Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=2)=[C:9](\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH2:10][CH3:11])=[CH:4][CH:3]=1.CCN(CC)CC.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:40]([O:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[CH:22][CH:23]=2)=[C:9](\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH2:10][CH3:11])=[CH:4][CH:3]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC/C(=C(/c1ccc(O)cc1)c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC/C(=C(\c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccc(OC(=O)c2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a solution of 12 (100 mg, 0.23 mmol) in CH2Cl2 (5 mL) was added Et3N (0.13 mL, 0.94 mmol) followed by the addition of benzoyl chloride (35 mg, 0.24 mmol). The reaction mixture was stirred at RT for 2 hr. The solution was washed with H2O (5 mL) and the organic layer dried (Na2SO4), and concentrated to provide a tan solid. This solid was then purified by chromatography (silica, 1:4 ethyl acetate/hexanes) to provide 19 as a white solid (80 mg, 67%). 1HNMR (400 MHz, DMSO-d6): δ 0.86 (t, 3H), 1.47 (s, 9H), 2.40 (q, 2H), 6.50 (d, J=16 Hz, 1H), 6.89 (d, J=8 Hz, 2H), 6.95 (d, J=8 Hz, 2H), 7.12-7.16 (m, 3H), 7.17-7.22 (m, 4H), 7.53 (d, J=8 Hz, 2H), 7.56 (d, J=16 Hz, 1H), 7.62-7.72 (m, 3H), 8.01 (d, J=8 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1.[F:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=1>>[NH2:39][C:36]1[N:37]=[CH:38][C:33]([C:19]2[CH:20]=[CH:21][C:22]([C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][C:5]3[N:6]=[CH:7][C:8]([C:9]#[N:10])=[CH:11][CH:12]=3)=[CH:23][C:18]=2[F:17])=[CH:34][N:35]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: N#Cc1ccc(Oc2ccccc2Br)nc1
Product: N#Cc1ccc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)nc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 6-(2-bromophenoxy)nicotinonitrile and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C22H14FN5O, 383.12; m/z found, 384.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.60 (dd, J=2.3, 0.8, 1H), 8.44 (d, J=1.6, 2H), 8.26 (dd, J=8.6, 2.3, 1H), 7.59 (dd, J=7.6, 1.8, 1H), 7.56-7.48 (m, 2H), 7.45-7.39 (m, 1H), 7.36-7.27 (m, 3H), 7.21 (dd, J=8.7, 0.7, 1H), 6.89 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)[C:14](O)=[O:15])=[CH:7][CH:6]=1)=[O:4].[Cl-].[NH4+]>C1COCC1.O.C(OCC)(=O)C>[OH:15][CH2:14][CH:13]([CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=1)[CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(CCC(CCc2ccc(C(=O)OC)cc2)C(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(CCC(CO)CCc2ccc(C(=O)OC)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
At −10° C., 54.1 ml (54.1 mmol) of a 1 M borane/THF complex solution are added dropwise to a solution of 10.4 g (27.1 mmol) of 4-[4-(methoxycarbonyl)phenyl]-2-{2-[4-(methoxy-carbonyl)phenyl]ethyl}butanoic acid in 260 ml of THF. The reaction mixture is then warmed to 0° C. and stirred at this temperature for 4 h. After the reaction has gone to completion, saturated ammonium chloride solution is added, the reaction mixture is diluted with water and ethyl acetate and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulfate and freed from the solvent under reduced pressure. This gives 8.73 g (23.56 mmol, 87% of theory) of a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:15]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[NH:18][C:17]2=[O:27])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:30]OS(=O)(=O)OC>CN(C)C=O>[F:1][C:2]1[C:15]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[N:18]([CH3:30])[C:17]2=[O:27])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: C#CCN1C(=O)COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
0.18 g of 3-(7-fluoro-3-oxo-4-propargyl-2H-1,4-benzoxazin-6-yl)-6-trifluoromethyl-2,4(1H,3H) -pyrimidinedione was added at room temperature in a dimethylformamide solution (2 ml) having suspended therein 0.02 g of sodium hydride (purity: 55%). After standing for 20 minutes, the solution was further added with 0.09 g of dimethylsulfuric acid and stirred overnight. Then dimethylformamide was distilled off and the residue was extracted with ethyl acetate by adding water. The extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off to obtain a crude product. This crude product was purified by preparative thin-layer chromatography using hexane/ethyl acetate (3:1) as developing solvent to obtain 0.15 g of the objective compound as a colorless viscous oil. It was solidified when left as it was.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:20]([O-:22])=[O:21])=[C:9]([CH:19]=1)[C:10]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18])=[O:11].C(N(CC)CC)C.[Cl:38][CH2:39][C:40](Cl)=[O:41]>CCOCC>[Cl:1][C:2]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:20]([O-:22])=[O:21])=[C:9]([CH:19]=1)[C:10]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][C:40](=[O:41])[CH2:39][Cl:38])=[O:11]
Reactant: O=C(OCCOCCO)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)CCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(CCl)OCCOCCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
5-Hydroxy-3-oxapentyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate (4 g, 0.009 mole) and triethylamine (2 ml) were dissolved in 200 ml of anhydrous ether in a 500 ml round-bottomed flask. Chloroacetyl chloride (5 g, 0.44 mole) was added dropwise. The solution was held at reflux for 4.5 hrs. A large amount of salt precipitated. The ether solution was washed two times with sodium bicarbonate and three times of water, dried over CaSO4 and concentrated to 3.6 g 5-(chloroacetoxy)3-oxapentyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate as a gum; nmr (CDCl3) δ 3.62-3.93 (m, 4H), 4.09 (s, 3H), 4.27-4.66 (m, 4H), 6.96-8.22 (m, 6H); ir (CHCl3) 1754, 1768 Cm-1.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[OH:18])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:19].Cl[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH:29][CH3:30])=[O:28])[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[OH:18])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:19][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH:29][CH3:30])=[O:28])[CH:22]=1
Reactant: Oc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1Br
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4O)sc3c2Br)ccn1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To the solution of 7-bromo-2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (50 mg, 0.145 mmol, 1.0 eq) in 1 mL of NMP was added 4-chloro-N-methylpicolinamide (29 mg, 0.174 mmol, 1.2 eq) and cesium carbonate (165 mg, 0.507 mmol, 3.5 eq) at room temperature. The reaction mixture was stirred at 80° C. for ca. 12 hours, thereafter the mixture was purified on the reverse phase HPLC. LC/MS (m/z) [479.0] (MH+)
Reaction SMILES: [Si]([O:18][C:19]1[CH:58]=[CH:57][C:22]([O:23][CH2:24][C@@H:25]([OH:56])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:55]=[CH:54][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([N:43]4[CH2:48][CH2:47][CH:46]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:45][CH2:44]4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:52]([O:51][C:49]([CH:46]1[CH2:45][CH2:44][N:43]([C:41]([N:38]2[CH2:39][CH2:40][CH:35]([NH:34][C:33]3[CH:54]=[CH:55][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:56])[CH2:24][O:23][C:22]4[CH:57]=[CH:58][C:19]([OH:18])=[CH:20][CH:21]=4)=[CH:31][CH:32]=3)[CH2:36][CH2:37]2)=[O:42])[CH2:48][CH2:47]1)=[O:50])[CH3:53]
Reactant: CCOC(=O)C1CCN(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)CC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCN(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)CC1
Yield: 78.1 %

Procedure:
Ethyl 1-({4-[4-(2-{[(2S)-3-(4-{[tert-butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-1-piperidinyl}carbonyl)-4-piperidinecarboxylate (0.17 g, 0.21 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.093 g, 0.164 mmol).
Reaction SMILES: C(C1C=CC=CC=1)(=[O:3])C.C[C:11]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:16]=[CH:15][C:14]=1[O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:12].Cl[O-]>>[F:28][C:27]([F:30])([F:29])[CH2:26][O:25][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:18][C:13]=1[C:11]([OH:12])=[O:3]
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: CC(=O)c1ccccc1
Agent: [O-]Cl
Product: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
replacing the methyl moiety of the acetophenone function of said 2,5-bis(2,2,2-trifluoroethoxy)acetophenone using hypochlorite to yield 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>CN(C=O)C.CCOC(C)=O>[Si:22]([O:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:3]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: O=C(OCc1ccccc1)C1CCC(O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CCC(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of benzyl 3-hydroxycyclopentanecarboxylate (1.0 g, 4.54 mmol) in 9 ml of degassed DMF was added imidazole (0.34 g, 4.99 mmol) and tert-butyldimethylsilyl chloride (0.75 g, 4.99 mmol). The mixture was stirred at ambient temperature for 4 hours, and then poured into 70 mL of water, and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water and brine and then dried over sodium sulfate. Filtration and concentration afforded the crude product which was subjected to chromatography on silica gel eluting with 5% EtOAc in hexanes to give benzyl 3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentanecarboxylate.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:35][CH2:36]OS(C3C=CC(C)=CC=3)(=O)=O)[N:7]=[C:8]3[C:17]4[C:12](=[C:13]([O:26]CC5C=CC=CC=5)[CH:14]=[CH:15][C:16]=4[O:18]CC4C=CC=CC=4)[C:11](=[O:34])[C:10]=1[C:9]=23.[CH3:48][N:49]([CH3:53])[CH2:50][CH2:51][NH2:52].[C:54](=[O:57])([O-])[O-].[K+].[K+].CS(C)=O>O>[CH3:48][N:49]([CH3:53])[CH2:50][CH2:51][NH:52][CH2:36][CH2:35][N:6]1[C:5]2[CH:4]=[CH:3][C:2]([NH:52][CH2:51][CH2:50][NH:49][CH2:48][CH2:54][OH:57])=[C:10]3[C:11](=[O:34])[C:12]4[C:17]([C:8]([C:9]=23)=[N:7]1)=[C:16]([OH:18])[CH:15]=[CH:14][C:13]=4[OH:26]
Reactant: Cc1ccc(S(=O)(=O)OCCn2nc3c4c(c(Cl)ccc42)C(=O)c2c(OCc4ccccc4)ccc(OCc4ccccc4)c2-3)cc1
Reactant: CN(C)CCN
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCNCCn1nc2c3c(c(NCCNCCO)ccc31)C(=O)c1c(O)ccc(O)c1-2
Temperature: 50 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
A mixture of 4.2 g (6.3 mmol) of 5-chloro-2-[2-[[(4-methylphenyl)sulfonyl]oxy]ethyl]-7,10-bis(phenylmethoxy)anthra[1,9-cd]pyrazol-6(2H)-one, 5.3 g (60 mmol) of N,N-dimethylethylenediamine, 17 g (12.6 mmol) of powdered potassium carbonate, and 35 ml of dimethylsulfoxide is stirred overnight at 50° C. The mixture is cooled and diluted with 50 ml of water. The solid is collected and washed with water. The solid is heated in dichloromethane, the solution filtered, then concentrated. Trituration of the residue with hot ethyl acetate gives 1.7 g of the dried product; mp 148°-153° C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[C:26]2[C:25](=[O:27])[C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[CH2:22][O:21][C:20]=2[CH:19]=[CH:18][CH:17]=1>CC(N(C)C)=O.C(OCC)(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4]([NH:15][C:16]1[C:26]2[C:25](=[O:27])[C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[CH2:22][O:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)=[O:5]
Reactant: Nc1cccc2c1C(=O)c1ccccc1CO2
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(O)(C(=O)Nc1cccc2c1C(=O)c1ccccc1CO2)C(F)(F)F
Temperature: -10 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
In dimethylacetamide (3 ml) was dissolved 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (0.17 g, 1.1 mmol), and thionyl chloride (80 μl, 1.1 mmol) was added thereto at -15° C., followed by stirring at -15 to -5° C. for one hour. To this reaction mixture was added 1-amino-6,11-dihydrodibenz[b,e]oxepin-11-one obtained in Reference Example 4 (0.17 g, 0.77 mmol), and the mixture was stirred overnight at room temperature. After concentration of the reaction mixture under reduced pressure, the obtained oily residue was dissolved in ethyl acetate (20 ml). The organic layer was washed successively with a 5% aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), followed by trituration with hexane to give Compound 1 (80 mg, 30%).
Reaction SMILES: [CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[N:14](C(OC(C)(C)C)=O)C=1C(OC)=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6]C=1)=O.FC(F)(F)C(O)=[O:36].[C:40]([O:43][CH2:44]C)(=[O:42])[CH3:41]>C(Cl)Cl>[CH2:10]([NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[NH:14][C:41]=1[C:40]([O:43][CH3:44])=[O:42])[C:1]([C:2]1[CH:4]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:36]
Reactant: CCOC(C)=O
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1c(NCCC(=O)c2ccccc2)c2ccc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCC(=O)c1ccccc1

Procedure:
Dissolve 3-[(phenacyl)methylamino]-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole from above in methylene chloride (3 mL). Add trifluoracetic acid (1 mL) and stir for 2 hours. Dilute into ethyl acetate and rinse with saturated sodium bicarbonate. Dry the organic phase over magnesium sulfate, filter and concentrate in vacuo to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(OC1C=C[C:25]([N+:28]([O-])=O)=CC=1)=O.N.[O:32]1CCOCC1>>[C:16]([C:10]1([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14][N:13]([C:25]([NH2:28])=[O:32])[CH2:12][CH2:11]1)#[N:17]
Reactant: C1COCCO1
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: N
Product: N#CC1(c2ccc([N+](=O)[O-])cc2)CCN(C(N)=O)CC1

Procedure:
The title compound is prepared from 4-(4-nitro-phenyl)-piperidine-4-carbonitrile (as prepared in Example 77, step (a)) using 4-nitro-phenyl chloroformate and ammonia in 1,4-dioxane according to the procedure in QSAR & Combinatorial Science, 23(10), 854-858 (2004).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[N+]([O-])(O)=O.[O:17]([CH2:21][CH2:22][NH2:23])[N+:18]([O-:20])=[O:19].C(OC(C)C)(C)C>>[O:17]([CH2:21][CH2:22][NH:23][C:6](=[O:8])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1])[N+:18]([O-:20])=[O:19]
Reactant: O=C(O)COc1ccccc1Cl
Reactant: NCCO[N+](=O)[O-]
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: O=C(COc1ccccc1Cl)NCCO[N+](=O)[O-]
Yield: 31.8 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.79 g of 2-chlorophenoxyacetic acid and 0.6 g of 2-nitroxyethylamine nitrate, 0.31 g of the title compound was obtained as colorless acicular prisms (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: S([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(O)(=O)=O.[OH-:14].[Na+]>>[OH:14][C:13]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccccc1S(=O)(=O)O
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)c1cccc(O)c1

Procedure:
The sulphobenzoic acid melt is pumped or injected under pressure, for example into previously taken molten 60 to 90% strength sodium hydroxide solution, in the course of which, merely by utilizing the heat thus liberated, the reaction temperature of, for example, 260° to 370° C. is reached, which is advantageous for the subsequent reaction to give 3-hydroxybenzoic acid. If it is intended to achieve, in this process variant, a limitation of the simultaneous increase in pressure, this can be effected by blowing off steam.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH2:16][CH2:15][C:14]=1[CH2:20][NH2:21].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:21][CH2:20][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=2[Cl:12])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: NCC1=C(Cl)C(Cl)=CCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)nc1NCc1cccc(Cl)c1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (3.86 g, 20 mmol), (2,3-dichlorocyclohexa-1,3-dienyl)methanamine (3.52 g, 20 mmol) and K2CO3 (4.14 g, 30 mmol) in DMF (100 mL) was stirred at 80° C. for 3 h. It was cooled to room temperature and poured into water (500 mL). It was extracted with EtOAc (300 mL×2). The combined organic layers were washed with brine (300 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with EtOAc/Pet Ether=1/6 to afford the desired product as a yellow solid (3.37 g, 51%); LC/MS: MS (ES+) m/e 332 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 4.82 (d, J=5.7 Hz, 2H), 6.84 (dd, J=0.9, 6.6 Hz, 1H), 7.28-7.34 (m, 2H), 7.55 (dd, J=2.1, 6.6 Hz, 1H), 8.48 (dd, J=0.9, 6.6 Hz, 1H), 9.22 (t, J=5.7 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](/[C:5](=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1)/[CH2:6][C:7]([OH:9])=O)=[O:4].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:33]1[C@@H:41]2[C@@H:36]([CH2:37][CH:38]=[CH:39][CH2:40]2)[CH2:35][NH:34]1>O1CCCC1>[CH3:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)/[CH:10]=[C:5](\[CH2:6][C:7]([N:34]1[CH2:35][C@H:36]2[C@H:41]([CH2:40][CH:39]=[CH:38][CH2:37]2)[CH2:33]1)=[O:9])/[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)/C(=C/c1cccc(C)c1)CC(=O)O
Reactant: C1=CC[C@H]2CNC[C@H]2C1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cccc(C)c1)CC(=O)N1C[C@H]2CC=CC[C@H]2C1
Temperature: -20 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
To a solution of (E)-3-methoxycarbonyl-4-(3-methylphenyl)-3-butenoic acid (1.05 g) in anhydrous tetrahydrofuran (20 ml) were added N-methylmorpholine (0.74 ml) and isobutyl chloroformate (0.75 ml) with stirring at -20° C. and the mixture was stirred for 20 minutes. To the mixture was added a solution of cis-3a,4,7,7a-tetrahydroisoindoline (773 mg) in anhydrous tetrahydrofuran (2 ml) with stirring at -20° C. After 1 hour, the deposit was filtered off and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 1N hydrochloric acid, saturated sodium bicarbonate solution, and brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (4/1) to give 446 mg of methyl (E)-2-(3-methylbenzylidene)-3-(cis-3a,4,7,7a-tetrahydro-2-isoindolinylcarbonyl)propionate as a colorless viscous oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.Br[CH2:26][CH2:27][CH2:28][C:29]([CH3:34])([CH3:33])[C:30](Cl)=[O:31].[Na+].[Cl-]>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([N:15]2[CH2:26][CH2:27][CH2:28][C:29]([CH3:34])([CH3:33])[C:30]2=[O:31])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Reactant: CC(C)(CCCBr)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)CCCN(C2c3cc4nonc4cc3OC(C)(C)C2O)C1=O
Temperature: 25 °C
Yield: 41 %

Procedure:
To 289 mg of (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole dissolved in 5 mL of ethyl acetate were added 149 mg of triethylamine. The mixture was dropwise added with 308 mg of 5-bromo-2,2-dimethylvaleryl chloride, followed by stirring at the room temperature for one and half hours. The mixture was added with 10 mL of saturated aqueous NaCl solution and twice extracted with ethyl acetate (each 20 mL). After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in 33 mL of dimethylformamide and was dropped with 1.24 g of 10% tetramethylammonium hydroxide solution under ice-cooling over 15-minute period. After the mixture was reacted under ice-cooling for one hour, the solvent was distilled off under reduced pressure and added with 10 mL of saturated aqueous NaCl solution and extracted twice with chloroform (each 20 mL). After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography (ethyl acetate:n-hexane=1:1, Rf=0.5) to obtain 174 mg of the intended compound as fine yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([C:17]2C=C[CH:20]=[CH:19][C:18]=2OC)[N:3]=1.O.[NH2:26][NH2:27].O1[CH2:33][CH2:32][O:31][CH2:30]C1>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:26][NH:27]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:33][C:32]=2[O:31][CH3:30])[N:3]=1
Reactant: C1COCCO1
Reactant: COc1ccccc1-c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: O
Product: COc1ccccc1-c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To the mixture of 4-{2-Amino-6-[2-(methyloxy)phenyl]-4-pyrimidinyl}-2-fluorobenzonitrile (306 mg) in 1,4-dioxane (30 mL) was added hydrazine monohydrate (2.5 mL), and the mixture was stirred overnight at 95° C. The reaction mixture was cooled to room temperature and filtered to remove some black solid (seemed to be Pd particle). Additional hydrazine monohydrate (1 mL) was added, and the resulting mixture was stirred for another 24 hours at 95° C. The solvent was evaporated, and the resulting residue was purified by RPHPLC (CH3CN/H2O w/0.1% NH4HCO3) to afford the title compound (43 mg) as a yellow solid. LC-MS (ES) m/z=333 [M+H]+. 1HNMR (400 MHz, DMSO-d6): δ 3.88 (s, 3H), 5.42 (s, 2H), 6.66 (s, 2H), 7.08 (m, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.46 (m, 1H), 7.58 (m, 2H), 7.78 (m, 2H), 7.98 (s, 1H), 11.60 (s, 1H).