Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:23]1([N:29]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N:31]=[C:30]2[C:38]2[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH:45]1[C:62]2[C:61]3[C:60]4[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=4[CH:54]=[CH:53][C:52]=3[CH:51]=[C:50](B(O)O)[C:49]=2[CH:48]=[CH:47][CH:46]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[C:23]1([N:29]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N:31]=[C:30]2[C:38]2[CH:43]=[C:42]([C:48]3[C:49]4[CH:50]=[CH:51][C:52]5[CH:53]=[CH:54][C:55]6[CH:56]=[CH:57][CH:58]=[CH:59][C:60]=6[C:61]=5[C:62]=4[CH:45]=[CH:46][CH:47]=3)[CH:41]=[CH:40][CH:39]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1cc2ccc3ccccc3c2c2ccccc12
Reactant: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: c1ccc(-n2c(-c3cccc(-c4cccc5c4ccc4ccc6ccccc6c45)c3)nc3ccccc32)cc1

Procedure:
913 mg (3 mmol) of tri-o-tolylphosphine and then 112 mg (0.5 mmol) of palladium(II) acetate are added to a vigorously stirred suspension of 17.5 g (50 mmol) of 1-phenyl-2-(4-bromophenyl)benzimidazole, 14.9 g (55 mmol) of benzo[c]phenanthrene-5-boronic acid and 25.5 g (120 mmol) of tripotassium phosphate in a mixture of 300 ml of toluene, 100 ml of dioxane and 400 ml of water, and the mixture is subsequently heated under reflux for 16 h. After the mixture has been cooled, the precipitated solid is filtered off with suction, washed three times with 50 ml of toluene, three times with 50 ml of ethanol:water (1:1, v:v) and three times with 100 ml of ethanol and recrystallised three times from DMF (about 7 ml/g). Yield: 16.8 g (34 mmol), 67.8%, purity 99.9% (HPLC).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([O:23]CC)=O)[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH2:29][NH:30][C:31]([NH:33][CH3:34])=[S:32]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:27][CH2:28][CH2:29][NH:30][C:31]([NH:33][CH3:34])=[S:32])=[O:23])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Reactant: CNC(=S)NCCN
Product: CNC(=S)NCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Yield: 32.2 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (10 mg, 0.028 mmol) described in example 92 and N-(2-aminoethyl)-N′-methylthiourea (48 mg, 0.364 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-N-(2-{[(methylamino)carbonothioyl]amino}ethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide(4 mg, 33% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.55 (br s, 1 H), 8.56 (s, 1 H), 7.40 (s, 1 H), 7.24-7.15 (m, 2 H), 7.05-7.00 (m, 2 H), 6.79 (br s, 1 H), 6.19 (br s, 1 H), 4.14 (s, 2 H), 3.75-3.70 (m, 4 H), 3.56 (s, 3 H), 2.95 (s, 3 H); HRMS m/z calcd for C21H23N5O3FS: 444.1506 Found: 444.1532.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:8][C:9]1[CH:21]=[CH:20][C:12]2[O:13][CH:14]([C:17](O)=[O:18])[CH2:15][O:16][C:11]=2[CH:10]=1>>[OH:8][C:9]1[CH:21]=[CH:20][C:12]2[O:13][CH:14]([C:17]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:18])[CH2:15][O:16][C:11]=2[CH:10]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)C1COc2cc(O)ccc2O1
Product: O=C(Nc1ccccc1)C1COc2cc(O)ccc2O1
Yield: 75 %

Procedure:
That compound is obtained in a yield of 75% starting frown aniline and 6-hydroxy-2,3-dihydro -1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: [CH2:1]([SH:5])[CH:2]([SH:4])[CH3:3].Cl[CH:7]([CH3:11])[C:8](=O)[CH3:9]>>[CH3:3][CH:2]1[CH2:1][S:5][C:8]([CH3:9])=[C:7]([CH3:11])[S:4]1
Reactant: CC(=O)C(C)Cl
Reactant: CC(S)CS
Product: CC1=C(C)SC(C)CS1
Yield: 36.5 %

Procedure:
The procedure of Example 1(a) is repeated, using 1,2-propanedithiol and 3-chloro-2-butanone to give 2,3-dihydro-2,5,6-trimethyl-1,4-dithiin as a clear green liquid, bp 49.5°-51°/0.7 mm, yield 36.5% NMR 1.36 (3d), 1.88 (6s), 2.4-3.6 (3m) (CDCl3). IR, 2905 (sh); 1605, 1410 (broad); 1250, 1155 (sh); 1065 (br); 730, 705.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(Br)cnc1N1CCOCC1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
To a vial containing 5-bromo-2-chloro-3-nitropyridine (0.99 g, 4.16 mmol) in DMSO (4.0 mL) was added morpholine (0.8 mL, 9.19 mmol) dropwise. The reaction was stirred at 23° C. and monitored with TLC and LC-MS. After 20 h, LC-MS showed that the reaction was complete, then the mixture was diluted with water. After extracting three times with EtOAc, the organic layers were combined then washed with brine and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated in vacuo to afford a yellow-orange solid as 4-(5-bromo-3-nitropyridin-2-yl)morpholine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (1H, d, J=2.3 Hz), 8.47 (1H, d, J=2.3 Hz), 3.70 (4H, m), 3.41 (4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[CH2:10])=[N:7][S:8][C:4]=2[CH:3]=1.[CH2:20]([NH2:23])[CH:21]=[CH2:22]>CN(C=O)C>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[CH2:10][NH:23][CH2:20][CH:21]=[CH2:22])=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: C=C(c1ccc(Cl)cc1)c1nsc2cc(Br)ccc12
Reactant: C=CCN
Solvent: CN(C)C=O
Product: C=CCNCC(c1ccc(Cl)cc1)c1nsc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 66 %

Procedure:
A mixture of 6-bromo-3-(1-(4-chlorophenyl)vinyl)benzo[d]isothiazole (600 mg, 1.71 mmol), DMF (3 mL) and allylamine (3 mL) was stirred at room temperature for 3 days. The reaction was partitioned between EtOAc and water. The organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography (DCM:MeOH, 20:1) to give N-(2-(6-bromobenzo[d]isothiazol-3-yl)-2-(4-chlorophenyl)ethyl)prop-2-en-1-amine (464 mg, 66%). 1H NMR (CDCl3, 400 MHz) δ □8.06 (d, J=1.6 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.41 (dd, J=8.8 Hz, J=1.6 Hz, 1H), 7.25 (m, 4H), 5.86 (m, 1H), 5.16 (dd, J=17.2 Hz, J=1.6 Hz, 1H), 5.08 (d, J=10.4 Hz, 1H), 4.72 (t, J=7.2 Hz, 1H), 3.62 (dd, J=12.0 Hz, J=8.0 Hz, 1H), 3.31 (m, 2H), 3.20 (dd, J=12.0 Hz, J=6.8 Hz, 1H).
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=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.C(O)C>[F:33][C:34]1[CH:39]=[C:38]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2cccc(F)c2)cc1
Temperature: 110 °C

Procedure:
Prepared according to the method described in Example 33a) from toluene (5 ml), ethanol (3 ml), aqueous sodium carbonate (2 M, 1 ml), (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.25 g), ethanol (1 ml), 3-fluorobenzeneboronic acid (0.16 g) and tetrakis(triphenylphosphine)palladium(0) (60 mg) with heating at 110° C. for 4 hours. The residue obtained after work up was purified by column chromatography over silica eluting with ethyl acetate to give the title compound after trituration with diethyl ether:hexane (1:1) as a white solid (0.13 g).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:17][C:18]1([CH3:39])[C:22]([CH3:24])([CH3:23])[O:21][B:20](C2C=CC(OC3C=CC=CC=3)=CC=2C)[O:19]1>>[C:9]1([N:6]2[C:5]3[CH:15]=[CH:16][C:2]([B:20]4[O:21][C:22]([CH3:24])([CH3:23])[C:18]([CH3:39])([CH3:17])[O:19]4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccc2c(c1)ncn2-c1ccccc1
Reactant: Cc1cc(Oc2ccccc2)ccc1B1OC(C)(C)C(C)(C)O1
Product: CC1(C)OB(c2ccc3c(c2)ncn3-c2ccccc2)OC1(C)C

Procedure:
Prepared from 5-bromo-1-phenyl-1H-benzoimidazole according to general Method I for borylation described above for preparation of 4,4,5,5-tetramethyl-2-(2-methyl-4-phenoxy-phenyl)-[1,3,2]dioxaborolane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]([C:13]([OH:15])=O)[CH2:5]2.Cl.[CH3:17][NH:18][CH3:19].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]([C:13]([N:18]([CH3:19])[CH3:17])=[O:15])[CH2:5]2
Reactant: CNC
Reactant: O=C(O)C1Cc2cc(Cl)ccc2NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C)C(=O)C1Cc2cc(Cl)ccc2NC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
6-Chloro-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxylic acid (3.00 g), dimethylamine hydrochloride (1.332 g), HOBt (2.042 g), WSC (3.093 g) and triethylamine (4.5 ml) were added to acetonitrile (150 ml). The reaction mixture was stirred at room temperature for 18 hours. 10% Aqueous citric acid solution was added to the reaction mixture. The precipitated pellets were collected by filtration and washed with water and IPE to obtain the entitled compound (1.276 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH3:14])[NH:11][CH2:10][CH:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N1[CH2:28][C@@H:27]([C:29]2C=CC=[CH:31][CH:30]=2)NC[C@@H]1C)=O)(C)(C)C>>[CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[NH:11][CH2:10][C@@H:9]1[C:15]1[CH:31]=[CH:30][CH:29]=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1CN[C@H](c2ccccc2)CN1C(=O)OC(C)(C)C
Reactant: CC1CN(Cc2ccccc2)C(C)CN1
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](c2ccccc2)CN1

Procedure:
trans-1-Benzyl-5-methyl-2-phenyl-piperazine was prepared in analogy to the preparation of benzyl-2,5-dimethyl-piperazine (see above) starting form trans-2-methyl-5-phenyl-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[N:6]=[CH:5]2.[NH2:20][C@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:20][C@H:21]4[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]4)=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: COc1ccc(Cn2ncc3cc(Br)ccc32)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2ncc3cc(N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)ccc32)cc1
Temperature: 80 °C
Yield: 83.3 %

Procedure:
To a solution of 5-bromo-1-(4-methoxybenzyl)-1H-indazole (870 mg, 2.75 mmol) in toluene (10 mL) was added in succession (S)-tert-butyl 3-aminopiperidine-1-carboxylate (660 mg, 3.3 mmol), sodium tert-butoxide (475 mg, 5 mmol), and rac-(±)-BINAP (180 mg, 0.29 mmol). The flask was evacuated and refilled with nitrogen three times, after which Pd2dba3 (83 mg, 1.5 mol %) was added. The flask was again purged with nitrogen three times, and was then heated to 80° C. overnight. The solution was cooled to room temperature and then filtered through a pad of celite, washing with additional toluene. The toluene solution was then loaded directly onto a silica gel column that had been packed with heptane. The column was flushed with 2 column volumes of heptane, and then eluted with 40/60-EtOAc/heptane to afford the title compound (1.00 g 82%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[N:8][CH:9]([CH3:13])[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].C(N(CC)CC)C.[CH2:30]([O:32][C:33](Cl)=[O:34])[CH3:31].C(Cl)(Cl)Cl>>[CH3:13][C:9]1[N:8]([C:33]([O:32][CH2:30][CH3:31])=[O:34])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([CH3:12])[N:10]=1
Reactant: CCOC(=O)C1=C(C)NC(C)N=C1c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(C)N=C(C)N(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]

Procedure:
To a solution of 5-ethoxycarbonyl-2,6-dimethyl-4-(2'-nitrophenyl)-dihydropyrimidine (756 mg, 2.49 millimole) and triethylamine (374 mg, 3.7 millimole) in 30 ml of chloroform ethyl chlorocarbonate (406 mg, 3.74 millimole) was added dropwise with stirring in ice and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with 2% aqueous NaOH solution and water, dried and evaporated to remove the solvent. The obtained oil (730 mg) was purified on silica gel by column chromatography and eluted with 1% MeOH/CHCl3 to obtain the title product as crystals. The crystals were recrystallized from acetone-n-hexane to obtain colorless prisms (m.p. 130°-131.5°, 290 mg, 31% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13].Cl>N1C=CC=CC=1>[C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:11][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)c1cc(Br)ccc1OC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
5′-bromo-2′-hydroxyacetophenone (compound 1) (863 mg, 4.65 mmol) was added to a pyridine solution (20 ml) that contained 4-nitrobenzoyl chloride (1.00 g, 4.65 mmol) in an ice bath. The obtained mixture was reacted at room temperature for 30 minutes, and the reaction solution was then poured into 1 N hydrochloric acid under cooling on ice. The obtained mixture was intensively stirred. The obtained precipitate was collected by filtration, and the filtrate was then washed with purified water, so as to obtain a product of interest, 4-nitrobenzoic acid 2-acetyl-4-bromophenyl ester (compound 2). Yield: 1.57 g (yield constant: 92.7%) 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 4H), 8.00 (s, 1H), 7.76-7.72 (m, 1H), 7.16 (d, J=8.7 Hz, 1H), 2.55 (s, 3H). MS m/z 365 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1.[Br:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>>[Br:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:3]=2)[CH:27]=1
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(Cl)n2)c1
Reactant: Brc1c[nH]cn1
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)c1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(3-trifluoromethylphenyl)-pyrimidine (example A.42) (0.65 g, 2.0 mmol) and commercially available 4-bromo-imidazole (0.44 g, 3.0 mmol) according to the general procedure IVa. Obtained as a light yellow solid (0.64 g, 73%). MS (ISP) 439.1 [(M+H)+]; mp 158.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH3:34][C@@H:35]1[CH2:40][NH:39][CH2:38][C@H:37]([CH3:41])[NH:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:39]2[CH2:38][C@H:37]([CH3:41])[NH:36][C@H:35]([CH3:34])[CH2:40]2)=[O:32])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)O)c1C)C(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)N3C[C@@H](C)N[C@@H](C)C3)c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[5-(2,6-dimethyl-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.26 mmol), (2R,6S)-2,6-dimethyl-piperazine (37 mg, 1.2 eq.), HOBt (50 mg, 1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) in DMF (0.2 M) was stirred at rt for overnight. The reaction was concentrated, diluted with DCM, washed with water, filtered and concentrated to give the titled compound.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[CH:14]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH2:13][NH:12][C:9]3=[CH:10][N:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[Na+].Cl>CO>[N:1]1([C:6]2[CH:7]=[C:8]3[C:14]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][NH:12][C:9]3=[CH:10][N:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCOC(=O)CCC1CNc2cnc(-n3cncn3)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1c[nH]c2cnc(-n3cncn3)cc12
Temperature: 50 °C
Yield: 601.6 %

Procedure:
To a solution of ethyl 3-(5-(1,2,4-triazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-3-yl)propionate (0.12 g, 0.42 mmol) in methanol (5 mL) was added NaOH (4M, 0.3 mL) and the mixture was heated at 50° C. for 4 hours. After cooling the solution was neutralised (6M, HCl) and the solvents evaporated in uacuo to give 3-(5-(1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)propionic acid (0.65 g) as a yellow solid. This was used without purification in the next step.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:9]=1[C:10]([O:12]C)=O)(=[O:7])=[O:6].[CH3:21][NH:22][CH3:23].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH3:21][N:22]([CH3:23])[C:10](=[O:12])[C:9]1[C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=[CH:17][C:8]=1[S:5]([NH:4][CH2:3][CH2:2][OH:1])(=[O:6])=[O:7]
Reactant: CNC
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CN(C)C(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Reaction time: 96 h
Yield: 87.7 %

Procedure:
A solution of methyl 2-[N-(2-hydroxyethyl)aminosulfonyl]-6-nitrobenzoate (4.58 g, 15.1 mmol) in absolute MeoH (50 ml) was added to a solution of dimethylamine (6.8 g, 0.15 mol) and potassium tertbutoxide (0.68 ml of a 0.262 M solution in tertbutanol) in absolute MeoH (100 ml). After stirring at 20°-25° C. for 4 days, solvents were removed under reduced pressure. The residue was dissolved in EtOAc and washed with 0.5N HCl followed by a saturated aqueous NaCl solution. The EtOAc extract was dried (Na2SO4), filtered and concentrated to give 4.2 g (88%) of product.
Reaction SMILES: O[C:2]1[C:3]2[N:4]([C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.P(Cl)(Cl)([Cl:21])=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:21][C:2]1[C:3]2[N:4]([C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc2ccccc2n2c(C(F)(F)F)nnc12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1nnc2c(Cl)nc3ccccc3n12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
In a flame-dried reaction flask under a dry nitrogen atmosphere, there were placed 3.0 g. (0.0118 mole) of 4-hydroxy-1-trifluoromethyl-[1,2,4]triazolo[4,3-a]quinoxaline and 30 ml. of phosphorus oxychloride in 2.38 g. (0.0236 mole) of triethylamine (3.3 ml.). The reaction mixture was then heated at 100° C. for a period of approximately 16 hours (i.e., overnight). Upon completion of this step, the spent mixture was cooled to room temperature, concentrated in vacuo and then partitioned between ice, water and ethanol, followed by extraction with ethyl acetate. The latter extract was next washed with saturated brine and dried over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there was obtained a residue which was subsequently dissolved in hot chloroform and filtered. The latter filtrate was then allowed to stand overnight at room temperature and filtered again. The final filtrate was then concentrated in vacuo to ultimately afford 1.4 g. of 4-chloro-1-trifluoromethyl[1,2,4] triazolo[4,3-a]quinoxaline in the form of a brownish-colored solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]1([CH3:17])[CH2:14][CH:13]([CH3:15])[CH2:12][C:11](=O)[CH2:10]1>>[CH3:8][C:9]1([CH3:17])[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[OH:7])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[OH:7])[CH2:10]1
Reactant: Oc1ccccc1
Reactant: CC1CC(=O)CC(C)(C)C1
Product: CC1CC(C)(C)CC(c2ccccc2O)(c2ccccc2O)C1

Procedure:
The amount of the phenol (A) added after the conversion of 3,3,5-trimethylcyclohexanone (B) has reached 90 mol % or over is preferably such that the total molar amount of the phenol (A) added (the total phenol (A) consisting of the phenol (A) introduced in carrying out the pre-reaction, the phenol (A) dropped in the form of a liquid mixture with 3,3,5-trimethylcyclohexanone (B) in the reaction mixture and the phenol (A) added after the conversion of 3,3,5-trimethylcyclohexanone (B) has reached 90 mol % or over) is 5 to 10 times, especially 6 to 8 times, based on the molar amount of 3,3,5-trimethylcyclohexanone (B). When the amount of the phenol (A) added after the conversion of 3,3,5-trimethylcyclohexanone (B) has reached 90 mol % or over falls within the above range, not only can the rise of the viscosity of the reaction mixture be suppressed to thereby ensure efficient operation but also the desired 3,3,5-trimethylcyclohexylidenebisphenol can be obtained at high yield. The degree of conversion (%) of 3,3,5-trimethylcyclohexanone (TMC) is defined by the formula: