Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20]>N1C=CC=CC=1>[C:18]([O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1)(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: O=C1c2ccccc2C(=O)c2cc(O)ccc21
Reactant: C=C(C)C(=O)Cl
Solvent: c1ccncc1
Product: C=C(C)C(=O)Oc1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
0.2 mol of 2-hydroxyanthraquinone is dissolved in 600 ml of pyridine under an inert gas in a 1,000 ml brown glass flask with a dropping funnel and thermometer. 0.24 mol of methacryloyl chloride is then added dropwise in the course of 15 minutes, with ice-cooling. After the mixture has been stirred at room temperature for 20 hours, the pyridine is removed on a rotary evaporator. The crude crystalline product is suspended in 500 ml of 0.1N HCl, the suspension is filtered, the solid is taken up in water again and, after washing with sodium bicarbonate solution and water, the crude product is dried in vacuo. Yield of crude product: 90% of theory. Recrystallisation of the crude product from ethylene glycol monomethyl ether gives a 58% yield of 2-anthraquinonyl methacrylate as a yellow crystalline product; melting point: 184°-186° C.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:22][CH2:23][CH3:24])(=[O:21])[C:12]1[CH:20]=[CH:19][C:17]([OH:18])=[C:14]([O:15][CH3:16])[CH:13]=1>>[C:1]1([C:7]#[C:8][CH2:9][O:18][C:17]2[CH:19]=[CH:20][C:12]([C:11]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][C:14]=2[O:15][CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCC#Cc1ccccc1
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Product: CCOC(=O)c1ccc(OCC#Cc2ccccc2)c(OC)c1
Yield: 70 %

Procedure:
3-Phenylprop-2-ynyl bromide was reacted with ethyl vanillate using the conditions described in Example 1 to give ethyl 4-(3-phenylprop-2-ynyloxy)-3-methoxybenzoate in 70% yield, m.p. 62°-65° C. Following the procedures described in the portion of Example 6 which is concerned with the preparation of starting materials the product so obtained was reacted with thiazol-2-yl-lithium and the resultant product was reacted with ethylmagnesium iodide to give the required starting material as an oil in 61% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([CH3:29])([CH3:28])[CH2:14]2)[N:5]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][C:39]([CH3:42])([CH3:41])[N:38]([O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[C:37]([CH3:51])([CH3:50])[CH2:36]2)[N:3]=1.[CH2:52]1[O:55][CH:53]1[CH3:54]>>[OH:55][CH:53]([CH3:54])[CH2:52][NH:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:19])([CH3:20])[N:16]([O:21][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[C:15]([CH3:28])([CH3:29])[CH2:14]2)[N:5]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:36][C:37]([CH3:51])([CH3:50])[N:38]([O:43][CH:44]3[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]3)[C:39]([CH3:41])([CH3:42])[CH2:40]2)[N:3]=1
Reactant: CC1CO1
Reactant: CC1(C)CC(CCCCNc2nc(N)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Product: CC(O)CNc1nc(NCCCCC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)nc(NCCCCC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)n1

Procedure:
The title compound is prepared from the reaction of the compound prepared in Example 22 with propylene oxide.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:17]C(=O)C)[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2([CH3:16])[CH2:15][CH2:14]2)[CH:8]=1.Cl>CCO>[CH3:1][C:2]1[N:3]=[C:4]([NH2:17])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2([CH3:16])[CH2:15][CH2:14]2)[CH:8]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccnc(C3(C)CC3)c2)s1
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)sc1-c1ccnc(C2(C)CC2)c1
Yield: 21.3 %

Procedure:
A mixture of N-{4-methyl-5-[2-(1-methyl-cyclopropyl)-pyridin-4-yl]-thiazol-2-yl}-acetamide (Step 401.3) (565 mg, 7 mmol), a 6N aqueous solution of HCl (3 mL) and EtOH (15 mL) is stirred for 3.5 h at 85° C., allowed to cool, quenched by addition of a saturated solution of NaHCO3 and extracted with DCM. The organic phase is washed with a saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH, 1:0→98:2) to afford 366 mg of the title compound as a yellow solid: ESI-MS: 246.1 [M+H]+; TLC: Rf=0.40 (DCM/MeOH, 9:1).
Reaction SMILES: [CH3:1][O-:2].[Na+].C([C@H]1COC(=O)N1[C:17](=[O:39])[C@@H:18]([O:36][CH2:37][CH3:38])[C@@H:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:23][C:22]=1[CH3:35])[OH:20])C1C=CC=CC=1>CO>[CH3:1][O:2][C:17](=[O:39])[C@@H:18]([O:36][CH2:37][CH3:38])[C@@H:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:23][C:22]=1[CH3:35])[OH:20]
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1C
Temperature: 0 °C
Yield: 69.4 %

Procedure:
A 5.4 M solution of sodium methoxide (7.3 ml, 39.5 mmol) was added to an ice-cooled and stirred suspension of (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one (17.6 g, 36 mmol) in dry methanol (87 ml). The mixture was stirred at 0° C. for 15 min, quenched and neutralized by the addition of dilute aqueous hydrochloric acid (1.0 M). The solution was concentrated under reduced pressure and the residue dissolved in ice water/ethyl acetate 1/1. The layers were separated and the aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed with ice water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, cyclohexane/AcOEt) to give 8.6 g (25 mmol, 69%) of the title compound as light yellow oil. According to 1H-NMR spectroscopy, one single diastereomer was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[N:24]=[C:25]([C:31]#[N:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])(=O)=O.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([O:15][N:24]=[C:25]([C:31]#[N:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)C(C#N)=NOS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=NOC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
N-Benzyloxycarbonyl-L-proline (1.25 g) and ethyl 2-methanesulfonyloxyimino-2-cyanoacetate (1.1 g) are dissolved in ethyl acetate (10 ml). To the solution is added triethylamine (0.7 ml) and the mixture is stirred at room temperature for 1 hour. After allowing to stand overnight, to the reaction mixture is added ethyl acetate. The mixture is washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off to give ethyl 2-(N-benzyloxycarbonyl-L-prolyloxyimino)-2-cyanoacetate (1.9 g) as an oily substance.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.F[C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH2:17][OH:18].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:27]>O>[N+:23]([C:20]1[CH:21]=[CH:22][C:15]([N:31]2[CH2:32][CH2:33][N:28]([CH2:26][CH3:27])[CH2:29][CH2:30]2)=[C:16]([CH2:17][OH:18])[CH:19]=1)([O-:25])=[O:24]
Reactant: CCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCN1CCN(c2ccc([N+](=O)[O-])cc2CO)CC1
Temperature: 140 °C
Reaction time: 14 h

Procedure:
4.24 g of potassium carbonate was added to N-methylpyrrolidone (4.24 mL) solution of 4.24 g of 2-fluoro-5-nitrobenzyl alcohol and 4.24 g of N-ethylpiperazine, and stirred at 140° C. for 14 hours. Water was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline water in that order, then dried with anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain the entitled compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([OH:19])=O)[N:3]=1.C([O:22][C:23](=[O:32])[CH2:24][NH:25][CH2:26][C:27]([O:29]CC)=[O:28])C>>[C:23]([CH2:24][N:25]([CH2:26][C:27]([OH:29])=[O:28])[C:17]([C:4]1[N:3]=[C:2]([Cl:1])[C:11]2[C:6]([C:5]=1[OH:16])=[CH:7][C:8]([O:12][CH:13]([CH3:14])[CH3:15])=[CH:9][CH:10]=2)=[O:19])([OH:32])=[O:22]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: CC(C)Oc1ccc2c(Cl)nc(C(=O)O)c(O)c2c1
Product: CC(C)Oc1ccc2c(Cl)nc(C(=O)N(CC(=O)O)CC(=O)O)c(O)c2c1

Procedure:
Prepared from 1-chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid and (ethoxycarbonylmethyl-amino)-acetic acid ethyl ester analogously to Example D-49 MS-(+)-ion: 397.0 amu.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.CO.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>[C:22]1([C:2]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(I)c1
Reactant: OB(O)c1ccccc1
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: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)OC)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.3 %

Procedure:
A mixture of dimethyl 2-iodoterephthalate (22.8 g, 71.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.14 g, 3.38 mmol) in toluene (120 mL) was stirred for 10 minutes. Aqueous sodium carbonate (2 M, 160 mL) and a solution in methanol (40 mL) of phenylboronic acid (10.4 g, 85.3 mmol) were then added and the reaction mixture was stirred at reflux for 15 hours. The reaction mixture was cooled to ambient temperature and extracted with ether. The organic phase was washed with water (2×) and brine, dried, and concentrated in vacuo to give dimethyl 2-phenylterephthalate as a dark brown oil (18.4 g) which was used without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N+:33]([C:36]1[C:41]2[O:42][CH2:43][O:44][C:40]=2[C:39]([C:45](O)=[O:46])=[CH:38][CH:37]=1)([O-:35])=[O:34].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:45]([C:39]2[C:40]3[O:44][CH2:43][O:42][C:41]=3[C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=2)=[O:46])[CH2:3][CH2:4]1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c2c1OCO2
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])c3c2OCO3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
4-Amino-1-methylpiperidine (Fluorochem; 325 mg, 2.84 mmol), HATU (1.09 g, 2.84 mmol) and 7-nitrobenzo[1,3]dioxole-4-carboxylic acid (WO 2003082827; 400 mg, 1.89 mmol) were stirred in DMF (5 mL) and diisopropylethylamine (0.99 ml, 5.68 mmol) added. The mixture was stirred for 2 hours at room temperature. The reaction mixture was loaded on to an SCX column, which was subsequently washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and the solid suspended in methanol and filtered off to yield the title compound as a yellow solid (295 mg, 51%).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].C(N(CC)CC)C.[CH2:20]=[C:21]([C:26](OS(F)(=O)=O)([F:28])[F:27])[C:22]([F:25])([F:24])[F:23]>C(OCC)C>[CH2:20]=[C:21]([C:26]([O:8][C:7]1[C:6]([F:9])=[C:5]([F:10])[C:4]([F:11])=[C:3]([F:12])[C:2]=1[F:1])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23]
Reactant: C=C(C(F)(F)F)C(F)(F)OS(=O)(=O)F
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(C(F)(F)F)C(F)(F)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
Pentafluorophenol (7.5 g, 0.040 mole) and triethylamine (4.5 g, 0.044 mole) in dry ethyl ether (7 ml) are added gradually to CH2═C(CF3)CF2OSO2F (11 g, 0.045 mole) in ethyl ether (14 ml) at 20° C. The reaction mixture is agitated at 20° C. for 30 minutes and washed in turn with water, dilute aqueous HCl, water, sodium bicarbonate solution, and water and the resulting ether solution is dried over MgSO4. Distillation of the dried mixture gives CH2═C(CF3)CF2OC6F5 (9.8 g, 73% yield, b.pt. 86-88° C. at 20 mm Hg).
Reaction SMILES: [O:1]1[C:10]2[CH2:9][CH2:8][CH:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Br:18]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:18][C:2]1[O:1][C:10]2[CH2:9][CH2:8][CH:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[NH:6][CH2:5][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)C1CCc2occc2CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C1CCc2oc(Br)cc2CN1
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4,5,7,8-tetrahydrofuro[3,2-c]azepine-6-carboxylate (0.21 mmol) in chloroform (0.5 mL) and acetic acid (0.5 mL) is treated with N-bromosuccinimide (0.21 mmol) at RT. After 1 hour, the reaction is poured over saturated aqueous NaHCO3, and extracted with ethyl acetate (2×5 mL). The organic layers are washed with brine, dried, and purified by silica chromatography (20% ethyl acetate/hexanes) to give tert-butyl 2-bromo-4,5,7,8-tetrahydrofuro[3,2-c]azepine-6-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)O.S(Cl)([Cl:27])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8]([Cl:27])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1cnn(-c2ccc(C(O)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Solvent: ClC(Cl)Cl
Product: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Reaction time: 3 h
Yield: 83.1 %

Procedure:
To a stirred mixture of 16 parts of 2-[3-chloro-4-[(4-chlorophenyl)hydroxymethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione and 150 parts of trichloromethane were added dropwise, during a period of 5 minutes, 16 parts of thionyl chloride. Upon completion, stirring was continued for 3 hours at reflux temperature. The reaction mixture was evaporated in vacuo. Methylbenzene was added and the whole was evaporated again, yielding 14 parts (83.1%) of 2-[3-chloro-4-[chloro(4-chlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione as a residue (intermediate 107).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C([O-])([O-])=O.[K+].[K+].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCOCC1>[CH2:24]([O:23][C:21]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
To 4.96 g (30 mmole) phenylalanine was added 76 mL of 1:1 mixture of water and dioxane, followed by 4.15 g (30 mmole) of K2CO3. After 10 min 2.87 mL of ethyl chloroformate (30 mmole) in 10 mL of dioxane was added dropwise, and the reaction mixture was allowed to stir. The reaction was monitored by TLC, and once complete (ca. 2 hrs) the solvent was stripped by rotary evaporation. The residue was reconstituted in 50 mL of 1N NaOH, then extracted with ethyl acetate. The aqueous layer was then acidified with 2N HCl to pH 2 and extracted 3× with ethyl acetate, after which the extract was dried over Na2SO4, filtered and the filtrate evaporated. The residue was pumped on high vacuum, after which it was recrystallized from Et2O/hexanes in two crops to give the title compound. NMR (300 MHZ, CD3OD): δ 7.22 (m, Ph, 5H), 4.38 (dd, Phe-α, 1H), 4.00 (q, CH3CH2OCOPhe, 2H), 3.17 (dd, Phe-β, 1H), 2.90 (dd, Phe-α, 1H), 1.17 (t, CH3CH2 OCOPhe, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9](OC)=O)[C:5]1=[O:13].[Cl:14][C:15]1[CH:22]=[CH:21][C:18](CCl)=[CH:17][CH:16]=1>C1C=CC=CC=1>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:9][CH:6]2[CH2:7][CH2:8][CH:4]([CH3:3])[C:5]2=[O:13])=[CH:17][CH:16]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: COC(=O)C1CCC(C)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1CCC(Cc2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into 126 ml of anhydrous benzene, 3.04 g of sodium hydride (prepared by washing 60 % oily sodium hydride with anhydrous benzene) were added, and then 18 g of methyl 3-methyl-2-oxocyclopentanecarboxylate were added to the thus formed mixture. After stirring the whole mixture for one hour at room temperature, 21.5 g of 4-chlorobenzyl chloride were added to the mixture and the thus obtained mixture was refluxed for 6 hours in an oil bath at 90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Br:19]Br.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:19][C:12]1[NH:11][C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)=[N:14][C:13]=1[C:15]([F:16])([F:17])[F:18]
Reactant: BrBr
Reactant: COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nc(C(F)(F)F)c(Br)[nH]2)cc1Cl
Reaction time: 72 h
Yield: 68.8 %

Procedure:
To a suspension of 55 (2.56 g, 0.0092 mol) in CHCl3 (75ml) was added dropwise with stirring a solution of bromine (1.55 g, 0.0096 mol) in CHCl3 (75 ml). After stirring for 3 days, saturated NaHCO3 was added, the layers separated and the aqueous layer extracted with CHCl3 (2 x). The organic extracts were dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product eluted with 1.5% CH3OH-CHCl3 to yield 2.25 g (69%) of 56, m.p. 228.30° C. (CHCl3). Analysis calculated for C11H7BrClF3N2O.
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[S:6]([CH3:9])(=[O:8])=[O:7])([OH:3])=O.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH:38][C:1]([CH2:4][N:5]([C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[S:6]([CH3:9])(=[O:7])=[O:8])=[O:3]
Reactant: CN(C)CCN
Reactant: CS(=O)(=O)N(CC(=O)O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)CN(c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared analogously to Example 18 from (Z)-3-{1-[4-(N-carboxymethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone, 2-dimethylamino-ethylamine, HOBt, TBTU and N-ethyl-N,N-diisopropylamine in DMF.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:30]=[C:31]([CH3:39])[C:32]3[N:36]=[C:35]([CH3:37])[NH:34][C:33]=3[CH:38]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:37][C:35]1[NH:34][C:33]2[CH:38]=[C:29]([O:28][C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)[CH:30]=[C:31]([CH3:39])[C:32]=2[N:36]=1
Reactant: Cc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc(C)[nH]c5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.16 g (0.59 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.15 g (0.55 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-2,4-dimethyl-1H-benzimidazole and 0.21 mL (1.2 mmol) DIPEA were combined in 2.0 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1>CN(C)C=O>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]2=[O:1])=[CH:20][CH:19]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2)C(=O)C1
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To a solution of 1,1-dimethylethyl 3-oxo-1-piperazinecarboxylate (500 mg, 2.497 mmol) in N,N-dimethylformamide (DMF) (8 mL) at room temperature under nitrogen was added sodium hydride (60% w/w in mineral oil, 120 mg, 3.00 mmol) and the resulting suspension was stirred at this temperature for 30 min. 1-Bromo-4-(bromomethyl)benzene (749 mg, 3.00 mmol) in DMF (5 mL) was then added via syringe. The resulting mixture was stirred at room temperature for 1.5 h then partitioned between AcOEt and water. The layers were separated and the aqueous phase was extracted three times with AcOEt. The combined organic phases were washed three times with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 25 G silica cartridge (gradient: 13 to 63% AcOEt in Hexanes) gave 1,1-dimethylethyl 4-[(4-bromophenyl)methyl]-3-oxo-1-piperazinecarboxylate (763 mg, 2.066 mmol, 83% yield) as an oil which solidified to a white solid over 16 h.