Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([NH:13][C:14]2[C:15]([N:20]([CH3:22])[CH3:21])=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])=[CH:9][N:8]=[CH:7][CH:6]=1.[CH3:28]CCCCCC.C(OCC)(=O)C>>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]([C:14]2[C:15]([N:20]([CH3:22])[CH3:21])=[N:16][CH:17]=[CH:18][CH:19]=2)[CH3:28])=[O:12])=[CH:9][N:8]=[CH:7][CH:6]=1
Reactant: CCCCCCC
Reactant: CN(C)c1ncccc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl
Solvent: CCOC(C)=O
Product: CN(C)c1ncccc1N(C)C(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 12, from 4-(2,5-dichloro-phenoxy)-N-(2-dimethylamino-pyridin-3-yl)-nicotinamide and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Colorless oil (67%). MS (ESI): m/z=417.088 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:7][C:6]=1[O:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].NN>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:22][CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(N2C(=O)c3ccccc3C2=O)ccc1C(C)(C)C
Agent: NN
Solvent: CCO
Product: COc1cc(N)ccc1C(C)(C)C
Yield: 82.2 %

Procedure:
A slurry of 2-(4-tert-butyl-3-methoxy-phenyl)isoindoline-1,3-dione (400 mg, 1.29 mmol) and NH2NH2 (207 mg, 203 μL, 6.47 mmol) in ethanol (10 mL) was refluxed for 3 h. The reaction was cooled and concentrated in vacuo. The residue was extracted with water (25 mL) and ethyl acetate (3×10 mL). The combined organic extracts were washed with water, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (25-40% ethyl acetate/hexanes) provided 4-tert-butyl-3-methoxy-aniline (190 mg, 82% yield) as light brown oil. 1H NMR (400.0 MHz, CDCl3) δ 6.97 (d, J=8.1 Hz, 1H), 6.17 (m, 2H), 3.71 (d, J=3.3 Hz, 3H), 3.53 (br s, 2H), 1.25 (d, J=3.3 Hz, 9H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24]([OH:26])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][O:37][CH:36]([CH2:40][NH2:41])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][O:37][CH:36]([CH2:40][NH:41][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][CH:22]=2)=[O:26])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C1
Product: CC(C)(C)OC(=O)N1CCOC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A67) and 2-aminomethyl-morpholine-4-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([NH:17]C(OC(C)(C)C)=O)[CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=O.C(OCC)(=O)C.Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[NH:17]1)=[O:25]
Reactant: COC(=O)[C@@H](CCCC(=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CCC[C@@H](c2ccc(Cl)cc2)N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.8 %

Procedure:
In nitrogen atmosphere, 4-chlorophenyl magnesium bromide (1.0 M, diethylether solution, 42 mL) was added to a THF solution (120 mL) of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester (CAS Register No. 183890-36-0, 9.00 g) over 20 min at −78° C. The resulting reaction solution was stirred at −78° C. to −40° C. for 1.5 hr and then quenched with a saturated ammonium chloride aqueous solution at −40° C. To this reaction solution, water was added. The resulting mixture was extracted with ethyl acetate. The obtained extract solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: heptane-ethyl acetate system) to give 9.53 g of (R)-2-tert-butoxycarbonylamino-6-(4-chlorophenyl)-6-oxohexanoic acid methyl ester. To an ethyl acetate solution (90 mL) of the (R)-2-tert-butoxycarbonylamino-6-(4-chlorophenyl)-6-oxohexanoic acid methyl ester (9.53 g), a 4 N hydrogen chloride-ethyl acetate solution (90 mL) was added at room temperature. The resulting reaction solution was stirred at room temperature for 12 hr and then concentrated under reduced pressure. A saturated sodium hydrogencarbonate aqueous solution was added to the residue for basification, and then chloroform was added thereto. The resulting reaction solution was stirred at room temperature for 2 hr. The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. To a methanol solution (150 mL) of the residue, sodium cyano borohydride (3.29 g) and then acetic acid (4.27 mL) were added at 0° C. The resulting reaction solution was stirred at 0° C. for 1 hr and further at room temperature for 1 hr, and then a saturated sodium hydrogencarbonate aqueous solution was added thereto. The resulting mixture was extracted with chloroform. The obtained extract solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: heptane-ethyl acetate system) and further solidified from a heptane-diisopropylether system to give 2.47 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[F:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:35]4[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)(C)OC(=O)NC1=NC2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
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: [K+]
Product: CC(C)(C)OC(=O)NC1=NC2(CS1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Temperature: 80 °C

Procedure:
A vial was charged with tert-butyl 3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate (0.454 g, 0.791 mmol), 2-fluoropyridin-3-ylboronic acid (0.167 g, 1.186 mmol), potassium carbonate (0.546 g, 3.95 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.091 g, 0.079 mmol). The vial was flushed with Ar (g), then dioxane (5.27 mL) and water (2.64 mL) were added in sequence. The vial was sealed and heated at 80° C. for one hour. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel chromatography (gradient elution 0-50% EtOAc:Hex) to afford tert-butyl 3-bromo-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate as a light yellow solid. MS m/z=545.1. Calc'd for C24H20BrFN4O3S: 543.41.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:7]>C1COCC1.CO.O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([NH:14][C@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C@H:8]2[C:6]([OH:7])=[O:5])(=[O:16])=[O:17])=[CH:19][CH:20]=1
Reactant: COC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Lithium hydroxide monohydrate (1.7 mmol) was added to a mixture of (1R,2S)-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid methyl ester in THF (8 mL), methanol (8mL) and water (8 mL). Reaction stirred at room temperature overnight. Organic solvents were removed from the mixture in vacuo. Remaining aqueous was washed with ether (2×15 mL). Aqueous layer was made acidic to litmus paper with 1 N hydrochloric acid. Mixture was extracted with ethyl acetate (2×20 mL). Combined extracts were washed with brine (1×10 mL) then dried (magnesium sulfate), filtered and concentrated in vacuo. The product (208 mg) was obtained as a white solid in 80% yield: 1H NMR (300 Mz, CDCl3) δ 7.70 (d, 2 H, J=8.8), 7.48 (d, 4 H, J=8.8), 6.20 (d, 1 H, J=9.5), 3.41 (m, 1 H), 2.81 (dd, 1 H, Jd=4.4, Jd=4.8), 2.03 (m, 1 H), 1.80 (m, 1 H), 1.62 (m, 1 H), 1.44 (m, 2 H), 1.25 (m, 2 H); MS m/e 316 (M−H)−.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)([CH3:13])[CH3:12]
Reactant: CC(C)n1cnc2c(NCc3ccccn3)nc(F)nc21
Reactant: CC[C@H](N)C(O)C(C)(C)C
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC[C@H](Nc1nc(NCc2ccccn2)c2ncn(C(C)C)c2n1)C(O)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-2-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.10 mL, 5.5 eq, 0.57 mmol) followed by (3RS,4S)-4-amino-2,2-dimethyl-hexan-3-ol (43 mg, 2.81 eq, 0.29 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine-(50 mL), dried,(NgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 5.9 mg (14%).(53% de 4S,3R: 47% de 4S,3S). 1H-NMR (d-CDCl3, 250 MHz): δ 1.00-1.04 (m, 12H, —NHCH(CH2CH3)CH(C(CH3OH), 1.56 & 1.58 (2×d, 6H, J=6.63 & 6.63 Hz, —CH(CH3)2), 1.67-1.90 (m, 2H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.56 (d, 1H, J=1.89 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.70-3.83 (m, 1H, —NHCH(CH2CH3)CH (C(CH3)3) OH), 4.58-4.69 (m, 1H, —CH(CH3)2), 4.88-4.98 (m, 2H, —HNCH2-Pyr), 5.23-5.39 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 6.71-6.80 (m, 1H, —HNCH2-Pyr), 7.17-7.24 (m, 1H, Pyr-H), 7.38 (d, 1H, J=7.90, Pyr-H), 7.57 (s, 1H, —N═CH—N—), 7.63-7.70 (m, 1H, Pyr-H), 8.61 (d, 1H, J=4.90 Hz, Pyr-H). FABMS m/z (relative intensity): 412 ([M+H]+, 100), 324 (75). Accurate Mass (M+H): Actual: 412.2825, Measured: 412.2835.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:15])[N:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)[C:6]=1[CH3:7].[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1)#[CH:17]>>[CH3:15][C:4]1[N:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)[C:6]([CH3:7])=[C:2]([C:17]#[C:16][C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)[N:3]=1
Reactant: C#Cc1cccc(C)c1
Reactant: Cc1nc(I)c(C)n1-c1cc[nH]c(=O)c1
Product: Cc1cccc(C#Cc2nc(C)n(-c3cc[nH]c(=O)c3)c2C)c1

Procedure:
The title compound, light brown solid, MS: m/e=304.1 (M+H+), was prepared in accordance with the general method of example 21a from 4-(4-iodo-2,5-dimethyl-imidazol-1-yl)-1H-pyridin-2-one and 1-Ethynyl-3-methyl-benzene.
Reaction SMILES: [CH:1]1([O:4][C:5]2[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([CH:12]=[CH:13][CH:14]=2)[C:8]([O:10]C)=[O:9])[CH2:3][CH2:2]1.[OH-].[Li+].O>C1COCC1.CO>[CH:1]1([O:4][C:5]2[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([CH:12]=[CH:13][CH:14]=2)[C:8]([OH:10])=[O:9])[CH2:2][CH2:3]1
Reactant: COC(=O)c1cccc(OC2CC2)c1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(OC2CC2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A solution of methyl 3-cyclopropoxy-2-nitrobenzoate (4.7 g, 19.81 mmol) in THF (30 mL) and MeOH (30 mL) was treated with a solution of lithium hydroxide (2.88 g, 120 mmol) in water (15 mL, 833 mmol). The mixture was stirred at room temperature for 2 hours. The organic solvents were removed under reduced pressure. The resulting aqueous slurry was diluted with water, acidified with 1M HCl and extracted with ethyl acetate (3×). The extracts were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to provide 3-cyclopropoxy-2-nitrobenzoic acid (4.35 g, 19.8 mmol, 98% yield) as a yellowish solid. HPLC: RT=2.186 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES):m/z=246 [M+Na]+; 1H NMR (400 MHz, chloroform-d) δ 7.76 (dd, J=7.7, 1.8 Hz, 1H), 7.68-7.46 (m, 2H), 4.02 (tt, J=6.0, 2.9 Hz, 1H), 1.00-0.52 (m, 4H).
Reaction SMILES: C(OC([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](=[O:23])[CH2:20][CH2:21][CH3:22])=[CH:14][C:13]=1C(CC)C([O-])=O)=O)C1C=CC=CC=1>CO.[Pd]>[C:19]([O:23][C:13]1[CH:14]=[C:15]([O:18][C:19](=[O:23])[CH2:20][CH2:21][CH3:22])[CH:16]=[CH:17][C:12]=1[NH2:11])(=[O:18])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(=O)Oc1ccc(NC(=O)OCc2ccccc2)c(C(CC)C(=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCCC(=O)Oc1ccc(N)c(OC(=O)CCC)c1
Reaction time: 0.33 h
Yield: 96 %

Procedure:
To a solution of 2-benzyloxycarbonylamino-5-butyryloxyphenylbutanoate (KCBG04) KCBG04 (0.05 g, 0.12 mmol) in MeOH (5 mL) was added Pd/C (10%, 4 mg) at room temperature. After stirring for 20 min under H2, the reaction mixture was filtered and evaporated in vacuo to give 2-amino-5-butyryloxyphenyl butanoate (KCBG06, 0.031 g, 96%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:27][S:28]([C:31]1[CH:40]=[CH:39][C:34]([O:35][CH2:36][CH2:37]O)=[CH:33][CH:32]=1)(=[O:30])=[O:29]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:37][CH2:36][O:35][C:34]2[CH:33]=[CH:32][C:31]([S:28]([NH2:27])(=[O:30])=[O:29])=[CH:40][CH:39]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: NS(=O)(=O)c1ccc(OCCO)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc(S(N)(=O)=O)cc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 47.2 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.905 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.218 g), stirred for 15 minutes and treated with the tosylate of 2-(4-aminosulfonylphenoxy)ethanol (1.67 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from ethyl acetate extraction was purified by HPLC (dichloromethane-ethyl acetate; 4:1) and crystallized from dichloromethane-hexane to provide 0.9 g of 4-[[2-[4-(amino-sulfonyl)phenoxy]ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 136°-137° C.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16](=[O:21])[NH:17][CH:18]1[CH2:20][CH2:19]1)=O)C1C=CC=CC=1>CO.[Pd]>[CH:18]1([NH:17][C:16]([C@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)=[O:21])[CH2:20][CH2:19]1
Reactant: O=C(NC1CC1)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(NC1CC1)[C@H]1CCCN1
Yield: 79.1 %

Procedure:
(R)-2-Cyclopropylcarbamoyl-pyrrolidine-1-carboxylic acid benzyl ester (2.6 g) was hydrogenated using 5% Pd/C (260 mg) in methanol (25 mL). The filtrate was concentrated to give 1.1 g (79%) of (R)-pyrrolidine-2-carboxylic acid cyclopropylamide.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=2)[N:4]=1.[SH:33][C:34]1[N:35]([CH3:39])[CH:36]=[CH:37][N:38]=1>>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=3)[N:4]=[C:3]([CH2:2][S:33][C:34]3[N:35]([CH3:39])[CH:36]=[CH:37][N:38]=3)[C:12]=2[C:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: Cn1ccnc1S
Reactant: COc1ccc(-c2c(C(=O)CC(C)C)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Product: COc1ccc(-c2c(C(=O)CC(C)C)c(CSc3nccn3C)nc3cc(OC)c(OC)cc23)cc1OC

Procedure:
According to the same manner as that described in Example 4, 2-bromomethyl-4-(3,4-dimethoxyphenyl)-3-isovaleryl-6,7-dimethoxyquinoline was reacted with 2-mercapto-1-methylimidazole to give 4-(3,4-dimethoxyphenyl)-3-isovaleryl-6,7-dimethoxy-2-[(1-methylimidazol-2-yl)thiomethyl]quinoline. This compound was recrystallized from ethanol to give colorless prisms. mp. 152°-153° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:24].C(N(CC)C(C)C)(C)C.[CH3:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>C(Cl)Cl>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:37](=[O:38])[C:36]4[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=4[CH3:34])=[C:3]([CH3:24])[CH:4]=3)=[O:7])[CH2:9][C:10]=12
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1NC(=O)c1ccccc1C
Yield: 65.9 %

Procedure:
A solution of 0.83 g of 10,11-dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.5 g of N,N-diisopropylethylamine and 0.6 g of 2-methylbenzoyl chloride in 50 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water, the organic layer dried with Na2SO4 and passed through a pad of hydrous magnesium silicate. Hexane is added at the boil to give 0.75 g of a solid which is crystallized from methylene chloride-hexane to give 0.61 g of the desired product, m.p. 125°-130° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH:10]1(/[CH:16]=[C:17](\B2OC(C)(C)C(C)(C)O2)/[CH2:18][OH:19])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[F-].[Cs+]>O1CCOCC1.C1(P([Pd-4](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)C=CC=CC=1>[CH:10]1(/[CH:16]=[C:17](\[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)/[CH2:18][OH:19])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC1(C)OB(/C(=C\C2CCCCC2)CO)OC1(C)C
Reactant: COc1ccc(Br)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COc1ccc(/C(=C\C2CCCCC2)CO)cc1
Yield: 58.3 %

Procedure:
Following the method of example 46a, Suzuki coupling of 1-bromo-4-methoxy-benzene (0.65 g, 3.48 mmol) with (E)-3-cyclohexyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) -prop-2-en-1-ol (1.05 g, 3.94 mmol) in the presence of tetrakis(triphenylphosphino)palladium(0) (0.25 g, 0.22 mmol) and cesium fluoride (1.69 g, 11 mmol) in dioxane (20 mL) gives the title compound (0.5 g). 1H-NMR (CDCl3) δ=0.92-2.15 (m, 10H), 2.62-2.77 (m, 1H), 3.82 (s, 3H), 4.23-4.29 (m, 2H), 6.02-6.11 (m, 1H), 6.86-6.94 (m, 2H), 7.11-7.17 (m, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([CH2:36][CH2:37][CH:38]=[O:39])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[BH4-].[Na+]>C1COCC1.CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[C:26]([CH2:36][CH2:37][CH2:38][OH:39])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1CCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1CCCO
Yield: 92.9 %

Procedure:
Compound 96B (5.5 g, 10.14 mmol) in THF (100 mL) and methanol (20 mL) was treated NaBH4 (0.767 g, 20.28 mmol). The reaction mixture was heated under reflux for 1 hour. The solvents were removed under vacuum. The residue was re-dissolved in EtOAc and treated with water. The organic layer was separated, and the aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography to give 5.13 g of the title compound 96C (93%): APCI (+)LC/MS: 545 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:10](OC)(=[O:13])[C:11]#[CH:12].CCOCC>CO.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:5]1[N:6]=[C:7]2[C:2](=[CH:3][CH:4]=1)[NH:1][CH:12]=[CH:11][C:10]2=[O:13]
Reactant: COc1ccc(N)cn1
Reactant: C#CC(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Product: COc1ccc2[nH]ccc(=O)c2n1
Yield: 8.1 %

Procedure:
5-Amino-2-methoxypyridine (55 g, 0.44 mol) in methanol (1000 ml) with methyl propiolate (40 ml, 0.44 mol) was stirred for 48 hours, then evaporated and the product purified by chromatography on silica gel (dichloromethane) followed by recrystallisation from dichloromethane-hexane (44.6 g, 48%). The unsaturated ester (10.5 g, 0.05 mol) in warm Dowtherm A (50 ml) was added over 3 minutes to refluxing Dowtherm A, and after a further 20 minutes at reflux the mixture was cooled and poured into ether. The precipate was filtered to give a white solid (6.26 g, 70%).
Reaction SMILES: [OH:1][CH:2]([CH2:6][OH:7])[CH2:3][NH:4][CH3:5].[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31](Cl)[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]>>[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([N:4]([CH2:3][CH:2]([OH:1])[CH2:6][OH:7])[CH3:5])[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: CNCC(O)CO
Product: CN(CC(O)CO)c1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using 2,3-dihydroxy-propyl-methylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 471 (M+H)+.