Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:3]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>COCCOC.O>[N:10]1([C:4]2[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([C:21]3[CH:20]=[CH:19][C:18]([O:17][C:16]([F:15])([F:27])[F:28])=[CH:23][CH:22]=3)[N:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: N#Cc1cc(Cl)nc(N2CCCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCCC2)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 76.8 %

Procedure:
A solution of nitrile 25A (2.58 g, 12.5 mmol) in DME (90 mL) was added with 4-trifluoromethoxy phenyl boronic acid (2.64 g, 1.0 mol eq,) and NaHCO3 (3.15 g, 3 mol eq,) suspended in water (45 mL). The mixture was degassed under vacuum, then Palladium Tetrakis was added (catalytic amount) and the reaction was stirred at 100° C. under inert atmosphere for 12 h. The solvent was removed under reduced pressure and water was added to the residue (80 mL). The aqueous phase was extracted with EtOAc (3×60 mL) and the combined organic layer was washed with brine (80 mL) and dried over Na2SO4. The solvent was evaporated under vacuum to afford 26C as deliquescent yellow solid (3.2 g, 9.6 mmol, 77% Yield). 1HNMR (DMSO, 400 MHz) δ 1.85 (m, 4H), 3.42 (m, 4H), 6.38 (s, 1H), 7.08 (s, 1H), 7.38 (d, 2H, J=8), 8.05 (d, 2H, J=8).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][N:9]=1.C1C=C([Cl:24])C=C(C(OO)=O)C=1>CCOC(C)=O>[Cl:24][C:10]1[CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)c1ccnc(-c2ccccc2Cl)c1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(Cl)nc(-c2ccccc2Cl)c1

Procedure:
To a solution of 2-(2-chlorophenyl)-4-(trifluoromethyl)pyridine (5.40 g, 21.0 mmol) in EtOAc (100 mL) was added mCPBA (7.25 g, 42.0 mmol) in EtOAc (100 mL) over 30 min and then the mixture was heated at reflux (caution: use shield) for 3 h. The reaction mixture was cooled and then washed twice with sat. aq. NaHCO3 and concentrated.
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5]([C@H:7]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])[C:9](=[O:22])[C@H:8]1[NH:23][C:24](=[O:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O>O1CCCC1>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:10]1[C@H:7]([CH2:5][OH:4])[C@H:8]([NH:23][C:24](=[O:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]1=[O:22]
Reactant: COC(=O)[C@@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CO)c(OC)c1
Reaction time: 1.5 h
Yield: 91.1 %

Procedure:
Under ice-cooling and stirring, 12 ml of an aqueous solution containing 570 mg of sodium borohydride is added to a solution of 2.06 g of cis-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester in 24 ml of tetrahydrofuran. The reaction mixture is stirred for 30 minutes under ice-cooling and then for 1.5 hours at room temperature. The tetrahydrofuran is distilled off in vacuo and an aqueous sodium chloride solution and ethyl acetate are added to the residue. The resulting ethyl acetate layer is separated and washed successively with an aqueous sodium hydrogen carbonate and an aqueous sodium chloride. It is then dried over magnesium sulfate and the solvent is distilled off in vacuo. Ether is added to the residue and the precipitated crystals are collected by filtration to give 1.75 g (91%) of cis-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-3-phenylacetamido-2-oxoazetidine, m.p. 152°-154° C.
Reaction SMILES: [ClH:1].[CH:2]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1>S(Cl)(Cl)=O>[ClH:1].[CH:2]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([Cl:1])=[O:18])=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc(OC2CCN(C3CCC3)CC2)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(OC2CCN(C3CCC3)CC2)cc1
Yield: 198.3 %

Procedure:
4-[(1-Cyclobutyl-4-piperidinyl)oxy]benzoic acid hydrochloride (D24) (0.20 g) was dissolved in thionyl chloride (10 ml) and heated under reflux for 1.5 h. The thionyl chloride was removed by evaporation and the residue evaporated from DCM (3×10 ml) to give the title compound (D25) (0.21 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@@H:18]2[NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[CH3:30][O:31][CH2:32][C:33](O)=[O:34]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@@H:18]2[N:22]([C:33](=[O:34])[CH2:32][O:31][CH3:30])[CH2:21][C@@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc(OC[C@H]2C[C@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: COCC(=O)O
Product: COCC(=O)N1C[C@@H](O)C[C@@H]1COc1cc(OC)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Yield: 60 %

Procedure:
The procedure described in Example 20 was repeated using (3S,5R)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (120 mg) with methoxyacetic acid (24 μl) to give the title compound as a white solid in 60% yield; NMR spectrum (DMSO-d6) 9.96 (s, 1H), 8.45 (s, 1H), 8.17-8.14 (m, 1H), 7.76-7.72 (m, 1H), 7.45 (t, 1H), 6.83 (s, 2H), 5.10 (m, 1H), 4.73-4.69 (m, 1H), 4.47-4.38 (m, 2H), 4.25 (dd, 1H), 4.10-3.98 (m, 2H), 3.94 (s, 3H), 3.51 (dd, 1H), 3.40 (s, 1H), 3.29 (s, 3H), 2.05-2.02 (m, 2H); Mass spectrum MH+ 491.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([CH2:11][CH2:12]O)[C:7]=2[CH:14]=1.C(Br)(Br)(Br)[Br:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:16][CH2:12][CH2:11][N:8]1[C:7]2[CH:14]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[N:10]=[CH:9]1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc2ncn(CCO)c2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2ncn(CCBr)c2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(6-methoxy-1H-benzo[d]imidazol-1-yl)ethanol (200 mg, 1.04 mmol) in DCM (6.0 mL), CBr4 (397 mg, 1.20 mmol) was added, then the reaction mixture was cooled to 0° C. and PPh3 (314 mg, 1.20 mmol) was added. After stirring at rt for 2 h the solvent was removed under reduced pressure to yield the title compound as a brown oil, which was used us such in the next step. LC-MS conditions B: tR=0.42 min, [M(79Br)+H]+=255.08.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[NH:4][C:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[CH:11]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)(Cl)Cl>[C:23]([NH:1][C:2]1[C:3](=[O:16])[NH:4][C:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[CH:11]=1)(=[O:25])[CH3:24]
Reactant: Nc1cc2c([nH]c1=O)CCc1ccccc1-2
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc2c([nH]c1=O)CCc1ccccc1-2

Procedure:
To 2.0 gm of 2-amino-5,6-dihydrobenzo[f]quinolin-3(4H)-one, in 100 ml of chloroform containing 1 ml of pyridine add 0.80 gm of acetyl chloride. Stir the reaction at room temperature for 5 hours. Filter and wash the solution with water. Remove the solvent by stripping to give the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([CH:8]=O)[CH:6]=[N:5][C:4]([S:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:3]1.[CH2:15]([O:17][CH2:18][C:19](OCC)=[O:20])[CH3:16].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH2:11]([S:10][C:4]1[N:5]=[CH:6][CH:7]2[CH:8]=[C:18]([O:17][CH2:15][CH3:16])[C:19](=[O:20])[NH:1][CH:2]2[N:3]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCSC1=NC(N)C(C=O)C=N1
Reactant: CCOCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCSC1=NC2NC(=O)C(OCC)=CC2C=N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Amino-2-butylsulfanyl-4,5-dihydro-pyrimidine-5-carbaldehyde (3 g, 14.2 mmol, funished by scaleup) and ethyl ethoxyacetate (2.34 g, 2.4 ml, 17.75 mmol) were stirred in 80 ml toluene at 0°-5° C. under nitrogen. Potassium t-butoxide (1.75 g, 15.6 mmol) was added gradually. The mixture was stirred to ambient temperature, and then to 65° C. for 48 hours. An additional 20 ml of toluene and 2.4 ml ethyl ethoxyacetate were added and the reaction was maintained at 65° C. over the weekend. The reaction mixture was concentrated in vacuo and triturated with EtOAc to remove the remaining starting aldehyde. The remaining solid was further triturated with chloroform to remove additional impurities. 3.66 g of 2-Butylsulfanyl-6-ethoxy-8,8a-dihydro-4aHpyrido[2,3-d]pyrimidin-7-one (1A) of a purity greater than 80% as judged by MS/HPLC and NMR was collected.
Reaction SMILES: C[O:2][C:3]1[N:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].B(Cl)(Cl)Cl>C(Cl)Cl>[OH:2][C:3]1[N:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1ccc(C=O)c(OC)n1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C=O)c(O)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.4 %

Procedure:
8.4 g (0.05 mol) 2,6-dimethoxy-nicotinaldehyde was solved in 75 ml methylene chloride. At 0° C. (0.2 mol) BCl3 as 1 molar solution in methylene chloride 200 ml was added and stirred at room temperature for 20 h. The mixture was poured on ice/water, neutralized and extracted with CH2Cl2. Evaporation of the solvent affords 5.7 g (75%) of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:33]=[CH:32][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:31])[C:15]([CH3:30])([CH2:24][CH2:25][C@@H:26]([CH3:29])[CH2:27][CH3:28])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:34](Cl)([CH3:37])(=[O:36])=[O:35].N1C=CC=CC=1>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:30])([CH2:24][CH2:25][C@@H:26]([CH3:29])[CH2:27][CH3:28])[C:14](=[O:31])[C:13]=1[C:8]1[NH:7][C:6]2[CH:32]=[CH:33][C:3]([NH:2][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CC[C@H](C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC[C@H](C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 43F (0.119 g, 0.240 mmol), mesyl chloride (0.075 mL, 0.970 mmol), and pyridine (0.157 mL, 1.94 mmol) in acetone (3 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give a yellow solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:39][S:40]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=[O:42])=[O:41])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=O.Cl.[O:68]=[C:69]1[CH:73]=[CH:72][C:71](=[O:74])[N:70]1[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][C:80]([NH:82][NH2:83])=[O:81]>>[O:74]=[C:71]1[CH:72]=[CH:73][C:69](=[O:68])[N:70]1[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][C:80]([NH:82][NH:83][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:39][S:40]([CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)(=[O:42])=[O:41])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:81]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)CS(=O)(=O)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Agent: Cl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)CS(=O)(=O)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
7.4 mg (7.9 mmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzylsulphonyl)-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and 6.2 mg (23.5 mmol) of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide hydrochloride were coupled and worked up in analogy to Intermediate 157. 6.9 mg (74% of theory) of the title compound were obtained as a solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=2[N:6]=1.C([Sn](CCCC)(CCCC)[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)CCC.C(OCC)(=O)C>O1CCOCC1.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>[N+:11]([C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[N:6][C:5]=2[CH:7]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc2oc(Cl)nc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2oc(-c3cccs3)nc2c1
Temperature: 100 °C
Yield: 0.6 %

Procedure:
A mixture of 2-chloro-5-nitrobenzo[d]oxazole (404 mg, 2.04 mmol), 2-(tributylstannyl)-thiophene (648 μL, 2.04 mmol) and tetrakis(triphenylphosphine)palladium (0) (40.8 mg) in dioxane (12.2 mL) was heated at 100° C. for 16 h under nitrogen. Ethyl acetate was added, the organic layer was washed with water, dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 10:90 v/v, and then purified by reverse phase HPLC to afford 3 mg (2%) of the title product (LCMS RT=6.95 min)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([CH3:12])[C:5]2=[N:6][CH:7]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)(C)C.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([N:17]3[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]3)=[CH:9][N:8]([CH3:12])[C:5]2=[N:6][CH:7]=1
Reactant: Cn1cc(I)c2cc(Br)cnc21
Reactant: CN1CCNCC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CN1CCN(c2cn(C)c3ncc(Br)cc23)CC1
Temperature: 25 °C

Procedure:
A solution of 5-bromo-3-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.445 mmol), 1-methylpiperazine (356.7 mg, 3.56 mmol), copper(I) iodide (84.8 mg, 0.445 mmol), K3PO4 (378 mg, 1.78 mmol), 1,2-ethanediol (138 mg, 2.225 mmol) in isopropyl alcohol (5 mL) in a sealed tubes was heated at 70° C. for 2 days. After cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo. The residue was taken up in EtOAc and the solution was washed with saturated NaHCO3, dried and concentrated. Purification by flash chromatography afforded the title compound. LCMS-ESI+: calc'd for C13H17BrN4 309.1 (M+H+); Found: 309.1 (M+H+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Br[C:10]1[S:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:14]=1.[OH-].[Na+]>C(OCC)(=O)C.O1CCCC1>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][C:10]1[S:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:14]=1
Reactant: COC(=O)c1cnc(Br)s1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(OCC(F)(F)F)s1
Yield: 79 %

Procedure:
To a tetrahydrofuran solution (5.0 mL) of sodium hydride (465 mg, 11.6 mmol) and 2,2,2-trifluoroethanol (1.70 mL, 23.3 mmol), methyl 2-bromothiazole-5-carboxylate (517 mg, 2.33 mmol) was added and the resultant mixture was stirred at room temperature for 2 hours. After completion of the reaction, 1 M sodium hydroxide aqueous solution was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of the title compound (444 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[O:12][C:13]1[CH:14]=[C:15]([C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])[CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Oc2cc(Cl)ccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
A mixture of 4-chloro-2-fluoronitrobenzene (10.4 g, 59.2 mmols), tert-butyl(1S)-1-(3-hydroxyphenyl)ethylcarbamate (13.4 g, 56.5 mmols), potassium carbonate (9.4 g, 68 mmols) and N,N-dimethylformamide (150 ml) was stirred at 100° C. for 1 hour. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography, and the resulting crystal was re-crystallized from hexane/ethyl acetate to give a crystal of tert-butyl(1S)-(-)-1-[3-(5-chloro-2-nitrophenoxy)phenyl]ethylcarbamate (15.7 g, 71%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[N+:12]([O-])=O)[CH:2]=[CH2:3].[NH4+].[Cl-].C(O)C>[Fe].O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[NH2:12])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C=CCOc1ccc(Br)cc1N
Yield: 100.9 %

Procedure:
A mixture of Example 66A (5.06 g, 19.69 mmol), iron powder (11.02 g, 196.9 mmol), NH4Cl (0.53 g, 9.85 mmol), ethanol (160 mL), and water (40 mL) were heated at 80° C. for 6 hours. The solution was filtered, concentrated with silica gel powder (18 g), and purified by flash chromatography eluting with 10% ethyl acetate in hexanes (1 L) to give the title compound (4.53 g, 97%). MS (DCI) m/z 227.91 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 4.54 (d, J=5.43 Hz, 2 H) 5.29 (dd, J=10.51, 1.36 Hz, 1 H) 5.40 (dd, J=17.46, 1.53 Hz, 1 H) 6.09 (m, 1 H) 6.65 (d, J=8.48 Hz, 1 H) 6.84 (m, 1 H) 6.91 (d, J=2.37 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](SC)=[N:7][C:8]([C:12]([F:21])([F:20])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.[CH3:35][C:36]1[NH:40][N:39]=[C:38]([NH2:41])[CH:37]=1>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:41][C:38]3[CH:37]=[C:36]([CH3:35])[NH:40][N:39]=3)=[N:7][C:8]([C:12]([F:21])([F:20])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(Br)ccc12
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3cc(Br)ccc23)n[nH]1
Temperature: 0 °C
Reaction time: 1.33 h
Yield: 3.9 %

Procedure:
To 7-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline (100 mg, 0.25 mmol) in DCM (3 mL) at 0° C. was added 70% meta-chloroperoxybenzoic acid (74 mg, 0.30 mmol) and the mixture was stirred at 0° C. for 80 min. Then additional 70% meta-chloroperoxybenzoic acid (70%, 15 mg, 0.086 mmol) was added and the mixture was stirred at 0° C. for 10 min. The mixture was diluted with DCM (10 mL), washed with saturated aq NaHCO3 (20 mL) and saturated aq sodium thiosulfate (20 mL), dried over Na2SO4 and concentrated under reduced pressure. To the residue (133 mg) at rt was added 5-methyl-1H-pyrazol-3-amine (92 mg, 0.96 mmol) in THF (3 mL). The mixture was stirred for 40 min and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex C-18 reverse phase column, eluted with gradient of solvent B=0.05% AcOH/ACN and solvent A=5% ACN/0.05% AcOH/H2O) to afford 7-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (4.42 mg, 3.1%). 1H NMR (300 MHz, DMSO-d6) δ 12.09-12.33 (m, 1H), 10.73-10.99 (m, 1H), 8.66 (s, 2H), 8.00 (d, J=5.5 Hz, 3H), 7.74-7.87 (m, 1H), 5.95 (br s, 1H), 2.16 (s, 3H); LC-MS (ESI) m/z 449/451 (M+H)+.
Reaction SMILES: C(Cl)(Cl)Cl.[N+:5]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([F:16])[CH:9]=1)([O-:7])=[O:6].[CH2:17]([Si](C)(C)C)[CH:18]=[CH2:19]>C(OCC)(=O)C.[Ti](Cl)(Cl)(Cl)Cl>[F:16][C:10]1[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:15]=[CH:14][C:11]=1[CH:12]([OH:13])[CH2:19][CH:18]=[CH2:17]
Reactant: C=CC[Si](C)(C)C
Reactant: O=Cc1ccc([N+](=O)[O-])cc1F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: C=CCC(O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.65 ml of titanium tetrachloride was added to a chloroform (12 ml) solution of 2.00 g of 4-nitro-2-fluoro-benzaldehyde produced according to the method described in U.S. Pat. No. 6,239,152, and the reaction liquid was stirred at room temperature for 10 minutes, and then 2.4 ml of allyl-trimethyl-silane was added to it, and the reaction liquid was stirred at room temperature for 20 minutes. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to obtain the entitled compound as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]3[O:30][CH2:29]3)=[C:22]([CH3:31])[CH:21]=2)[CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[CH2:32]([NH2:36])[CH2:33][CH2:34][CH3:35]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]([OH:30])[CH2:29][NH:36][CH2:32][CH2:33][CH2:34][CH3:35])=[C:22]([CH3:31])[CH:21]=2)[CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(c2ccc(OCC3CO3)c(C)c2)C2CCCc3ccccc32)cc1
Reactant: CCCCN
Solvent: CCO
Product: CCCCNCC(O)COc1ccc(C(c2ccc(OC)cc2)C2CCCc3ccccc32)cc1C

Procedure:
A mixture of (4-methoxyphenyl)-(3-methyl-4-(2,3-epoxypropyloxy)phenyl)-1,2,3,4-tetrahydronaphth-1-yl-methane (300 mg, 0.001 mol), n-butyl amine (1.0 m, 0.01 mol) and ethanol (15 ml) was refluxed for 8 hrs. Ethanol was distilled off and the residue was passed through a basic alumina column using hexane:ethyl acetate as the eluent. Solvent was distilled off to give the title compound. Yield 212 mg, (60.05%).