Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:9]([NH2:10])=[CH:8][N:7]=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[N:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C1C(C(O)=O)=CN=C(C2C=CC(C(F)(F)F)=CC=2)N=1.[C:44]([O:48][C:49](=[O:64])[C:50]([O:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][C:61](O)=[O:62])[CH:55]=1)([CH3:52])[CH3:51])([CH3:47])([CH3:46])[CH3:45].COC(=O)CC1C=CC=C(O)C=1.BrC(C)(C)C(OC(C)(C)C)=O>>[C:44]([O:48][C:49](=[O:64])[C:50]([O:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][C:61](=[O:62])[NH:10][C:9]2[C:4]([CH:1]3[CH2:2][CH2:3]3)=[N:5][C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=3)=[N:7][CH:8]=2)[CH:55]=1)([CH3:52])[CH3:51])([CH3:46])([CH3:45])[CH3:47]
Reactant: Nc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CC(=O)O)c1
Agent: CC(C)(C)OC(=O)C(C)(C)Br
Agent: COC(=O)Cc1cccc(O)c1
Agent: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C(F)(F)F
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CC(=O)Nc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c1

Procedure:
In analogy to the procedures described in example 26B] and 124C], 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylamine (prepared from 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid, see example 133], in analogy to the procedures described in examples 125B] and 125C]) was reacted with 2-(3-carboxymethyl-phenoxy)-2-methyl-propionic acid tert-butyl ester (prepared from (3-hydroxy-phenyl)-acetic acid methyl ester and tert-butyl alpha-bromoisobutyrate, in analogy to the procedure described in example 52A], followed by saponification in analogy the procedure described in example 124A]) to give 2-(3-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylcarbamoyl]-methyl}-phenoxy)-2-methyl-propionic acid tert-butyl ester, which was subsequently cleaved with trifluoroacetic acid to yield the title compound as light yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[N:10]=[C:9]2I.C([Mg]Cl)(C)C.[CH2:25]([Sn:29]([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:31][CH2:32][CH2:33][CH3:34])Cl)[CH2:26][CH2:27][CH3:28]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[N:10]=[C:9]2[Sn:29]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: Cn1nc(I)c2cc(Oc3cccc(Cl)c3)ccc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(Oc3cccc(Cl)c3)cc12
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
5-(3-Chlorophenoxy)-3-iodo-1-methyl-1H-indazole (0.154 g, 400 μmol) was dissolved in THF (3.00 mL). The colorless solution was cooled to −16° C. (NaCl/ice bath) then isopropylmagnesium chloride (2M in THF, 224 μL, 448 μmol) was added dropwise at −16° C. The reaction mixture was stirred at −16° C. for 20 min then tributylchlorostannane (150 mg, 125 μL, 460 μmol) was added slowly. The reaction mixture was warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with dichloromethane, and the combined organics dried over MgSO4 and concentrated to a yellow oil. The residue was dried under high vacuum to give 5-(3-chlorophenoxy)-1-methyl-3-(tributylstannyl)-1H-indazole. The mass of this material was greater than the theoretical yield of the desired product. The yield was assumed to be quantitative, and the material was used directly in the next step without further purification.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Na].[H-].[Na+].[CH:18]([O:20][CH2:21][CH2:22]Cl)=[CH2:19].CS(C)=[O:26]>O>[O:20]1[CH2:21][CH2:22][C:13]2([C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:6][C:5]3[C:14]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:19][C:18]1=[O:26]
Reactant: c1ccc2c(c1)Cc1ccccc1O2
Reactant: C=COCCCl
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: O=C1CC2(CCO1)c1ccccc1Oc1ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of xanthene (18.2 g.) in dimethyl sulphoxide (150 ml.) is added dropwise over 20 minutes at room temperature to a solution of sodium methylsulphinylmethide [prepared in the usual way from sodium hydride (12 g. of a 60% dispersion in mineral oil) and dimethyl sulphoxide (150 ml.)] with stirring in an atmosphere of nitrogen. The blood-red mixture is stirred at room temperature for a further 30 minutes, cooled to 10° C., and 2-chloroethyl vinyl ether (21.3 g.) is then added dropwise during 30 minutes. Water (750 ml.) is added to the now colourless mixture, and the mixture is extracted three times with ether. The combined ether extracts are dried over MgSO4 and evaporated to dryness. The residue of 9,9-bis(2'-vinyloxyethyl)xanthene (28.0 g.) is dissolved in acetone (150 ml.) and treated with excess Jones reagent (chromic acid in acetone) at 10° C. Methanol is then added, and the solvent is evaporated. To the residue water is added, and the mixture is extracted three times with ethyl acetate. The combined extracts are washed with saturated sodium hydrogen carbonate solution, then with water, dried over MgSO4 and evaporated to dryness. The solid residue is recrystallised from ethanol to give xanthene-9-spiro-4'-tetrahydropyran-2'-one, m.p. 156°-159° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[CH3:17])(=O)=O.[Br-:18].[Li+]>CC(C)=O>[Br:18][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[CH3:17]
Reactant: [Br-]
Reactant: Cc1ccc([N+](=O)[O-])cc1CCOS(C)(=O)=O
Agent: [Li+]
Solvent: CC(C)=O
Product: Cc1ccc([N+](=O)[O-])cc1CCBr
Yield: 98.3 %

Procedure:
A mixture of 2-(2-methanesulfonyloxyethyl)-1-methyl-4-nitrobenzene (4.0 g) and lithium bromide (6.6 g) in acetone (250 mL) was boiled under reflux for 3½ h. The resulting mixture was cooled and filtered. The residue was purified by flash chromatography on silicagel (eluent:ethyl acetate/heptane 1:2) to give the title compound (3.7 g). 1H NMR (DMSO-d6): 2.45 (s, 3H); 3.25 (t, 2H); 3.80 (t, 2H); 7.50 (d, 1H); 8.05 (dd, 1H); 8.15 (d, 1H).
Reaction SMILES: C(O)[C:2](N)([CH2:5][OH:6])CO.[Mg+2].[Cl-].[Cl-].SC[C@H]([C@@H](CS)O)[OH:15].P(O[CH2:33][C@H:34]1O[C@@H:37]([N:39]2C3N=CN=C(N)C=3N=C2)[C@H:36](O)[C@@H:35]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O>O>[C:5]([OH:6])(=[O:15])[C:2]1[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH2:39]
Reactant: NC(CO)(CO)CO
Reactant: O[C@H](CS)[C@H](O)CS
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Product: Nc1ccccc1C(=O)O
Temperature: 65 °C

Procedure:
10 units of restriction enzyme SalI (product of Takara Shuzo Co.) was added to 200 μl of the SalI reaction solution containing 3 μg of pCE53 plasmid DNA prepared as above and 9 μg of the chromosomal DNA. The mixture was allowed to react to 37° C. for 60 minutes and heated at 65° C. for 10 minutes to stop the reaction. Then, 40 μl of the T4 ligase buffer (pH 7.6) consisting of 660 mM Tris, 66 mM MgCl2 and 100 mM dithiothreitol, 40 μl of 5 mM ATP, 0.4 μl of T4 ligase (product of Takara Shuzo Co., 1 unit/μl) and 120 μl of H2O were added to the digest. The mixture was allowed to react at 12° C. for 16 hours.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[N:8]=1)=O.[C:22]1([NH:32]N)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>>[OH:20][C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:32]([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: NNc1cccc2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(O)c2)ccc1=O
Product: O=c1ccn(-c2cccc(O)c2)nc1-c1ccnn1-c1cccc2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-hydroxyphenyl)-1H-pyridazin-4-one (A-17) and naphthalen-1-yl-hydrazine according to the method described for example 91. MS: M=381.1 (M+H)+
Reaction SMILES: [C:1](=[O:22])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]>CN(C=O)C>[ClH:32].[ClH:32].[ClH:32].[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[CH2:45][CH2:44][N:43]([C:1]([O:2][CH2:3][CH2:4][N:5]3[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]3)=[O:22])[CH2:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: CN1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(CCOC(=O)N2CCN(c3ccc(Cl)c(Cl)c3)CC2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.8 %

Procedure:
2-(4-Methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (Intermediate 4; 680 mg, 2.2 mmol) was dissolved in DMF (20 mL). DIPEA (0.76 mL, 4.4 mmol) and 4-(3,4-dichlorophenyl)piperazine (508 mg, 2.2 mmol) were added and the reaction mixture was stirred at room temperature for 24 hours, and the reaction mixture was then concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 400:8:1 mixture of DCM:EtOH:NH3, followed by a 200:8:1 mixture of DCM:EtOH:NH3) followed by reverse phase column chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-100%). The residue was dissolved in DCM (10 mL) and 2M HCl in Et2O (3 mL) was added. The reaction mixture was then concentrated in vacuo to give 2-(4-methylpiperazin-1-yl)ethyl 4-(3,4-dichlorophenyl)piperazine-1-carboxylate trihydrochloride (182 mg, 17%) as a white solid.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][C@@H:7]([CH:9]2[CH2:11][N@@:10]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[O:6][C:5]1=[O:24])([CH3:3])[CH3:2].[CH3:25][C:26]1([CH3:41])[CH2:31][N:30]([C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[CH3:39])[C:29](=[O:40])[CH2:28][NH:27]1>C1(C)C=CC=CC=1>[CH3:25][C:26]1([CH3:41])[CH2:31][N:30]([C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[CH3:39])[C:29](=[O:40])[CH2:28][N:27]1[CH2:11][C@H:9]([NH:10][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[C@@H:7]1[CH2:8][C@@H:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:24])[O:6]1
Reactant: CC(C)[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reactant: Cc1ccc(F)cc1N1CC(C)(C)NCC1=O
Agent: CC(C)[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)CC1=O
Yield: 100.3 %

Procedure:
A solution of 863 mg of (3S,5S)-3-isopropyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]dihydrofuran-2-one obtained in Example (1g) (2.43 mmol) and 805 mg of 5,5-dimethyl-1-(5-fluoro-2-methylphenyl)piperazin-2-one obtained in Example (70d) (3.40 mmol) in toluene (30 ml) was stirred at 110° C. for two hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=5/1-3/1) to obtain 1.44 g of the title compound (yield: 99%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([OH:30])=[C:24]([O:31][CH3:32])[CH:23]=1>>[OH:30][C:25]1[C:24]([O:31][CH3:32])=[CH:23][C:22]([CH2:21][CH2:20][NH:19][C:2]2[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:27][C:26]=1[O:28][CH3:29]
Reactant: COc1cc(CCN)cc(OC)c1O
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: COc1cc(CCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)C)C2=O)cc(OC)c1O

Procedure:
The title compound was prepared from 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-(2-aminoethyl)-2,6-dimethoxyphenol in a similar manner as described for Example 118. 1H NMR (THF-d8, 500 MHz): δ 1.53 (d, 6H), 2.45 (t, 2H), 3.11 (q, 2H), 3.73 (s, 6H), 4.31-4.39 (m, 1H), 6.03 (s, 2H), 6.47 (t, 1H), 7.22 (s, 1H), 7.46-7.50 (m, 3H), 7.55-7.57 (m, 2H); 13C NMR (125 MHz, THF-d8): δ 19.57, 35.92, 45.47, 46.98, 55.93, 106.13, 106.56, 126.64, 127.87, 128.56, 129.34, 131.86, 135.49, 135.64, 148.12, 158.61; Mass Spectrum: M+H+ 447.
Reaction SMILES: Cl.[C:2]1([C:8]2[S:12][C:11]3=[N:13][C:14]([NH:16][C:17]([C@@H:19]4[CH2:24][O:23][CH2:22][CH2:21][NH:20]4)=[O:18])=[CH:15][N:10]3[CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][C:26]([O:29][C:30]([NH:32][C@@H:33]([C:40](O)=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])([CH3:28])[CH3:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:26]([O:29][C:30](=[O:31])[NH:32][C@@H:33]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:40](=[O:41])[N:20]1[CH2:21][CH2:22][O:23][CH2:24][C@@H:19]1[C:17](=[O:18])[NH:16][C:14]1[N:13]=[C:11]2[N:10]([CH:15]=1)[CH:9]=[C:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[S:12]2)([CH3:28])([CH3:25])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: O=C(Nc1cn2cc(-c3ccccc3)sc2n1)[C@@H]1COCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCOC[C@@H]1C(=O)Nc1cn2cc(-c3ccccc3)sc2n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
Compound 16 (0.063 mmol), Boc-D-α-phenylglycine (0.126 mmol), and BOP (0.126) were added to dichloromethane (1.9 mL). Triethylamine (3.15 mmol) was added dropwise and the reaction mixture was stirred at room temperature overnight. The mixture was diluted in dichloromethane, washed sequentially with saturated solution of NaHCO3, water, and brine. The organic layers were gathered, dried, filtered, and concentrated under reduced pressure. The residue was purified by semi-preparative HPLC to give compound A22 as a white solid in 6% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.41 (s, 2H), 1.44 (s, 7H), 1.83-2.09 (m, 1H), 2.64-3.90 (m, 4H), 4.33-4.68 (m, 1H), 5.19-6.09 (m, 2H), 7.29-7.45 (m, 9H), 7.50-7.582 (m, 2H), 7.60-7.64 (m, 1H); MS (ESI, EI+) m/z=562.29 (MH+).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[C:10](=[CH:13][N:14]([CH3:16])C)[NH:9][C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[C:19]([CH3:22])([O-])[CH3:20].[K+].[C:24](O)(=O)[CH3:25]>CN(C)C=O.O1CCCC1>[C:1]1([N:7]2[C:11](=[O:12])[C:10]3=[CH:13][NH:14][C:16]4[CH2:24][CH2:25][CH2:20][CH2:19][C:22]=4[N:9]3[C:8]2=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)[O-]
Reactant: CN(C)C=C1NC(=O)N(c2ccccc2)C1=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=c1c2c[nH]c3c(n-2c(=O)n1-c1ccccc1)CCCC3
Reaction time: 0.5 h

Procedure:
To a solution of 3-Phenyl-5-(dimethylaminomethylene)-imidazoline-2,4-dione (1.3 g) in dimethylformamide (20 mL) at 0° C. was added 1M potassium tert-butoxide (5 mL ) in tetrahydrofuran. After 5 min 2-Chlorocycloxeanone (700 mg) was added and the mixture was stirred for 30 min. Acetic acid (1 mL) was added and the solvent was removed at reduced pressure. To the resulting residue was added ammonium acetate (10 gm) and acetic acid (25 ml) and the mixture was heated to reflux for 4 h. The solvent was removed at reduced pressure and water (50 mL) was added. The resulting solid was collected, washed with methanol and dried to yield 2-Phenyl-6,7,8,9-tetrahydro-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (Compound 21) as an off white solid, m.p. 236°-240° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=1)[C:10]([CH3:32])([CH3:31])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[C:23]([NH:22][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:32])([CH3:31])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)c3ccccc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)c2ccccc2)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 53.6 %

Procedure:
A mixture of 2-(3-benzoylamino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (984 mg, 2.3 mmol) in methanol (15 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 50° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(3-benzoylamino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (494 mg, 44%) as a white solid: LC/MS m/e calcd for C25H24N2O3 (M+H)+: 401.48, observed: 401.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1>CN(C)C=O.CCN(CN(CC)CC)CC.C(Cl)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:12][N:11]([CH2:5][CH3:4])[CH2:10][CH3:9])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: CCN(CC)CN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CCN(CC)CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 1, a solution of 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide, N,N,N',N'-tetraethyldiaminomethane and acetyl chloride (in 0.25 molar excess compared to the N,N,N',N'-tetraethyldiaminomethane) are reacted together to give 8-chloro-1-[2-(diethylamino)ethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5](O)=O.[CH3:14][NH:15][NH2:16].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:14][N:15]([C:5](=[S:26])[C:4]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:3]=1[O:2][CH3:1])[NH2:16]
Reactant: COc1ccc(OC)c(C(=O)O)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(OC)c(C(=S)N(C)N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.8 %

Procedure:
Preparation of 2.5-Dimethoxythiobenzoic acid N-methylhydrazine DCC (4.5 g, 21.8 mmol) was added in one portion to a solution of 2,5-dimethoxybenzoic acid (3.6 g, 20 mol), methylhydrazine (1.2 ml, 23 mmol) and DMAP (30 mg, cat. ) in CH2Cl2 (60 ml) cooled in an ice bath. The reaction mixture was stirred overnight at room temperature. The slurry was cooled at −20° C. for 1 h and filtered. The CH2Cl2 solution was evaporated and the residue was dried in vacuum. The resulting crude product was dissolved in toluene (50 ml). To this solution was added Lawesson's reagent (5.8 g, 14 mmol). The mixture was refluxed for 40 min, cooled to room temperature, and directly subjected to silica gel column chromatography (eluent: 25% to 35% ethyl acetate in hexanes) to give the 2,5-dimethoxythiobenzoic acid N-methylhydrazide (3.7 g, yield: 82%) as off-white solid. 1H NMR (300 MHz, CDCl3): δ 6.88-6.80(m, 3H), 5.46 (s, 2H), 3.84(s, 3H), 3.82 (s, 3H), 3.28(s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([OH:23])[N:14]([C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:24]>CO>[NH2:24][C:2]1[C:11]2[N:12]=[C:13]([OH:23])[N:14]([C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: C[C@@H](c1ccccc1)n1c(O)nc2c(Cl)nc3ccccc3c21
Reactant: N
Solvent: CO
Product: C[C@@H](c1ccccc1)n1c(O)nc2c(N)nc3ccccc3c21
Temperature: 135 °C

Procedure:
4-Chloro-1-[(1S)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-ol (4.0 g, 12 mmol) and ammonia (65 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 135° C. over two nights. The volatiles were removed under reduced pressure. The crude product was purified twice by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.2:3.8:96). The chromatographed product was washed with acetonitrile and diethyl ether several times and dried in a vacuum oven to provide 260 mg of 4-amino-1-[(1S)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-ol as an off-white solid, mp 292-295° C.
Reaction SMILES: ClC(Cl)([O:4][C:5](=O)[O:6]C(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2([C:34]([F:37])([F:36])[F:35])[O:25][N:24]=[C:23]([C:26]3[CH:27]=[CH:28][C:29]([Cl:33])=[C:30]([CH:32]=3)[NH2:31])[CH2:22]2)[CH:17]=[C:18]([Cl:20])[CH:19]=1.O1CCCC1.[C:43]1([CH3:49])[CH:48]=CC=C[CH:44]=1>>[Cl:33][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH2:22][C:21]([C:16]3[CH:17]=[C:18]([Cl:20])[CH:19]=[C:14]([Cl:13])[CH:15]=3)([C:34]([F:36])([F:35])[F:37])[O:25][N:24]=2)=[CH:32][C:30]=1[NH:31][C:5](=[O:4])[O:6][C:43]([CH3:49])([CH3:48])[CH3:44]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccccc1
Reactant: Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Triphosgene (6.3 g) was dissolved in toluene (50 mL), and thereto was added dropwise a solution of 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-chloroaniline (8.7 g) obtained by Reference Production Example 20 in toluene (50 mL) and tetrahydrofuran (10 mL) at room temperature. To the reaction solution was added toluene (50 mL), and the mixture was stirred at 80° C. for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and thereto was added tert-butanol (100 mL). To this solution was added dropwise triethylamine (14.6 g) at room temperature, and the mixture was stirred at the same temperature for 16 hours. To the reaction mixture was added an aqueous saturated sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain tert-butyl {2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}carbamate (9.81 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.[F:19][C:20]([F:30])([F:29])[C:21](=O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[F:19][C:20]([F:29])([F:30])[C:21]1[NH:13][C:14]2=[N:15][NH:16][CH:17]=[C:18]2[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:2]([F:12])([F:11])[F:1])[C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Product: CCOC(=O)C1=C(C(F)(F)F)Nc2n[nH]cc2C1c1ccccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.