Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[C:9]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][CH2:18]1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[C:10]1([C:9]2([CH:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:24])[CH2:21][CH2:22]3)[CH2:2][O:16]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C(c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(C2(c3ccccc3)CO2)CC1
Temperature: 55 °C
Reaction time: 36 h

Procedure:
A mixture of trimethylsulfoxonium iodide (2.402 g, 10.91 mmol) and sodium hydride (0.436 g, 10.91 mmol) in THF (20 mL) was heated at 55° C. for 3 h then a solution of compound 87 (2.82 g, 8.73 mmol) in THF (10 mL) was added. The reaction mixture was stirred for 36 h, quenched with water, extracted with ether and the combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated to afford compound 88 used as a crude in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>[Cl-].[Cl-].[Zn+2]>[OH:8][C:7]1[C:2]([CH3:1])=[C:3]([OH:9])[CH:4]=[CH:5][C:6]=1[C:10](=[O:12])[CH3:11]
Reactant: Cc1c(O)cccc1O
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(=O)c1ccc(O)c(C)c1O
Temperature: 105 °C

Procedure:
A mixture of 2-methyl-benzene-1,3-diol, acetic anhydride and ZnCl2 was heated at 150-60° C. for 3.5 h, and processed as reported in the literature. (Pearson. D. E. et. al., Synthesis, 533, 1972 and the references cited therein). The crude was purified using flash chromatography (silica gel, 0-5% CH3CN in chloroform) to obtain the title compound. Yield, 73%; mp, 65-66° C. (EtOAc-PE 60-80° C.); MS (CI): 195 (M++29), 169 (M++1); analysis: C9H10O3 requires C, 65.05; H, 6.07; found C, 65.44; H, 6.62%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH2:37].[N:39]([CH2:42][C:43]1[O:44][CH:45]=[CH:46][CH:47]=1)=[C:40]=[O:41]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:40]([NH:39][CH2:42][C:43]1[O:44][CH:45]=[CH:46][CH:47]=1)=[O:41]
Reactant: O=C=NCc1ccco1
Reactant: Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccco1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 34 %

Procedure:
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine bis(trifluoroacetate) and 2-(isocyanatomethyl)furan as the starting materials in 34% yield. LCMS for C23H21ClN7O2(M+H)+: m/z=462.1. 1H NMR (400 MHz, DMSO-d6): δ 9.96 (s, 1H), 9.31 (s, 1H), 8.97 (m, 1H), 8.30 (m, 2H), 8.18 (s, 1H), 7.89 (m, 1H), 7.71 (d, 1H), 7.60 (d, 1H), 7.56 (d, 1H), 6.95-7.02 (m, 2H), 6.41 (dd, 1H), 6.28 (dd, 1H), 4.29 (d, 2H), 2.96 (m, 4H).
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.[C:31]([O-:34])(=[S:33])[CH3:32].[K+].P(O)(O)([O-])=O.[Na+].O>C(O)=O>[C:31]([S:33][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:34])[CH3:32]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Reactant: CC([O-])=S
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC(C)=O)CS[C@H]12)c1csc(N)n1
Reaction time: 0.08 h

Procedure:
A solution of the syn isomer of 4.55 g of 3-acetoxymethyl-7-[{2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl}amino]-ceph-3-eme-4-carboxylic acid, 1.7 g of potassium thioacetate. 2 g of deshydrated monosodium phosphate 1.05 g sodium acid carbonate and 20 ml of distilled water was heated at 70° C. for 90 minutes and the mixture was acidified with 2 ml of formic acid and was extracted 4 times with 60 ml of methyl acetate (insolubles vacuum filtered). The organic solution was washed with water and evaporated to dryness. The residue was dissolved in 20 ml of acetone containing 10% of water and 0.5 g of activated carbon were added thereto. The mixture was stirred for 5 minutes and was vacuum filtered and the filter was washed with acetone containing 10% of water. The filter eas evaporated to dryness and the residue was treated with absolute ethanol and was vacuum filtered. The product was washed with alcohol and then with ether to obtain 1.9 g of the pure syn isomer of 3-acetylthiomethyl-7-[{2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl}amino]-ceph-3-eme-4-carboxylic acid which was identical to the product of Example 6.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C(NC(C)C)(C)C.[Li].[O:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21](=[O:28])[O:20][CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>C1COCC1>[OH:20][CH2:19][CH2:18][O:17][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21](=[O:28])[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]
Reactant: O=C1OCCOc2ccccc21
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(=O)c1ccccc1OCCO
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a solution of tert-butyl acetate (7.96 g, 68.5 mmol) in anhydrous THF (100 mL) was added freshly prepared lithium diisopropyl amine (37 mL, 1.85 M in THF) dropwise over 15 min at −78° C., and the mixture was stirred at −78° C. for 30 min. 2H-benzo[e][1,4]dioxepin-5(3H)-one (10.2 g, 62.3 mmol) was added dropwise as a solution in THF (50 mL) at −78 C, and stirring was continued for 30 min. Saturated NaHCO3 solution was added and the mixture was extracted with EtOAc. The organic layer was dried (Na2SO4), and concentrated under reduced pressure to give the title compound (6.0 g, 77.9%) as a yellow oil, which was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[O:10][CH:11]=[CH:12][C:5]=2[CH2:4]1)[CH3:2].[C:13]([C:16]1[CH:21]=[CH:20][C:19](F)=[C:18]([Cl:23])[CH:17]=1)(=[O:15])[NH2:14]>>[C:13]([C:16]1[CH:21]=[CH:20][C:19]([O:9][CH:7]2[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[CH:12]=[CH:11][O:10][C:6]2=3)=[C:18]([Cl:23])[CH:17]=1)(=[O:15])[NH2:14]
Reactant: CCN1Cc2ccoc2C(O)C1
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Product: CCN1Cc2ccoc2C(Oc2ccc(C(N)=O)cc2Cl)C1

Procedure:
The same method as in Example 1 was conducted using 5-ethyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridin-7-ol (Reference Example 34) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[C:16]([C:21]([OH:23])=O)=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12].C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl.CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[C:16]([C:21]([Cl:27])=[O:23])=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(-c2ccccc2C(=O)O)cc(OC)c1OC
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(-c2ccccc2C(=O)Cl)cc(OC)c1OC
Reaction time: 2 h

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve 3′,4′,5′-Trimethoxy-biphenyl-2-carboxylic acid (56) (54 mg, 0.18 mmol) in anhydrous DCM (1.3 mL) and add anhydrous DMF (1 drop, cat. amount). Then add slowly oxalyl chloride (21 μL, 0.24 mmol) by keeping temperature at ca. 20° C. with a water bath and stir the turbid mixture for additional 2 h at it Remove solvent and dry in vacuum to obtain crude 3′,4′,5′-Trimethoxy-biphenyl-2-carbonyl chloride (57) as a yellow solid. No further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15](O)=[O:16])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H]1[BH2][H][BH2]1.C([O-])([O-])=O.[K+].[K+]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:15][OH:16])[CH2:13][CH2:14]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(NC1(CO)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of 1-(benzyloxycarbonylamino)cyclopropanecarboxylic acid (500 mg, 2.1 mmol) in tetrahydrofuran (5 mL) at 0° C. was added B2H6. THF (1M, 2.1 mL, 2.1 mmol). The mixture was stirred at ambient temperature overnight, treated with K2CO3 (1.0 g in 5 mL H2O) and extracted with methylene chloride (3×10 mL). The organic layer was washed with brine (10 mL) and dried over Na2SO4. After evaporating the solvent, the residue was by chromatography (1:1 ethyl acetate:hexane) to give the title compound as a white solid (200 mg, 43%). 1H-NMR (300 MHz, CDCl3) δ7.35 (m, 5H), 5.30 (br s, 1H), 5.10 (s, 2H), 3.61 (s, 2H), 3.02 (br s, 1H), 0.86 (s, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][NH:23][CH3:24].CC(C)([O-])C.[Na+]>>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([N:23]([CH2:22][CH2:21][N:20]([CH3:25])[CH3:19])[CH3:24])[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCCN(C)C
Reactant: CC(C)(C)OC(=O)NCc1cc(Br)cc(Cl)c1F
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CN(C)CCN(C)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1

Procedure:
was prepared according to Scheme C1 (step A) from (5-bromo-3-chloro-2-fluoro-benzyl)-carbamic acid tert-butyl ester (300 mg, 0.89 mmol), N,N,N′-trimethyl-ethylenediamine (136 mg, 1.3 mmol), sodium tert-butoxide (170 mg, 1.8 mmol) and di-μ-bromobis(tri-tert-butylphosphino)dipalladium (I) [CAS 185812-86-6] (34 mg, 0.04 mmol). MS (LC-MS): 360.3 [M]+; tR (HPLC conditions c): 4.15 min.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].C1(C)C=CC(S(O[CH2:27][C:28]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH:29]=2)(=O)=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:28]1([CH2:27][N:9]2[CH2:8][CH2:7][CH:6]([C:4](=[O:5])[C:3]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:2]=3[F:1])[CH2:11][CH2:10]2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:29]=1
Reactant: O=C(c1ccc(F)cc1F)C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2=Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1ccc(F)cc1F)C1CCN(CC2=Cc3ccccc32)CC1

Procedure:
0.0019 mole of 4-(2,4-difluorobenzoyl)piperidine, 0.0019 mole of benzocyclobuten-1-ylmethyl para-toluenesulfonate and 0.04 mole of triethylamine dissolved in 50 ml of toluene are mixed and then brought to reflux for 18 hours. The reaction medium is then extracted with 1N hydrochloric acid and the aqueous phase is alkalinized and extracted with dichloromethane. The oil obtained is purified on a silica column using a mixture of cyclohexane and acetone (93:7 V/V) as eluent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([O:16]CC)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)cnn1-c1ccc(F)cc1
Reaction time: 2 h
Yield: 78.3 %

Procedure:
Then, ethyl 1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylate (17.7 g) and sodium hydroxide (3.5 g) were added to a mixed solvent of ethanol (80 ml)-water (80 ml), and the mixture was stirred at a refluxing temperature for 2 h. After the reaction, ethanol was evaporated and dilute hydrochloric acid was added. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was recrystallized from ethyl acetate to give the title compound (12.3 g), melting point: 165–166° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[N:3]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[O:24][CH3:23])=[N:3]3)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COc1ccccc1CN
Reactant: O=S(=O)(Nc1cccc2nc(Cl)ccc12)c1ccc(F)cc1
Product: COc1ccccc1CNc1ccc2c(NS(=O)(=O)c3ccc(F)cc3)cccc2n1

Procedure:
N-(2-Chloro-quinolin-5-yl)-4-fluoro-benzenesulfonamide (200 mg, 0.593 mmol) and 2-methoxybenzylamine (171 mg, 1.25 mmol) were stirred in a sealed tube at 120° C. overnight. The reaction mixture was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). The title compound was obtained as a yellow solid (87 mg, 33%), MS: m/e=438.1 ((M+H+).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH3:8][CH:9]([CH2:12][CH2:13][CH3:14])[CH2:10]O>C1C=CC=CC=1>[OH:4][CH2:3][CH2:2][N:1]1[CH2:5][CH2:6][O:7][CH:8]1[CH:9]([CH3:10])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(C)CO
Reactant: OCCNCCO
Solvent: c1ccccc1
Product: CCCC(C)C1OCCN1CCO
Yield: 104.9 %

Procedure:
A one-liter three-necked flask was charged with 100.1 g diethanol amine and 100 ml benzene, followed by addition in droplets of 100.2 g 2-methylpentanol. The flask was then immersed in an oil bath, and the reaction admixture was allowed to react for 8 hours under reflux condition. Benzene was removed from the admixture thereby providing 187 g N-hydroxyethyl-2-(1-methylbutyl)-1,3-oxazolidine. 100 g of the resulting 2-(1-methylbutyl)-3-oxazolidine ethanol were mixed at room temperature with 51.5 g xylylene diisocyanate and allowed to react at 50° C. for one hour and at 80° C. for 8 hours. The yield was 151 g.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[C:19]([C:29]2([CH3:42])[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[S:20][C:21]=1[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[N:23]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[C:3]([C:17]2[N:18]=[C:19]([C:29]3([CH3:42])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[N:23]=2)=[CH:4][CH:5]=[CH:6][C:7]=1[NH:8][S:9]([C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: Cc1nccc(-c2sc(C3(C)CCN(C(=O)OC(C)(C)C)CC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nccc(-c2sc(C3(C)CCNCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate (98 mg, 0.160 mmol) in dichloromethane (DCM) (2 mL) was added TFA (0.5 mL, 6.49 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was purified using RP-HPLC. The TFA salt was neutralized to the title compound (26 mg). MS (ESI): 514.2 [M+1]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([CH3:15])=[CH:13][C:8]([O:9][CH2:10][CH2:11][NH2:12])=[C:7]([CH:16]([CH3:18])[CH3:17])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[OH:26][C:27]1[C:28]([CH3:39])=[C:29]([C:32]([O:37][CH3:38])=[C:33]([CH3:36])[C:34]=1[CH3:35])[CH2:30]Cl>CN(C)C=O>[OH:26][C:27]1[C:28]([CH3:39])=[C:29]([C:32]([O:37][CH3:38])=[C:33]([CH3:36])[C:34]=1[CH3:35])[CH2:30][NH:12][CH2:11][CH2:10][O:9][C:8]1[CH:13]=[C:14]([CH3:15])[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]=1[CH:16]([CH3:18])[CH3:17]
Reactant: COc1c(C)c(C)c(O)c(C)c1CCl
Reactant: CC(=O)Nc1cc(C(C)C)c(OCCN)cc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(C)c(C)c(O)c(C)c1CNCCOc1cc(C)c(NC(C)=O)cc1C(C)C
Temperature: 25 °C
Yield: 5.8 %

Procedure:
2-(4-Acetylamino-2-isopropyl-5-methylphenoxy)ethylamine (1.0 g) and triethylamine (0.50 g) were dissolved in N,N-dimethylformamide (20 ml), and 3-hydroxy-6-methoxy-2,4,5-trimethylbenzyl chloride (0.86 g) dissolved in N,N-dimethylformamide (10 ml) was added dropwise while stirring the mixture at room temperature. The mixture was stirred for 5 hours. After the completion of the reaction, the solvent was distilled off, and water and ethyl acetate were added. The mixture was stirred and an insoluble matter was collected by filtration. The obtained solid was recrystallized from ethyl acetate to give 100 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([N:36]3[CH2:41][CH2:40][N:39]([CH:42]([CH3:44])[CH3:43])[CH2:38][CH2:37]3)=[C:29]3[C:33]=2[C:32](=[O:34])[N:31]([CH3:35])[CH2:30]3)[C:21]([Cl:45])=[CH:20][N:19]=1>>[Cl:45][C:21]1[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([N:36]3[CH2:37][CH2:38][N:39]([CH:42]([CH3:44])[CH3:43])[CH2:40][CH2:41]3)=[C:29]3[C:33]=2[C:32](=[O:34])[N:31]([CH3:35])[CH2:30]3)=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CC(C)N1CCN(c2ccc(Nc3nc(Cl)ncc3Cl)c3c2CN(C)C3=O)CC1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCN(C(C)C)CC5)c5c4C(=O)N(C)C5)n3)cc2CC1

Procedure:
The title compound was prepared from 3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (35 mg, 0.16 mmol) and 7-(2,5-dichloropyrimidin-4-ylamino)-4-(4-isopropylpiperazin-1-yl)-2-methyl-2,3-dihydroisoindol-1-one (70 mg, 0.2 mmol) in an analogous manner to Example 946 to afford a pale yellow solid (60 mg, 60%). Mp: 190-2° C. LCMS (m/e) 619 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 10.60 (s, 1H), 8.63 (d, J=8 Hz, 1H), 8.09 (s, 1H), 7.39 (s, 1H), 7.29 (m, 1H), 7.10 (m, 2H), 6.92 (s, 1H), 4.39 (s, 2H), 3.60 (m, 2H), 3.40 (s, 3H), 3.23 (s, 3H), 3.15-2.86 (m, 8H), 2.84-2.60 (m, 10H), 1.82 (m, 1H), 1.12 (d, J=6 Hz, 6H).
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:10][CH:9]=[C:8]([CH3:11])[C:7]=2[CH:12]=1)N.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]2[NH:1][C:3]3[C:12]([C:22]=2[CH2:21]1)=[C:7]1[C:8]([CH3:11])=[CH:9][S:10][C:6]1=[CH:5][CH:4]=3)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1csc2ccc(NN)cc12
Reactant: O=C1CCN(Cc2ccccc2)CC1
Product: Cc1csc2ccc3[nH]c4c(c3c12)CN(Cc1ccccc1)CC4

Procedure:
The compound is formed analogously to the compound described in Example 5, from 10.1 g of 5-hydrazino-3-methylbenzothiophene and 10 ml of benzyl-4-piperidone. Melting point: 93° C.
Reaction SMILES: [C:1]1(=O)[CH:8]2[N:4]3[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2.Cl.[CH2:12]([O:19][NH2:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1.C(O)C>[C:13]1([CH2:12][O:19][N:20]=[C:1]2[CH:8]3[N:4]4[CH2:5][CH:6]([CH2:9][CH:2]2[CH2:3]4)[CH2:7]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1C2CC3CC1N(C3)C2
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: c1ccc(CON=C2C3CC4CC2N(C4)C3)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Hexahydro-2,6-methano-1H-pyrrolizin-1-one (N. Speckamp, Tetrahedron, 27, 3143 (1971)), 1.45 g, 11.0 mmol, was dissolved in a 1:1 solution of pyridine/ethanol (20 mL). O-Benzyl hydroxylamine hydrochloride (1.85 g, 11.6 mmol) was added and the solution was stirred for 20 hours at room temperature. Removal of the solvents in vacuo afforded a solid which was purified by chromatography on silica gel eluting with 10% MeOH (NH3)/CHCl3 to give hexahydro-1-[(phenylmethoxy) imino]-2,6-methano-1H-pyrrolizine.
Reaction SMILES: C([C:3]1([CH2:19][O:20][CH3:21])[CH2:8][C:7]([C:9]([O:11]C)=[O:10])=[CH:6][CH:5]=[C:4]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C.O.[OH-].[Li+].[CH2:25]1COC[CH2:26]1>O>[CH2:25]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[CH:5]=[CH:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:3]=1[CH2:19][O:20][CH3:21])[CH3:26]
Reactant: C1CCOC1
Reactant: CCC1(COC)CC(C(=O)OC)=CC=C1c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCc1ccccc1-c1ccc(C(=O)O)cc1COC
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of methyl 2-ethyl-2-(methoxymethyl)-1,1′-biphenyl-4-carboxylate (12 g, 0.0422 mol) in THF (150 mL) and water (30 mL), was added lithium hydroxide monohydrate (5.31 g, 0.127 mol) in portions. After 12 h at RT, the reaction mixture was concentrated and the aqueous phase was acidified using conc. HCl and extracted with EtOAc. Then the organic layers were washed with water and brine solution. The solvents were dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a white solid (9 g, 80%). 1H NMR (DMSO-d6, 300 MHz) δ 12.9 (1H, bs), 8.08 (1H, s), 7.88-7.90 (1H, m), 7.34-7.35 (2H, m), 7.21-7.25 (2H, m), 7.03-7.05 (1H, m), 4.04-4.13 (2H, m), 3.16-3.18 (3H, s), 2.29-2.38 (1H, m), 2.19-2.24 (1H, m), 0.92-0.95 (3H, m). LC/MS (Method A): 269.0 (M−H)−. HPLC (Method B) Rt 5.06 min (Purity: 97.4%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[Br:12][CH2:13][CH2:14]Br>O.CCOC(C)=O>[Br:12][CH2:13][CH2:14][O:11][C:6]1[CH:5]=[C:4]([Cl:3])[CH:9]=[C:8]([Cl:10])[CH:7]=1
Reactant: BrCCBr
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1cc(Cl)cc(OCCBr)c1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
To a solution of NaOH (2.45 g, 61.3 mmol) in water (20 mL) was added 3,5-dichlorophenol (5 g, 30.7 mmol). The solution was heated at reflux for 1 h and was cooled to room temperature. 1,2-Dibromoethane (11.52 g, 61.3 mmol) was added and the reaction was heated at reflux for 24 h. The cooled solution was diluted with EtOAc and the organic solution was washed sequentially with HCl (1N, 1×), water (1×), and brine (1×). The organic solution was dried (MgSO4), filtered, and concentrated. Purification by flash chromatography (hexanes to 5% EtOAc in hexanes ) provided the title compound (3.79 g). 1H NMR (400 MHz, CDCl3) δ 6.98 (m, 1H), 6.82 (m, 2H), 4.25 (t, 2H), 3.61 (t, 2H).