Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@H:46]([O:56][C@@H:57]2[O:124][C@H:123]([CH2:125][O:126]C(=O)C3C=CC=CC=3)[C@@H:78]([O:79][C@@H:80]3[O:112][C@H:111]([CH2:113][O:114]C(=O)C4C=CC=CC=4)[C@@H:101]([O:102]C(=O)C4C=CC=CC=4)[C@H:91]([O:92]C(=O)C4C=CC=CC=4)[C@H:81]3[O:82]C(=O)C3C=CC=CC=3)[C@H:68]([O:69]C(=O)C3C=CC=CC=3)[C@H:58]2[O:59]C(=O)C2C=CC=CC=2)[C@@H:45]([CH2:135][O:136][CH2:137][C:138]2[CH:143]=[CH:142][CH:141]=[CH:140][CH:139]=2)[O:44][C@@H:10]1[O:11][C@H:12]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][N:14]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C@@H:13]1[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@H:46]([O:56][C@@H:57]2[O:124][C@H:123]([CH2:125][OH:126])[C@@H:78]([O:79][C@@H:80]3[O:112][C@H:111]([CH2:113][OH:114])[C@@H:101]([OH:102])[C@H:91]([OH:92])[C@H:81]3[OH:82])[C@H:68]([OH:69])[C@H:58]2[OH:59])[C@@H:45]([CH2:135][O:136][CH2:137][C:138]2[CH:139]=[CH:140][CH:141]=[CH:142][CH:143]=2)[O:44][C@@H:10]1[O:11][C@H:12]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][N:14]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C@@H:13]1[CH2:35][O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](O[C@H]3[C@H](OCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H](O[C@@H]4[C@@H](COCc5ccccc5)N(C(=O)OCc5ccccc5)C[C@H]4OCc4ccccc4)O[C@@H]3COCc3ccccc3)O[C@@H]2COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(OCc1ccccc1)N1C[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](O[C@@H]3O[C@H](CO)[C@@H](O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@H](O)[C@H]3O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 55.7 %

Procedure:
The compound (295.8 mg, 0.15 mmol) synthesized in Example 19 (19e) was dissolved in methanol (6 mL) and potassium carbonate (20 mg, 0.14 mmol) was added thereto, followed by stirring of the mixture at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated aqueous sodium hydrogencarbonate (10 mL) and saturated brine (10 mL). The mixture was neutralized with methanol-hydrochloric acid and the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (methylene chloride:methanol, 30:1-20:1-10:1, V/V) to obtain the desired title compound (100.7 mg, 55.8%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH2:12][CH3:13])[C:6]=2[N:7]=1.[CH3:15][NH2:16]>CN(C=O)C.CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:16][CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH2:12][CH3:13])[C:6]=2[N:7]=1
Reactant: CN
Reactant: CCCc1csc2c(Cl)nc(Cl)nc12
Solvent: CO
Solvent: CN(C)C=O
Product: CCCc1csc2c(NC)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
To 10 ml of a solution of 100 mg (0.41 mmol) of 2,4-dichloro-7-propylthieno[3,2-d]pyrimidine in DMF was added 40% methylamine solution in methanol under ice cooling. The reaction mixture was stirred at the same temperature for one hour and then allowed to resume room temperature, followed by stirring for further 2 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/2) to give 50 mg (yield: 51.5%) of the title compound.
Reaction SMILES: C(OC([N:6]=[S:7]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C@H:24]([CH3:27])[CH2:25][OH:26])[C:20]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)=[CH:19][N:18]=2)=[CH:12][CH:11]=1)([CH3:9])=[O:8])=O)C.CC[O-].[Na+]>>[OH:26][CH2:25][C@H:24]([NH:23][C:21]1[C:20]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[CH:19][N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([S:7]([CH3:9])(=[NH:6])=[O:8])=[CH:15][CH:14]=2)[N:22]=1)[CH3:27]
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](C)CO)n2)cc1
Agent: CC[O-]
Agent: [Na+]
Product: C[C@H](CO)Nc1nc(Nc2ccc(S(C)(=N)=O)cc2)ncc1-c1cccs1
Yield: 44 %

Procedure:
In the reaction of (RS)—N-(ethoxycarbonyl)-S-(4-{[4-{[(R)-2-hydroxy-1-methyl-ethyl]-amino}-5-(2-thienyl)pyrimidine-2-yl]amino}phenyl)-S-methylsulfoximide (94 mg, 0.2 mmol) with sodium ethylate (49 mg, 0.7 mmol) according to procedure 14, the desired product is obtained in 44% yield (35 mg) after chromatographic purification (silica gel, dichloromethane/methanol (9/1)).
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1.[NH:20]1[C:30]2[C:25](=[C:26]([O:31][CH2:32][CH:33]3[O:35][CH2:34]3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][C:21]1=[O:22]>C(O)(C)C>[NH:20]1[C:30]2[C:25](=[C:26]([O:31][CH2:32][CH:33]([OH:35])[CH2:34][NH:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]3[CH:6]=[CH:7][C:8]([C:11]4[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=4)=[CH:9][CH:10]=3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][C:21]1=[O:22]
Reactant: CC(C)(N)CNc1ccc(C2=NNC(=O)CC2)cc1
Reactant: O=C1CCc2c(cccc2OCC2CO2)N1
Solvent: CC(C)O
Product: CC(C)(CNc1ccc(C2=NNC(=O)CC2)cc1)NCC(O)COc1cccc2c1CCC(=O)N2
Reaction time: 20 h
Yield: 49.9 %

Procedure:
3.1 g of 6-[4-(2-amino-2-methylpropylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone obtained in Example 1, (3) and 2.2 g of 1-(3,4-dihydrocarbostyril-5-yloxy) -2,3-epoxypropane were dissolved in 30 ml of isopropyl alcohol and heated with stirring for 20 hours. After the end of the reaction, the reaction solution was concentrated under reduced pressure. The residue was separated by silica gel chromatography (chloroformmethanbol=10:1). Recrystallization from dichloromethane -isopropanol gave 2.4 g of 6-[4-[2-[3-(3,4-di hydrocarbostyril-5-yloxy)2-hydroxypropylamino]-2-methylpropylamino]phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].C1(C)C=CC=CC=1>N1CCCCC1.C(O)(=O)C.O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[C:24]3[S:20][C:21](=[O:26])[NH:22][C:23]3=[O:25])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(CCOc2ccc(C=O)cc2)cc1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Yield: 80 %

Procedure:
1 g (3.7 mmole) 4-[2-(4-Methylmercaptophenyl)ethoxy]benzaldehyde, 1.09 (9.25 mmole) 2,4-thiazolidinedione, 5 drops of piperidine, 6 drops of acetic acid and toluene were refluxed with water separation in a Dean-Stark apparatus for 1 hour. The heat was removed and the crystals were recrystallized in dichloromethane:methanol (95:5) to give 1.1 g (yield 80%) of 5-(4-[2-(4-methylmercaptophenyl)ethoxy]benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH:5]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:5]2[CH:47]([OH:51])[C:48]([CH3:50])([CH3:49])[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)[NH:11][C:6]=2[C:7]([Cl:10])=[CH:8][CH:9]=1)=[O:20]
Reactant: CC(C)C=O
Reactant: COC(=O)c1ccc(Cl)c(N=Cc2cccc(Br)c2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(Cl)c2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a stirred mixture solution of 3-[(3-bromo-benzylidene)-amino]-4-chloro-benzoic acid methyl ester (39.8 g, 113.2 mmol) and ytterbium(III) triflate hydrate (10.5 g, 16.9 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (10.4 mL, 113.2 mmol) and water (2.1 mL, 113.2 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-8-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (48 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrClNO3 (M+H)+: 425.73, observed: 405.9 & 407.9.
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:20]=[CH:19][C:18]=3[N:31]=2)=[CH:11][C:10]=1[O:32][CH3:33])C1C=CC=CC=1.[N+](C1C=CC(S([O:46][CH2:47][C@@H:48]2[CH2:50][C:49]2([F:52])[F:51])(=O)=O)=CC=1)([O-])=O>>[F:52][C:49]1([F:51])[CH2:50][C@H:48]1[CH2:47][O:46][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:20]=[CH:19][C:18]=3[N:31]=2)=[CH:11][C:10]=1[O:32][CH3:33]
Reactant: COc1cc(-c2nc3cnc(OC[C@H](C)NC(C)=O)cc3o2)ccc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CC2(F)F)cc1
Product: COc1cc(-c2nc3cnc(OC[C@H](C)NC(C)=O)cc3o2)ccc1OC[C@@H]1CC1(F)F

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)-3-methoxyphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and ((1S)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate, and in the same manner as in Step D of Example 68, the title compound was obtained.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])=[C:16]([CH:26]([CH3:28])[CH3:27])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br>>[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]1[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14][NH:15][C:16]=1[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1O
Reactant: Fc1cccc(CBr)c1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1OCc1cccc(F)c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 11 using 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-5-isopropyl-1H-pyrazole instead of 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-1-(2-hydroxyethyl)-5-trifluoromethyl-1H-pyrazole and using 3-fluorobenzyl bromide instead of benzyl bromide.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:17]([CH3:21])=[C:18]([O:19]C)[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[OH:19][C:18]1[C:13]2[O:12][CH2:11][C@H:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:30])=[C:16]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:17]=1[CH3:21]
Reactant: COc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OC[C@@H]2c1ccc(C(C)C)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(O)c2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Temperature: 25 °C
Yield: 78.3 %

Procedure:
To a solution of (+)-N-((3R)-3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (500 mg, 1.22 mmol) obtained in Example 52 in dichloromethane (20 mL) was added dropwise at −78° C. under an argon atmosphere boron tribromide (1.0 M dichloromethane solution, 3.0 mL, 3.0 mmol). The reaction solution was warmed to room temperature, added to an aqueous saturated sodium hydrogen carbonate solution, and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to synthesize 378 mg (yield: 78%) of the title compound. Melting point: 202-203° C. (ethyl acetate-hexane). [α]D20=+79.00 (c=0.49, chloroform).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:7]2[CH2:8][N:9]([CH:12]3[CH2:15][O:14][CH2:13]3)[CH2:10][CH2:11][N:6]2[N:5]=1)([O-])=O>[Pd].CO>[O:14]1[CH2:15][CH:12]([N:9]2[CH2:10][CH2:11][N:6]3[N:5]=[C:4]([NH2:1])[CH:16]=[C:7]3[CH2:8]2)[CH2:13]1
Reactant: O=[N+]([O-])c1cc2n(n1)CCN(C1COC1)C2
Agent: [Pd]
Solvent: CO
Product: Nc1cc2n(n1)CCN(C1COC1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A 50-mL single-neck round-bottomed flask was purged with nitrogen and charged with 155a (0.20 g, 0.89 mmol), 10% palladium on carbon (50% wet, 89 mg), and methanol (10 mL). The mixture was evacuated, charged with hydrogen gas, and stirred for 2 h at room temperature. The hydrogen was then evacuated and nitrogen was charged into the bottle. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 155b (140 mg, 81%). MS: [M+H]+ 195.1
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([N:12]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH2:16][CH2:15]2)[CH3:13])=[O:11])[C:5]([CH3:24])=[CH:4][N:3]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[CH:21]1([CH2:20][N:17]2[CH2:18][CH2:19][CH:14]([N:12]([CH3:13])[C:10](=[O:11])[CH2:9][NH:8][C:6]3[C:5]([CH3:24])=[CH:4][N:3]=[C:2]([NH:32][CH2:31][C:30]4[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[N:7]=3)[CH2:15][CH2:16]2)[CH2:23][CH2:22]1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cnc(Cl)nc1NCC(=O)N(C)C1CCN(CC2CC2)CC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncc(C)c(NCC(=O)N(C)C3CCN(CC4CC4)CC3)n2)cc1
Yield: 36 %

Procedure:
A solution of Compound 106 (93 mg), 4-methoxybenzylamine (345 μL) and diisopropylethylamine (45.5 μL) in n-butanol (1.5 mL) was stirred overnight under reflux. Subsequently, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1 to 4:1) to give 43 mg (36% yield) of the desired product as a white amorphous.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:11](O)([CH3:14])([CH3:13])[CH3:12].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: CC(C)(C)O
Reactant: Cc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.6 %

Procedure:
A mixture of 11.3 g of 6-methylnicotinic acid, 5.0 g of 4-dimethylaminopyridine, 18.3 g of t-butyl alcohol, 22.4 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 280 ml of dichloromethane is stirred at room temperature for 2 days. The reaction mixture is washed with water, dried over magnesium sulfate, and concentrated. The residue is chromatographed on silica gel with chloroform to give 7.1 g of t-butyl 6-methylnicotinate as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[O:11])[CH2:4][CH2:3]1.C([Cl:19])(=O)C>C(O)(C)C>[ClH:19].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[O:11])[CH2:4][CH2:3]1
Reactant: CC(=O)Cl
Agent: CN1CCN(c2ccccc2C=O)CC1
Solvent: CC(C)O
Product: Cl
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
2-(4-Methyl-1-piperazinyl)benzaldehyde (7.8 g, 38 mmol) was dissolved in 0.1% aqueous isopropanol (62 mL) at 20-25° C. under a nitrogen atmosphere and then 2.8 mL (40 mmol) of neat acetyl chloride was slowly added. The resulting slurry was cooled to 0-5° C., granulated for 1 hour, and then filtered. The cake was washed with cold (0-5° C.) isopropanol (8 mL) followed by hexanes (16 mL) and then dried in vacuo at 25-30° C. The title compound (7.9 g, 83% yield) was obtained as a light yellow solid. If desired, the title compound can be recrystallized from refluxing isopropanol (6 L/kg of solid) to afford rod-like crystals (mp 225-226° C.) which were recovered in 93% yield. 1H NMR (CDCl3) δ 12.3 (s, 1H), 10.1 (s, 1H), 7.71 (m, 1H), 7.69 (m, 1H), 7.15 (m, 1H), 7.05 (m, 1H), 3.62 (m, 2H), 3.51 (m 2H), 3.26 (m, 4H), and 2.86 (s, 3H). 13C NMR (CDCl3) δ 191.24, 152.24, 135.70, 134.30, 128.55, 124.03, 119.75, 54.00, 49.94 and 43.74. Anal. Calcd for C12H16N2O HCl: C, 59.87; H, 7.12; N, 11.64. Found: C, 59.98; H, 7.23; N, 11.65.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=3)[C:10]([C:19](N(C)C)=O)=[N:9]2)[CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.[CH3:32][Si:33]([CH3:47])([CH3:46])[CH2:34][CH2:35][O:36][CH2:37][N:38]1[CH:42]=[CH:41][N:40]=[C:39]1[C:43](=[O:45])[CH3:44]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:43]([C:39]4[N:38]([CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:32])([CH3:47])[CH3:46])[CH:42]=[CH:41][N:40]=4)([OH:45])[CH3:44])[CH:15]=3)[C:10]([CH3:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccc2c(C(=O)N(C)C)nn(-c3ccnc(N)n3)c2c1
Reactant: CC(=O)c1nccn1COCC[Si](C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3nccn3COCC[Si](C)(C)C)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-ethynyl-N,N-dimethylindazole-3-carboxamide (200 mg, 0.8 mmol) in THF (2 mL) at −78° C. under nitrogen was added 2M LDA in THF (1.40 mL, 2.81 mmol). After 1 hour, 1-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)ethanone (771.45 mg, 3.21 mmol) in THF (1.0 mL) was added. After stirring for 15 minutes, the reaction mixture was allowed to warm to RT and stirred for 2 hr. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (3 mL) and the volatiles were removed in vacuo. The reaction mixture was diluted with DCM (10 ml) and washed with water (2 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage, 1-12% methanol gradient in DCM) to surrender the title compound as a yellow solid: 1H NMR (500 MHz, DMSO) delta −0.19 (9H, s), 0.83-0.77 (2H, m), 2.01 (3H, s), 2.57 (3H, s), 3.59-3.49 (2H, m), 5.62 (1H, d, J=10.3 Hz), 5.78 (1H, d, J=10.2 Hz), 6.42 (1H, s), 6.86 (1H, d, J=1.1 Hz), 6.96 (2H, s), 7.03 (1 H, d, J=5.5 Hz), 7.27 (1H, d, J=1.0 Hz), 7.36 (1H, dd, J=8.1, 1.1 Hz), 7.84 (1H, d, J=8.2 Hz), 8.25 (1H, d, J=5.5 Hz), 8.85 (1H, s); LC-MS: m/z=+490.10 (M+H)+
Reaction SMILES: [CH3:1][C:2]([CH3:8])([C:6]#[CH:7])[CH2:3][CH2:4][OH:5].[CH3:9][O:10][C:11]([C:13]1[S:14][C:15](I)=[CH:16][C:17]=1[N:18]([CH:28]1[CH2:33][CH2:32][CH:31]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:30][CH2:29]1)[C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]1)=[O:20])=[O:12].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[CH3:9][O:10][C:11]([C:13]1[S:14][C:15]([C:7]#[C:6][C:2]([CH3:8])([CH3:1])[CH2:3][CH2:4][OH:5])=[CH:16][C:17]=1[N:18]([CH:28]1[CH2:29][CH2:30][CH:31]([O:34][Si:35]([C:38]([CH3:39])([CH3:41])[CH3:40])([CH3:36])[CH3:37])[CH2:32][CH2:33]1)[C:19]([CH:21]1[CH2:22][CH2:23][CH:24]([CH3:27])[CH2:25][CH2:26]1)=[O:20])=[O:12]
Reactant: COC(=O)c1sc(I)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Reactant: C#CC(C)(C)CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C#CC(C)(C)CCO)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Yield: 90.2 %

Procedure:
A solution of the 3,3-dimethyl-pent-4-yn-1-ol (600 mg, 5.36 mmol), 3-[[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-(4-methyl-cyclohexanecarbonyl)-amino]-5-iodo-thiophene-2-carboxylic acid methyl ester (2767 mg, 4.46 mmol) and triethylamine (10.8 mL, 77.48 mmol) in DMF (25 mL) was degassed for 10 minutes with nitrogen. PdCl2(PPh3)2 (314 mg, 0.45 mmol) and CuI (170 mg, 0.90 mmol) was added and the resulting mixture was degassed with nitrogen for an additional 5 minutes after which the reaction was placed in a 80° C. oil bath and heated for 3.5 h. The reaction was cooled and partitioned between ethyl acetate and sat. NaHCO3. The organic layer was separated, washed with 5% LiCl, brine, dried over Na2SO4 and concentrated to give a dark brown foam. Purification by flash column chromatography on silica gel using 30% ethyl acetate in hexanes then 5% methanol in ethyl acetate provided 3-[[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-(4-methyl-cyclohexanecarbonyl)-amino]-5-(5-hydroxy-3,3-dimethyl-pent-1-ynyl)-thiophene-2-carboxylic acid methyl ester (2.43 g, 90%) as a pale yellow foam.
Reaction SMILES: N1C=CC=CC=1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.NC1C=C2C(=CC=1)C(=O)CCC2.[OH-].[Na+].[N+](C1C=CC([N:43]([C:47]2[CH:56]=[CH:55][C:54]3[C:53](=[O:57])[CH2:52][CH2:51][CH2:50][C:49]=3[CH:48]=2)[C:44](=[O:46])[O-])=CC=1)([O-])=O.Cl.[F:59][C:60]1[CH:65]=[CH:64][C:63]([CH:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)=[CH:62][CH:61]=1>C(OCC)(=O)C.CS(C)=O.O1CCCC1>[F:59][C:60]1[CH:65]=[CH:64][C:63]([CH:66]2[CH2:67][CH2:68][N:69]([C:44]([NH:43][C:47]3[CH:56]=[CH:55][C:54]4[C:53](=[O:57])[CH2:52][CH2:51][CH2:50][C:49]=4[CH:48]=3)=[O:46])[CH2:70][CH2:71]2)=[CH:62][CH:61]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: O=C1CCCc2cc(N(C(=O)[O-])c3ccc([N+](=O)[O-])cc3)ccc21
Agent: Cl
Agent: Nc1ccc2c(c1)CCCC2=O
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1CCCc2cc(NC(=O)N3CCC(c4ccc(F)cc4)CC3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
Pyridine(9.95 ml, 123 mmol) and 4-nitrophenyl chloroformate (12.4 g, 61.5 mmol) was added to a tetrahydrofuran(300 ml)solution of 6-amino-3,4-dihydro-1(2H)-naphthalenone(9.92 g, 61.5 mmol)obtained in Reference Example 96, which was stirred at room temperature for 3 hours. The solvent was distilled out under reduced pressure. 1N Hydrochloric acid was added to the residue to powder, which was washed with ethanol. 4N Aqueous sodium hydroxide solution was added to a dimethylsulfoxide (33 ml)solution of the resulting 4-nitrophenyl-5-oxo-5,6,7,8-tetrahydro-2-naphthalenylcarbamate (2.20 g, 6.74 mmol) and 4-(4-fluorophenyl)piperidine hydrochloride (1.60 g, 7.42 mmol), which was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, which was washed with 1N hydrochloric acid, aqueous potassium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resulting residue was purified by alumina B column chromatography (development solvent ethyl acetate), and powdered with isopropyl ether and hexane, to give the titled compound (1.89 g).