Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:7]=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1.[Li+].[OH-]>C1COCC1.O>[Cl:12][C:9]1[N:8]=[CH:7][C:6]([CH:5]=[CH:4][C:3]([OH:13])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)C=Cc1ccc(Cl)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C=Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
3-(6-Chloro-pyridin-3-yl)-acrylic acid methyl ester (107 mg, 0.541 mmol) in THF was added to a solution of 0.5 N-LiOH (2 eq) and the mixture was stirred for 3 hrs at room temperature. The resulting residue was dissolved in H2O and then washed three times with Et2O, neutralized with 1N HCl to pH 5˜7. The resulting solid filtered and washed with H2O and then dried in vacuo to give 3-(6-chloro-pyridin-3-yl)-acrylic acid (80 mg, 80%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@H:24]([OH:39])[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([OH:38])=[C:31]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:32]=1>>[O:18]=[C:16]1[NH:15][C:14](=[O:19])[CH:13]([CH2:12][C:11]2[CH:20]=[CH:21][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][C@H:24]([OH:39])[CH2:25][O:26][C:27]4[CH:28]=[CH:29][C:30]([OH:38])=[C:31]([NH:33][S:34]([CH3:37])(=[O:35])=[O:36])[CH:32]=4)[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[S:17]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CNC2CCN(c3ccc(CC4SC(=O)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and N-[5-((2S)-3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 14) according to the procedure of Example 73 as a grey solid; mp>70° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.45–1.55 (m, 2 H), 1.85–2.00 (m, 2 H), 2.60–2.90 (m, 6 H), 2.94 (s, 3 H), 3.23 (dd, J=14.0, 3.8 Hz, 1 H), 3.60–4.00 (m, 5 H), 4.49 (dd, J=8.8, 3.9 Hz, 1 H), 6.64 (dd, J=8.8, 3.0 Hz, 1 H), 6.75–6.90 (m, 4 H), 7.04 (d, J=8.6 Hz, 2 H); MS (ES) m/z: 564.8 (MH+, 100%); HRMS Calcd. for C25H33N4O7S2 (MH+): 565.1791. Found: 565.1783.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1Cl)([O-:3])=[O:2].Cl.[CH2:16]([O:18][NH2:19])[CH3:17].C(N(CC)CC)C>CO>[N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH:19][O:18][CH2:16][CH3:17])([O-:3])=[O:2]
Reactant: CCON
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCONc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A suspension of 10.0 g. (0.046 mole) of 2,6-dinitro-4-methylchlorobenzene in 100 ml. of methanol was prepared, and to the suspension there was added 7.6 g. (0.092 mole) of ethoxyamine hydrochloride, and 13.9 g. (0.138 mole) of triethylamine. The reaction mixture was stirred for about 30 minutes at room temperature and then heated and stirred for about 30 minutes at about 50° C., after which an additional 16.7 g. (0.20 mole) of ethoxyamine hydrochloride was added, and the reaction mixture was stirred and refluxed for about 24 hours. An NMR spectrum of the reaction mixture indicated the presence of the desired product in about 70 percent yield. The reaction product mixture was poured over a mixture of ice and water, and the aqueous mixture filtered. The solid obtained was recrystallized from petroleum ether (b.p. 60°-71° C.) to yield 5.5 g. of product having a melting point of about 64°-66° C. The product was identified by its NMR spectrum as 2,6-dinitro-N-ethoxy-p-toluidine.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]1[CH2:8][CH2:7][N:6]([CH:9]2[CH2:14][CH2:13][C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)([OH:15])[CH2:11][CH2:10]2)[CH2:5]1.[N+](C1C=CC([O:32][C:33]([N:35]2[CH:39]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[C:42]([F:47])[CH:41]=3)[CH:38]([CH:48]3[CH2:50][CH2:49]3)[O:37][C:36]2=[O:51])=O)=CC=1)([O-])=O>>[ClH:1].[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:12]2([OH:15])[CH2:11][CH2:10][CH:9]([N:6]3[CH2:7][CH2:8][C@@H:4]([NH:3][C:33]([N:35]4[C@@H:39]([C:40]5[CH:45]=[CH:44][C:43]([F:46])=[C:42]([F:47])[CH:41]=5)[C@H:38]([CH:48]5[CH2:50][CH2:49]5)[O:37][C:36]4=[O:51])=[O:32])[CH2:5]3)[CH2:14][CH2:13]2)=[CH:21][CH:20]=1
Reactant: N[C@@H]1CCN(C2CCC(O)(c3ccc(F)cc3)CC2)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1C(=O)OC(C2CC2)C1c1ccc(F)c(F)c1
Agent: Cl
Product: O=C(N[C@@H]1CCN(C2CCC(O)(c3ccc(F)cc3)CC2)C1)N1C(=O)O[C@@H](C2CC2)[C@@H]1c1ccc(F)c(F)c1

Procedure:
This compound was prepared from the product of Example 35, Step D and the product of Example 43, Step C by a procedure similar to that described in Example 25, Step E. ##STR87##
Reaction SMILES: [CH2:1]([C:5]1[NH:14][C:13](=[O:15])[C:12]2[C:7](=[CH:8][C:9]([C:16]([O:18]C)=[O:17])=[CH:10][CH:11]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[K+].O>O.O1CCOCC1>[CH2:1]([C:5]1[NH:14][C:13](=[O:15])[C:12]2[C:7](=[CH:8][C:9]([C:16]([OH:18])=[O:17])=[CH:10][CH:11]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc2c(=O)[nH]c(CC(C)C)nc2c1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Cc1nc2cc(C(=O)O)ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 2-isobutyl-4-oxo-3,4-dihydroquinazoline-7-carboxylate (55.8 mg, 0.21 mmol), KOH (0.3 g, 5.3 mmol) in water/dioxane (2 mL/5 mL) was stirred at room temperature for 1 h. The reaction mixture was poured into water (50 mL) and the solution was adjusted to pH to 4-5. The mixture was extracted with ethyl acetate (3×20 mL) and dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product. MS (ESI): 246 (MH+).
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=1.C(N(CC)CC)C>C(O)CCC>[C:1]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:2]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1Nc1cccc(-c2ccccc2)c1

Procedure:
[1,1′-biphenyl]-3-amine (8.49 g, 50.2 mmol), 2-chloro-3-nitropyridine (7.23 g, 45.6 mmol), triethylamine (6.99 mL, 50.2 mmol), and 200 mL of butanol were added to a 1 L round bottom flask. The mixture was refluxed overnight under nitrogen. The next day the solvent was evaporated, and the residue was taken up in dichloromethane and washed twice with water. The organic layer was dried over magnesium sulfate, filtered, and evaporated leaving an orange oil. 14.61 g, assume quantitative yield (13.29 g).
Reaction SMILES: C(O[C:6](=[O:31])[NH:7][C@H:8]([C:10](=[O:30])[NH:11][C@H:12]([B:17]1[O:25][C@H:24]2[C@:19]([CH3:29])([C@H:20]3[CH2:26][C@@H:22]([CH2:23]2)[C:21]3([CH3:28])[CH3:27])[O:18]1)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:9])(C)(C)C.[C:32]1([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C@@H:39]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)C(O)=O)[CH:33]=1>>[C:32]1([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C@@H:39]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[C:6]([NH:7][C@H:8]([C:10](=[O:30])[NH:11][C@H:12]([B:17]2[O:25][C@H:24]3[C@:19]([CH3:29])([C@H:20]4[CH2:26][C@@H:22]([CH2:23]3)[C:21]4([CH3:27])[CH3:28])[O:18]2)[CH2:13][CH:14]([CH3:15])[CH3:16])[CH3:9])=[O:31])[CH:33]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc1
Product: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)cc1

Procedure:
The title compound is prepared as described in example 1 but using {(S)-1-[(R)-3-Methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester and (S)-2-(Biphenyl-3-ylamino)-3-(4-methoxy-phenyl)-propionic acid.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:23])[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:7]2[C:16]([CH3:22])=[CH:17][C:18]([CH3:21])=[C:19]([CH3:20])[C:6]=2[O:5]1.C([O-])(=O)C.[Na+].C(#N)C>O>[Br:1][C:17]1[C:18]([CH3:21])=[C:19]([CH3:20])[C:6]2[O:5][C:4]([CH3:23])([CH3:3])[CH:8]([C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=3)[C:7]=2[C:16]=1[CH3:22]
Reactant: BrBr
Reactant: Cc1ccc(C2c3c(C)cc(C)c(C)c3OC2(C)C)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C2c3c(C)c(Br)c(C)c(C)c3OC2(C)C)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Bromine (29.3 mL) was added dropwise to a mixture of 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran (145 g), sodium acetate (50.9 g) and acetonitrile (2175 mL) at 0 to 5° C. The mixture was stirred at 0 to 10° C. for 1 hour and water (725 mL) was added thereto. Precipitated crystals were filtered to obtain the title the compound (175 g, 94.2%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5](CN=C=O)[CH:4]=[C:3]([CH2:11][N:12]=[C:13]=[O:14])C=1.C1(CN=C=O)C(C[N:22]=[C:23]=[O:24])=CC=CC=1>>[CH2:1]([N:22]=[C:23]=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:11][N:12]=[C:13]=[O:14]
Reactant: O=C=NCc1ccccc1CN=C=O
Reactant: O=C=NCc1cccc(CN=C=O)c1
Product: O=C=NCCCCCCN=C=O

Procedure:
The same isocyanuration reaction as in Production Example 1 was carried out except that 3,290 g of hexamethylene diisocyanate and 210 g of "Takenate 500" (xylylene diisocyanate produced by Takeda Chemical Industry Co., Ltd.) were used instead of 3,500 g of hexamethylene diisocyanate, and the amount of the isocyanuration catalyst used in production Example 1 was changed to 4.7 g. There was obtained 4,219 g of the reaction mixture containing the deactivated catalyst.
Reaction SMILES: [N:1]([C@H:4]1[CH2:7][C@H:6]([C:8]([O:10]C)=[O:9])[CH2:5]1)=[N+:2]=[N-:3].O.[OH-].[Na+]>CO>[N:1]([C@H:4]1[CH2:7][C@H:6]([C:8]([OH:10])=[O:9])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: COC(=O)[C@H]1C[C@H](N=[N+]=[N-])C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=N[C@H]1C[C@H](C(=O)O)C1

Procedure:
To a solution of trans methyl 3-azidocyclobutane carboxylate (2.38 g, 15.3 mmol) in methanol (5 ml) was added water (5 ml). The resulting cloudy mixture was stirred vigorously and treated dropwise (0.5 h) with an aqueous solution of sodium hydroxide (1 N, 15.3 ml) at such a rate that the temperature was kept under 25° C. The reaction mixture was stirred at 23° C. for 2 h and the methanol was evaporated in vacuo to a slightly yellow residue which was diluted with water (10 ml). The aqueous solution was washed with ether (2×10 ml), acidified with 1 N hydrochloric acid and extracted with dichloromethane (4×25 ml). The organic extracts were combined, washed with water, dried over anhydrous sodium sulfate and concentrated to a colorless oil which solidified on standing; 2.02 g, 93%; mp 39°-41° C. Anal. calcd for C5H7N3O2 : C 42.55, H 5.00, N 29.78; found: C 42.41; H 5.02, N 29.59; ir (KBr) νmax : 2100 (N3) and 1705 cm-1 with shoulder at 1735 (C=O of carboxylic acid); 1Hmr (CDCl3) δ: 4.19 (1H, m, H-1) and 3.5-2.0 ppm (5H, H-2, H-3, H-4).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:21])[NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:24]I>O1CCOCC1>[CH3:24][N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:21])[NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1ccccc1Cl)Oc1ccc2c(c1)CCCN2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1CCCc2cc(OC(=O)Nc3ccccc3Cl)ccc21
Reaction time: 0.33 h

Procedure:
A solution of 1 of 2-chloro-phenyl -carbamic acid-1, 2, 3, 4-tetrahydro-quinolin-6-yl ester (0.302 g., 1.5 mmol) in dry dioxane (5 ml) was added to a stirred suspension of sodium hydride (0.036 g., 1.5 mmol) in dry dioxane (5 ml) at −10° C. during 5 min. The reaction mixture was stirred for 20 min. Then methyl iodide (0.122 ml, 1.8 mmol) was added to the stirring reaction mixture. Stirring was continued for additional 1.5 hours during which the temperature was allowed to rise to room temperature (34° C.). The reaction mixture was quenched with water (0.2 ml), concentrated under vaccum, diluted with water (5 ml), extracted with chloroform (2×5 ml) and dried over sodium sulphate. The combined fractions of chloroform were concentrated under vaccum. The residue was chromatographed on silica gel using 30:70 chloroform: hexane (30:70) as eluant to give 2o; yield: 0.50 g. (47.5%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH2:17][CH2:16][C@H:15]([NH:18][S:19]([C:22]4[S:30][C:29]5[C:24](=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=4)(=[O:21])=[O:20])[C:14]3=[O:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C1(O)C=CC=CC=1.C([O-])(=O)C.[NH4+:43]>>[NH2:43][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH2:17][CH2:16][C@H:15]([NH:18][S:19]([C:22]4[S:30][C:29]5[C:24](=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=4)(=[O:21])=[O:20])[C:14]3=[O:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C1[C@@H](NS(=O)(=O)c2cc3ncccc3s2)CCN1Cc1ccc2ccnc(Cl)c2c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Oc1ccccc1
Product: Nc1nccc2ccc(CN3CC[C@H](NS(=O)(=O)c4cc5ncccc5s4)C3=O)cc12
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
Thieno[3,2-b]pyridine-2-sulfonic acid [1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide (1.36 g, 2.88 mmol) and phenol (2.22 g, 23.6 mmol) are melted together with stirring at 70° C. for 5 minutes. Ammonium acetate (2.71 g, 28.8 mmol) is added and the reaction mixture is heated to 90° C. and stirred overnight. Additional ammonium acetate (0.50 g, 5.31 mmol) is added and the reaction is heated for 20 more hours. The reaction is cooled and the residue is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN. The appropriate product fractions are lyophilized to provide the title compound as a white solid. The enantiomeric purity is 90.5% ee as determined by analytical Chiralpak AS RP-HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6](Cl)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[C:12]=2[F:20])[N:3]=1.O.[NH3:22]>>[Cl:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[C:12]=2[F:20])[N:5]=[C:6]([NH2:22])[C:7]=1[O:8][CH3:9]
Reactant: N
Reactant: COc1c(Cl)nc(-c2ccc(Cl)c(OC)c2F)nc1Cl
Solvent: O
Product: COc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1Cl
Temperature: 125 °C
Yield: 88 %

Procedure:
4,6-Dichloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-methoxy-pyrimidine (500 mg, 1.5 mmol) was suspended in ammonia saturated ethanol (10 mL) and heated in a CEM microwave at 125° C. for 30 min The mixture was poured into 15 mL water and extracted with ethyl acetate thrice. The combined organic phases were washed once with brine, dried and evaporated to give the title compound (420 mg, 88% yield: 1H NMR (DMSO-d6) δ 7.59 (dd, 1H), 7.45 (br s, 2H), 7.39 (dd, 1H), 3.91 (s, 3H), 3.76 (s, 3H).
Reaction SMILES: C(O)C.[N+:4]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][C:8]=1[NH:18][C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])([O-])=O>C(O)(=O)C>[NH2:4][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][C:8]=1[NH:18][C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(NC(=O)CCCC(C)C)c1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N)c(NC(=O)CCCC(C)C)c1
Yield: 25.4 %

Procedure:
A solution of 2.00 g of ethyl 3-butyrylamino-4-nitrobenzoate in 10 ml of N,N-dimethylformamide was added dropwise to a slurry of 0.428 g of 60% sodium hydride and 10 ml of N,N-dimethylformamide at room temperature, and the mixture was stirred for 30 minutes. A solution of 1.46 g of isopropyl iodide in 10 ml of N,N-dimethylformamide was then added dropwise thereto, and the mixture was stirred at 100° C. for 5 days. The reaction solution was poured into a mixed solution of 80 g of dilute hydrochloric acid and 80 g of ethyl acetate for separation. The resulting organic layer was washed with 50 g of water, and was then concentrated under reduced pressure. The residue was purified through silica-gel column chromatography (eluent: a mixture of hexane and ethyl acetate at a ratio of 4:1) to obtain 0.260 g of crude ethyl 4-nitro-3-(N-i-propylbutyrylamino)benzoate. Subsequently, 3 ml of ethanol and 2 ml of acetic acid were added to 0.260 g of ethyl 4-nitro-3-(N-i-propylbutyrylamino)benzoate at room temperature, and 0.519 g of reduced iron were further added thereto. The mixture was heat-refluxed for 4 hours. The solid material was removed using a filtration aid, and the filtrate was concentrated. The residue were added 30 ml of ethyl acetate and 30 ml of dilute hydrochloric acid for separation. The organic layer was washed with 30 ml of water, and was then concentrated under reduced pressure. The residue was purified through preparative thin-layer silica-gel chromatography (developing eluent: a mixture of hexane and ethyl acetate at a ratio of 1:1) to give 0.06 g of ethyl 4-amino-3-(N-i-propylbutyrylamino)benzoate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>C(O)C.O1CCOCC1>[ClH:24].[ClH:24].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][N:20]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(C(=O)O)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)c1cnc(NC2CCNCC2)nc1

Procedure:
A solution of 2-(1-tert-butoxycarbonyl-piperidin-4-ylamino)-pyrimidine-5-carboxylic acid (0.18 g, 0.56 mmol) in ethanol (5 mL) and 4 M HCl in dioxane (10 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 223.3 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]([CH:20]3[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:9]=2)[N:4]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])[N:3]=1.[CH:28]1([B-](F)(F)F)[CH2:30][CH2:29]1.[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=CC=1.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>[CH:20]1([N:12]([CH2:11][C:7]2[CH:6]=[C:5]3[C:10]([C:2]([CH:28]4[CH2:30][CH2:29]4)=[N:3][N:4]3[CH2:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:9][CH:8]=2)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:22][CH2:21]1
Reactant: COCCCn1nc(Br)c2ccc(CN(C(=O)OC(C)(C)C)C3CC3)cc21
Reactant: F[B-](F)(F)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COCCCn1nc(C2CC2)c2ccc(CN(C(=O)OC(C)(C)C)C3CC3)cc21
Temperature: 100 °C
Reaction time: 24 h
Yield: 41.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (20 mg) was added to a solution of tert-butyl {[3-bromo-1-(3-methoxypropyl)-1H-indazol-6-yl]methyl}cyclopropylcarbamate (150 mg), potassium cyclopropyltrifluoroborate (73 mg) and potassium phosphate (254 mg) in toluene (3 ml)-water (1 ml) under argon atmosphere and the mixture was stirred at 100° C. for 24 hours. Potassium cyclopropyltrifluoroborate (24 mg), potassium phosphate (73 mg) and tetrakis(triphenylphosphine)palladium(0) (20 mg) were added to the reaction mixture and it was stirred further at 100° C. for 24 hours. Water was added to the reaction mixture under ice-cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane to n-hexane/ethyl acetate=2/1) to give tert-butyl cyclopropyl{[3-cyclopropyl-1-(3-methoxypropyl)-1H-indazol-6-yl]methyl}carbamate (57 mg) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([Cl:12])[N:4]=1)#[N:2].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>O1CCCC1.O>[C:9]([C:8]1[C:3]([C:1]#[N:2])=[N:4][C:5]([Cl:12])=[C:6]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)#[N:10]
Reactant: Oc1ccccc1
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1nc(Cl)c(Oc2ccccc2)nc1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
2,3-Dicyano-5,6-dichloropyrazine (1.00 g; 0.005 mole) was dissolved in 50 ml of tetrahydrofuran, and the solution was cooled to -15° to -10° C. A solution of 0.47 g (0.005 mole) of phenol and 0.21 g (0.005 mole) of sodium hydroxide in 25 ml of water was added dropwise over the period of 30 minutes. The mixture was stirred at -15° to -10° C. for 1 hour. The reaction mixture was poured into 100 ml of ice water, and the precipitate was collected by filtration. The precipitate was dissolved in 50 ml of chloroform, washed with 20 ml of a dilute aqueous solution of sodium hydroxide and 30 ml of water, dried over anhydrous calcium chloride, and concentrated under reduced pressure. The crude product was chromatographed on a column containing 60 g of silica gel using benzene as an eluent to afford 0.65 g (yield 50%) of 2,3-dicyano-5-chloro-6-phenoxypyrazine.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:34]([O:36]CC)=[O:35])[CH2:25][C:24]3[C:19](=[C:20]([O:32][CH3:33])[C:21]([O:30][CH3:31])=[C:22]([O:28][CH3:29])[C:23]=3[O:26][CH3:27])[CH2:18]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2([C:34]([OH:36])=[O:35])[CH2:25][C:24]3[C:19](=[C:20]([O:32][CH3:33])[C:21]([O:30][CH3:31])=[C:22]([O:28][CH3:29])[C:23]=3[O:26][CH3:27])[CH2:18]2)=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1(c2ccc(OCc3ccccc3)cc2)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c2c(c(OC)c(OC)c1OC)CC(C(=O)O)(c1ccc(OCc3ccccc3)cc1)C2
Yield: 76.2 %

Procedure:
An aqueous sodium hydroxide solution (3 N, 0.204 ml, 0.612 mmols) was added to an ethanol (4 ml) solution of ethyl 2-(4-benzyloxyphenyl)-4,5,6,7-tetramethoxy-2-indancarboxylate (150 mg, 0.305 mmols), and heated under reflux for 6 hours. The reaction mixture was concentrated in vacuo, and was made acidic by adding 1 N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by recrystallization (from hexane-ethyl acetate) to obtain the entitled compound (108 mg) as crystals.