Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: COc1cccc(C=O)c1
Product: COc1cccc(C=CC(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)c1

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and m-anisaldehyde (77 ul, 0.633 mmol) similar to Example 6 and isolated as a light yellow solid (74 mg, 27%). 1H NMR (CDCl3): 7.67 (d, J=15.6 Hz, 1H), 7.44 (d, J=15.6 Hz, 1H), 7.34 (s, 1H), 7.30 (dd, J=2.4, 5.7 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 7.11 (dd, J=3.2, 8.9 Hz, 2H), 6.97 (dd, J=0.9, 2.7 Hz, 1H), 6.93 (d, J=9.0 Hz, 1H), 4.44-4.33 (m, 4H), 3.83 (s, 3H).
Reaction SMILES: [ClH:1].CO[C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([CH2:14][N:15](C)[CH2:16][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:23]=3[CH2:22][CH2:21]1)=[O:19])[CH2:7]2.C1C[O:39][CH2:38]C1>O1CCOCC1>[ClH:1].[CH3:13][O:12][C:11]1[C:10]([O:39][CH3:38])=[C:9]2[C:6]([CH2:7][CH:8]2[CH2:14][NH:15][CH2:16][CH2:17][C:18]([N:20]2[CH2:26][CH2:25][C:24]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:23]=3[CH2:22][CH2:21]2)=[O:19])=[CH:5][CH:4]=1
Reactant: C1CCOC1
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3cc(OC)c(OC)cc31)CC2
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)CCN(C(=O)CCNCC1Cc3ccc(OC)c(OC)c31)CC2

Procedure:
Obtained in the same manner as the product of Example 1, but with replacement of the [(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl]methylamine in Step 4 by the product of Preparation 1 and of the THF by dioxane.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@@H:20]3[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@H:19]3[C@@H:18]([C:26]([NH:28][NH2:29])=[O:27])[O:17]2)=[C:4]([F:32])[CH:3]=1.C(N(C(C)C)CC)(C)C.[C:42](Cl)(=[O:44])[CH3:43]>CN(C=O)C>[C:42]([NH:29][NH:28][C:26]([C@@H:18]1[C@H:19]2[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]2)[C@H:16]([N:11]2[CH:10]=[N:9][C:8]3[C:12]2=[N:13][CH:14]=[N:15][C:7]=3[NH:6][C:5]2[CH:30]=[CH:31][C:2]([Cl:1])=[CH:3][C:4]=2[F:32])[O:17]1)=[O:27])(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@H](n1cnc3c(Nc4ccc(Cl)cc4F)ncnc31)O[C@@H]2C(=O)NN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NNC(=O)[C@H]1O[C@@H](n2cnc3c(Nc4ccc(Cl)cc4F)ncnc32)[C@@H]2OC(C)(C)O[C@H]21
Temperature: 0 °C
Reaction time: 5 h
Yield: 45.8 %

Procedure:
To a stirred solution of (3aR,4S,6R,6aR)-6-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole4-carbohydrazide (50 mg) in N,N′-dimethylformamide (2 ml) at 0° C. was added diisopropylethylamine (28 μl) and acetyl chloride (9 mg). The reaction mixture was stirred at 0 ° C. for 5 h. The mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was washed with brine (20 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by automated preparative HPLC (gradient profile 5-95% (ii) over 18.5 min) to give the title compound (25 mg).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]=2[S:9][C:10]=1[NH2:11])=[O:5])C.[C:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18].Cl>O1CCOCC1>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C:17]1[N:18]=[C:4]([OH:5])[C:6]2[C:7]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:8]=3[S:9][C:10]=2[N:11]=1)[CH3:24]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)c1c(N)sc2c1CCCCC2
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)Cc1nc(O)c2c3c(sc2n1)CCCCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.3 %

Procedure:
A mixture of 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid ethyl ester (7 g, 0.02928 mol) and ethyl cyanoacetate (6.5 g, 0.05857 mol) in 72 ml of 1,4-dioxane was saturated with HCl gas while cooling the mixture. The mixture was stirred for 18 h at ambient temperature, then quenched with solid NaHCO3, diluted with 100 ml water and extracted with ethyl acetate (100 ml×3). The organic layer was separated, dried over Na2SO4 and concentrated under vacuum. The crude solid was triturated with diethyl ether (100 ml) to give (4-hydroxy-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benz[a]azulen-2-yl)-acetic acid ethyl ester (5.5 g, 62%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 11.84 (brs, 1H), 4.18-4.28 (m, 2H), 3.78 (s, 2H), 3.22-3.32 (m, 2H), 2.80-2.90 (m, 2H), 1.83-1.93 (m, 2H), 1.58-1.75 (m, 5H), 1.26 (t, 3H); LC-MS: [M+H]=307.1 m/z.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:20]([C:29](O)=[O:30])=[C:19]([CH3:32])[NH:18][C:17]=2[CH3:33])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]1([CH2:40][CH2:41][CH2:42][NH2:43])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C.Cl.Cl>CN(C)C1C=CN=CC=1.ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[C:17]([CH3:33])=[N:18][C:19]([CH3:32])=[C:20]([C:29](=[O:30])[NH:43][CH2:42][CH2:41][CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCCc1ccccc1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)=C(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: Cc1nc(C)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(-c2cccc(Cl)c2)c1C(=O)NCCCc1ccccc1

Procedure:
1.13 g (2.37 mmol) of 4-[5-carboxy-4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-carbonyl] piperazine-1-carboxylic acid-t-butyl ester, 0.51 ml (3.59 mmol) of 3-phenylpropylamine, 548 mg (2.86 mmol) of WSC hydrochloride and 21 mg (0.17 mmol) of 4-dimethylaminopyridine were stirred in 10 ml of dichloromethane at room temperature overnight. After adding 25 ml of water and 25 ml of 1 N hydrochloric acid, the reaction mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (chloroform/methanol=300/1) to obtain the title compound.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[N+:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[C:13]2[NH2:19])([O-:9])=[O:8]>N1C=CC=CC=1>[N+:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[C:13]2[NH:19][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])([O-:9])=[O:8]
Reactant: CCCC(=O)Cl
Reactant: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 5 °C
Reaction time: 12 h

Procedure:
0.58 cm3 of butyryl chloride is added to 1 g of 5-nitro-1H-indazole-3-amine, prepared as described in, SU 742430 (CA: 94 :65676) in 25 cm3 of pyridine, and cooled to about 5° C. The reaction medium is allowed to return to about 19° C. over 12 hours. The insoluble material present is filtered off and the filtrate is then evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 15 cm3 of ethyl acetate and 15 cm3 of distilled water. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume) and collecting 20 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 50° C.), 480 mg of N-[5-nitro-1H-indazol-3-yl]butanamide are thus obtained in the form of a white solid.
Reaction SMILES: [C:1]([C:4]1[NH:8][C:7]([C:9]([O:11]C)=[O:10])=[C:6]([Cl:13])[CH:5]=1)(=[O:3])[CH3:2].CO.[Li+].[OH-]>C1COCC1>[C:1]([C:4]1[NH:8][C:7]([C:9]([OH:11])=[O:10])=[C:6]([Cl:13])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1[nH]c(C(C)=O)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1cc(Cl)c(C(=O)O)[nH]1
Temperature: 60 °C
Yield: 94.6 %

Procedure:
Methyl 5-acetyl-3-chloro-1H-pyrrole-2-carboxylate (0.034 g, 0.169 mmol) was dissolved in THF (1 mL), methanol (1 mL) and 1N LiOH (1 mL). The reaction mixture was heated to 60° C. and stirred. The reaction mixture was evaporated and purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.030 g, 76%) as an impure product which was used with no further purification. LCMS: m/z 186.0 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C(N(CC)CC)C>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH:20][OH:21])=[NH:18])=[CH:16][C:10]=3[N:9]=2)=[CH:6][CH:7]=1
Reactant: NO
Reactant: N#Cc1ccc2[nH]c(-c3ccc(F)cc3)nc2c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: N=C(NO)c1ccc2[nH]c(-c3ccc(F)cc3)nc2c1
Reaction time: 6 h
Yield: 85 %

Procedure:
2-(4-Fluoro-phenyl)-1H-benzoimidazole-5-carbonitrile (1.898 g, 8 mmol; example 1), hydroxylamine hydrochloride (3.34 g, 48 mmol) and triethylamine (5.67 g, 56 mmol) were heated at reflux in 85 ml of ethanol for 6 hours. Heating was continued for further 6 hours after addition of 3 equivalents of hydroxylamine hydrochloride and triethylamine each and molecular sieve (3 Å). The molecular sieve was filtered, the solvent evaporated and the solid recrystallized from methanol. Yield: 85%. MS: m/e=271.05 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:15]=[N:16][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:18][CH:19]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][OH:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:15]=[N:16][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH2:35][OH:36])[CH2:24][CH2:25]4)=[CH:18][CH:19]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: OCCBr
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)nn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CCO)CC4)nn3)nc2n1C1CCCC1
Yield: 12.7 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(6-piperazin-1-yl-pyridazin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.229 mmol) and 2-bromo ethanol (143 mg, 1.14 mmol) gave 7-cyclopentyl-2-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyridazin-3-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (14 mg, 13%).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH2:8]([C@@:15]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH2:20][CH:21]=[CH2:22])[CH2:16][C:17]([OH:19])=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCCCCC.CO>[CH2:8]([C@@:15]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH2:20][CH:21]=[CH2:22])[CH2:16][C:17]([O:19][CH3:1])=[O:18])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=CC[C@@](CC(=O)O)(Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: CCCCCC
Product: C=CC[C@@](CC(=O)OC)(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A total of 5 ml of a 2 molar solution of trimethylsilyldiazomethane in hexane is added in portions to a solution of 490 mg of (S)-2-benzyl-2-tert-butoxycarbonylaminopent-4-enecarboxylic acid in 8 ml of methanol while stirring at room temperature. After the reaction is complete, the excess trimethylsilyldiazomethane is destroyed by dropwise addition of glacial acetic acid, and the volatile constituents are stripped off in a rotary evaporator at 40° C. The residue is purified on a column (silica gel, mobile phase: methylene chloride:methanol=95:5).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][CH3:56])=[CH:51][CH:50]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:55]([C:52]4[CH:53]=[CH:54][C:49]([O:48][CH3:47])=[CH:50][CH:51]=4)[CH3:56])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CNc1ccc(OC)cc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)c2ccc(OC)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with N-(4-methoxy-phenyl)-N-methyl-amine (Aldrich) to give the title compound. LC-MS (ES+) 784 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]OS(C1C=CC(C)=CC=1)(=O)=O.[CH-:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.[Na+]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][C:16]1[CH2:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1cc[cH-]c1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCC1=CC=CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
To a solution of 19.7 g(85.7 mmol) 2-methoxyethyltosylate as prepared in step (a) in 200 ml THF cooled to 0° C. was added 55 ml of 2.0M (110 mmol) sodium cyclopentadienylide in THF. The reaction mixture was allowed to warm to room temperature and was stirred for 16 h. 100 ml concentrated aqueous saline solution was added and the product extracted with diethyl ether (3×75 ml). The combined organic fractions were dried over sodium sulphate for 16 hrs, filtered and the solvents removed under reduced pressure using a rotary evaporator to yield a brown oil. The crude product was distilled under reduced pressure (b.p. 40-°44° C. at 2-3 mm Hg) to give 4.5 g of a colourless oil (37.7 mmol, 44.0%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:26]1([CH2:32][S:33][CH:34]([C:38](O)=[O:39])[C:35](O)=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[OH:39][C:38]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])[O:10][C:35](=[O:36])[C:34]=1[S:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)c1ccccc1O
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccccc2O)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 2'-hydroxyacetophenone (0.722 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (1.95 g, 11.6 mmol), chlorotrimethylsilane (1.48 mL, 11.6 mmol), THF (116 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 189° C.; 1H NMR (400 MHz, DMSO-d6) δ 4.01 (s, 2 H), 6.97 (s, 1 H), 7.25 (m, 7 H), 7.71 (d, 1 H), 10.75 (s, 1 H), 11.85 (bs, 1 H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:22]([O-:24])=[O:23])[CH:8]=2)[N:3]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>CCCCO>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N+:22]([O-:24])=[O:23])[CH:8]=3)[N:3]=[C:2]([NH:28][CH2:27][CH2:25][OH:26])[N:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccc([N+](=O)[O-])cc23)cc1
Reactant: NCCO
Solvent: CCCCO
Product: COc1ccc(N(C)c2nc(NCCO)nc3ccc([N+](=O)[O-])cc23)cc1
Temperature: 120 °C

Procedure:
A mixture of 77 mg (0.22 mmol) of (2-chloro-6-nitro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine and 68 mg (1.12 mmol) of ethanolamine in n-BuOH was heated at 120° C. for 18 hours. The reaction mixture concentrated and the isolation was done by preparative HPLC to give the title compound. 1H NMR (DMSO-d6) δ 8.2-7.1 (7H), 3.83 (3H), 3.82 (s, 2H), 3.62 (d, 3H), 3.56 (s, 2H); LC-MS (ESI+; 294 ([M+H]+)).
Reaction SMILES: [C:1]([CH:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)(=[O:3])[NH2:2].CCN(CC)CC.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>C(Cl)Cl>[C:24]([N:9]1[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][CH:4]1[C:1](=[O:3])[NH2:2])(=[O:27])[CH:25]=[CH2:26]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNC(C(N)=O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.9 %

Procedure:
To a solution of tert-butyl 3-carbamoylpiperazine-1-carboxylate (300 mg, 1.31 mmol) and Et3N (396 mg, 3.93 mmol) in DCM (5 mL) at 0° C., acryloyl chloride (130 mg, 1.44 mmol) in DCM (1 mL) was added and the resulting mixture was stirred at room temperature for 1.5 h. The mixture was partitioned between DCM and saturated NaHCO3 aqueous solution. The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=30:1) to afford the desired product (200 mg, 53.9% yield) as an off-white solid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-c3ccc(Cl)cc3)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(-c2ccc3c(c2)CCNC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of 6-(4-chlorophenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.5 g, 1.45 mmol) in dichloromethane (6 ml) was added trifluoroacetic acid (3 ml). The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and the residue partitioned between dichloromethane (3×20 ml) and 1N sodium hydroxide solution (30 ml). The combined organic phases were dried over potassium carbonate, filtered and evaporated under reduced pressure to give an oil. The oil was purified by flash chromatography using dichloromethane/methanol/ammonia 95:5:1 as eluant to afford the title compound as a solid (0.27 g, 76%); δH (CDCl3) 2.9 (2H, t, CH2), 3.24 (2H, t, CH2), 4.1 (2H, s, CH2), and 7.04-7.55 (7H, m, ArH).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][CH:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=1>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:39]=[CH:38][C:25]([O:26][CH:27]([C:28]([O:30][CH3:31])=[O:29])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:24][CH:23]=2)[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)C(Oc1ccc(CBr)cc1)c1ccccc1
Reactant: CCCCc1nn(-c2ccccc2Cl)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48.2 %

Procedure:
A mixture of 64 mg (0.254 mmol) of the product of Step C, 6.1 mg (0.254 mmol) of sodium hydride, and 0.5 mL of DMF was stirred under N2 at room temperature for 2.5 hours. To this was then added 100 mg (0.299 mmol) of methyl 2-(4-bromomethylphenoxy)-2-phenylacetate (from Example 1, Step C), dissolved in a minimal amount of DMF. Stirring was continued for 48 hours. The mixture was then partitioned between 5 mL H2O and 8 mL EtOAc, and the aqueous layer was further extracted with 2×8 mL EtOAc. The combined organic layers were washed with 2×10 mL H2O and 1×10 mL brine, and dried over anhydrous Na2SO4. The filtrate was evaporated in vacuo, and the residue flash chromatographed over 40 mL silica gel (gradient elution with 0.5% to 2.0% methanol in CH2Cl2) to give 62 mg of the title compound as a colorless oil (48%), homogeneous by TLC in 50:1 CH2Cl2 --MeOH.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:10](=[O:19])[CH:9]2[CH2:20][CH2:21][CH:22]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.[CH3:38][N:39]([CH2:47][CH:48]([OH:57])[CH:49]([OH:56])[CH:50]([OH:55])[CH:51]([OH:54])[CH2:52][OH:53])[C:40](=[O:46])[CH2:41][CH2:42][CH2:43][CH:44]=[CH2:45].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][N:39]([CH2:47][CH:48]([OH:57])[CH:49]([OH:56])[CH:50]([OH:55])[CH:51]([OH:54])[CH2:52][OH:53])[C:40](=[O:46])[CH2:41][CH2:42][CH2:43][CH:44]=[CH:45][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:9]([CH2:20][CH2:21][CH:22]([O:30][Si:31]([C:34]([CH3:35])([CH3:37])[CH3:36])([CH3:32])[CH3:33])[C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[C:10](=[O:19])[N:11]2[C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1ccc(Br)cc1)c1ccc(F)cc1
Reactant: C=CCCCC(=O)N(C)CC(O)C(O)C(O)C(O)CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(O)C(O)C(O)C(O)CO)C(=O)CCCC=Cc1ccc(C2C(CCC(O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
110 mg of 4-(4-bromophenyl)-3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-1-(4-fluorophenyl)azetidin-2-one and 136 mg of N-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)hex-5-enamide are initially charged in 300 μl of triethylamine under argon in a closed tube which had been heated thoroughly beforehand. After addition of 6 mg of palladium acetate and 14 mg of triphenylphosphine, the mixture is stirred at 100° C. for 4 h. The reaction mixture is then taken up in dichloromethane, filtered and concentrated using a rotary evaporator. Purification of the residue using an SiO2 cartridge (dichloromethane/methanol 20:1-5:1) gives the product. C43H58F2N2O8Si (796)