Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].[CH3:14][NH:15][CH2:16][CH:17]([CH3:19])[CH3:18]>>[CH2:16]([N:15]([CH3:14])[C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][N:9]=1)=[O:13])[CH:17]([CH3:19])[CH3:18]
Reactant: CNCC(C)C
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Product: CC(C)CN(C)C(=O)c1ccc(C(=O)O)cn1
Yield: 75 %

Procedure:
The title compound was synthesized as described for Intermediate example I-94 in 75% yield starting from 5-(methoxycarbonyl)pyridine-2-carboxylic acid and n-methylisobutylamine; MS (APPI/APCI) m/z 237[M+H+].
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][C:37]1[S:41][C:40]([CH:42]=[O:43])=[N:39][CH:38]=1>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([CH:42]([C:40]2[S:41][C:37]([CH3:36])=[CH:38][N:39]=2)[OH:43])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cnc(C=O)s1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Product: Cc1cnc(C(O)c2nc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(N3C[C@@H](C)O[C@@H](C)C3)c(Cl)c2F)s1

Procedure:
Starting materials: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and 5-methylthiazole-2-carbaldehyde.
Reaction SMILES: NC(N)=O.[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>>[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:32]([NH:31][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=2[Cl:23])=[O:33])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1)(=[O:15])=[O:16]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: Nc1ccc(Cl)c(S(=O)(=O)N2CCSCC2)c1O
Agent: NC(N)=O
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)N2CCSCC2)c1O)Nc1cccc(Cl)c1Cl
Yield: 28 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 4-chloro-2-hydroxy-3-(4-thiomorpholinylsufonyl)aniline (120 mg, 0.36 mmol) and 2,3-dichlorophenylisocyanate(68 mg, 0.36 mmol) were coupled to form the desired urea (50 mg, 28%). 1H NMR (MeOD-d4): δ 8.31 (m, 1H), 8.05 (m, 1H), 7.26 (m, 2H), 7.08 (m, 1H), 3.61 (m, 4H), 2.69 (m, 4H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[C:30]1[CH:29]=[C:28]([C:27]2[CH2:26][C:25](=[O:41])[NH:24][C:9]3[CH:10]=[C:11]([C:20]([F:23])([F:21])[F:22])[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:13][C:8]=3[N:7]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccccn3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M40) (165 mg, 0.36 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (81 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:23])=[C:5]([C:14]([O:21][CH3:22])=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:36](O)=[O:37]>>[CH3:1][O:2][C:3]1[C:4]([CH3:23])=[C:5]([C:14]([O:21][CH3:22])=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH:8]=1)[CH:36]=[O:37]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1c(C)c(Cc2ccc(O)cc2)c(OC)c(OC)c1OC
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1c(C)c(Cc2ccc(O)c(C=O)c2)c(OC)c(OC)c1OC
Temperature: 80 °C
Yield: 78 %

Procedure:
4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)phenol (14.5 g, 45.60 mmol) and hexamethylenetetramine (8.30 g, 59.29 mmol) were dissolved in trifluoroacetic acid (100 ml) and the solution was stirred under heating at 80° C. for 4 hours. After the completion of reaction, the solvent was removed by distillation and to the obtained residue, water (100 ml) was added. The resulting solution was stirred for 30 minutes and extracted with methylene chloride. The extract was washed with water and then dried, the solvent was removed by distillation and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=4:1) to obtain the titled compound (12.20 g, 35.26 mmol, 78%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:20]1([CH2:23][C:24](N(OC)C)=[O:25])[CH2:22][CH2:21]1>C1COCC1>[CH:20]1([CH2:23][C:24](=[O:25])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)[CH2:22][CH2:21]1
Reactant: CON(C)C(=O)CC1CC1
Reactant: CSc1nccc(C)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1nccc(CC(=O)CC2CC2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-methyl-2-(methylthio)pyrimidine (5.63 mL, 40.4 mmol) in THF (20 mL) at −10° C., LiHMDS (60.6 mL, 60.6 mmol) (1N in MBTE) was added dropwise under nitrogen. The reaction mixture coagulated, and stopped stirring. For this, additional THF (40 mL) was added to dissolve the highly viscous mixture. The reaction was warmed up to rt and was stirred for 30 minutes. The reaction mixture was re-cooled to −10° C., then 2-cyclopropyl-N-methoxy-N-methylacetamide (7.47 g, 40.4 mmol) was added dropwise. The reaction mixture was warmed up to rt, then stirred for an additional 2 hours. The reaction was partitioned between ammonium chloride solution and EtOAc. The organic layer was separated, and the aqueous layer was back-extracted. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo. The crude product was purified by Biotage™ silica gel chromatography [100 g SNAP column, 10% EtOAc/heptane to 100% EtOAc] to obtain the desired product, which was still contaminated significantly with the starting material, 4-methyl-2-(methylthio)pyrimidine (5.63 g, 48% yield). The product was carried on to the next step without further purification. MS (ES+): m/z=223.2/224.3 (100/50) [MH+]. HPLC: tR=0.84 minute over 3 minutes. Purity: 77% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.C([Li])CCC.[F:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[F:47])[CH2:42][OH:43]>>[F:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[F:47])[CH2:42][O:43][C:5]1[N:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1
Reactant: CS(=O)(=O)c1nc(OC2CCCCC2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: OCc1ccc(F)c(F)c1
Agent: [Li]CCCC
Product: Fc1ccc(COc2nc(OC3CCCCC3)c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)cc1F

Procedure:
2-(Methylsulfonyl)-4-(cyclohexyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (LRf product) (Example 52, Step A), (24 mg, 0.045 mmol) was reacted with 1 equivalent each of n-butyl lithium and 3,4-difluorobenzyl alcohol by the procedure described in Reference Examples 6 and 7. Workup and flash column chromatography on silica gel (eluted with 93/7 hexanes/ethyl acetate) afforded the title compound. HPLC/MS: m/e=577 (M++1); Rt=5.34 min; 1H-NMR 500 MHz (CDCl3): 1.28-1.40 (m, 3H), 1.40-1.55 (m, 2M), 1.50-1.60 (m, 2H), 1.60-1.70 (m, 2H), 1.8-1.90 (m, 2H), 5.26 (m, J=4 Hz, 1H), 5.40 (s, 2H), 7.03 (d, J=8 Hz, 2H), 7.05 (d, J=1 Hz), 7.15-7.27 (m, 5H), 7.34 (d over multiplet, J=2 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][O:20][CH3:21])[C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:8]3[CH:7]=[C:6]4[C:11]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)=[CH:10][CH:9]=3)[C:14](=[O:22])[C@@H:15]2[CH2:19][O:20][CH3:21])=[O:32])=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COCC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)Nc1ccc(Cl)cc1

Procedure:
The title compound is prepared as described in EXAMPLE 436 using 1-(4-amino-quinazoline-7-ylmethyl)-3-methoxymethyl-piperazine-2-one, EXAMPLE 75, and 4-chlorophenyl isocyanate. 1H NMR (DMSO-d6, 300 MHz) δ9.77 (bs, 2H), 8.81 (s, 1H), 8.70 (s, 1H), 8.40 (d, 1H), 7.64 (d, 1H), 7.61 (s, 1H), 7.49 (d, 2H), 7.28 (d, 2H), 4.88 (m, 1H), 4.80 (AB, 2H), 4.19 (m, 1H), 3.96 (m, 1H), 3.74-3.42 (m, 4H), 3.28 (s, 3H). ESI MS, [M+H]+=455,457 (Cl pattern). Anal. (C22H23ClN6O3.TFA.1.5H2O) C, H, N.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=[CH:16][CH:15]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:24]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:24][C:3]1[CH:2]=[CH:1][C:13]2[N:12]([C:14]3[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=[CH:16][CH:15]=3)[C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cnccc1-n1c2ccccc2c2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnccc1-n1c2ccccc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
62.5 g (207 mmol) of methyl 4-carbazol-9-ylnicotinate in 2000 ml of DMF are cooled to −10° C., 37.3 g (207 mmol) of N-bromosuccinimide are added in portions, and the mixture is stirred at room temperature for 6 h. 500 ml of water are subsequently added to the mixture, which is then extracted with CH2Cl2. The organic phase is dried over MgSO4, and the solvent is removed in vacuo. The product is washed by stirring with hot toluene and filtered off with suction. Yield: 71 g (186 mmol), 90% of theory, purity according to 1H-NMR about 98%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=O)[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:20][C:19]2[CH:18]=[C:17]([C:15]3[CH:14]=[CH:13][N:12]=[C:11]([NH:10][CH2:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)[N:16]=3)[CH:24]=[CH:23][CH:22]=2)[CH2:28][CH2:27]1
Reactant: CN1CCNCC1
Reactant: O=Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Product: CN1CCN(Cc2cccc(-c3ccnc(NCCc4ccc(O)cc4)n3)c2)CC1

Procedure:
Intermediate 28 was coupled with N-methyl piperazine following procedure F. LC-MS showed the product had the expected M+H+ of 404. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (d, 1H) 7.9 (m, 2H) 7.4 (m, 2H) 7.1 (d, 2H) 7.0 (d, 1H) 6.7 (d, 2H) 5.2 (m, 1H) 3.7 (m, 2H) 3.6 (s, 2H) 2.9 (m, 2H) 2.7 (s, 8H) 2.4 (s, 3H).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[Na].[Cl-].C([O-])(=O)CC([O-])=O>C(O)C>[C:2]1([CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([O:15][CH2:16][CH3:17])=[O:14])[CH2:1][CH2:5][CH2:4][CH:3]=1
Reactant: C1=CCC=C1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: O=C([O-])CC(=O)[O-]
Agent: [Cl-]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C1=CCCC1
Reaction time: 17 h

Procedure:
To 174 g (2.63 mol) of freshly depolymerized cyclopentadiene, cooled and maintained at -78 C., was added 87.5 g (2.50 mol) gaseous HCl. Meanwhile, 152 mL (1.0 mol) diethyl malonate was added to a solution of 21.4 g (0.93 mol) sodium in 400 mL absolute ethanol. After HCl addition to the cyclopentadiene was complete, the crude yellow chloride, maintained at -78 C., was added in 1 mL portions to the malonate solution. With addition of each 1 ml portion of the malonate solution, considerable heat was produced, the yellow color rapidly dissipated, and copious white precipitate formed. After addition of all of the malonate, the suspension was stirred for 17 hrs, after which most of the ethanol was removed by rotary evaporation, and the reaction was quenched with 200 mL water and extracted 5×, each with 100 mL of diethyl ether. The combined extracts were dried over MgSO4, filtered, and concentrated to a clear yellow oil. Distillation of a portion of this material under 0.5 mm Hg pressure yielded 19.091 g clear, light green oil, bp 91-94 C.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][N:4]=1)[NH2:2].[C:15](OCC)(OCC)(OCC)[CH3:16]>>[CH3:15][C:16]1[N:8]2[CH:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]=[N:4][C:3]2=[N:1][N:2]=1
Reactant: NNc1ncc(-c2ccccc2)cn1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc2ncc(-c3ccccc3)cn12

Procedure:
A mixture of 3.0 g. of 2-hydrazino-5-phenylpyrimidine and 30 ml. of triethyl orthoacetate is heated under reflux overnight. The material which separates is collected, washed with hexane, and crystallized from acetone-hexane to give 2.2 g. of the product of the Example, m.p. 199°-200° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([O:15][CH3:16])=[C:7]([CH3:17])[C:4]=1[CH:5]=[O:6].Br[C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[O:29][CH2:28][CH2:27][O:26]2)=[CH:21][CH:20]=1.[Mg].O>C1COCC1>[OH:6][CH:5]([C:4]1[C:7]([CH3:17])=[C:8]([O:15][CH3:16])[C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:3]=1[O:2][CH3:1])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[O:26][CH2:27][CH2:28][O:29]2)=[CH:21][CH:20]=1
Reactant: Brc1ccc(C2OCCO2)cc1
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)c(C(O)c2ccc(C3OCCO3)cc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
To an ice-cold solution of 2,3,4,5-tetramethoxy-6-methylbenzaldehyde (5.03 g, 20.94 mmol) in THF (200 ml) was added dropwise a Grignard reagent prepared from 2-(4-bromophenyl)-1,3-dioxolane (12.0 g, 52.4 mmol) and magnesium (1.40 g, 57.6 mmol), and then stirred at room temperature for 4 hours. The reaction mixture was poured into water and was extracted with ether. After the extract was washed with water and dried, and then the solvent was distilled off. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate=3:1) to yield the title compound (7.80 g, 20.0 mmol, yield 96%).
Reaction SMILES: Br[C:2]1[C:3]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:21](B1C2CCCC1CCC2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[ClH:37]>Cl[Pd]Cl.O.CN(C=O)C>[ClH:37].[CH2:21]([C:2]1[C:3]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Reactant: Cc1csc(Nc2ncccc2Br)n1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(Nc2ncccc2Cc2ccccc2)n1
Temperature: 60 °C
Yield: 50.6 %

Procedure:
A mixture of mL 3-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (70 mg, 0.26 mmol), Cs2CO3 (250 mg, 0.78 mmol), PdCl2 (dppf) (21.2 mg, 0.026 mmol), and DMF (2 mL) and water (0.5 mL) was purged with nitrogen and 9-benzyl-9-bora-bicyclo[3.3.1]nonane (1.5 mL, 0.78 mmol) was added and heated to 60° C. overnight. Additional 9-benzyl-9-bora-bicyclo[3.3.1]nonane (1.5 mL, 0.78 mmol) was added and heated again overnight. Poured into water and extracted with ether. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (10% EtOAc in hexanes) to afford the title compound (41.7 mg, 50.6% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 8.30 (d, 1H), 7.62 (d, 1H), 7.35-7.10 (m, 6H), 6.82 (s, 1H), 4.21 (s, 2H), 2.32 (s, 3H); Mass spectrum (esi) m/z=282.2 (100)(M+H—HCl).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5](=[O:27])[CH2:6][CH:7]1[C:11](O)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]([C:19]2[N:20]=[N:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[N:9]=[C:8]1[CH3:26]>CO>[CH3:3][O:4][C:5](=[O:27])[CH2:6][C:7]1[C:8]([CH3:26])=[N:9][N:10]([C:19]2[N:20]=[N:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[C:11]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)CC1C(C)=NN(c2ccc(Cl)nn2)C1(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)Cc1c(C)nn(-c2ccc(Cl)nn2)c1-c1ccccc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
0.111 g (2.772 mmol) of 2-molar aqueous sodium hydroxide solution was added to 0.200 g (0.554 mmol) of methyl[1-(6-chloropyridazin-3-yl)-5-hydroxy-3-methyl-5-phenyl-4,5-dihydro-1H-pyrazol-4-yl]acetate in 8 ml of methanol, and the mixture was stirred at 20° C. for 1 h. The methanol was removed under reduced pressure and the residue was poured into a mixture of 10 ml of water and 15 ml of dichloromethane. The aqueous phase was extracted with 15 ml of dichloromethane, acidified with concentrated hydrochloric acid (pH=3) and extracted three times with in each case 15 ml of dichloromethane. Drying of the combined organic phases and removal of the solvent under reduced pressure gave 0.207 g (99% of theory) of a brown wax-like solid, melting point 55° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.Cl[CH2:18][C:19](Cl)=[O:20].CCCCCCCCCC.[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:10]2[C:11](=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH2:18][C:19]1=[O:20]
Reactant: Cc1ccc(Nc2c(F)cccc2Cl)cc1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCCCCC
Product: Cc1ccc2c(c1)CC(=O)N2c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Alternatively, a mixture of 169.8 g of crude N-(2′-chloro-6′-fluorophenyl)-4-methylaniline, 172 ml (2.15 mol) of chloroacetyl chloride in 580 ml of toluene is heated under a nitrogen atmosphere for 2 hours at 70°. The reaction is cooled to room temperature, 450 ml of decane is added, and the volatiles are distilled off under 200 mbar pressure at 62-72°. To the mixture is added 150 ml of toluene and 385 g of aluminum chloride (2.87 mol) slowly at 20-40°. The mixture is heated at 120° for 5 hours, cooled to 20°, and added over 30 minutes to 800 ml of ethyl acetate. The mixture is quenched by addition to a pre-cooled solution of 67 ml of 37% hydrochloric acid in 800 ml of water at 20±10°, and the resultant mixture is filtered through a pad of Celite. The organic layer is separated and the volatiles are distilled off. To the residue is added 100 ml of heptane and the mixture is cooled to 0° over a 30 minute period and stirred for one hour. The mixture is filtered and the filter cake is washed three times with 45 ml of heptane. To the crude product is added 90 g of charcoal (DARCO G-60) and 4500 ml of methanol. The mixture is heated to reflux for two hours, cooled to room temperature, and filtered through a pad of Celite. After distilling off 4390 ml of methanol, the mixture is cooled to 15°. The product is collected by filtration, washed three times with 30 ml of methanol, and dried to give N-(2′-chloro-6′-fluorophenyl)-5-methyloxindole.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].C(N(CC)CC)C.[C:15]1([C:21](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl>[C:15]1([C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:1]2[CH:5]=[CH:4][N:3]=[C:2]2[CH:6]=[O:7])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ncc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.4 %

Procedure:
1.5 g of 2-imidazole carboxaldehyde was dissolved in 20 ml of dimethylformamide, 2.18 ml of triethylamine and 4.3 g of triphenylmethyl chloride were added to the above solution, and then the resulting mixture was stirred at room temperature for 24 hours. A saturated sodium bicarbonate aqueous solution and chloroform were added to the reaction solution, and the resulting organic layer was collected, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue was subjected to silica gel chromatography eluted with dichloromethane-methanol (50:1) to obtain 4.717 g of 1-triphenylmethyl-2-imidazole carboxaldehyde.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].O.[F:6][CH:7]([F:21])[O:8][C:9]1[C:10]([F:20])=[C:11]([CH:15]=[C:16]([F:19])[C:17]=1[F:18])[C:12]([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:21][CH:7]([F:6])[O:8][C:9]1[C:10]([F:20])=[C:11]([C:15]([N+:1]([O-:4])=[O:2])=[C:16]([F:19])[C:17]=1[F:18])[C:12]([OH:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(F)c(F)c(OC(F)F)c1F
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1c(F)c(OC(F)F)c(F)c(F)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
20 ml of concentrated aqueous nitric acid (d=1.42) were added dropwise, whilst stirring and cooling with water, to a solution of 15.0 g (0.062 moles) of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid [(XXV), X=X'=F] (prepared as described in Preparation 1, 2 or 3) in 40 ml of concentrated aqueous sulfuric acid, and the mixture was stirred at 60° C. for 7 hours. At the end of this time, it was allowed to stand to cool to room temperature, and then the reaction mixture was poured into ice-water, and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate; the solvent was then removed by evaporation under reduced pressure, to give 16.6 g of 3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoic acid as a yellow powder, melting at 77°-80° C.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].FC1C=CC(N)=CC=1>C(Cl)Cl.C1(C)C=CC=CC=1.FC1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:3])[CH:10]=1
Reactant: BrBr
Reactant: Nc1ccccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Nc1ccc(F)cc1
Agent: [Br-]
Solvent: Fc1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Nc1ccc(Br)cc1F

Procedure:
In a suitable aprotic solvent (e.g., CH2Cl2, toluene, fluorobenzene, or the like) 1 mole of tetrabutylammonium bromide is dissolved and stirred as 1 mole of Br2 (bromine) is added. This mixture of tetrabutylammonium trihalide and solvent is cooled to 10° before 1 mole of 2-fluoroaniline or 4-fluoroanilin, or a mixture of both, is added. The reaction takes place immediately to produce 4-bromo-2-fluoroaniline.HBr, or 2-bromo-4-fluoroaniline.HBr, or a mixture of the two. The salt is then collected and dried before carrying it up to the next step. Catalyst and solvent are recovered for recycle.