Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:35])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][N:31]([CH3:34])[CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:37]>>[ClH:1].[NH2:37][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:35])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][N:31]([CH3:34])[CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: Cn1ccc(S(=O)(=O)Nc2cccc(-c3nc(C4CCOCC4)sc3-c3ccnc(Cl)n3)c2F)c1
Agent: [OH-]
Product: Cl
Product: Cn1ccc(S(=O)(=O)Nc2cccc(-c3nc(C4CCOCC4)sc3-c3ccnc(N)n3)c2F)c1

Procedure:
Following a procedure analogous to the procedure described in Example 282 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrrole-3-sulfonamide (260 mg, 0.487 mmol) and ammonium hydroxide (10 ml), the title compound was obtained as a white solid (132 mg, 49.2%). 1HNMR (MEOD-d4): δ ppm 7.92-7.93 (d, J=6.4 Hz, 1H), 7.50-7.54 (t, J=7.6 Hz, 1H), 7.16-7.23 (m, 2H), 7.12 (s, 1H), 6.31-6.64 (t, J=2.4 Hz, 1H), 6.30-6.32 (d, J=6.0 Hz, 1H), 6.23 (s, 1H), 3.94-3.97 (dd, J1=11.4 Hz, J2=2.4 Hz, 2H), 3.57 (s, 3H), 3.47-3.53 (t, J1=11.4 Hz, 2H), 3.26-3.28 (m, 1H), 1.98-2.01 (dd, J1=11.8 Hz, J2=1.2 Hz, 2H), 1.76-1.86 (dd, J1=12.1 Hz, J2=4.4 Hz, 2H); MS: 515.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:6]2[S:13][C:12]([S:14]([CH3:16])=[O:15])=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1.FC1C=C(N[C:44]([NH:46][C:47](=[O:55])[CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[S:45])C=CC=1OC1C2SC(SC)=CC=2N=CN=1>>[F:1][C:2]1[CH:20]=[C:19]([NH:21][C:44]([NH:46][C:47](=[O:55])[CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[S:45])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:6]2[S:13][C:12]([S:14]([CH3:16])=[O:15])=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: CS(=O)c1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: CSc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Product: CS(=O)c1cc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Yield: 36 %

Procedure:
Starting from the compound 285 and following the procedure described above for the synthesis of compound 283 (scheme 64, step 4, example 225), title compound 286 was obtained in 36% yield as an off-white solid. 1H NMR (DMSO-d6) δ (ppm): 12.45(s, 1H), 11.83(s, 1H), 8.80(s, 1H), 8.13(s, 1H), 7.93(dd, 1H, J1=2.3 Hz, J2=10.9 Hz), 7.55 (t, 1H, J=8.6 Hz), 7.48 (m, 1H), 7.34-7.31(m, 4H), 7.28-7.25(m, 1H), 3.81(s, 2H), 3.08(s, 3H). MS (m/z): 501.0(M+H) (found).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([NH:17][CH2:18][CH2:19][C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:27])[N:14]=[C:13]([O:28][CH3:29])[N:12]=2)[CH:8]=[CH:7][C:6]1=[O:30].O.[NH2:33][NH2:34]>CO.C(Cl)Cl>[Cl:27][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:20]=1[CH2:19][CH2:18][NH:17][C:15]1[N:14]=[C:13]([O:28][CH3:29])[N:12]=[C:11]([C:9]2[CH:8]=[CH:7][C:6](=[O:30])[N:5]([CH2:4][C:3]([NH:33][NH2:34])=[O:2])[CH:10]=2)[CH:16]=1
Reactant: NN
Reactant: COC(=O)Cn1cc(-c2cc(NCCc3c(F)cccc3Cl)nc(OC)n2)ccc1=O
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1nc(NCCc2c(F)cccc2Cl)cc(-c2ccc(=O)n(CC(=O)NN)c2)n1
Reaction time: 15 h

Procedure:
A solution of (5-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-2-oxo-2H-pyridin-1-yl)-acetic acid methyl ester [220 mg, 0.49 mmol, Example 22(d)] in a mixture of MeOH (5 mL) and DCM (2 mL) is treated with hydrazine hydrate (0.18 mL, 5.8 mmol). After 15 hours at 20° C., the mixture is concentrated to give (5-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-2-oxo-2H-pyridin-1-yl)-acetic acid hydrazide. MS: 447 (M+H). This material is used without further purification.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:16](OC)[CH2:17][Cl:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:8][CH:9]1[CH2:10][O:11][CH:16]([CH2:17][Cl:18])[O:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CCl)OC
Reactant: OCC(CO)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: ClCC1OCC(OCc2ccccc2)CO1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
A mixture of 5.0 g of 2-benzyloxy-1,3-propanediol, 3.5 g of chloroacetaldehyde dimethyl acetal and 0.3 g of p-toluenesulfonic acid was heated via oil bath through the temperature range 25° to 130° C in a three-necked, round-bottomed flask equipped with stirrer, thermometer and condenser. The by-product methanol, removed by distillation during the course of reaction, amounted to 63% of theory. The reaction mixture was cooled to room temperature and dissolved in ether. The ether solution was washed with 10% sodium carbonate and then with water. After drying over anhydrous sodium sulfate, the ether was removed under reduced pressure. Distillation of the crude oil gave 3.3 g of 5-benzyloxy-2-chloromethyl-1,3-dioxane; b.p. 100°-105° C/0.025 mm Hg; nD25 1.5228. The nmr spectrum was consistent with the assigned structure and showed the cis isomer content to be 30 ± 5%, the remainder being the trans isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[S:14]([C@H:17]1[CH2:21][N:20]([C:22]([C:24]2([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:26][CH2:25]2)=[O:23])[C@H:19]([C:34](O)=[O:35])[CH2:18]1)(=[O:16])=[O:15].[CH:37]1([NH:40][C:41](=[O:49])[C:42](=[O:48])[C@@H:43]([NH2:47])[CH2:44][CH2:45][CH3:46])[CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[S:14]([C@H:17]1[CH2:21][N:20]([C:22]([C:24]2([C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[CH2:25][CH2:26]2)=[O:23])[C@H:19]([C:34]([NH:47][C@@H:43]([CH2:44][CH2:45][CH3:46])[C:42](=[O:48])[C:41]([NH:40][CH:37]2[CH2:39][CH2:38]2)=[O:49])=[O:35])[CH2:18]1)(=[O:15])=[O:16]
Reactant: CCC[C@H](N)C(=O)C(=O)NC1CC1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(N3CCOCC3)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(N3CCOCC3)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-4-(2-Chloro-4-morpholin-4-yl-benzenesulfonyl)-1-[1-(4-chloro-phenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid and (S)-3-Amino-2-oxo-hexanoic acid cyclopropylamide in step 1. MS (m/e)=719.20 [M+H+].
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[N:20]([C:24]2[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=2)[CH:21]=[CH:22][N:23]=1.[CH3:31]C(C)([O-])C.[Na+]>C(O)C.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>[CH3:18][C:19]1[N:20]([C:24]2[CH:29]=[CH:28][C:27]([S:1][C:2]3[CH:3]=[C:4]([C:8]4([C:14]([O:16][CH2:17][CH3:31])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[CH:5]=[CH:6][CH:7]=3)=[CH:26][CH:25]=2)[CH:21]=[CH:22][N:23]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1nccn1-c1ccc(I)cc1
Reactant: COC(=O)C1(c2cccc(S)c2)CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(c2cccc(Sc3ccc(-n4ccnc4C)cc3)c2)CCOCC1
Reaction time: 8 h
Yield: 60.9 %

Procedure:
A solution of methyl 4-(3-mercaptophenyl)-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate (1.04 g, 3.5 mmol), 4-(2-methylimidazol-1-yl)phenyliodide (0.89 g, 3.5 mmol), sodium t-butoxide (673 mg, 7 mmol) and tetrakis(triphenylphosphine)palladium (162 mg, 0.14 mmol) in dry ethanol (20 ml) was heated to reflux with stirring overnight. Volatiles were remeved by evaporation and the residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were washed with brine (100 ml), dried (magnesium sulfat) and concentrated to dryness to give 1.09 g of crude product as a brown liquid. Purification by column chromatography (silica-gel, 50 g; methanol in dichloromethane, increasing the ratio of methanol from 0% to 4%) afforded the titled compound (0.90 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Li+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(F)ccc1OCC#Cc1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(F)ccc1OCC#Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
100 mg (0.28 mmol) of methyl 5-fluoro-2-[3-(4-trifluoromethylphenyl)prop-2-ynyloxy]benzoate are dissolved in 2 ml of methanol and 2 ml of water, and 20.3 mg (0.85 mmol) of lithium hydroxide are added. After stirring at room temperature for 12 h, the crystals which have separated out are filtered off with suction, washed with water, 1 N hydrochloric acid and petroleum ether and dried on a clay dish. 74.9 mg (0.20 mmol, 71% of theory) of the title compound are isolated.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:10]1CCCC1.[Br:15][C:16]([F:26])([F:25])[C:17]([F:24])([F:23])[CH2:18][CH2:19][CH2:20][CH2:21]O.C(N(CC)CC)C>O>[CH:1]1([C:7]([OH:8])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:15][C:16]([F:25])([F:26])[C:17]([F:23])([F:24])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(Cl)C1CCCCC1
Reactant: C1CCOC1
Reactant: OCCCCC(F)(F)C(F)(F)Br
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCC(F)(F)C(F)(F)Br
Product: O=C(O)C1CCCCC1
Reaction time: 6 h
Yield: 90 %

Procedure:
A 300 mL reactor was charged under nitrogen with 14.7 g (100 mmol/1.3 equivalents) of cyclohexanecarbonyl chloride and 150 mL of tetrahydrofuran (a dehydrated product), followed by putting it in an ice bath. 20.0 g (79.0 mmol/1.0 equivalent) of 6-bromo-5,5,6,6-tetrafluorohexan-1-ol was added thereto, followed by adding dropwise of 12.0 g (119 mmol/1.5 equivalents) of triethylamine. After the dropping, stirring was conducted at 60 degrees for 6 hours. Then, 100 mL of water was added, and extraction was conducted two times with 200 mL of diisopropyl ether. The obtained organic layer was washed further with diluted hydrochloric acid, sodium bicarbonate water and brine, followed by removing water by sodium sulfate and conducting filtration. Then, isopropyl ether was distilled out, thereby obtaining 27.5 g of the target 6-bromo-5,5,6,6-tetrafluorohexane cyclohexanecarboxylate. Upon this, purity was 94%, and yield was 90%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=C(C)N=C(S(C)(=O)=O)N=1.C(=O)([O-])[O-:14].[K+].[K+].[C:19]([O:22][CH2:23]C)(=[O:21])[CH3:20].CCCCCC>CC(C)=O>[OH:14][CH:20]([CH:2]([CH3:7])[CH3:1])[C:19]([O:22][CH3:23])=[O:21]
Reactant: Cc1cc(C)nc(S(C)(=O)=O)n1
Reactant: CCOC(C)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COC(=O)C(O)C(C)C
Yield: 42 %

Procedure:
1.5g of the product of (b) and 2.llg (0.011 moles) of 4,6-dimethyl-2-methanesulphonyl pyrimidine were dissolved in 20ml acetone. 1.6g of potassium carbonate were added and the reaction mixture refluxed for 4 hours. Following thin layer chromatography to establish that the reaction had reached completion, the mixture was evaporated to dryness and 10ml water added. Solvent extraction using chloroform followed and the chloroform extracts were dried over anhydrous sodium sulphate and the solvent evaporated off. The oil resulting was subjected to flash column chromatography using ethyl acetate: hexane (1:1) as eluant to yield 1.1g (yield 42%) of the title compound as a colourless oil.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].[C:13]1([C:19]2(S([O-])(=O)=O)[CH:24]=[CH:23][C:22]([CH3:25])=[C:21](CC3CCCCC3)[CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCO>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:25][CH:22]1[CH2:21][CH2:20][CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:24][CH2:23]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC1=C(CC2CCCCC2)CC(c2ccccc2)(S(=O)(=O)[O-])C=C1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CC1CCC(c2ccccc2)CC1)C(=O)OCC

Procedure:
Diethyl malonate (3.1 g, 19.7 mmol, 1.5 equiv) was added dropwise to a solution of sodium (1.25 g, 54.0 mmol, 4.0 equiv) in EtOH (50 mL). 4-Phenyl-cyclohexylmethyl-p-toluene sulfonate (˜13.1 mmol, ˜1.0 equiv, the crude product from the previous step) was added as a solution in 50 mL of EtOH. The resulting mixture was refluxed for 8 h. The reaction mixture was cooled and evaporated to dryness and then dissolved in water (150 mL) and the crude product extracted with 3×100 mL EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on SiO2 using 10% EtOAc in hexanes to give the desired product as a colorless oil (2.79 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]2([CH3:19])[CH2:18][CH2:17]2)=[O:14])[CH2:9][CH2:8]1.[F:20][C:21]1[CH:26]=[C:25](O)[CH:24]=[CH:23][C:22]=1[CH2:28][C:29]([O:31][CH3:32])=[O:30].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:20][C:21]1[CH:26]=[C:25]([CH:24]=[CH:23][C:22]=1[CH2:28][C:29]([O:31][CH3:32])=[O:30])[O:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]2([CH3:19])[CH2:18][CH2:17]2)=[O:14])[CH2:9][CH2:8]1
Reactant: COC(=O)Cc1ccc(O)cc1F
Reactant: CC1(OC(=O)N2CCC([C@H]3C[C@H]3CCO)CC2)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OC3(C)CC3)CC2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-methylcyclopropyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate (Intermediate 9, 0.484 g, 1.81 mmol) in 5 ml anhydrous dichloromethane at RT was added a solution of methyl (2-fluoro-4-hydroxyphenyl)acetate (0.400 g, 2.17 mmol) in 10 ml anhydrous dichloromethane, triphenylphosphine, polymer-bound (1.42 g, 4.10 mmol), and di-tert-butyl azodicarboxylate (0.834 g, 3.61 mmol). The reaction mixture was stirred at RT for 3 hours. It was filtered by Celite and concentrated. The residue was purified on Biotage column (50 g silica gel) using a gradient eluent of 0-50% ethyl acetate in hexanes (1000 ml) to afford the title compound. LC/MS (m/z) 434.2 (M+H)+.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[OH:26][C:27]1([C:33](O)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:33]([C:27]5([OH:26])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)=[O:34])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C1(O)CCCCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1(O)CCCCC1

Procedure:
The title compound, white solid (14.9 mg, 39.9%), MS (ISP) m/z=457.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and 1-hydroxycyclohexanecarboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:28][NH:29][O:30][CH3:31].C(N(CC)CC)C>O1CCCC1.C(#N)C>[CH3:31][O:30][N:29]([CH3:28])[C:12]([CH:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 120.3 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (5.00 g) in tetrahydrofuran (62.1 mL), 1,1′-carbonyldiimidazole (6.05 g) was added and the mixture was stirred at room temperature for an hour. To the reaction mixture, a solution of N,O-dimethylhydroxylamine hydrochloride (3.64 g) and triethylamine (4.02 g) in acetonitrile (62.1 mL) was added and the mixture was stirred at the same temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and water was added to the resulting residue. Extraction was conducted with ethyl acetate and the combined organic layers were washed with an aqueous solution of 5% citric acid and saturated brine. The washed organic layers were dried over anhydrous sodium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate as a pale yellow oil (7.30 g).
Reaction SMILES: COC1C=CC(C2C(C)(C)C3C(CC=2)=CC(OC)=CC=3)=C(N)C=1.Cl.[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[C:29](O)=O.FC1C=[C:47](C=CC=1OCCN1CCCCC1)[CH2:48][NH:49][C:50]1[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[CH:52][C:51]=1[C:58]1[C:59]([CH3:71])([CH3:70])[C:60]2[C:65]([CH2:66][CH:67]=1)=[CH:64][C:63]([O:68][CH3:69])=[CH:62][CH:61]=2>>[CH2:48]([N:49]([CH2:29][C:28]1[CH:32]=[CH:33][C:34]([O:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:26]([F:25])[CH:27]=1)[C:50]1[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[CH:52][C:51]=1[C:58]1[C:59]([CH3:70])([CH3:71])[C:60]2[C:65]([CH2:66][CH:67]=1)=[CH:64][C:63]([O:68][CH3:69])=[CH:62][CH:61]=2)[CH3:47]
Reactant: COc1ccc2c(c1)CC=C(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2(C)C
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Agent: COc1ccc(C2=CCc3cc(OC)ccc3C2(C)C)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1C1=CCc2cc(OC)ccc2C1(C)C

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,1-dimethyl-1,4-dihydronaphthalen-2-yl)phenylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 114, [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxy-1,1-dimethyl-1,4-dihydronaphthalen-2-yl)phenyl]amine (316 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxy-1,1-dimethyl-1,4-dihydronaphthalen-2-yl)phenyl]amine (82 mg). The total amount of this compound was used according to an analogous synthetic method to Example 111 to provide the title compound (62 mg).
Reaction SMILES: C([Li])CCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][N:33]1[C:37]([CH:38]=[O:39])=[CH:36][N:35]=[C:34]1[CH3:40].O>O1CCCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([CH:38]([C:37]3[N:33]([CH3:32])[C:34]([CH3:40])=[N:35][CH:36]=3)[OH:39])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: Cc1ncc(C=O)n1C
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 23 °C
Reaction time: 0.05 h

Procedure:
A solution of n-butyllithium in hexanes (1.6 M, 1.5 mL, 2.3 mmol) was added dropwise to a stirring solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (1 g, 2.3 mmol, Intermediate 10) in tetrahydrofuran (18 mL) at −78° C. After 3 minutes, a solution of 1,2-dimethyl-1H-imidazole-5-carbaldehyde (347 mg, 2.8 mmol) in tetrahydrofuran (5 mL) was added dropwise. After 5 minutes, the flask was placed into an ice-water bath. After 30 minutes, water (10 mL) was added and the biphasic mixture was allowed to warm to 23° C. The mixture was partitioned between half-saturated sodium chloride solution (50 mL) and ethyl acetate (100 mL). The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Silica gel (3 g) was added to the filtrate and the solvent was removed by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a column of silica gel for purification. Elution with ethyl acetate initially, grading to 7% methanol-ethyl acetate provided the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:33])=[CH:14][C:15]([F:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:33][C:13]1[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:37](=[O:38])[CH2:36][O:35][CH3:34])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:15]([F:32])[CH:14]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Reactant: COCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COCC(=O)Nc1nc2ccc(Oc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)c(F)cc3Cl)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide (100 mg, 0.207 mmol) produced in Example C52(v) in pyridine (2.0 mL) was added methoxyacetyl chloride (30 μL, 0.331 mmol), and the mixture was stirred at room temperature for 2 hr. Methoxyacetyl chloride (15 μL, 0.165 mmol) was further added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (25 mL), washed with 5% aqueous sodium hydrogen carbonate solution (25 mL) and saturated brine (25 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=70/30→20/80), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give the title compound (74.5 mg, 65%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH2:11][C:12]#[N:13].CO/[CH:17]=[CH:18]/[C:19](=O)[CH3:20].N12CCN(CC1)CC2.COCCOCCO>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:11]([C:12]#[N:13])[C:10]1=[O:14]
Reactant: CO/C=C/C(C)=O
Reactant: N#CCC(=O)Nc1ccc(F)cc1Cl
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: COCCOCCO
Product: Cc1ccc(C#N)c(=O)n1-c1ccc(F)cc1Cl
Temperature: 130 °C
Reaction time: 3 h
Yield: 30.4 %

Procedure:
A mixture of N-(2-chloro-4-fluorophenyl)-2-cyanoacetamide (2.00 g, 9.40 mmol), (3E)-4-methoxybut-3-en-2-one (1.13 g, 11.2 mmol), 1,4-diazabicyclo[2.2.2]octane (1.05 g, 9.40 mmol) and 2-(2-methoxyethoxy)ethanol (20 mL) was stirred at 130° C. for 3 hr. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid, water (×2) and saturated brine, dried over anhydrous magnesium sulfate, and filtered through a silica gel pad. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (100 g, ethyl acetate/hexane=2/98→50/50). The obtained residue was washed with ethyl acetate/hexane and collected by filtration to give the title compound (0.75 g, 30%) as a pale-yellow solid.