfate, filtered, and concentrated in vacuo to an oily residue. The residue was flushed through a 20 g mega bond elut silica column with 0 to 5% methanol/ethyl acetate. The desired fractions were concentrated in vacuo to afford the title compound. 1H NMR: 8.55 (bs,1H), 8.41 (bs,1H), 7.78 (d,1H,J=8 Hz), 7.72 (d,2H,J=12 Hz), 7.6 (d,2H,J=12 Hz), 7.52 (d,2H,J=12 Hz), 7.35 (d,2H,J=12 Hz), 7.29 (m,1H), 4.95 (s,1H), 3.15 (q,2H,J=8 Hz), 1.45 (t,3H,J=8 Hz). MS calcd. 377.5; MS (M+1) 378.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: Cc1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc1

Procedure:
The title compound was prepared from the product of Example 65A and 4-methylphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 320.0 (M+H)+, retention time 1.37 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1>CO.[C].[Pd]>[NH2:12][C:11]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cnc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cnc(N)c(N)c1

Procedure:
1 Gram of methyl 6-amino-5-nitronicotinate was dissolved in 10 m of methanol. To this solution was added 0.1 g of 5%-palladium-carbon, then hydrogen gas was absorbed at room temperature under a normal pressure. The reaction was stopped when the stoichiometric amount of hydrogen was absorbed. The catalyst was removed from the reaction mixture by filtration, and the solvent was removed by evaporation. The residue thus obtained was recrystallized from ethanol to yield 0.8 g of methyl 5,6-diaminonicotinate in the form of yellow needle-like crystals. Melting point: 154°-155° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]#[C:21][C:22]([C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1C(OC(C)(C)C)=O)=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:37][OH:38].C(=O)(O)[O-].[Na+]>CCO>[Si:1]([O:18][CH2:19][C:20]1[O:38][N:37]=[C:22]([C@@H:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)[CH:21]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)C#CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[Si](OCc1cc([C@@H]2CCCN2)no1)(c1ccccc1)c1ccccc1
Yield: 40.1 %

Procedure:
To an EtOH (10 mL) solution of the compound (492 mg) obtained in Example 3-(1), hydroxylamine hydrochloride (139 mg) was added and the mixture was heated under reflux for 17 hours. To the reaction mixture, saturated aqueous sodium bicarbonate (50 ml) was added and the organic layer extracted with AcOEt was dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by neutral silica gel chromatography (AcOEt→MeOH/CHCl3) to give the titled compound (163 mg, brown oil.)
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:13](Cl)(Cl)[C:14]([OH:16])=[O:15].[CH2:19]([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)C>[CH2:1]([O:8][C@@H:13]1[C@@H:10]([OH:11])[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:9]([CH2:10][O:11][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:16][CH:14]1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCOCc1ccccc1
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Solvent: CCOCC
Product: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Yield: 85 %

Procedure:
Freshly distilled benzyloxyacetaldehyde (150 mg, 1.0 mmol) was added to a stirring solution of (2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one trichloroacetate (27.3 mg, 67 mmol) in diethyl ether (330 μL, 3.0 M) at −20° C. After complete consumption of the starting material was determined by TLC analysis (24 h), the reaction mixture was diluted with ethyl acetate, washed with saturated NH4Cl, brine, dried over anhydrous Na2SO4 and concentrated in vacuo. Flash chromatography (19:1 dichloromethane:diethyl ether) afforded the title compound as a clear, colorless oil in 85% yield (104 mg, 0.69 mmol), 95% ee, and 11:1 dr. 1H NMR (300 MHz, CDCl3) δ 7.31 (m, 15H, Ar—H), 5.38 (m, 1H, OCHO), 4.83 (m, 1H, CHCH2), 4.55 (br, m, 5H), 4.12 (br m, 1H, 3.64 (br m, 4H, CHO), 3.30 (m, 1H, CHO); 13C NMR (75 MHz, CDCl3) δ (α-anomer) 90.4 (C-1), 74.6 (C-3), and 68.9 (C-6); (β-anomer) 97.3 (C-1), 76.9 (C-3), 69.2 (C-6), which is consistent with previously reported values (Ito et al. (1980) Carbohydrate Res. 86:193).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[C:21]([CH2:23][N:24]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[S:25]([CH3:28])(=[O:27])=[O:26])#[N:22]>CN(C=O)C>[C:21]([CH2:23][N:24]([C:29]1[CH:35]=[CH:34][C:32]([NH:33]/[C:4](=[C:11]2\[C:12](=[O:20])[NH:13][C:14]3[C:19]\2=[CH:18][CH:17]=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:31][CH:30]=1)[S:25]([CH3:28])(=[O:27])=[O:26])#[N:22]
Reactant: CS(=O)(=O)N(CC#N)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)Nc2ccccc21)c1ccccc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)N(CC#N)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 11 from 3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-(N-cyanomethyl-N-methylsulphonyl-amino)-aniline in DMF.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[N:22][CH:23]=[C:24]([CH:27]=2)[CH:25]=[O:26])O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:25]([C:24]1[CH:27]=[C:20]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=2)[CH:21]=[N:22][CH:23]=1)=[O:26]
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Reactant: COc1cc(Br)ccc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(-c2cncc(C=O)c2)ccc1C#N
Temperature: 90 °C
Yield: 90.2 %

Procedure:
A mixture of 4-bromo-2-methoxybenzonitrile (0.424 g, 2.000 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinaldehyde (0.466 g, 2.000 mmol), tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.050 mmol) and sodium carbonate (2M in water, 2.00 mL, 4.00 mmol) in DME (50 mL) was heated to 90° C. for 6 h. After filtration through a pad of dry Na2SO4 and concentration, the residue was purified by column and yielded a colorless solid (430 mg). 1H NMR (400 MHz, CDCl3): δ 4.04 (s, 3H), 6.99 (s, 1H), 7.27 (d, J=4.7 Hz, 1H), 7.71 (d, J=7.9 Hz, 1H), 8.34 (t, J=2 Hz, 1H), 9.07 (d, J=2.36 Hz, 1H), 9.12 (d, J=1.9 Hz, 1H), 10.22 (s, 1H).
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].[H-].[Na+].[CH3:18][O:19][CH2:20][CH2:21][SH:22]>CN(C=O)C>[CH3:18][O:19][CH2:20][CH2:21][S:22][C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6]
Reactant: Cc1c(C(=O)O)ccc(C(F)(F)F)c1F
Reactant: COCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCSc1c(C(F)(F)F)ccc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.45 g (6.53 mmol) of 3-fluoro-2-methyl-4-trifluoromethylbenzoic acid were initially charged in 40 ml of DMF. 809 mg (20.2 mmol) of NaH were added a little at a time. After the evolution of gas had ceased, 1.20 g (13.1 mmol) of 2-methoxyethanethiol were added a little at a time. The mixture was stirred at RT for 10 minutes and then heated at 80° C. for 15 h. The reaction mixture was cooled and concentrated under reduced pressure, and for work-up water was added and the mixture was acidified with 1M HCl. The product precipitated and was removed by filtration. The product was then washed with water and n-heptane. What was isolated were 1.7 g of the pure product.
Reaction SMILES: C.C1C(Br)=C(Br)[NH:4]C=1C(O)=[O:10].[S:12]([O-:22])(=[O:21])([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)=[O:13].[Na+].[N+]([O-])(O)=O.N([O-])=O.[Na+]>O>[OH-:10].[S:12]([C:14]1[CH:15]=[CH:16][C:17]([N+:20]#[N:4])=[CH:18][CH:19]=1)([OH:22])(=[O:21])=[O:13]
Reactant: Nc1ccc(S(=O)(=O)[O-])cc1
Reactant: O=C(O)c1cc(Br)c(Br)[nH]1
Agent: C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: N#[N+]c1ccc(S(=O)(=O)O)cc1
Product: [OH-]
Reaction time: 0.02 h

Procedure:
This example illustrates another method for preparing a carbon black product of the present invention. A pin pelletizer was charged with 200 g of a carbon black with a CTAB surface area of 350 m2/g and a DBPA of 120. A solution of 44.2 g of sodium sulfanilate in 95 g of water at 70° C. was added and the pelletizer was run for one minute. Twenty grams of water was added followed by 39.6 g of concentrated nitric acid. The pelletizer was run for an additional minute. Twenty grams of water was added followed by a solution of 16.76 g of sodium nitrite in 35 g of water, forming 4-sulfobenzenediazonium hydroxide inner salt in situ, which reacted with the carbon black. After running the pelletizer for five minutes, a solution of 11.22 g of sodium hydroxide in 35 g of water was added. The pelletizer was run for an additional two minutes and the resulting a carbon black product was subsequently dried. Soxhlet extraction with ethanol overnight gave a carbon black product with 3.3% sulfur, compared against 0.5% for the untreated carbon black. This shows that 77% of the p-C6H4SO3-- groups were attached to the carbon black product. Therefore, the carbon black product had 0.88 mmol/g of attached p-C6H4SO3 -- groups.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH:12]([OH:17])[CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2>O1CCCC1.C([BH-](CC)CC)C.[Li+]>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]([OH:16])[CH2:13][CH:12]([OH:17])[CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CC(O)CC2=O
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c2c(nc3ccccc13)CC(O)CC2O
Reaction time: 0.5 h

Procedure:
A suspension of 9-amino-3,4-dihydro-3-hydroxyacridin-I (2H)-one (2.07 g) in tetrahydrofuran (125 ml), lithium triethylborohydride (1 molar in tetrahydrofuran, 27 ml) was allowed to stand for 0.5 hrs. The reaction mixture was quenched with methanol. The mixture was preadsorbed on silica, and flash chromatographed on silica gel (1:2: 17-dichloromethane:triethylamine). The appropriate fractions were collected. Evaporation of the more polar fractions gave 0.541(25.8%) of 9-amino1,2,3,4-tetrahydro-1,3-acridinediol, mp 139°-141 ° C.
Reaction SMILES: Br[C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:21])[C@:16]1([CH3:17])[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]1)=[CH:10][CH2:9]3.[O:22]=O.[OH-].[Na+].Cl>N1C=CC=CC=1.O>[OH:22][C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:21])[C@:16]1([CH3:17])[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]1)=[CH:10][CH2:9]3
Reactant: C[C@]12CCCCC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@H](Br)C[C@@H]12
Reactant: O=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: C[C@]12CCCCC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@H](O)C[C@@H]12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 16α-Bromo-5-androsten-17-one (7.92 g, 20 mmoles) in pyridine (300 ml) and water (64 ml) in an oxygen atmosphere was added 36 ml (36 mmoles) of 1N NaOH. After stirring the mixture for 15 minutes at room temperature under O2, it was added to 1 L of ice water containing 330 ml of concentrated HCl. The crystallized precipitate which formed was filtered off, washed with water, and recrystallized from methanol as leaflets (2, 80 g), mp 168°-172°. HPLC of the mother liquor on a silica gel column using isopropyl alcohol n-hexane as eluent furnished an additional 1.4 g of light yellow prisms, mp 170°-174°. The total yield of 16α-ol was 3.94 g (68.4%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[N:35]3[CH:39]=[CH:38][CH:37]=[CH:36]3)[CH2:24][CH:23]2[OH:40])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[N:35]3[CH:39]=[CH:38][CH:37]=[CH:36]3)[CH2:24][C:23]2=[O:40])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:11]
Reactant: O=C(NC1(C(=O)NC2CCN(c3cc(F)ccc3-n3cccc3)CC2O)CCCCC1)c1cc2ccccc2o1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NC1(C(=O)NC2CCN(c3cc(F)ccc3-n3cccc3)CC2=O)CCCCC1)c1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To the solution 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-[2-(pyrrol-1-yl)-5-fluorophenyl]piperidin-3-ol (1.8 g) obtained in Step 1 in 10 ml of dimethylsulfoxide, was added 2 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (1.8 g) was added to the reaction mixture, which was then stirred for about 2 hours at room temperature. The reaction mixture was diluted with 50 ml of ethyl acetate, washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 1.5 g of the titled compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][O:60][CH2:59][C:58]1=[O:63]>C(Cl)Cl.C1COCC1>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:55][CH2:56][N:57]4[CH2:62][CH2:61][O:60][CH2:59][C:58]4=[O:63])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: O=C1COCCN1CCO
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN1CCOCC1=O
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.6 %

Procedure:
Diethyl azodicarboxylate (400 mg, 2.3 mmol) was added dropwise to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.78 mmol), (prepared as described for the starting material in Example 2), triphenylphosphine (615 mg, 2.3 mmol) and 4-(2-hydroxyethyl)-3-morpholinone (170 mg, 1.17 mmol), (EP 580402A2), in methylene chloride (5 ml) under nitrogen. The mixture was stirred for 4 hours at ambient temperature, methylene chloride (5 ml) was added and stirring was continued for a further 18 hours at ambient temperature. THF (5 ml). 4-(2-hydroxyethyl)-3-morpholinone (113 mg, 0.78 mmol). triphenylphosphine (204 mg, 0.78 mmol) were added and diethyl azodicarboxylate (136 mg, 0.78 mmol) was then added dropwise. The mixture was stirred for 5 minutes at ambient temperature, and was purified by pouring directly onto a silica column, eluting with methylene chloride/ethyl acetate/methanol (5/4/1). The purified solid was dissolved in methylene chloride and 2M methanolic hydrogen chloride (0.5 ml) was added. The mixture was concentrated by evaporation and then diluted with ether. The resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(3-oxomorpholino)ethoxy)quinazoline hydrochloride (150 mg, 39%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][N:11]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([N:11]([CH2:24][C:25]([F:28])([F:26])[F:27])[CH2:10][CH2:9][S:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:3][CH:4]=2)=[CH:13][C:14]=1[C:20]([F:21])([F:22])[F:23])#[N:17]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(N(CCSc2ccc(N)cc2)CC(F)(F)F)cc1C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(SCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.2 %

Procedure:
A solution of 4-[{2-[(4-aminophenyl)thio]ethyl}(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.038 g, 0.091 mmol; see Example 74A) in CH2Cl2 (4 mL) was treated under N2 with TEA (0.010 g, 0.099 mmol) and MsCl (0.011 g, 0.099 mmol) and stirred at rt. After 4 h, additional TEA (0.0046 g, 0.046 mmol) and MsCl (0.0052 g, 0.046 mmol) were added and stirred at rt. After 1 h, the mixture was concentrated in vacuo and the residue taken up in CHCl3 (4 mL) and heated at 70° C. for 2 h. Upon cooling, additional TEA (0.0046 g, 0.046 mmol) and MsCl (0.0052 g, 0.046 mmol) were added and heated at 70° C. for 12 h. Upon cooling, additional TEA (0.0092 g, 0.091 mmol) and MsCl (0.0104 g, 0.091 mmol) were added and heated at 70° C. for 4 h. The mixture was partitioned between EtOAc and 0.1N HCl. The organic phase was washed with 0.1N HCl and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (5-80% EtOAc/hexanes gradient) to give the title compound (0.025 g, 55% yield): MS (ES) m/z 496 (M−1).