Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:30]=[N:31][N:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[CH:33]=1.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:28][C:29]3[CH:30]=[N:31][N:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])[CH:33]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccccc1-n1cc(CBr)cn1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: O=c1n(Cc2cnn(-c3ccccc3Cl)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 65 °C
Reaction time: 2 h

Procedure:
27 mg (0.09 mmol) of the compound from Example 5A were dissolved in 2 ml of acetonitrile, and 58 mg (0.18 mmol) of cesium carbonate and 24 mg (0.09 mmol) of the compound from Example 43A were added. The mixture was stirred at 65° C. for 2 h and then at RT for 20 h. For work-up, 5 ml of water were added and the mixture was extracted twice with in each case 10 ml of ethyl acetate. The organic phase was washed once with 5 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 25 mg (56% of theory) of the target compound.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([C:12]2[C:13]([Cl:27])=[CH:14][C:15]([Cl:26])=[C:16]([S:18][CH:19]([CH3:25])[C:20]([O:22]CC)=[O:21])[CH:17]=2)=[N:6][N:7]([CH3:11])[C:8]=1[S:9][CH3:10]>C(O)C.O>[Cl:3][C:4]1[C:5]([C:12]2[C:13]([Cl:27])=[CH:14][C:15]([Cl:26])=[C:16]([S:18][CH:19]([CH3:25])[C:20]([OH:22])=[O:21])[CH:17]=2)=[N:6][N:7]([CH3:11])[C:8]=1[S:9][CH3:10]
Reactant: CCOC(=O)C(C)Sc1cc(-c2nn(C)c(SC)c2Cl)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1c(Cl)c(-c2cc(SC(C)C(=O)O)c(Cl)cc2Cl)nn1C
Yield: 81.6 %

Procedure:
After addition of NaOH (0.31 g, in pellet form, 95% content) to a solution of ethyl 2-[5-(4-chloro-1-methyl-5-methylthio-1H-pyrazol-3-yl)-2,4-dichlorophenylthio]propionate (2.28 g, 5.18 mmoles) in 50 ml ethanol, several drops of water added, thereby conducting the reaction for 3 hours at room temperature. Then the solvent was removed by evaporation of the resulting solution under reduced pressure. Water and ethyl acetate were added to the residue and the formed aqueous layer was separated. The aqueous layer was acidified with hydrochloric acid. The objective product was extracted from the aqueous layer with ethyl acetate. The extract solution was washed with water, dehydrated, and evaporated to dryness, giving crystals (1.74 g) of the title compound, m.p. 180.0° C., yield 81.6%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:20]([O:21][CH3:22])=[CH:19][C:12]2[NH:13][C:14](=[O:18])[CH2:15][CH2:16][CH2:17][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)C1C=CC=CC=1>CN(C=O)C.O>[CH2:25]([N:13]1[C:14](=[O:18])[CH2:15][CH2:16][CH2:17][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:20]([O:21][CH3:22])=[CH:19][C:12]1=2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2c(cc1OCc1ccccc1)CCCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCc1ccccc1
Product: COc1cc2c(cc1OCc1ccccc1)CCCC(=O)N2Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 7-benzyloxy-8-methoxy-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (297 mg, 1.0 mmol) and NaH (80 mg, 2 mmol) was stirred in DMF (5 mL) for 10 minute at rt and the appropriate benzyl bromide or benzyl chloride (1.1 mmol) added. The mixture was stirred o/n at rt. After addition of water the organics extracted with ethyl acetate, washed with water, brine, dried (MgSO4), filtered and concentrated. The crude yellow oil was purified by flash chromatography (hexane/EtOAc 1:0 to 1:1) and the resultant solid stirred in Et2O, filtered and dried under vacuum.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.O(CC)CC.C([Li])CCC.[N:16]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:26]([C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[N:16]=[CH:17][CH:18]=[CH:19]2)[OH:27]
Reactant: c1ccsc1
Reactant: O=Cc1ccc2ncccc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccc2ncccc2c1)c1cccs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
To a stirred and cooled (-5°/0° C.) solution of 5.4 parts of thiophene in 21.3 parts of 1,1'-oxybisethane were added portionwise 43.5 parts of a solution of n. butyllithium in hexanes 1.6M. After stirring for 20 min. at 0° C., there was added a solution of 5 parts of intermediate 16, namely 6-quinolinecarboxaldehyde, in 71.2 parts of tetrahydrofuran. Stirring at 0° C. was continued for 1 hour and then the reaction mixture was poured into 200 parts of ice-water. The product was extracted with 1,1'-oxybisethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 95:5). The eluent of the desired fraction was evaporated, yielding 2.4 parts (31.1%) of α-(2-thienyl)-6-quinolinemethanol (interm. 17).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][NH2:9])[CH:3]=1.[CH:10](O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:10]=[N:9][N:8]=[C:4]2[CH:3]=1
Reactant: NNc1cc(Br)ccn1
Reactant: O=CO
Product: Brc1ccn2cnnc2c1
Temperature: 100 °C
Yield: 90 %

Procedure:
4-Bromo-2-hydrazinylpyridine (compound 41.1) was suspended in formic acid (3 mL). The mixture was heated at 100° C. for one hour, then upon complete reaction, the mixture cooled to room temperature. The volatile organics were removed under reduced pressure, then water (50 mL) was added to the residue. The solids that formed were filtered, washed with water and dried under reduced pressure at 50° C. to give 1.68 g (90%) of the title compound as an off-white solid. m/z (ES+) 198, 200 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:29][CH:28]([NH2:30])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:41](Cl)([O:43]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:17])([F:18])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:27][CH:28]([N:30]=[C:41]=[O:43])[CH2:29]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N)C3)ccc2n1CC1CCC(F)(F)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N=C=O)C3)ccc2n1CC1CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)azetidin-3-amine (125 mg, 0.29 mmol) (see Example 102 for preparation) and DIPEA (109 uL, 81 mg, 0.63 mmol) in THF (6 mL) was added to a solution of triphosgene (34 mg, 0.14 mmol) in THF (6 mL) at 0° C. The reaction mixture was stirred for 30 at 0° C. and 30 min at room temperature, then directly used for next step.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([S:14]([C:17]2[C:18]([S:34][CH3:35])=[N:19][N:20]3[C:25](Cl)=[CH:24][C:23]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([S:14]([C:17]2[C:18]([S:34][CH3:35])=[N:19][N:20]3[C:25]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:24][C:23]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CSc1nn2c(Cl)cc(CN3CCOCC3)nc2c1S(=O)(=O)c1ccccc1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CSc1nn2c(N3CCN(C)CC3)cc(CN3CCOCC3)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.6 %

Procedure:
0.4 g (4 mmol) of 1-methyl-piperazine was added to a solution of 0.9 g (2 mmol) of 3-benzenesulphonyl-7-chloro-2-methylsulphanyl-5-morpholin-4-ylmethyl-pyrazolo[1,5-a]pyrimidine in 20 ml of DMF and stirred at RT for 4 hrs. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2 and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH/NH40H 80:1:1) and crystallization from EtOH yielded 0.80 g (77%) of 3-benzenesulphonyl-7-(4-methyl-piperazin-1-yl)-2-methylsulphanyl-5-morpholin-4-ylmethyl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p.199-201°.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]2[N:22]([CH3:23])[N:21]=[N:20][N:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:4][C:3]=1[O:24][CH3:25].N#N.[CH:28]1([C:31]#[CH:32])[CH2:30][CH2:29]1.C(N(C(C)C)C(C)C)C>C1COCC1.CCOC(C)=O.[Cu](I)I.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:28]1([C:31]#[C:32][C:2]2[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]3[N:22]([CH3:23])[N:21]=[N:20][N:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][C:3]=2[O:24][CH3:25])[CH2:30][CH2:29]1
Reactant: C#CC1CC1
Reactant: COc1ccc(CON=C(c2ccccc2)c2nnnn2C)nc1Br
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CON=C(c2ccccc2)c2nnnn2C)nc1C#CC1CC1
Reaction time: 0.33 h
Yield: 57.4 %

Procedure:
To a stirred solution of N-[(6-bromo-5-methoxypyridin-2-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.150 g, 0.372 mmol, 1 eq.) in 2 ml dry THF “degassed” with N2, was added cyclopropylacetylene (0.073 g, 1.11 mmol, 3 eq.) followed by N-ethyldiisopropylamine (0.191 g, 1.48 mmol, 4 eq.), Copper Iodide (0.010 g, 0.056 mmol, 0.15 eq.) and Tetrakis(triphenylphosphine)palladium (0.042 g, 0.037 mmol, 0.1 eq.). The reaction was microwaved 120° C./normal/fixed hold/pre stir 100 s for 1200 s. The reaction was diluted with EtOAc and filtered through a “celite” plug. The solvent was evaporated and the residue purified by chromatography on silica gel to give N-{[6-(cyclopropylethynyl)-5-methoxypyridin-2-yl]methoxy}-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.083 g, 57% yield) as a yellow viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[Cl:25][C:26]1[N:27]=[N:28][C:29](Cl)=[CH:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O.O>[Cl:25][C:26]1[N:27]=[N:28][C:29]([N:23]2[CH:24]=[C:20]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([S:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)(=[O:12])=[O:13])[CH:7]=3)[CH:21]=[N:22]2)=[CH:30][CH:31]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3ccc(Cl)nn3)c2)c2ccc(F)cc21
Temperature: 100 °C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 512 mg; 1.50 mmol), 3,6-dichloropyridazine (450 mg; 3.02 mmol) and K2CO3 (828 mg; 5.99 mmol) in MeCN (15.0 mL) was stirred at 100° C. for 16 hours under nitrogen. The reaction mixture was diluted with EtOAc (30 mL) and water (10 mL). The organic layer was separated, washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by a silica gel column chromatography (petroleum ether/EtOAc=4/1 to 2/1) to afford 620 mg (91%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:8]2[C:9]([O:13][CH3:14])=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][N:5]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:23])C=1>ClCCl>[CH2:1]([NH:3][C:4]1[C:8]2[C:9]([O:13][CH3:14])=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:23])[N:5]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCNc1nsc2cccc(OC)c12
Solvent: ClCCl
Product: CCNC1=NS(=O)c2cccc(OC)c21
Reaction time: 0.5 h

Procedure:
90 mg (0.43 mmol) Ethyl-(4-Methoxy-benzo[d]isothiazol-3-yl)-amine, prepared in analogy to compound example 32, was dissolved in 10 ml dichloromethane. The solution was cooled to 0 C and 100 mg of a 70% m-chlor-perbenzoic acid was added portion wise. The cooling bath was removed and stirring was continued for 30 min at room temperature. The solution was poured into Na2CO3-solution. The layers were separated and the organic layer was washed with Na2CO3-solution and water. The organic layer was dried over NaSO4 and concentrated. The crude product was purified by reverse-phase HPLC (eluent acetonitrile/water) to yield 40 mg (0.18 mmol) of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][C:8]2=[N+:9]([O-:12])[O:10][N:11]=[C:7]2[CH:6]=1.NO.O>CO>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][C:8](=[N:9][OH:12])[C:7](=[N:11][OH:10])[CH:6]=1
Reactant: [O-][n+]1onc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc21
Agent: NO
Solvent: O
Solvent: CO
Product: ON=C1C=CC(Oc2ccc(C(F)(F)F)cc2Cl)=CC1=NO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-(2-chloro-4-trifluoromethylphenoxy)benzo-2,1,3-oxadiazole N-oxide (20.0 g, 61.0 mmol) and hydroxylamine (4.0 g, 120.00 mmol) in 50 ml of methanol is stirred at 45° for 18 hours. The reaction is cooled to RT and 10 ml of water is added. The resulting white solid which precipitates is collected and dried to give 4-(2-chloro-4-trifluoromethylphenoxy)-ortho-benzoquinone dioxime.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[C:11]2=[O:26])=[CH:6][CH:5]=1)([O-])=O.NC1C=CC=CC=1.[N+](C1C=CC(N)=CC=1)([O-])=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1.C1COCC1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:19][CH:20]=3)[C:11]2=[O:26])=[CH:6][CH:5]=1
Reactant: O=c1n(-c2ccc([N+](=O)[O-])cc2)cnn1-c1ccc(OC(F)(F)F)cc1
Agent: Nc1ccc([N+](=O)[O-])cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1ccc(-n2cnn(-c3ccc(OC(F)(F)F)cc3)c2=O)cc1

Procedure:
4-(4-Nitrophenyl)-2-(4-trifluoromethoxyphenyl)-2,4-dihydro-[1,2,4]triazol-3-one. The title compound was prepared according to the procedure in Henbach, DE 2724891 A1, 1978, with modifications to three steps: In the addition of the aniline, 4-nitroaniline was used instead of 3,5-dichloroaniline and dry THF was used as solvent instead of toluene. In the formation of the triazolinone ring, triphosgene (0.65 equiv) was used instead of phosgene: mp 136-140° C.; 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J=8.8 Hz, 2H), 8.05 (d, J=8.8 Hz, 2H), 7.99 (s, 1H), 7.89 (d, J=9.3 Hz, 2H), 7.32 (d, J=9.3 Hz, 2H); ESIMS m/z 367 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]C)=[O:17])=[C:11]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([O:20][CH2:21][C:22]([F:23])([F:24])[F:25])[CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccc(NC(=O)OC(C)(C)C)cc1OCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)c(OCC(F)(F)F)c1

Procedure:
To a stirred solution of methyl 4-(tert-butyloxycarbonyl-amino)-2-(2,2,2-trifluoroethoxy)phenylacetate (0.90 g, 2.5 mmol) in MeOH (15 mL) was added aqueous NaOH (2.5 mL of a 3 N solution, 7.5 mmol). The mixture was refluxed for 1 h. The solvents were removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and 0.25 M aqueous citric acid (25 mL). The organic phase was separated, washed with water (25 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 4-(tert-butyloxycarbonylamino)-2-(2,2,2-trifluoroethoxy)-phenylacetic acid as an amorphous solid (HPLC retention time=8.8 min (method A)).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([N+:12]([O-])=O)=[C:7]([CH3:15])[C:6]=1[Cl:16]>[Pt].C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([NH2:12])=[C:7]([CH3:15])[C:6]=1[Cl:16]
Reactant: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1Oc1ccc(-c2ccccc2)cc1Cl
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1cc(N)c(C)c(Cl)c1Oc1ccc(-c2ccccc2)cc1Cl
Yield: 84.5 %

Procedure:
A 500 milliliter rocking Parr hydrogenator was charged with a solution of 13.5 grams (0.035 moles) of 4-(2-chloro-4-phenylphenoxy)-2,5-dimethyl-3-chloro-nitrobenzene prepared in Part A and 135 milliliters of toluene. To this solution was added 1.0 gram of a catalyst of 5% platinum on carbon and the reactor was sealed. The reactor was purged twice with nitrogen and then twice with hydrogen. Hydrogen was then introduced to a pressure of 31 psi and this pressure was maintained until the hydrogen up-take ceased, i.e., about 1.5 hours. The material was removed from the rector, filtered and concentrated (toluene removed under vacuum) to give a viscous oil. Crystallization from a hexane-ethyl acetate mixture afforded 10.6 grams of a tan powder having a melting point of 117° C.-119° C. Elemental analysis of the tan powder indicated the following:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH:24]([CH2:39][CH2:40][CH2:41][C:42]1([CH3:47])[O:46][CH2:45][CH2:44][O:43]1)[CH2:25][O:26][CH:27]1[C:35](=[O:36])[CH2:34][CH2:33][C:32]2([CH3:37])[CH:28]1[CH2:29][CH2:30][C:31]2=[O:38]>ClCCl>[CH3:37][C:32]12[C:31](=[O:38])[CH2:30][CH2:29][CH:28]1[CH:27]([O:26][CH2:25][C:24](=[O:23])[CH2:39][CH2:40][CH2:41][C:42]1([CH3:47])[O:43][CH2:44][CH2:45][O:46]1)[C:35](=[O:36])[CH2:34][CH2:33]2
Reactant: CC1(CCCC(O)COC2C(=O)CCC3(C)C(=O)CCC23)OCCO1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC1(CCCC(=O)COC2C(=O)CCC3(C)C(=O)CCC23)OCCO1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Dess-Martin periodinane (10.28 g, 24.24 mmol) was added to a solution of the 4-[2-hydroxy-5-(2-methyl-[1,3]dioxolan-2-yl)-pentyloxy]-7a-methyl-hexahydro-indene-1,5-dione (7.8 g, 22.03 mmol) in dichloromethane (100 mL) at room temperature. The reaction mixture was then stirred at room temperature for 14 h. The reaction was quenched with saturated potassium bicarbonate solution (20 mL). The aqueous solution was extracted with dichloromethane (2×100 mL) and the combined organic layer was dried with magnesium sulfate. The resulting solution was filtered, concentrated and the resulting residue purified by flash chromatography using 30% ethyl acetate in hexane to yield the title compound as an oil.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:10]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:11]([C:17]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:12]([O:14]CC)=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.OS([O-])(=O)=O.[K+]>O.CO>[CH2:24]([N:10]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:11]([C:17]1([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C:12]([OH:14])=[O:13])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)C(N(Cc1ccccc1)Cc1ccccc1)C1(O)CCCCC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(N(Cc1ccccc1)Cc1ccccc1)C1(O)CCCCC1
Temperature: 60 °C

Procedure:
KOH (1.44 g, 25.6 mmol, Eq: 6) in H2O (20 mL) was added to as solution of ethyl 2-(dibenzylamino)-2-(1-hydroxycyclohexyl)acetate (1.63 g, 4.27 mmol, Eq: 1.00) in MeOH (60 mL) and the mixture was heated to 60° C. After 18 h the reaction was cooled to RT and diluted with 100 mL H2O. The pH of the reaction was adjusted to about 4 using sat. KHSO4, and extracted with EtOAc. The combined extracts were washed with H2O, dried over Na2SO4 and concentrated the title compound as a white foam (1.44 g, 95%) which was used without purification. MS m/e 354.1 (MH+).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N+:23]([C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of methyl salicylate (7.6 g, 0.05 mol), 4-chloro-3-nitrobenzotrifluoride (7.46 ml, 0.05 mol) and potassium carbonate (4.14 g, 0.03 mol) in dimethylformamide (50 ml) was stirred under argon, in an oil bath at 150° C., for three hours. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate was evaporated and the residue flash chromatographed (silica gel, ethyl acetate/hexane) to give the title compound. 1H NMR (250 MHz, CDCl3) δ8.29 (d, 1H), 8.05 (dd, 1H), 7.61 (m, 2H), 7.4 (t, 1H), 7.25 (t, 1H), 6.85 (d, 1H), 3.7 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8](SC)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)[CH:2]=[CH2:3].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[CH3:40][N:39]([CH3:41])[C:37](=[O:38])[CH2:36][N:33]1[CH2:32][CH2:31][N:30]([C:27]2[CH:28]=[CH:29][C:24]([NH:23][C:8]3[N:7]=[C:6]4[N:5]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=5)[N:4]([CH2:1][C:2]#[CH:3])[C:12](=[O:13])[C:11]4=[CH:10][N:9]=3)=[CH:25][CH:26]=2)[CH2:35][CH2:34]1
Reactant: CN(C)C(=O)CN1CCN(c2ccc(N)cc2)CC1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(C)n1
Product: C#CCn1c(=O)c2cnc(Nc3ccc(N4CCN(CC(=O)N(C)C)CC4)cc3)nc2n1-c1cccc(C)n1

Procedure:
34.3 mg of the entitled compound was obtained as a yellow solid in the same manner as in Example 113-1 to 113-2, for which, however, 2-allyl-1-(6-methylpyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one was used in place of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one used in Example 113-1, and 2-[4-(4-aminophenyl)piperazin-1-yl]-N,N-dimethylacetamide was used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.