Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH:20][C:21]([NH:23][C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[N:27]=[C:26]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:25]=2)=[O:22])=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.[CH3:49][O:50][CH2:51][CH2:52][O:53][CH2:54][C:55](Cl)=[O:56]>C(Cl)Cl.CN(C=O)C>[C:36]([C:26]1[CH:25]=[C:24]([NH:23][C:21](=[O:22])[NH:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([O:9][CH2:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[NH:1][C:55](=[O:56])[CH2:54][O:53][CH2:52][CH2:51][O:50][CH3:49])=[CH:11][CH:12]=2)[N:28]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[N:27]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: COCCOCC(=O)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccncc3N)c3ccccc23)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOCC(=O)Nc1cnccc1COc1ccc(NC(=O)Nc2cc(C(C)(C)C)nn2-c2ccc(C)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(4-((3-aminopyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate C) (50 mg, 0.10 mmol) and DIPEA (33.5 μl, 0.19 mmol) in anhydrous DCM (1.0 mL) and anhydrous DMF (0.2 mL) was added 2-(2-methoxyethoxy)acetyl chloride (15 μl, 0.11 mmol). The reaction mixture was stirred for 12 hr at RT. LC-MS indicated 50% conversion to the desired product. 2-(2-methoxyethoxy)acetyl chloride (15 μl, 0.11 mmol) was added and the reaction mixture stirred at RT. After 6 hr, LC-MS indicated the reaction had gone to completion. MeOH (2.0 mL) and AcOH (5 drops) were added and the reaction mixture was subjected to SCX capture and release, eluting with 1% NH3 in MeOH. The solvent was removed in vacuo and the crude material purified by column chromatography (4 g, 0-10% MeOH in EtOAc, gradient elution) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-3-yl)-2-(2-methoxyethoxy)acetamide (Example 17) as a white solid (27 mg, 43%): m/z 637 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9 H, s), 2.39 (3 H, s), 3.18 (3 H, s), 3.36 (2 H, m), 3.61 (2 H, m), 4.14 (2H, s), 5.33 (2H, s), 6.35 (1H, s), 6.97 (1H, d), 7.35 (2H, d), 7.43 (2H, d), 7.67-7.55 (4H, m), 7.92 (1H, d), 8.27 (1H, d), 8.46 (1H, d), 8.58 (1H, s), 8.74 (1H, s), 8.80 (1H, s), 9.65 (1H, s).
Reaction SMILES: [H-].[Na+].[CH3:3]I.[Si:5]([O:12][C@H:13]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:15]([CH2:25][OH:26])[CH2:14]1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].O>O1CCCC1.C(OCC)(=O)C>[Si:5]([O:12][C@H:13]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:15]([CH2:25][O:26][CH3:3])[CH2:14]1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of sodium hydride (60% in oil, 816 mg) and methyl iodide (4.9 ml) in tetrahydrofuran (50 ml), which was heated at 50°-60° C., was added dropwise a solution of (2S,4R)-4-(tert-butyldimethylsilyloxy)-1-(tert-butoxycarbonyl)-2-hydroxymethylpyrrolidine (5.2 g) in tetrahydrofuran (10 ml). After stirring for two hours, the reaction mixture was poured into a mixture of water and ethyl acetate, the organic layer was separated, washed in turn with saturated aqueous sodium sulfite and brine, dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (200 ml) eluting with a mixture of hexane and ethyl acetate (4:1, V/V) to give (2S,4R)-4-(tert-butyldimethylsilyloxy)-1-(tert-butoxycarbonyl)-2-methoxymethylpyrrolidine (4.5 g).
Reaction SMILES: C[O:2][C:3]([C:7]1[CH:12]=[CH:11][N:10]2[C:13]([C:16]3[CH:17]=[CH:18][C:19]([F:30])=[C:20]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)=[CH:14][N:15]=[C:9]2[N:8]=1)(OC)[CH3:4].C(=O)([O-])O.[Na+].C(OCC)C>Cl>[C:3]([C:7]1[CH:12]=[CH:11][N:10]2[C:13]([C:16]3[CH:17]=[CH:18][C:19]([F:30])=[C:20]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)=[CH:14][N:15]=[C:9]2[N:8]=1)(=[O:2])[CH3:4]
Reactant: COC(C)(OC)c1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)c1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1
Temperature: 50 °C
Reaction time: 15 h
Yield: 76.5 %

Procedure:
A suspension of crude 5′-[7-(1,1-dimethoxyethyl)imidazo[1,2-α]pyrimidin-3-yl]-2′-fluorobiphenyl-2-carbonitrile (1.21 g) in 2.5N hydrochloric acid (40 ml) was stirred at 50° C. for 15 h. After cooling to ambient temperature the mixture was made neutral with solid sodium hydrogencarbonate, added portionwise over 15 min. The aqueous was extracted with 2% methanol in dichloromethane (2×75 ml), the organics combined, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography on silica, eluting with dichloromethane (+0.5% triethylamine) on a gradient of methanol (1-5%) gave a solid. Trituration with diethyl ether afforded 5′-(7-acetylimidazo[1,2-α]pyrimidin-3-yl)-2′-fluorobiphenyl-2-carbonitrile (0.82 g, 77%) as a yellow solid: δH (360 MHz, CDCl3) 2.83 (3H, s), 7.44 (1H, t, J 9), 7.53-7.74 (6H, m), 7.87 (1H, dd, J 8 and 1), 8.12 (1H, s), 8.92 (1H, d, J 7); m/z (ES+) 357 (M++H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2>>[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: Cc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 77.4 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-chloro-1,3-dihydro-indol-2-one as starting materials to give 2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (58 mg, 77.4%) as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:23]=[C:22]2[C:12]([NH:13][CH:14]=[C:15]2[CH2:16][CH:17]([C:19]([OH:21])=[O:20])[NH2:18])=[CH:11][CH:10]=1.[CH2:24]([O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)[C:25]#[C:26][CH3:27]>O.O1CCOCC1>[CH2:24]([O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:18][CH:17]([CH2:16][C:15]2[C:22]3[C:12](=[CH:11][CH:10]=[C:9]([CH3:8])[CH:23]=3)[NH:13][CH:14]=2)[C:19]([OH:21])=[O:20])(=[O:37])=[O:36])=[CH:31][CH:30]=1)[C:25]#[C:26][CH3:27]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc2[nH]cc(CC(N)C(=O)O)c2c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)NC(Cc2c[nH]c3ccc(C)cc23)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.6 %

Procedure:
Triethylamine (0.38 mL, 2.75 mmol) was added to a solution of 5-methyl-DL-tryptophan (0.20 g, 0.92 mmol) and 4-but-2-ynyloxy-benzenesulfonyl chloride (0.25 g, 1.01 mmol) in H2O-dioxane (1.6 mL/2.4 mL) at room temperature. The reaction mixture was stirred for 20 hours at room temperature. The mixture was then concentrated and acidified with HCl. The mixture was extracted with ethyl acetate (3×10 mL). The organic solution was washed with H2O and brine, dried over Na2SO4, and concentrated. The residue was purified by RP-HPLC to give 0.32 g (81%) of the title compound as a pale yellow solid. Mp=45-46° C.; 1H NMR (DMSO-d6): 400 MHz δ 12.54 (bs, 1H), 10.64 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.53 (m, 2H), 7.17 (d, J=8.0 Hz, 1H), 7.00 (m, 2H), 6.95 (m, 2H), 6.86 (dd J=8.0, 4.0 Hz, 1H), 4.78 (q, J=2.4 Hz, 2H), 3.81 (q, J=7.6 Hz, 1H), 3.00 (dd J=14.4, 6.8 Hz, 1H), 2.79 (dd J=14.4, 7.8 Hz, 1H), 2.33 (s, 3H), 1.82 (t, J=2.4 Hz, 3H); HRMS: calcd for C22H23N2O5S (ESI+, [M+H]1+), 427.1322; found 427.1327; LCMS m/z (ESI) [M+H]1+ 427, retention time=2.69 min.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)(O)[CH:11]([N:13]2[N:17]=[N:16][CH:15]=[N:14]2)[CH3:12])=[CH:6][CH:5]=1.C(N(S(F)(F)[F:38])CC)C.[OH-].[K+].O>ClCCl>[F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)([F:38])[CH:11]([N:13]2[N:17]=[N:16][CH:15]=[N:14]2)[CH3:12])=[CH:6][CH:5]=1
Reactant: CC(n1ncnn1)C(O)(c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(n1ncnn1)C(F)(c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1
Reaction time: 18 h
Yield: 90.7 %

Procedure:
A solution of 1,1-bis(4-trifluoromethoxyphenyl)-2-(1,2,3,4-2H-tetrazol-2-yl)propan-1-ol (3.5 g) prepared as described in Example 3 in dichloromethane (50 cm3) was added dropwise to a stirred solution of diethylaminosulphurtrifluoride (1.51 g) kept at a temperature of -70° C. under a nitrogen atmosphere. After 1 hour a further quantity of diethylaminosulphurtrifluoride (1.5 g) was added and the mixture stirred for 18 hours at the ambient temperture, during which time any vapours emitted were vented through a column of potassium hydroxide pellets. Water (30 cm3) was added carefully to the mixture, the organic layer separated and washed with more water (3×30 cm3), dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure. The residual oil (4.5 g) was purified by hplc using a silica gel column eluted with a mixture of hexane (5 parts by volume and ethylacetate (1 part by volume) to yield 1,1-bis(4-trifluoromethoxyphenyl)-1-fluoro- 2-(1,2,3,4-2H-tetrazol-2-yl)propane as an oil (3.19 g) which crystallised on standing (mp. 68°-70° C.).
Reaction SMILES: [N+:1]([C:4]1[C:5]([S:10]Cl)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:12][CH2:13][CH2:14]S>C(O)=O>[N+:1]([C:4]1[C:5]([S:10][CH2:14][CH2:13][NH2:12])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccnc1SCl
Reactant: NCCS
Solvent: O=CO
Product: NCCSc1ncccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
The 3-nitro-2-pyridinesulfenyl chloride was added to a solution of 2-aminoethanethiol (4.1 grams, 36.19 mmol) in 230 mL of 90% formic acid. The solution was vigorously stirred for one hour. The resulting precipitate was removed by filtration, and a large volume of diethylether was added to the supernatant. The precipitate was collected, dissolved in warm methanol, and reprecipitated with diethyl ether. 3-Nitro-2-pyridinesulfenyl-ethylamine was obtained in 68% overall yield.
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[C:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O.C([O-])=O.[Na+].CO>[Pd].[C].O>[C:12]([C:9]1[CH:10]=[CH:11][CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(OS(C)(=O)=O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cccc(C(C)(C)C)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
In a nitrogen atmosphere, 2,4-di-tert-butylphenyl methanesulfonate (500 g, 1.76 mols), sodium formate (239 g, 3.52 mols), methanol (2400 g) and water (600 g) were mixed at 25° C., and with stirring, 10 mass % Pd/carbon (50 mass water-containing product) (30 g) (as metal palladium; 0.3 mass % relative to 2,4-di-tert-butylphenyl methanesulfonate) as supported by a carbon carrier having a specific surface area of 780 m2/g (by BET method) was put into it. Still kept stirred, this was heated up to 65° C., taking 1 hour, and reacted for 6 hours. Water (100 mL) was added to the reaction liquid and Pd-carbon was separated through filtration, then heptane (500 g) was added to the filtrate. The organic layer obtained after extraction was concentrated under reduced pressure to give crude 1,3-di-tert-butylbenzene (331 g, yield 99% by mass). The result is shown in Table I-1.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[C:15]([CH3:17])=[CH2:16])[CH2:6][CH2:5]1)[CH3:2].[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:25]3[CH:26]=[CH:27][C:22]([CH2:21][C:20]([O:19][CH3:18])=[O:29])=[CH:23][CH:24]=3)=[CH:9][C:8]=2[CH:15]([CH3:17])[CH3:16])[CH2:6][CH2:5]1)[CH3:2]
Reactant: C#Cc1ccc(C2(OCC)CC2)c(C(=C)C)c1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC1(c2ccc(C#Cc3ccc(CC(=O)OC)cc3)cc2C(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-isopropenylbenzene (Intermediate 103, 120.0 mg, 0.52 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 150.0 mg, 0.52 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (32.0 mg, 0.17 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (121 mg, 0.17 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 140.0 mg (71%) of the title compound as a pale-yellow oil.
Reaction SMILES: [SH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].N1C=CN=C1.[Si:12](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[Si:12]([O:5][CH2:4][CH:3]([OH:6])[CH2:2][SH:1])([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCC(O)CS
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCC(O)CS)(c1ccccc1)c1ccccc1
Reaction time: 18 h
Yield: 88.1 %

Procedure:
To a solution of 3-mercapto-1,2-propanediol (5.00 g, 46.23 mmol) and imidazole (3.78 g, 55.47 mmol) in dimethylformamide (30 mL) was added t-butyldiphenylsilyl chloride (12.71 g, 46.23 mmol) at room temperature. After stirring for 18 h the reaction was quenched by the addition of saturated sodium bicarbonate and the mixture was extracted with ether (3×). The combined ether extracts were washed with water (2×), brine, dried and concentrated to give a yellow oil. The crude material was purified by flash chromatography with a mixture of hexanes and ethyl acetate (90:10) to give the compound as a colourless oil (14.12 g) in 88% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][CH:25]=1>>[CH3:22][C:7]1([CH3:21])[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=3)[C:16]=2[C:17](=[O:18])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:30][C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)=[CH:23][C:6]1=2
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: OCc1ccncc1
Product: CC1(C)c2cc(OCc3ccncc3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and pyridin-4-yl-methanol.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([NH:8]CC2C=CC=CC=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][CH3:19])=[O:17])[CH2:3]1.[H][H]>[Pd].CO>[NH2:8][CH:7]1[CH2:6][CH2:5][N:4]([C:16]([O:18][CH3:19])=[O:17])[CH2:3][CH:2]1[CH3:1]
Reactant: [H][H]
Reactant: COC(=O)N1CCC(NCc2ccccc2)C(C)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)N1CCC(N)C(C)C1

Procedure:
A mixture of 40 parts of methyl 3-methyl-4-[(phenylmethyl)amino]-1-piperidinecarboxylate and 160 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated to dry. The residue was distilled (bp. 80° C. at 0.1 mm. pressure). The distillate was further purified by gas-chromatography (at 215° C. and at 10 lbs/sq. inch), yielding 8.6 parts of methyl 4-amino-3-methyl-1-piperidinecarboxylate (interm. 27)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]2)[CH:3]=1.C[N:31](C=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:31])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]2)[CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](O)CC3)c12
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](O)CC3)c12

Procedure:
Prepared analogously to example 1.4 from 7 g 4-[4-fluoro-2-(trans-4-hydroxycyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid in DMF.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:28]OC(=O)C(C)(C)C)[C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:17][CH:16]=2)[C:10](=[O:36])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1.[CH2:45]([SH:47])[CH3:46]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]([CH2:28][S:47][CH2:45][CH3:46])[C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:19][CH:20]=2)[C:10](=[O:36])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OCN(c1ccc(CN2CCN(Cc3ccccc3)C(=O)C2=O)cc1)c1ncccn1
Reactant: CCS
Agent: Cl
Solvent: C1COCCO1
Product: CCSCN(c1ccc(CN2CCN(Cc3ccccc3)C(=O)C2=O)cc1)c1ncccn1
Yield: 86.8 %

Procedure:
In 10 ml of ethyl mercaptan was dissolved 1.0 g of 1-benzyl-4-{4-[N-pivaloyloxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine, and 0.01 ml of 5.7 N hydrogen chloride-dioxane solution was added thereto, after which the resulting mixture was subjected to reaction at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was distilled under reduced pressure, and 50 ml of diisopropyl ether was added to the crystals thus obtained, after which the resulting crystals were filtered. The crystals thus obtained were recrystallized from isopropyl alcohol to obtain 0.8 g (86.8% yield) of white crystalline 1-benzyl-4-{4-[N-ethylthiomethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine having a melting point of 144° C.
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH3:8])=[O:6])[CH3:3].CC1(C)[C@@H]2CC[C@@]1(CS(O)(=O)=O)C(=O)C2.ClC(Cl)(Cl)C(=N)O[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][O:1][C@H:2]([C@H:4]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH3:8])=[O:6])[CH3:3])=[CH:35][CH:36]=1
Reactant: COC(=O)[C@@H](CCC(C)C)[C@H](C)O
Reactant: COc1ccc(COC(=N)C(Cl)(Cl)Cl)cc1
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: COC(=O)[C@@H](CCC(C)C)[C@H](C)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 76.7 %

Procedure:
To a solution of (S)-methyl 2-((S)-1-hydroxyethyl)-5-methylhexanoate (5.00 g, 26.6 mmol) and ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid (camphorsulfonic acid, CSA; 0.617 g, 2.66 mmol) in DCM (53.1 mL) was added 4-methoxybenzyl 2,2,2-trichloroacetimidate (8.27 mL, 39.8 mmol) at 0° C. The reaction mixture was removed from the cold bath and stirred at room temperature for 17 h. Hexane (50 mL) was added to the reaction and the precipitate was removed by filtration. The solids were washed with hexanes (2×10 mL), Celite® (2 scoopula tip-fulls) was added to the combined filtrate and washes, and the solvent was removed under reduced pressure. The resulting adsorbed material was directly loaded onto a column and purified using flash column chromatography (80 g SiO2, 0→35% EtOAc/hexanes) to afford the title compound (6.3 g, 20.4 mmol, 77%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.24-7.16 (m, 2H), 6.89-6.79 (m, 2H), 4.49 (d, J=11.2 Hz, 1H), 4.33 (d, J=11.1 Hz, 1H), 3.75 (s, 3H), 3.74-3.62 (m, 4H), 2.49 (ddd, J=10.7, 8.2, 4.0 Hz, 1H), 1.62-1.40 (m, 3H), 1.23-1.16 (m, 3H), 1.16-1.03 (m, 2H), 0.87 (d, J=3.9 Hz, 3H), 0.85 (d, J=3.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 175.03, 159.10, 130.63, 129.14, 113.62, 76.16, 70.71, 55.11, 52.64, 51.25, 36.58, 27.97, 26.00, 22.69, 22.17, 17.08; ESIMS m/z 331 ([M+Na]+).
Reaction SMILES: [C:1]1([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]2[CH2:11][CH:10](S(C3C(C)=CC=CC=3)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:28]#[N:29].[K+].O>CS(C)=O>[C:1]1([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]2[CH2:11][CH:10]([C:28]#[N:29])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [C-]#N
Reactant: Cc1ccccc1S(=O)(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 100 °C
Yield: 69 %

Procedure:
To a solution of 1.0 g. (2.54 mmoles) of 1-diphenylmethyl-3-toluenesulfonylazetidine in 10 ml of dimethylsulfoxide is added 547 mg (8.4 mmoles; 3.3 equivalents) of potassium cyanide, and the mixture is heated to 100° C. for 15 minutes. After cooling, the mixture is mixed with water and extracted with ether. The extract is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is dissolved in ether, treated with active carbon, and filtered. The filtrate is evaporated to yield 435 mg of 1-diphenylmethyl-3-cyanoazetidine having mp. 153° to 154° C. as needles in 69% yield. From the mother liquor, the same product having mp. 149° to 152° C. is obtained in 6.3% yield. Total yield is 75.3%. The product is recrystallized from ether to yield the pure product having mp. 158° to 159° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:24])[CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH3:13])=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:24])[CH:12]([O:14][C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH3:13])=[CH:6][CH:5]=1
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(Oc1ccc(N)cc1)C(=O)Oc1ccc(N)cc1
Reaction time: 0.5 h
Yield: 61 %

Procedure:
2-(4-nitrophenoxy)-propionic acid 4-nitrophenyl ester (30 grams, 90.28 mmoles) was dissolved in ethyl acetate (600 ml) in a pressure vessel, palladium on carbon (50% wet, 6 grams) was added and the mixture stirred under an atmosphere of Hydrogen (5 Kg) for 30 minutes. The catalyst was removed by filtration and the solvent distilled off under reduced pressure. The residue was triturated in cold diisopropyl ether, filtered and dried to give pure 2-(4-aminophenoxy)-propionic acid 4-amino-phenyl ester (15 grams) as off-white powder. The product has a melting point of 109-111° C. The product was characterized by 1H NMR (CDCl3) δ 1.75 (d, 3H, CH3), 3.50 (bs, 2H, NH2), 4.90 (q, 1H, CH), 6.65 (m, 4H, Ar), 6.80 (m, 4H, Ar).