Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([CH3:31])[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[C:32](O)(=[O:34])[CH3:33]>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][C@@H:3]([CH3:31])[CH2:2][NH:1][C:32](=[O:34])[CH3:33])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: C[C@@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CC(=O)O
Product: CC(=O)NC[C@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 60 %

Procedure:
The procedure described in Example 1 was repeated using acetic acid and 5-[(1S)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine to give the title compound in 60% yield; NMR spectrum (DMSO-d6) 1.40 (d, 3H), 1.80 (s, 3H), 3.40 (m, 1H), 3.62 (m, 1H), 4.85 (m, 1H), 5.30 (s, 2H), 7.23 (m, 2H), 7.30 (d, 1H), 7.36 (m, 1H), 7.57 (m, 2H), 7.71 (t, 1H), 7.87 (td, 1H), 8.12 (d, 1H), 8.22 (t, 1H), 8.49 (s, 1H), 8.58 (d, 1H), 10.00 (s, 1H); Mass Spectrum MH+ 478.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3=[N:14][C:15]4[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([CH2:22][OH:23])[C:16]=4[N:12]3[CH2:11][CH2:10][CH2:9]2)=[C:4]([Cl:24])[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3=[N:14][C:15]4[C:16](=[C:17]([CH:22]=[O:23])[CH:18]=[CH:19][C:20]=4[Cl:21])[N:12]3[CH2:11][CH2:10][CH2:9]2)=[C:4]([Cl:24])[CH:3]=1
Reactant: OCc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Br)cc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Product: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of [1-(4-bromo-2-chlorophenyl)-9-chloro-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (1.24 g, 2.924 mmol) in dimethylsulfoxide (25.0 mL) was added Dess-Martin reagent (1.36 g, 3.216 mmol). The reaction mixture was stirred at room temperature for 2 hrs. The mixture was quenched with aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium thiosulfate and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was washed with ethyl acetate/diisopropyl ether to give the title compound as a pale yellow solid (1.20 g, 2.82 mmol, 97%).
Reaction SMILES: I.I.[CH:3]1([N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:10]([NH2:12])=[NH:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:36][OH:37].[OH2:38]>>[C:36]([OH:38])(=[O:37])[CH3:3].[C:36]([OH:38])(=[O:37])[CH3:3].[C:36]([OH:38])(=[O:37])[CH3:3].[CH:3]1([N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:10]([NH2:12])=[NH:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CO
Reactant: O
Agent: I
Agent: N=C(N)N(CCCCCCCCNCCCCCCCCC1CCCCC1)C1CCCCC1
Product: CC(=O)O

Procedure:
10.2 g (0.011 mol) of 1,17-biscyclohexylguanidino-9-azaheptadecane dihydroiodide in 150 ml of methanol/water (1:1) were filtered through a column containing 250 g of ion exchanger (OH- form). The free guanidine base obtained after working up was dissolved in methanol and converted into the triacetate with excess glacial acetic acid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3]OS(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+].[C:19]([O:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20]>CCOC(C)=O.O>[C:19]([O:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:3][C:2]([F:13])([F:12])[F:1])[CH2:27]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCCN(CC(F)(F)F)C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
Trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (0.42 g, 1.8 mmol) was dissolved in a mixture of 1.5 mL of EtOAc and 1.5 mL of H2O containing 0.95 g of NaHCO3 (7.5 mmol). The resulting suspension was warmed to 50 C. A solution of racemic piperidin-3-yl-carbamic acid tert-butyl ester (0.30 g, 1.5 mmol) in 1 mL of EtOAc was added dropwise over a 30 minute period. The reaction mixture was left stirring at 50° C. for one hour before being cooled to RT. The organic phase was separated and the aqueous layer was back extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered and evaporated to give 0.38 g of racemic [1-(2,2,2-trifluoro-ethyl)-piperidin-3-yl]-carbamic acid tert-butyl ester as a colorless oil which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][O:25][C:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1>>[CH3:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][O:19][C:26]3([O:25][CH3:24])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCO)c1
Reactant: COC1=CCCCC1
Product: COC1(OCCOCn2c(C)nc(C(C)C)c2Sc2cc(C)cc(C)c2)CCCCC1
Yield: 74.9 %

Procedure:
The compound 1 (502 mg, 1.50 mmol) was converted to the acetal with 1-methoxycyclohexene (1.68 g, 15.0 mmol) in the same manner as the example 2 to give the compound 3 (502 mg, 72%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>C1COCC1>[OH:2][CH:1]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH3:17])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: Cc1ccccc1C(O)c1cnccc1-c1cccc(C#N)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (15 mg, 0.075 mmol) in THF (1 mL) at −78° C. was added 0.5 M 4-methylphenylmagnesium bromide in THF (0.3 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified-by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[hydroxy-(2-methyl-phenyl)-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.C[O-].[Na+].[CH2:15]([O:17][C:18](=[O:32])[CH:19]=[CH:20][C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[C:27]([Br:30])[CH:26]=[C:25]([F:31])[CH:24]=2)[CH3:16].[NH4+].[Cl-]>CCO>[Br:30][C:27]1[C:28]2[CH:29]=[C:21]3[CH:20]([CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:32])[CH:2]([C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:3](=[O:5])[N:22]3[C:23]=2[CH:24]=[C:25]([F:31])[CH:26]=1
Reactant: CCOC(=O)C=Cc1cc2c(Br)cc(F)cc2[nH]1
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CC1c2cc3c(Br)cc(F)cc3n2C(=O)C1C(=O)OCC
Reaction time: 0.08 h
Yield: 89.4 %

Procedure:
To a solution of diethyl malonate (1.67 g, 10.4 mmol) in EtOH (30 mL) at r.t. was added sodium methoxide (2.26 mL, 25% solution in MeOH). The mixture was stirred for 5 minutes and a solution of the compound of Step 3 (1.3 g, 4.2 mmol) in EtOH (10 mL) was added. The mixture was stirred at 75° C. for 12 hours, saturated aqueous NH4Cl was added and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 20% EtOAc to give 1.6 g of the title compound.
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=O)[CH:3]=[CH:2]1.[NH2:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[SH:18]>CO>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:10]=1[N:9]=[C:4]1[C:3](=[CH:2][C:1](=[O:8])[CH:6]=[CH:5]1)[S:18]2
Reactant: O=C1C=CC(=O)C=C1
Reactant: COc1cccc(S)c1N
Solvent: CO
Product: COc1cccc2sc3cc(=O)ccc-3nc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of p-benzoquinone (3.0 g) in 15 ml methanol was added 2-amino-3-methoxythiophenol (2.2 g) dissolved in 10 ml methanol. The mixture was stirred at room temperature for 45 minutes and concentrated in vacuo. The residue was triturated with ether and filtered. The resulting dark solid was chromatographed on silica gel and eluted with EtOAc, to afford the desired compound, m.p. 206°-207°.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([Sn](C)(C)C)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:29][C:30]1[C:31]([Cl:37])=[N:32][CH:33]=[N:34][C:35]=1Cl>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:35]5[C:30]([NH2:29])=[C:31]([Cl:37])[N:32]=[CH:33][N:34]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: C[C@H](Nc1nccc(-n2cnc3cc([Sn](C)(C)C)ccc32)n1)c1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ncnc(Cl)c4N)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 424, starting from 2-[(S)-1-Phenylethylamino]-4-[5-trimethylstannylbenzimidazol-1-yl]pyrimidine and 5-amino-4,6-dichloropyrimidine. Mass spectrum (ESI) 443.4 (M+).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[C:18]([NH:30][CH3:31])[N:17]=2)[CH:13]=[CH:14][CH:15]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32]I>>[CH2:1]([N:9]([C:10]1[CH:11]=[C:12]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[C:18]([NH:30][CH3:31])[N:17]=2)[CH:13]=[CH:14][CH:15]=1)[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CNc1nc(-c2cccc(NC(=O)c3ccccc3)c2)c2cc(OC)c(OC)cc2n1
Product: CNc1nc(-c2cccc(N(C)Cc3ccccc3)c2)c2cc(OC)c(OC)cc2n1
Yield: 35 %

Procedure:
Starting from 100 mg of 4-(3-benzylaminophenyl)-6,7-dimethoxy-2-methylaminoquinazoline obtained in Example 38 and 71.0 mg of methyl iodide, 35.0 mg of the title compound was obtained as a pale yellow oil in the same manner as in Example 38.
Reaction SMILES: [C:1]1([CH:7](O)[C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.Cl.[C:38]([CH2:40][NH:41][C:42]([C@@H:44]1[CH2:48][C@@H:47]([S:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)(=[O:51])=[O:50])[CH2:46][NH:45]1)=[O:43])#[N:39]>ClCCl>[C:38]([CH2:40][NH:41][C:42]([C@@H:44]1[CH2:48][C@@H:47]([S:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)(=[O:50])=[O:51])[CH2:46][N:45]1[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([F:11])([F:10])[F:9])=[O:43])#[N:39]
Reactant: OC(c1ccccc1)C(F)(F)F
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1C(c1ccccc1)C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 1-phenyl-2,2,2-trifluoroethanol (0.4 mmole) in dichloromethane (1.4 ml) was added at −50° C. diisopropylethyl amine (2.0 mmole) and triflic anhydride (0.42 mmole) and stirring was continued at −50° for 1 h. To the mixture was added at −50° C. a solution of (2S,4R)-4-benzenesulfonyl-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride (0.4 mmole) prepared in analogy to experiment K1 in dichloromethane (0.4 ml) and stirring was continued at 22° C. for 2 d. The mixture was partitioned between ethyl acetate and water, the organic layer was dried, evaporated and the residue was chromatographed on silica to give (2S,4R)-4-benzenesulfonyl-1-(2,2,2-trifluoro-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless solid. MS: 452.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:14]([Cl:15])=[C:13]2[C:5]([C:6]3[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:20])[C:7]=3[Br:21])=[CH:4][C:3]=1[F:22].N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30].[OH-].[Na+]>C(Cl)Cl.N1C=CC=CC=1.C(Cl)(=O)C.CCO>[C:29]([NH:1][C:2]1[C:14]([Cl:15])=[C:13]2[C:5]([C:6]3[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:20])[C:7]=3[Br:21])=[CH:4][C:3]=1[F:22])(=[O:31])[CH3:30]
Reactant: CCCCC12CCC(=O)C(Br)=C1c1cc(F)c(N)c(Cl)c1C2
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCO
Product: CCCCC12CCC(=O)C(Br)=C1c1cc(F)c(NC(C)=O)c(Cl)c1C2
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A partial solution of 7-amino-4-bromo-9a-butyl-8-chloro-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.940 g, 2.44 mmol) in CH2Cl2 (7.5 mL) was cooled in an ice bath and treated successively with pyridine (0.202 mL, 2.5 mmol) and acetyl chloride (0.178 mL, 2.5 mmol). The reaction mixture was placed under a N2 atmosphere and stirred at room temperature. Additional pyridine (0.01 mL, 0.12 mmol and 0.039 mL, 0.48 mmol) was added after 4 and 5 hours, respectively; and additional acetyl chloride (0.009 mL, 0.12 mmol; 0.035 mL, 0.49 mmol; and 0.175 mL, 2.45 mmol) was added after 4, 5, and 5.5 hours, respectively. After stirring overnight at room temperature, the mixture was treated with EtOH (10 mL) and 5N NaOH (ca. 1 mL), stirred briefly, and then partitioned between EtOAc and water. The organic phase was washed with brine, dried over MgSO4, filtered, and evaporated under vacuum to provide 7-(acetylamino)-4-bromo-9a-butyl-8-chloro-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (1.02 g, 98%) as an orange solid.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19].C(=O)([O-])O.[Na+]>CC(C)=O.O>[CH2:1]([O:8][C:9]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NCCCCCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7.06 ml (47 mmol) of chloroformic acid benzyl ester are added dropwise to a solution of 5.52 g (47 mmol) of 6-aminohexan-1-ol and 3.95 g (47 mmol) of sodium hydrogen carbonate in 100 ml of acetone and 50 ml of water. The mixture is stirred at room temperature for 18 hours and concentrated to approximately 70 ml, and the white precipitate is filtered off, washed with approximately 20 ml of water, taken up in 250 ml of methylene chloride and dried over magnesium sulfate; the magnesium sulfate is filtered off and the residue is concentrated to dryness by evaporation. 6-(N-benzyloxycarbonylamino)hexan-1-ol is obtained in the form of white crystals having a melting point of 58°-60°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:45])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:42]=3)=[C:18]([O:43][CH3:44])[CH:17]=2)[CH:10]([O:46][CH3:47])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:35])([F:36])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH:10]5[O:46][CH3:47])=[O:45])=[CH:17][C:18]=4[O:43][CH3:44])=[N:42][C:27]2=3)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2OC)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)NC2CCNCC2OC)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1.5 h
Yield: 37.2 %

Procedure:
To a mixture of 0.050 g (0.075 mmole) of rac-(3S,4R)-4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-3-methoxy-piperidine-1-carboxylic acid tert-butyl ester (I-56) and 1 mL of dichloromethane was added 1 mL of trifluoroacetic acid-dichloromethane (25:75). The mixture was stirred for 1.5 hours, and then concentrated under reduced pressure. The residue was dissolved in methanol, and the mixture neutralized by the addition of 1M sodium hydroxide at 0 degrees. The mixture was purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient, 1:99-90:10) to give 0.0156 g of rac-(3S,4R)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(3-methoxy-piperidin-4-yl)-benzamide (I-57).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:13]([CH3:12])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1ccccc1
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN(c1ccccc1)c1ccc(C(C)(C)C)cc1
Yield: 97.8 %

Procedure:
According to general procedure B, 4-tert-butylbromobenzene (117 mg, 0.55 mmol) reacted with N-methylaniline (54 mg, 0.50 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (58 mg, 0.60 mmol) in toluene at 100° C. for 2 h to give the title compound (117 mg, 98%): 1H-NMR (300 MHz, CDCl3): δ 7.36 (t, 2H, J=8.1 Hz), 7.29 (t, 2H, J=7.5 and 7.8 Hz), 7.04 (dd, 4H, J=8.1 Hz), 6.94 (t, 1H, J=7.2 Hz and 7.5 Hz), 3.34 (s, 3H), 1.38 (s, 9H). 13C{1H}-NMR (100 MHz, CDCl3): δ 149.17, 146.36, 144.77, 129.02, 126.05, 121.23, 120.18, 118.94, 40.20, 34.18, 31.45. GC/MS(EI): m/z 239 (M+), 224
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:15])[C:6]1[CH:14]=[CH:13][CH:12]=[C:8]([C:9](Cl)=[O:10])[CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>ClCCl>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:5]([C:6]2[CH:14]=[CH:13][CH:12]=[C:8]([C:9](=[O:10])[C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)[CH:7]=2)=[O:15])=[CH:20][CH:19]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)c1cccc(C(=O)c2ccc(F)cc2)c1
Temperature: 0 °C
Yield: 71.2 %

Procedure:
Aluminum trichloride (6.53 g, 49.5 mmol) was added to a solution of isophthaloyl dichloride (5.0 g, 24.8 mmol) in dichloromethane (100 mL). After heating at reflux for 30 min, the monofluorobenzene (2.835 g, 29.5 mmol) was added and stirring was continued at reflux. After stirring over 12 h, the reaction mixture was poured onto the crushed ice. The resulting solution was neutralized with 10% NaOH (100 mL), and extracted with dichloromethane (3×100 mL). The combined organic layer was washed with water, followed by brine and dried over Na2SO4. After the organic layer was concentrated under reduced pressure, purification using flash chromatography (silica gel, hexanes:ethyl acetate, 60:40) afforded 1,3-bis-(4-fluorobenzoyl)benzene 12 (3.37 g, 10.5 mmol) as a white solid in a 42% yield; 1H NMR (500 MHz, CDCl3): δ 8.130 (t, J=1.5 Hz, 1H, ArH), 8.00 (dd, J=7.5 Hz, 1.5 Hz, 1H, ArH), 7.87 (m, 4H, ArH), 7.64 (t, J=8.0 Hz, 1H, ArH), 7.18 (m, 4H, ArH).
Reaction SMILES: [N:1]1[C:6]([C:7]([OH:9])=O)=[C:5]([C:10]([OH:12])=[O:11])[CH:4]=[CH:3][CH:2]=1>C(OC(=O)C)(=O)C>[N:1]1[C:6]2[C:7]([O:12][C:10](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: O=C(O)c1cccnc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2ncccc21
Temperature: 70 °C
Yield: 97 %

Procedure:
A suspension of 2-methyloxazolo 5,4-b!pyridine-5,6-dicarboxylic acid (4.84 g, 0.0218 mol) in acetic anhydride (150 mL) is slowly heated to 70° C. at which point all the solids dissolve forming a yellow solution. The reaction mixture is heated at 70° C. overnight, cooled to room temperature, and concentrated in vacuo. Xylene is added to remove excess acetic anhydride by codistillation. 2-Methyloxazolo 5,4-b!pyridine-5,6-dicarboxylic anhydride is obtained as a pale yellow solid in 97% yield melting point 194°-196° C.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3](=[O:25])[S:4][C:5]1[C:10]([Cl:11])=[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:8]=[C:7]([Br:21])[C:6]=1[CH2:22][CH:23]=[O:24].[BH4-].[Na+]>C1COCC1.CO>[CH3:26][N:2]([CH3:1])[C:3](=[O:25])[S:4][C:5]1[C:10]([Cl:11])=[C:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH:8]=[C:7]([Br:21])[C:6]=1[CH2:22][CH2:23][OH:24]
Reactant: COc1ccc(Cc2cc(Br)c(CC=O)c(SC(=O)N(C)C)c2Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cc2cc(Br)c(CCO)c(SC(=O)N(C)C)c2Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
To a solution of compound 219 (1.46 g, 3.18 mmol) in THF/MeOH (70 mL/7 mL) were added NaBH4 (132 mg, 3.50 mmol) at 0° C. under nitrogen atmosphere. After stirring at 0° C. for 2 hrs, the reaction mixture was quenched with saturated NaHCO4 (50 mL) and extracted with ethyl acetate (100 mL×2). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the compound 220 (1.02 g, 2.22 mmol, 70%).
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH2:14](O)[CH2:15][CH2:16]CC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCCCC)(=O)C>[C:1]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: CCCCCO
Reactant: CCOC(=O)C(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCOC(C)=O
Product: CCCCCOC(=O)C(O)c1ccccc1
Reaction time: 4 h

Procedure:
A 100 mL three-neck flask, equipped with a magnetic stir bar, a Claisen adapter with a thermocouple and a subsurface nitrogen inlet, and a short path condenser, was charged with 7.94 grams of ethyl mandelate, 40 mL of 1-pentanol, and 0.75 gram of p-toluenesulfonic acid. The reaction was stirred at 120°-132° C. for 4.0 hours with a nitrogen sweep. The reaction mixture was taken up in butyl acetate, extracted with dilute aqueous sodium hydroxide, washed three times with water, dried over magnesium sulfate, and filtered. Solvent was removed by rotary evaporation to yield 8.3 grams of a straw-colored liquid.
Reaction SMILES: [CH:1]1([CH:6]([NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)[C:7]2[S:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:6]([NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[C:7]2[S:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2sc3ccccc3c2C)C2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCC2)sc2ccccc12
Yield: 94.5 %

Procedure:
To a mixture of methyl 4-{[cyclopentyl(3-methyl-1-benzothiophen-2-yl)methyl]amino}benzoate (1.56 g) synthesized above, tetrahydrofuran (20 mL) and ethanol (20 mL) was added 1N aqueous sodium hydroxide solution (20.0 mL), and the mixture was stirred with heating under reflux for 4 hr, and concentrated under reduced pressure. The residue was dissolved in water (40 mL), and 1N hydrochloric acid (20.0 mL) was added at 0° C. The resulting precipitate was collected by filtration, and the obtained pale-brown solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (1.42 g, 95%) as a pale-brown solid.