Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]=[CH:6][C:7](=[O:9])[CH:8]=1.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH2:13]>C(O)(C)C>[CH3:1][O:2][C:3]1[C:4](=[O:10])[C:5]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12]([CH3:13])=[CH:11][C:6]=2[C:7](=[O:9])[CH:8]=1
Reactant: C=C(C)c1ccccc1
Reactant: COC1=CC(=O)C=CC1=O
Solvent: CC(C)O
Product: COC1=CC(=O)c2cc(C)c3ccccc3c2C1=O
Yield: 2.5 %

Procedure:
2-Methoxy-1,4-benzoquinone (30.0 g, 72 mM) and α-Methylstyrene (236 g, 2.0 M) were dissolved in 290 ml of isopropanol and refluxed for 30 hours. The reaction solution was subjected to vacuum distillation to recover isopropanol and α-Methylstyrene, and the reaction solution was concentrated. The resulting product was purified by chromatography to give to 1.38 g (5.47 mM) of 3-Methoxy-9-methyl-1,4-phenanthrenequinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]1[CH2:39][O:38][CH2:37][CH2:36][O:35]1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:39][O:38][CH2:37][CH2:36][O:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: O=S(=O)(OCC1COCCO1)C(F)(F)F
Product: COc1cn(C(CC2COCCO2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
346 mg (purity 93%, 0.86 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in the presence of 0.95 ml (0.95 mmol, 1.1 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 430 mg (purity 90%, 1.55 mmol, 1.8 eq.) of 1,4-dioxan-2-ylmethyl trifluoromethanesulphonate (racemate) were reacted according to General Method 7B. Yield: 133 mg (33% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:17])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(Br)c1
Yield: 91 %

Procedure:
A stirred solution of (3-bromophenyl)acetic acid (10.0 g, 0.0465 mol) and concentrated sulfuric acid (4.5 mL) in MeOH (230 mL) was heated at 40° C. for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was mixed with water (50 mL) and DCM (100 mL). The layers were separated and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-10% EtOAc/hexanes) to give the title compound (19.8 g, 91% yield) as a colorless oil.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[C:6]([C:10]1[CH:15]=[C:14]([SH:16])[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[OH:21])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:6]([C:10]1[CH:15]=[C:14]([S:16][CH:3]([CH3:4])[CH2:2][CH:1]=[O:5])[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[OH:21])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C/C=C/C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(CC=O)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 2 h

Procedure:
3.12 Grams of crotonaldehyde (0.042 mole) are added dropwise over a 15 minute period at 17°-22° C. to a solution of 10.8 grams of 2,6-di-tert-butyl-4-mercaptophenol (0.044 moles) and 0.5 gram of triethylamine in 20 ml of toluene and allowed to react in a nitrogen atmosphere at room temperature for 30 minutes and then at 50°-55° C. for two hours. Analysis indicates that the reaction is substantially complete at this point. The product, isolated as a light yellow liquid, is obtained in nearly quantitative yield after stripping off volatiles at 40° to 50° C. at 0.15 mm. Hg.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>ClCCl>[CH:13]1([NH:16][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:15][CH2:14]1
Reactant: Fc1ccc2c(Cl)ncnc2c1
Reactant: NC1CC1
Solvent: ClCCl
Product: Fc1ccc2c(NC3CC3)ncnc2c1
Yield: 36.9 %

Procedure:
4-Chloro-7-fluoro-quinazoline (0.73 g, 4 mmol) and cyclopropylamine (0.23 g, 4 mmol) are stirred in dichloromethane at ambient temperature overnight. The solid product is precipitated with hexanes, filtered, and washed with hexane and ethyl acetate, affording 0.3 g of desired Cyclopropyl-(7-fluoro-quinazolin-4-yl)-amine. The filtrate is concentrated and precipitated with hexanes, yielding an additional 0.35, for a combined yield of 80%. LC/MS m/z=204 [M+H]+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>O.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>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: OB(O)c1cccc(Cl)c1
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
Solvent: O
Product: Clc1cccc(-c2ccc3ccccc3n2)c1
Yield: 77.5 %

Procedure:
2-chloroquinoline (9.25 g, 56.5 mmol), (3-chlorophenyl)boronic acid (9.28 g, 59.4 mmol), Pd(PPh3)4 (1.634 g, 1.413 mmol) were charged into the reaction flask with 300 mL of 1,2-dimethoxyethane. Sodium carbonate (14.98 g, 141 mmol) was dissolved in 50 mL of water and was charged into the reaction flask. The reaction flask was then evacuated and back-filled with nitrogen then was heated to reflux for 20 hours. The organic layer was separated and dried over magnesium sulfate. The organics were filtered and stripped under vacuum. The crude residue was passed through a silica gel column using 5-25% ethyl acetate/hexanes yielding 2-(3-chlorophenyl)quinoline (10.5 g, 77% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.CCN(CC)CC.[CH:26]([Si:29](OS(C(F)(F)F)(=O)=O)([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])([CH3:28])[CH3:27]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:12][CH2:13][CH:14]([CH2:17][O:18][Si:29]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:26]([CH3:28])[CH3:27])[CH2:15][CH2:16]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: OCC1CCN(c2nnc3ccc(F)cn23)CC1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](OCC1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of Intermediate 54a (470 mg, 1.88 mmol) and Et3N (390 μL, 2.82 mmol) in DCM (5 mL) was added triisopropylsilyltrifluoromethane sulfonate (607 μL, 2.26 mmol) and the mixture stirred at RT for 0.5 h. The mixture was washed with sat. aq. NaHCO3 solution, dried and concentrated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane, then 10% MeOH in EtOAc, to give the title compound as a pale yellow solid (565 mg, 74%). LCMS (Method 3): Rt 5.21 min, m/z 407 [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH:26]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:29][C:30]([OH:32])=[O:31].N1CCCCC1.Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=2)=[CH:11][C:10]=1/[CH:26]=[CH:29]/[C:30]([OH:32])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccccc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 110.1 %

Procedure:
A mixture of 4-benzyloxy-4′-(trifluoromethoxy)biphenyl-3-carbaldehyde (4.0 g, 9.336 mmol), malonic acid (2.137 g, 20.539 mmol), pyridine (4.3 ml) and piperidine (184 μl, 1.867 mmol) was refluxed for 1 hour under argon atmosphere. The reaction mixture was cooled to room temperature, adjusted to pH 1 by addition of 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (4.26 g, 97.0%) as a white solid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:8][C:7]=1[Cl:16].C(N(C(C)C)C(C)C)C>ClCCl>[Cl:16][C:7]1[CH:8]=[C:9]([S:12]([NH2:15])(=[O:13])=[O:14])[CH:10]=[CH:11][C:6]=1[N:5]=[C:1]=[O:2]
Reactant: Nc1ccc(S(N)(=O)=O)cc1Cl
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(N=C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a round bottom flask containing a solution of phosgene (1.573 mL) in dichloromethane (5 mL) was added 4-amino-3-chlorobenzenesulfonamide (0.206 g) and N-ethyl-N-isopropylpropan-2-amine (0.521 mL). The resulting clear solution was stirred at room temperature overnight. The mixture was concentrated and further dried under vacuum to provide the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[CH2:8][N:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]1[CH2:16]O>>[Cl:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[CH2:8][N:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]1[CH2:16][Cl:3]
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(CO)n(Cc2ccccc2Cl)c1C
Product: Cc1nc(CCl)n(Cc2ccccc2Cl)c1C
Temperature: 50 °C

Procedure:
To 3 ml of thionyl chloride is added 2.39 g (9.5 mmol) of 1-(2′-chlorobenzyl)-4,5-dimethyl-2-hydroxymethyl-imidazole. The mixture is heated at 50° C. for about 5 min., and the thionyl chloride is evaporated in vacuo. The residue is dissolved in 10 ml of dichloromethane, then evaporated in vacuo. This is repeated twice to give 1-(2′-chlorobenzyl)-4,5-dimethyl-2-chloromethylimidazole as a cream colored foam which is used in next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)/[C:3]=1[CH2:20][CH2:21][N:22]([OH:26])C(N)=O.ClC1C=C(C=CC=1)C(OO)=[O:32]>ClCCl>[NH:22]([CH2:21][CH2:20][C:3]1/[C:4](=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:19])=[O:32])=[CH:16][CH:17]=2)/[C:5]2[C:10]([C:2]=1[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)[OH:26]
Reactant: CSc1ccc(/C=C2/C(CCN(O)C(N)=O)=C(C)c3ccccc32)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1=C(CCNO)/C(=C/c2ccc(S(C)=O)cc2)c2ccccc21

Procedure:
To a solution of the hydroxylamine from Example 16, Step 6 (130 mg, 0.40 mmol) in dichloromethane (5 mL) at 0° C. was added in one portion 85% m-chloroperoxy benzoic acid (90 mg, 0.44 mmol, 1.1 eq.). After 45 minutes the reaction mixture was diluted with dichloromethane and washed successively with 1N aqueous sodium hydroxide, water, brine, dried over MgSO4 and evaporated to dryness. The residue was chromatographed on silica gel eluting with a 30:1 mixture of dichloromethane:methanol to yield the title compound as yellow oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([OH:24])[CH:12]=[C:13]([Cl:23])[C:14]=1[O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C(=O)N([Br:32])C(=O)C1>CN(C=O)C.O>[Br:32][C:12]1[C:13]([Cl:23])=[C:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:10][C:11]=1[OH:24]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(O)cc(Cl)c1O[Si](C)(C)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(O)c(Br)c(Cl)c1O[Si](C)(C)C(C)(C)C
Yield: 70 %

Procedure:
A solution of 0.050 g (0.12 mmol) of 16 and 0.023 g (0.12 mmol) of NBS in 2 mL of DMF under argon was stirred at 25° C. for 1 day. The reaction mixture was diluted with 30 mL of water, extracted three times with diethyl ether (40 mL each), and the combined extracts were washed with brine (30 mL), dried (MgSO4), and concentrated to give 0.042 g (70% yield). This material was used in next step without purification. 1H NMR (CDCl3) δ 6.53 (s, 1H, Ar, C6-H), 1.03 (s, 9H, t-Bu), 0.96 (s, 9H, t-Bu), 0.22 (s, 6H, Me), 0.17 (s, 6H, Me); 13C NMR (CDCl3) δ 148.3 (s), 147.4 (s), 138.8 (s), 127.0 (s), 106.9 (d), 102.9 (s), 26.2 (q, t-Bu), 18.8 (s), −3.3 (q, Me), −3.5 (q, Me).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:20][C:19](=O)[C:18]3[C:13](=[CH:14][C:15]([F:31])=[C:16]([O:22][C:23]4[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:30])[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[Li+].[Cl-].O=P(Cl)(Cl)[Cl:36].CCN(C(C)C)C(C)C>C(#N)C>[Cl:36][C:19]1[C:18]2[C:13](=[CH:14][C:15]([F:31])=[C:16]([O:22][C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH:17]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]2)[N:20]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(Oc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2nc(Cl)c3cc(Oc4c(C)cccc4C)c(F)cc3n2)c1
Temperature: 25 °C

Procedure:
A mixture of the above 1-[6-(2,6-dimethyl-phenoxy)-7-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (5.0 g, 12 mmol), LiCl (2.5 g, 59 mmol), POCl3 (5.5 ml, 59 mmol), DIEA (10 mL, 59 mmol), and acetonitrile (ACN) (50 mL) was heated to reflux for 6 h. The mixture was allowed to cool to rt and then concentrated. The residue was taken up in a minimal amount of DCM and passed through a pad of silica gel, eluting with 50:50 hexanes/EtOAc. The resulting solution was concentrated to provide the titled compound. (5.2 g, >99%). 1H NMR (500 MHz, DMSO-d6): 9.13 (d, J=0.6 Hz, 1H), 8.23 (d, J=0.6 Hz, 1H), 7.92 (d, J=10.7 Hz, 1H), 7.23-7.19 (m, 3H), 7.07 (d, J=8.6 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 2.19 (s, 6H), 1.40 (t, J=7.1 Hz, 3H).
Reaction SMILES: O.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.[F:29][C:30]1[CH:59]=[CH:58][CH:57]=[C:56]([F:60])[C:31]=1[C:32]([NH:34][C:35]1[CH:39]=[CH:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47]CC3C=CC=CC=3)=[CH:43][C:42]=2[CH3:55])[N:36]=1)=[O:33]>[Pd].C(OCC)(=O)C>[F:29][C:30]1[CH:59]=[CH:58][CH:57]=[C:56]([F:60])[C:31]=1[C:32]([NH:34][C:35]1[CH:39]=[CH:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][C:42]=2[CH3:55])[N:36]=1)=[O:33]
Reactant: Cc1cc(OCc2ccccc2)ccc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(O)ccc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Reaction time: 1.5 h

Procedure:
To 10% palladium on carbon 50% wt water, degussa type E101 NE/W (406 mg, 3.82 mmol) was added under vacuum a solution of 2,6-difluoro-N-[1-({2-methyl-4-[(phenylmethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl]benzamide (for a preparation see Example 47)(1.79 g, 4.13 mmol) in ethyl acetate (30 ml). The suspension was hydrogenated at ambient temperature for 1.5 h. The suspension was filtered through a celite cartridge (10 g) and the cartridge washed with methanol (100 ml). The solvent was removed in vacuo to give the title compound as a grey foam (1.34 g);
Reaction SMILES: [CH2:1]([C:3]1[C:8]([NH2:9])=[CH:7][C:6]([N+:10]([O-])=O)=[CH:5][N:4]=1)[CH3:2].[H][H]>CO>[NH2:10][C:6]1[CH:7]=[C:8]([NH2:9])[C:3]([CH2:1][CH3:2])=[N:4][CH:5]=1
Reactant: CCc1ncc([N+](=O)[O-])cc1N
Reactant: [H][H]
Solvent: CO
Product: CCc1ncc(N)cc1N

Procedure:
9 g of the nitro compound of Stage 1 are hydrogenated in methanol on platinum with hydrogen at standard pressure and at room temperature. On taking up the theoretical amount of hydrogen the mixture is filtered off from the catalyst and concentrated. The residue (6.8 g) is used in Stage 3 without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:28]1[N:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=1>CN1C(=O)CCC1.C(OCC)(=O)C>[F:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:28]4[N:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(F)c(N2CCC(C3CCNCC3)CC2)n1
Reactant: Fc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ncc(F)c(N2CCC(C3CCN(c4ncc(F)cn4)CC3)CC2)n1
Temperature: 70 °C

Procedure:
1-(5-fluoro-2-methylpyrimidin-4-yl)-4,4′-bipiperidine (16 mg, 0.058 mmol) and cesium carbonate (57 mg, 0.17 mmol) were stirred in NMP (0.6 ml) and 2-chloro-5-fluoropyrimidine (0.014 mL, 0.116 mmol) was added. The mixture was heated at 70° C. for 1 h. The reaction was cooled down to r.t. and diluted with ethyl acetate (5 mL) and was washed with water 2 mL (×1) and brine 2 mL (×1). The organic phase was dried over magnesium sulfate, filtered, and concentrated on rotavapor. The crude material was purified by preparative TLC with 30% acetone: hexane to yield the titled compound. LC-MS: 375.06 (M+H). Examples reported in Table 14 are prepared in accordance with Procedure 14.1.
Reaction SMILES: C1(O)(O)CCCC1.N1C=CC=CC=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C([O:28][C:29](=[O:31])[CH3:30])(=O)C>ClCCl>[C:29]([O:28][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21])(=[O:31])[CH3:30]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)OC(C)=O
Agent: OC1(O)CCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 7 (10 g, 40 mmol, 1 equiv) and pyridine (22.6 mL, 280 mmol, 7 equiv) in dichloromethane (200 mL) was added p-toluenesulfonyl chloride (11.4 g, 60 mmol, 1.5 equiv). The mixture stirred at room temperature overnight. Pyridine (22.6 mL, 280 mmol, 7 equiv) and acetic anhydride (21.9 mL, 232 mmol, 5.8 equiv) were added at room temperature and the mixture was stirred overnight. The reaction was cooled to 5° C. and quenched with 2 N aq NaOH to pH 7. The aqueous layer was separated and extracted with dichloromethane (2×50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. The resulting semi-solid was dissolved in isopropyl acetate (100 mL) and concentrated to dryness. This was repeated 2 more times. The resulting semi-solid was triturated in methyl tert-butyl ether (250 mL), filtered and dried under vacuum to afford 8.1 g of 8 (45%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.I[C:12]1[C:20]2[C:15](=[N:16][CH:17]=[N:18][C:19]=2[NH2:21])[N:14]([CH:22]([CH3:24])[CH3:23])[N:13]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.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>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[C:20]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1ccc(O)cc1
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: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc(O)cc2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 34.3 %

Procedure:
A solution of 4-Hydroxyphenylboronic acid (30 mg, 0.14 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA56 (12 mg, 32% yield). ESI-MS (M+H)+ m/z calcd 270.1, found 270.1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:17]([CH3:28])[CH:16]=1.C(N(CC)CC)C.[CH:36]1([N:41]=[C:42]=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1>CN(C)C=O>[CH:36]1([NH:41][C:42]([N:25]2[CH2:26][CH2:27][CH:22]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:7]4[C:6]5[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[CH:5]=5)[N:10]=[CH:9][N:8]=4)=[CH:16][C:17]=3[CH3:28])[CH2:23][CH2:24]2)=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C=NC1CCCC1
Reactant: COc1ccc2ncnc(Nc3ccc(OC4CCNCC4)c(C)c3)c2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2ncnc(Nc3ccc(OC4CCN(C(=O)NC5CCCC5)CC4)c(C)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
To a suspension of (6-Methoxy-quinazolin-4-yl)-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-amine hydrochloride (150 mg, 0.251 mmol) in N,N-dimethylformamide (1.5mL) was added triethylamine (143 μL, 1.03 mmol) and cyclopentyl isocyanate (0.343 mmol). The reaction was stirred at room temperature overnight The reaction was then filtered through a 0.45 μm PTFE membrane filter and purified by preparatory HPLC. 36.3 mg of 4-[4-(6-Methoxy-quinazolin-4-ylamino)-2-methyl-phenoxy]-piperidine-1-carboxylic acid cyclopentylamide was isolated. 1H NMR (300 MHz, DMSO d6) δ 9.505 (s, 1H), 8.436 (s, 1H), 7.904 (d, J=0.9 Hz, 1H), 7.707 (d, J=3.0 Hz, 1H), 7.498-7.458 (dd, J=9.0, 3.0 Hz, 1H), 7.571-7.513 (m, 2H), 7.045 (d, J=3.0 Hz, 1H), 6.28 (d, J=2.3 Hz, 1H), 4.564-4.514 (m, 1H), 3.962-3.894 (m, 1H), 3.950 (s, 3H), 3.677-3.599 (m, 2H), 3.246-3.163 (m, 2H), 2.216 (s, 3H), 1.928-1.863 (m, 2H), 1.862-1.751 (m, 2H) 1.671-1.518 (m, 4H), 1.517-1.365 (m, 4H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:28]1[CH:33]=[CH:32][C:31]([O:34][Si](C(C)C)(C(C)C)C(C)C)=[CH:30][C:29]=1[CH2:45][C:46]([CH3:49])([CH3:48])[CH3:47].O>C1COCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]=1[CH2:45][C:46]([CH3:49])([CH3:48])[CH3:47]
Reactant: COc1ccc(F)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2CC(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C)c1
Reaction time: 0.25 h

Procedure:
A 1.0M solution of tetrabutylammonium fluoride in THF (73.6 mL) was added to a solution of ((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)oxy)triisopropylsilane (total amount) obtained in Example 2, step F, in THF (30 mL) at room temperature, and the mixture was stirred for 15 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.68 g) as a pale-yellow amorphous solid.