Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C([O-])([O-])=O.[K+].[K+].[C:18]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CCOC(C)=O>CC#N>[C:18]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:2][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(CCC(=O)c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 17 h
Yield: 80 %

Procedure:
3-Chloropropiophenone (7.14 g, 24.4 mmol). K2CO3 (8.79 g, 1.50 equiv) and KI (1.41 mg, 0.2 equiv) were added to a solution of the purified 1-(tert-butyloxycarbonyl)homopiperazine (8.486 g, 42.4 mmol) in CH3CN (60 mL). The reaction mixture was stirred at 70° C. for 17 h and then AcOEt (200 mL) was added to the cooled mixture. The precipitated solid was removed by filtration and washed with AcOEt (50 mL). The combined filtrate was evaporated to afford an oil which was purified by column chromatography (SiO2, 0%-20% CH3CN/AcOEt) to give 1-(tert-Butyloxycarbonyl)-4-(3-phenyl-3-oxopropyl)homopiperazine: 11.27 g, 80% yield, pale yellow oil: 1H NMR (CDCl3, 300 MHz) δ 1.40-1.65 (m, 9H), 1.80-1.95 (m, 2H), 2.65-2.85 (m, 4H), 3.01 (t, 2H, J=6.9 Hz), 3.19 (t, 2H, J=6.9 Hz), 3.35-3.55 (m, 4H), 7.47 (t, 2H, J=7.7 Hz), 7.55-7.65 (m, 1H), 7.90-8.02 (m, 2H). The purity was determined by RPLC/MS (Method B). RPLC tR=5.53 min (95%), 220 nm; ESI/MS m/e 333.4 (M++H, C19H29N2O3).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]([CH3:30])([NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)=[O:8])[CH3:5].[Li+].[OH-].Cl>O1CCOCC1.C(OCC)(=O)C>[CH3:30][C:4]([NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]=1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=1)=[O:8])([CH3:5])[C:3]([OH:31])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccsc2c1OCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)c1ccc2ccsc2c1OCc1ccc(C(F)(F)F)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
308 mg 2-methyl-2-{[7-(4-trifluoromethyl-benzyloxy)-benzo[b]thiophene-6-carbonyl]-amino}-propionic acid methyl ester was dissolved in 5 ml of 1,4-dioxane. To this was added 3.4 ml of 1 M LiOH (aq), and the reaction was stirred for 1 h at 60° C. and overnight at room temperature. The reaction mixture was diluted with 10 ml of ethyl acetate, acidified to pH 3 with 2N HCl (aq) and extracted with 10 ml ethyl acetate four times. The combined organic layers were washed with brine, dried over sodium sulphate and concentrated in vacuo to give 299 mg of 2-methyl-2-{[7-(4-trifluoromethyl-benzyloxy)-benzo[b]thiophene-6-carbonyl]-amino}-propionic acid.
Reaction SMILES: [S:1]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](C(OC)=O)[S:3][C:2]1=[S:14].O.[Br-].[Li+].O>CN(C)P(=O)(N(C)C)N(C)C>[S:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[S:1][C:2]1=[S:14]
Reactant: COC(=O)c1sc(=S)sc1C(=O)OC
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COC(=O)c1csc(=S)s1
Temperature: 25 °C
Yield: 70 %

Procedure:
30 Grams (0.12 mol) of dimethyl 1,3-dithiol-2-thion-4,5-dicarboxylate synthesized according to the method of G. C. Papavassiliou, et al [Synthetic Metals, Vol. 27 (1988) B-373-B378] was dissolved in 30 ml of hexamethylphosphorictriamide (HMPA), and 12.6 g (0.12 mol) of lithium bromide monohydrate was added. The resultant mixture was heated at 60° C. for 1 hour, the reaction mixture was allowed to cool to room temperature, 200 ml of water was added, and a yellow solid formed was separated by filtering and washed with water. The solid obtained was dried and recrystallized from carbon tetrachloride to give 16.2 g of yellow acicular crystals of methyl 1,3-dithiol-2-thione-4-carboxylate (yield 70%).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:22]=[C:21]([N:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][C:4]=1[C:5]([C:7]1[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=O.C(OC(=O)C)(=O)C.[CH3:34][N:35]([CH3:45])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]([CH3:44])[CH3:43])[CH:37]=1>Cl>[CH3:43][N:42]([CH3:44])[C:38]1[CH:37]=[C:36]([N:35]([CH3:45])[CH3:34])[CH:41]=[CH:40][C:39]=1[C:5]1([C:4]2[CH:19]=[CH:20][C:21]([N:23]([CH3:24])[CH3:25])=[CH:22][C:3]=2[N:2]([CH3:26])[CH3:1])[C:7]2[C:8](=[CH:12][CH:13]=[C:14]([N:16]([CH3:17])[CH3:18])[CH:15]=2)[C:9](=[O:10])[O:11]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CN(C)c1ccc(C(=O)O)c(C(=O)c2ccc(N(C)C)cc2N(C)C)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccc(N(C)C)cc32)c(N(C)C)c1

Procedure:
A mixture of 2-(2,4-bis(dimethylamino)benzoyl)-4-(dimethylamino)benzoic acid or the 5-(dimethylamino) isomer thereof (10 g.), N,N,N'-tetramethyl-m-phenylenediamine (2.30 g.) and acetic anhydride (50 ml.) was warmed (at 30°- 35° C.) during one hour. More N,N,N',N'-tetramethyl-m-phenylenediamine (1.15 g.) was added and warming was continued. The mixture was diluted with dilute hydrochloric acid (10%) and ice and filtered. The filtrate was made alkaline. Crystallization of the product from toluene afforded 3,3-bis(2,4-bis(dimethylamino)phenyl)-5-(dimethylamino)phthalide (I: X= Y2 = Y 4 = Z5 = (CH3)2N, Z4 = Z6 = Z7 = H) (m.p. 188°-192° C.) or the 6-(dimethylamino) isomer thereof.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:10][NH:11][C:12]2[C:16]([C:17](O)=[O:18])=[CH:15][NH:14][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.B.O1CCCC1.CO>C1COCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:10][NH:11][C:12]2[C:16]([CH2:17][OH:18])=[CH:15][NH:14][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(CNc2n[nH]cc2C(=O)O)cc1OC1CCCC1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CNc2n[nH]cc2CO)cc1OC1CCCC1
Temperature: -15 °C
Reaction time: 72 h
Yield: 86.6 %

Procedure:
Pure 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-pyrazolecarboxylic acid (compound 3) (1.32 g, 4.0 mmol) was dissolved in 50 ml of THF and cooled to -15° C. under nitrogen. Borane-tetrahydrofuran (30 ml of 1 M solution, 30 mmol) was added over 30 minutes and the resulting solution was stirred for 72 hours at room temperature. Methanol (30 ml) was added to the reaction and the solvent was evaporated under reduced pressure. The residue was treated with 160 ml of methanol and evaporated again. The crude product was treated with 30 ml of 10% aqueous ammonia and some brine and then extracted with three 50 ml portions of ethyl acetate. Evaporation of the solvent afforded 1.1 g of crude 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-hydroxymethylpyrazole which was purified by flash chromatography on 30 g of flash chromatography silica gel. Elution with ethyl acetate/hexane (1:4) afforded a small amount of material which was discarded. Elution with 60 ml of 1:1 ethyl acetate/hexane gave 600 mg of 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-hydroxymethylpyrazole which was recrystallized from 2 ml of toluene to give 500 mg of pure 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-hydroxymethylpyrazole (compound 4) mp 129-130° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:25]=[O:26]>>[CH3:31][O:30][C:29]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][C:22]=1[O:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(C=O)cc1O
Reactant: BrCCCCCCOCCCCCCc1ccccc1
Product: COc1ccc(C=O)cc1OCCCCCCOCCCCCCc1ccccc1

Procedure:
Reaction of 1-bromo-6-(6-phenylhex-1-yloxy)hexane and 3-hydroxy-4-methoxy benzaldehyde analogous to the procedure of preparation 3, affords the title compound as a pale yellow oil. MS (m/z) 413.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:9][N:8]2[C:10]3[CH:11]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:13]=[CH:14][C:15]=3[C:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:7]2[C:6]2[CH:27]=[CH:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:30][C:5]=2[O:4][CH2:3]1.C(OC)(OC)OC.[CH3:46][N:47]([CH2:55][CH:56]=O)[C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51].[BH3-]C#N.[Na+]>>[C:50]([O:49][C:48]([N:47]([CH3:46])[CH2:55][CH2:56][NH:1][C@@H:2]1[CH2:9][N:8]2[C:10]3[CH:11]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:13]=[CH:14][C:15]=3[C:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:7]2[C:6]2[CH:27]=[CH:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:30][C:5]=2[O:4][CH2:3]1)=[O:54])([CH3:53])([CH3:52])[CH3:51]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N)COc1cc(OCc2ccccn2)ccc1-3
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](NCCN(C)C(=O)OC(C)(C)C)COc1cc(OCc2ccccn2)ccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (7R)-7-amino-14-cyclohexyl-3-(pyridin-2-ylmethoxy)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate was dissolved in HC(OMe)3 (50 eq) and a solution of tert-butyl methyl(2-oxoethyl)carbamate (1.6 eq, prepared according to Tetrahedron 2002, 58, 1719-1737) in HC(OMe)3 (50 eq) was added. The mixture was stirred overnight at RT to allow formation of the imine. All volatiles were evaporated and the residual material was dissolved in MeOH/HOAc (0.05 M). NaCNBH3 (1 eq) was added and the mixture was stirred at RT for 1 h. Some formation of the N-formyl product was observed alongside formation of the desired product. The solution was used directly in the next step. (ES+) m/z 669 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:6]([O:11][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:5]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1OCCCCCCCCCCCCCC
Yield: 29.7 %

Procedure:
A mixture of 1.0 g (6.6 mmol) of 3,4-dihydroxybenzoic acid methyl ester, 4.1 ml (14 mmol) of 1-bromotetradecane and 2.5 g (17.9 mmol) of potassium carbonate in 50 ml of DMF was stirred and heated at 100° for 65 hours. The solvent was removed using high vacuum, water was added to the residue and the product was extracted with ethyl acetate. The dried extract was concentrated to a solid which was recrystallized from methanol-water to give 1.1 g (30% yield, mp 49°-50°) of 3,4-bis(tetradecyloxy)benzoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[S:22]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[Cl:1])[N:8]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Reactant: Nc1nc(-c2sccc2Cl)cs1
Product: O=S(=O)(Nc1nc(-c2sccc2Cl)cs1)c1cc(Cl)c(Cl)cc1Cl

Procedure:
The title compound was prepared from 4-(3-chloro-2-thienyl)-1,3-thiazol-2-amine (59 mg) and 2,4,5-trichlorobenzenesulfonyl chloride (76 mg) as described in the synthetic METHOD B to give a white solid (9.2 mg) with purity >90%: MS (pos) m/z 459.2, 461.2, 463.2.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C@H:21]([CH2:25][C:26]([O:28]CC)=[O:27])[CH2:20][CH2:19]4)=[CH:10][C:5]=2[O:4][CH:3]=1.O[Li].O>C1COCC1.O>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C@H:21]([CH2:25][C:26]([OH:28])=[O:27])[CH2:20][CH2:19]4)=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc4c(C)coc4c3)ccc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1coc2cc(OCCCOc3ccc4c(c3)CC[C@H]4CC(=O)O)ccc12
Temperature: 45 °C
Reaction time: 4 h
Yield: 21.8 %

Procedure:
To a solution of ethyl ((1S)-5-{3-[(3-methyl-1-benzofuran-6-yl)oxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (119 mg, 0.29 mmol) (Example 64) in THF (4.2 mL) was added a solution of LiOH.H2O (15 mg, 0.35 mmol) in water (1.4 mL). The mixture was stirred for 4 h at 45° C. and then 12 h at rt. The reaction mixture was concentrated under reduced pressure, water was added, and the aqueous phase was washed with a small volume of Et2O. The pH was adjusted to below 3 with HCl (1 N aqueous solution), and the aqueous phase was extracted with excess EtOAc. The combined EtOAc extracts were dried, filtered, and concentrated under reduced pressure to give 24 mg (22%) of the title compound as a solid. 1H NMR (300 MHz, CDCl3): δ 7.44-7.22 (m, 2H), 7.08 (d, 1H), 6.98 (s, 1H), 6.89 (d, 1H), 6.80 (s, 1H), 6.72 (d, 1H), 4.32-4.04 (m, 4H), 3.63-3.44 (m, 1H), 2.98-2.76 (m, 3H), 2.58-2.37 (m, 2H), 2.37-2.14 (m, 5H), 1.88-1.70 (m, 1H); LC-MS: RT=3.53 min, (M+H)+ 381.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: C1COCCN1
Solvent: O
Product: CCOC(=O)c1c(N2CCOCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 150 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
To a stirred solution of 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 11 step B, 100 mg, 0.29 mmol) in a sealed tube was added morpholine (0.038 ml, 0.43 mmol). Then the mixture was stirred at 150° C. for 3 h. After cooling, this reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford a crude residue which was purified by flash column chromatography (100-200 mesh silica, eluting with 10% ethyl acetate in hexane) to give 6-chloro-2-morpholin-4-yl-4-phenyl-quinoline-3-carboxylic acid ethyl ester (65 mg, 57%) as pale yellow solid. LC-MS: 397 (M+H)+.
Reaction SMILES: [CH2:1](Br)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:10][C:11]1[C:28]([CH3:29])=[CH:27][C:14]([O:15][CH2:16][C:17]([N:19]([CH3:26])[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:18])=[C:13]([CH3:30])[C:12]=1[CH3:31].C(N(CC)CC)C.[Cl-].[NH4+]>C(#N)C>[NH2:10][C:11]1[C:28]([CH3:29])=[CH:27][C:14]([O:15][CH2:16][C:17]([N:19]([CH3:26])[CH:20]2[CH2:25][CH2:24][N:23]([CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:22][CH2:21]2)=[O:18])=[C:13]([CH3:30])[C:12]=1[CH3:31]
Reactant: Cc1cc(OCC(=O)N(C)C2CCNCC2)c(C)c(C)c1N
Reactant: BrCCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(OCC(=O)N(C)C2CCN(CCc3ccccc3)CC2)c(C)c(C)c1N
Temperature: 60 °C
Reaction time: 5 h
Yield: 88.1 %

Procedure:
200 mg of phenethyl bromide was added to a mixture solution of 350 mg of the Compound (1) obtained in the Example 1 and 172 mg of triethylamine in 5 ml of acetonitrile, and the mixture was stirred for 5 hours at 60° C. Then, 5 ml of saturated ammonium chloride solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried and concentrated under reduced pressure to give a residue. The obtained residue was purified by amine-coated silica gel (Fuji Silysia Chemical Ltd.; NH-DM1020) column chromatography (methylene chloride:methanol=20:1) to give 390 mg (83%) of the above-mentioned compound (28).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][CH2:11]OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: COCOC
Reactant: Oc1ccc(Br)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COCOc1ccc(Br)cc1
Reaction time: 1 h
Yield: 57.9 %

Procedure:
To a solution of 4-bromophenol (0.50 g, 2.89 mmol) and dimethoxymethane (2.6 mL, 29.39 mmol) in DCM (60 mL) was added P2O5 (1.50 g, 10.57 mmol). The reaction mixture was stirred at for 1 h and insoluble precipitate was filtered off. Solid Na2CO3 was added to the solution and stirred for additional 10 min. The solid was filtered off and the solution was concentrated. Purification on a silica gel column gave the desired product as a clear oil (363 mg). NMR (CDCl3): 7.38 (d, 2H), 6.93 (d, 2H), 5.15 (s, 2H), 3.47 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].[F:17][C:18]1[CH:27]=[C:26]([CH:28]=O)[C:21]2[O:22][CH2:23][O:24][CH2:25][C:20]=2[CH:19]=1>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]#[N:16])=[C:2]([N:1]=[CH:28][C:26]3[C:21]4[O:22][CH2:23][O:24][CH2:25][C:20]=4[CH:19]=[C:18]([F:17])[CH:27]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cc(F)cc2c1OCOC2
Reactant: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1cc(F)cc2c1OCOC2
Yield: 60 %

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile (100 mg) was then suspended in EtOH (4 mL) and 6-fluoro-4H-1,3-benzodioxine-8-carbaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain A29 as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (103 mg, 60% yield).
Reaction SMILES: [CH:1]1([N:4]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:5]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[F:20])[O:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1.[F:27][C:28]([F:39])([F:38])[C:29]1([CH2:32]OS(C)(=O)=O)[CH2:31][CH2:30]1>>[CH:1]1([N:4]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:32][C:29]3([C:28]([F:39])([F:38])[F:27])[CH2:31][CH2:30]3)[CH2:23][CH2:22]2)[C:5]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[F:20])[O:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2cc(C(=O)N(C3CCNCC3)C3CC3)no2)c(F)c1
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Product: N#Cc1ccc(-c2cc(C(=O)N(C3CC3)C3CCN(CC4(C(F)(F)F)CC4)CC3)no2)c(F)c1

Procedure:
The title compound is prepared from 5-(4-cyano-2-fluoro-phenyl)-isoxazole-3-carboxylic acid cyclopropyl-piperidin-4-yl-amide and methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester following a procedure analogous to that described for Example 3. LC (method 3): tR=1.35 min; Mass spectrum (ESI+): m/z=477 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:13][C:14]2[CH:19]=[C:18](F)[CH:17]=[CH:16][C:15]=2[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH3:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:13][C:14]2[CH:19]=[C:18]([N:30]3[CH2:29][CH2:28][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31]3)[CH:17]=[CH:16][C:15]=2[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH3:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(C(C)Nc2cc(F)ccc2C(=O)C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)cc(C(C)Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)C(F)(F)F)c1
Yield: 26.5 %

Procedure:
1-(2-(1-(3,5-Dimethoxyphenyl)ethylamino)-4-fluorophenyl)-2,2,2-trifluoroethanone (600 mg, 1.62 mmol), t-butyl piperazine-1-carboxylate (300 mg, 1.62 mmol), N,N-diisopropylethylamine (418 mg, 3.24 mmol) were stirred at 80° C. in dry acetonitrile (25 mL) for 21 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 20% ethyl acetate in hexanes to afford the title compound (231 mg, 27% yield). 1H NMR (400 MHz, CDCl3): δ 9.30 (d, 1H), 7.59 (d, 1H), 6.48 (s, 2H), 6.33 (s, 1H), 6.13 (d, 1H), 5.68 (s, 1H), 4.44 (m, 1H), 3.43 (m, 4H), 3.25 (m, 2H), 3.20 (m, 2H), 1.59 (d, 3H), 1.46 (s, 9H); MS (ESI) m/z: Calculated for C27H34F3N3O5: 537.25; Observed: 560.3 (M++Na).
Reaction SMILES: [CH3:1][C:2]([NH2:24])([CH3:23])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)[CH:5]=1.[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([C@@H:44]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH2:45]Br)=[C:37]2[C:42]=1[NH:41][C:40](=[O:43])[CH:39]=[CH:38]2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[I-].[Na+].C(=O)([O-])O.[Na+]>CN1CCCC1=O.O>[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH:44]([O:47][Si:48]([C:51]([CH3:52])([CH3:54])[CH3:53])([CH3:50])[CH3:49])[CH2:45][NH:24][C:2]([CH3:1])([CH3:23])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][C:13]34[CH2:22][CH:17]5[CH2:16][CH:15]([CH2:21][CH:19]([CH2:18]5)[CH2:20]3)[CH2:14]4)[CH:5]=2)=[C:37]2[C:42]=1[NH:41][C:40](=[O:43])[CH:39]=[CH:38]2)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(N)Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1)NCC(O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 120 °C
Yield: 34 %

Procedure:
To a solution of Intermediate 87 (0.981 g, 3.0 mmol) and (R)-8-(benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)quinolin-2(1H)-one (1.463 g, 2.99 mmol) in N-methylpyrrolidinone (5 mL) was added sodium iodide (0.471 g, 3.14 mmol) and sodium hydrogencarbonate (0.352 g, 4.19 mmol). The reaction mixture was heated at 120° C. for 4 hours and poured into excess water. The organic layer was extracted with diethyl ether and washed with water. The solvent was removed under reduced pressure and the crude was purified by column chromatography with silica gel, eluting with dichloromethane/methanol (from 90:1 to 90:2) to give 0.748 g (34% yield) of the title compound.
Reaction SMILES: [C:1]([C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17]C)=O)=[CH:9][CH:8]=1)([CH3:5])[CH3:4])#[N:2].[CH3:19][NH2:20]>CO>[C:1]([C:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]([NH:20][CH3:19])=[O:17])=[CH:11][CH:12]=1)([CH3:4])[CH3:5])#[N:2]
Reactant: COC(=O)CCc1ccc(NC(C)(C)C#N)cc1
Reactant: CN
Solvent: CO
Product: CNC(=O)CCc1ccc(NC(C)(C)C#N)cc1
Temperature: 0 °C

Procedure:
To a solution of compound 37 (20 mg, 0.08 mmol) in CH3OH (3 mL) was added dropwise a solution of the CH3NH2 in CH3OH (3 mL) at 0° C. with stirring. The reaction mixture was stirred at 0° C. for 6 h. The ice-water was added into the reaction mixture. The aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to give compound 38 (25 mg) as a light yellow oil. The crude product was used directly for the next step without purification. 1H NMR (400 MHz, CDCl3) δ7.09 (d, 2H, J=8.2 Hz), 6.86 (d, 2H, J=8.2 Hz), 2.90 (t, 2H, J=7.4 Hz), 2.77 (d, 3H, J=4.8 Hz), 2.43 (t, 2H, J=7.4 Hz), 1.68 (s, 6H).