Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClCCl.[Br:16]Br>O>[Br:16][C:4]1[CH:5]=[CH:6][C:1]([S:7][CH3:8])=[CH:2][CH:3]=1
Reactant: BrBr
Reactant: CSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CSc1ccc(Br)cc1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
A one-liter four-necked flask equipped with a stirrer, thermometer, dropping funnel and Liebig condenser was charged with 124.2 g (1.00 mole) of thioanisole, and 0.13 g (0.001 mole) of aluminum chloride and 200 g of dichloromethane, and 160 g (1.0 mole) of bromine was added dropwise with stirring at 5° C. over 4 hours. Thereafter, the reaction was further allowed to proceed for 2 hours. After completion of the reaction, 50 g of water was added, and phase separation was effected, whereby a 4-bromothioanisole-containing organic layer was obtained. The dichloromethane was distilled off from the organic layer obtained, whereby 203.1 g of crude 4-bromothioanisolve was obtained. The purity of the thus-obtained crude 4-bromothioanisole was 90.1% as determined by gas chromatography.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:5][CH:4]=1.[NH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1>N1C=CC=CC=1>[S:28]1[CH:29]=[CH:30][N:31]=[C:27]1[NH:26][S:20]([C:17]1[CH:18]=[CH:19][C:14]([S:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:25])([F:24])[F:1])=[CH:4][CH:5]=2)(=[O:13])=[O:12])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: Nc1nccs1
Reactant: O=S(=O)(Cl)c1ccc(S(=O)(=O)CCc2ccc(C(F)(F)F)cc2)cc1
Solvent: c1ccncc1
Product: O=S(=O)(CCc1ccc(C(F)(F)F)cc1)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reaction time: 8 h
Yield: 6.4 %

Procedure:
To 4-[2-(4-Trifluoromethyl-phenyl)-ethanesulfonyl]-benzenesulfonyl chloride (1288 mg, 0.003120 mol) and 2-aminothiazole (0.31 g, 0.0031 mol) was added pyridine (20 mL). After stirring overnight, the reaction mixture was concentrated, dissolved in DMSO (4 mL) and purified by reversed phase chromatography (Phenomenex 250×30 mm 15 micron C18 column. 40 mL/min. Gradient 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8 TFA). The compound was further purified on silica gel (CHCl3-10% MeOH in CHCl3) to give 94 mg of a light brown solid. LCMS: M+477.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:17](O)=[O:18])[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[CH3:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24].CN(C(O[N:35]1N=N[C:37]2[CH:38]=C[CH:40]=[CH:41][C:36]1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:21]([N:22]([CH2:25][CH3:26])[C:23]1[CH:38]=[CH:37][C:36]([NH:35][C:17]([C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:14][CH2:13][C:12]3[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:18])=[C:41]([CH3:40])[CH:24]=1)[CH3:20]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CC
Reactant: COC(=O)C1(C(=O)O)CCc2cccc(OC)c2C1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)C2(C(=O)OC)CCc3cccc(OC)c3C2)c(C)c1
Reaction time: 8 h
Yield: 41.5 %

Procedure:
The crude acid from Example 12A (180 mg) was dissolved in DMF (1.5 mL) and N′,N′-diethyl-2-methyl-1,4-phenylenediamine monohydrogenchloride (150 mg, 0.7 mmol), Et3N (202 mg, 2.0 mmol), and TBTU (225 mg, 0.7 mmol) were added at ambient temperature. The mixture was stirred overnight and purified by column chromatography to provide the titled compound (120 mg, 25% over 2 steps). 1H NMR (300 MHz, DMSO-D6) δ 8.94 (s, 1H), 7.06 (t, J=7.8 Hz, 2H), 6.83 (d, J=9.0 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 6.43 (m, 2H), 3.78 (s, 3H), 3.67 (s, 3H), 3.29 (q, J=6.9 Hz, 4H), 3.09 (s, 2H), 2.73 (m, 2H), 2.30 (m, 2H), 1.99 (s, 3H), and 1.05 (t, J=6.6 Hz, 6H). MS (ESI) positive ion 425 (M+H)+; negative ion 423 (M−H)−.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].Cl.[OH:11][CH:12]1[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([OH:18])[C@H:15]([OH:16])[C@H:13]1[NH2:14].C([O-])(O)=O.[Na+]>O>[Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5]([NH:14][C@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[CH:12]=[O:11])=[O:6]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C[C@H](NC(=O)OCC(Cl)(Cl)Cl)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 8 h
Yield: 90.4 %

Procedure:
2,2,2-Trichloroethoxycarbonyl chloride (200 g, 0.944 mol) is added portionwise to a solution of D-glucosamine hydrochloride (v, 200 g, 0.927 mol) and NaHCO3 (200 g, 2.4 mol) in water (4 L) in a 10 L 3-neck round-bottom flask and the resulting mixture is mechanically stirred overnight at room temperature. The white precipitate that forms is collected by filtration using a 2 L fritted funnel washed with ether (2 L), and dried at high vacuum for 3 hours to give 297 g (90%) of 2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-D-glucose as a white solid (MW 354.57).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Br:13]N1C(=O)CCC1=O.C(OCC)(=O)C.O>CN(C=O)C>[Br:13][C:7]1[C:8]([F:9])=[C:2]([F:1])[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:6]
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(F)c(F)c1Br
Reaction time: 8 h

Procedure:
2-Bromo-3,4-difluoro-6-nitroaniline was prepared using an adaptation of the method of Mitchell et al. (Mitchell, R. H. et al., J. Org. Chem. 44: 4733 (1979)). To a solution of 4,5-difluoro-2-nitroaniline (500 mg, 2.87 mmol) in DMF (25 mL) under N2 was added all at once N-bromosuccinimide (511 mg, 2.87 mmol) in dry DMF (16 mL). The reaction was allowed to stir overnight. TLC (1:1 hexanes:ethyl acetate) showed still some starting material present. Additional N-bromosuccinimide (100 mg) was added and the reaction stirred another 12 h. The solution was then poured into 100 ml H2O and the resulting cloudy suspension extracted with 3×20 mL methylene chloride. The combined organic phases were washed with 4×25 mL H2O and 25 mL saturated NaCl solution and dried (MgSO4). The MgSO4 was vacuum filtered and the solvent rotary evaporated to yield a yellow brown oil which slowly crystallized to yield 700 mg (96%). 1H NMR (CDCl3) δ 6.70 (br s, 2H, NH2), 7.99 (m, 1H, H-5).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][CH2:8][CH:9](O)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([CH:9]2[C:21]3[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:22]=3)[CH2:6][NH:7][CH2:8]2)[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1ccc(C(O)CNCc2ccc(C)cc2)cc1OC
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CNCc3ccc(C)cc32)cc1OC
Yield: 98.3 %

Procedure:
530 mg of α-[[(4-methylbenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol was dissolved in 4 ml of trifluoroacetic acid, and after adding thereto 0.12 ml of conc. sulfuric acid under ice cooling, the mixture was allowed to react for 30 minutes. The reaction solution was concentrated, and subjected to azeotropic distillation with toluene 2 times. After adding chloroform, the mixture was basified by addition of 28% aqueous ammonia. By a separating procedure, the chlorofrom layer was collected, was washed with water once, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane, giving 490 mg of 4-(3,4-dimethoxyphenyl)-6-methyl-1,2,3,4-tetrahydroisoquinoline (melting point: 94°-96° C.).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:11]=1[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:25][CH3:26])(=[O:24])[CH2:20][C:21]([CH3:23])=O.[NH2:27]/[C:28](/[CH3:34])=[CH:29]\[C:30]([O:32][CH3:33])=[O:31]>CC(O)C>[CH3:23][CH:21]1[C:20]([C:19]([O:25][CH3:26])=[O:24])=[C:12]([C:11]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:10]=2[CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]([CH3:34])[NH:27]1
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1cc(Cl)ccc1COCc1ccccc1
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)C(C(=O)OC)=C1c1cc(Cl)ccc1COCc1ccccc1
Temperature: 25 °C

Procedure:
To a 250 ml round bottomed flask was added the compound (2c) (5.70 g, 22.90 mmol), methyl acetoacetate (2.66 g, 22.90 mmol), methyl 3-aminocrotonate (2.64 g, 22.90 mmol) and 2-propanol (30 ml). The flask was equipped with a stirring bar, reflux condenser and argon inlet and the mixture was heated at reflux for 20 hours with stirring. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The crude product was chromatographed on 300 g of silica gel using 1:3 ethyl acetate-hexanes as eluant. The yellow oil obtained from the chromatography was triturated with ethyl ether and the resulting crystals of pure compound (2d) were collected on a first and dried. mp 156-158° C. 'H NMR (CDCl3) δ2.26 (s, 6H), 3.50 (s, 6H), 4.69 (s, 2H), 4.95 (s 2H), 5.00 (s, 1H), 5.95 (br s, 1H), 7.00-7.60 (m, 8H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH:11]1([CH2:14][OH:15])[CH2:13][CH2:12]1.CC(C)([O-])C.[K+]>CN(C)C=O>[CH:11]1([CH2:14][O:15][C:2]2[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)[CH2:13][CH2:12]1
Reactant: OCC1CC1
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(OCC2CC2)cn1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A solution of 5-chloropyrazine-2-carboxylic acid (1.00 g, 6.31 mmol), cyclopropyl carbinol (1.00 mL, 12.4 mmol) and potassium tert-butoxide (2.00 g, 17.8 mmol) in dimethylformamide (20.0 mL) is heated at 100° C. for 3 hours. The reaction is cooled to room temperature, quenched with 1 M hydrochloric acid. The mixture is extracted with ethyl acetate and isopropyl alcohol/chloroform (1/10), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.10 g, 90%) as a grayish solid. This acid is used directly without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1>C(O)C.O.Cl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Yield: 54.9 %

Procedure:
A mixture of 0.15 g (0.48 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20) and 0.078 g (0.57 mmole) of 4-amino-benzoic acid in 15 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then cooled and partially concentrated under reduced pressure. The resulting solid was collected by filtration, washed with water and dried to give 0.11 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-20)
Reaction SMILES: [I:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[C:14]([NH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)(=[O:16])[CH3:15]>C(O)C>[I-:1].[CH3:13][O:12][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][N+:21]2[CH:22]=[CH:23][C:18]([NH:17][C:14](=[O:16])[CH3:15])=[CH:19][CH:20]=2)[CH:9]=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: CC(=O)Nc1ccncc1
Reactant: COc1ccc(CCI)cc1OC
Solvent: CCO
Product: COc1ccc(CC[n+]2ccc(NC(C)=O)cc2)cc1OC
Product: [I-]
Yield: 67.7 %

Procedure:
1-(2-Iodoethyl)-3,4-dimethoxybenzene (29.3 g.) and 4-acetamidopyridine (14.0 g.) in absolute ethanol (100 ml.) were refluxed for 2.5 hours. The resulting crystalline material was collected and recrystallised from ethanol to give the title compound (29.1 g.), m.p. 201°-202°C. (Found: C, 47.9; H, 4.9; N, 6.3; C17H21IN2O3 requires C, 47.7; H, 4.9; N, 6.5%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([Cl:11])=[O:10])[CH2:2]2.C(N(CC)C(C)C)(C)C.[N:21]1[C:30]2[C:25](=[CH:26][C:27]([NH2:31])=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1>CN(C1C=CN=CC=1)C>[ClH:11].[N:21]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:9]([CH:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:10])=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: Nc1ccc2nccnc2c1
Reactant: O=C(Cl)C1CN2CCC1CC2
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: O=C(Nc1ccc2nccnc2c1)C1CN2CCC1CC2

Procedure:
In analogy to the method described in Example 2, 250 mg (2.57 mmol) of 3-quinuclidinecarbonyl chloride, 461 mg (3.57 mmol) of N,N-diisopropylethylamine, catalytic amounts of DMAP (approx. 1 mg) and 173 mg (1.19 mmol) of 6-quinoxalinylamine are reacted.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:35]=O)[S:33][CH:34]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH2:6]([N:7]([CH2:35][C:32]1[S:33][CH:34]=[C:30]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)[CH:31]=1)[CH2:8][CH3:4])[CH3:5]
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)cs1
Temperature: 150 °C
Yield: 6.4 %

Procedure:
To 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (400 mg, 1.08 mmol) in dioxane and water (4 mL/1 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (462 mg, 1.94 mmol), Pd(PPh3)4 (100 mg) and K2CO3 (447 mg, 3.24 mmol). The reaction mixture was heated at 150° C. for 20 minutes by microwave irradiation. The organic phase was concentrated and redissolved in DMSO (10 mL). The resulting solution was split to eight. NaBH3CN (30 mg), ZnCl2 (30 mg) and N-ethylethanamine (50 mg) were added. The mixture was heated to 100° C. for 30 minutes which was then filtered and purified by HPLC with TFA to afford the title compound (16 mg).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[Br:44].C([O-])([O-])=O.[Na+].[Na+].O>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.O1CCCC1>[Br:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:33]1[C:32]([C:19]2[CH:20]=[CH:21][C:16]([C:8]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)=[CH:17][CH:18]=2)=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)OC1(C)C
Reactant: Brc1ccccc1-c1ccccc1Br
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: C1CCOC1
Solvent: O
Product: Brc1ccccc1-c1ccccc1-c1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Temperature: 80 °C
Yield: 61.6 %

Procedure:
A mixture of Compound 2 (3.00 g, 7.57 mmol), 2,2′-dibromo-1,1′-biphenyl (4.72 g, 15.1 mmol), tetrakis(triphenylphosphine)palladium(0) (0.350 g, 0.303 mmol), Na2CO3 (3.18 g, 30.0 mmol), H2O (30 mL) and tetrahydrofuran (THF) (50 mL) was degassed with argon for about 44 min while stirring. The reaction mixture was then maintained under argon at about 80° C. while stirring. Upon confirming consumption of the starting material by TLC (SiO2, 19:1-CH2Cl2:acetone), the reaction was cooled to RT and poured over CH2Cl2 (ca. 250 mL). The organics were then washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified via flash chromatography (SiO2, 100% CH2Cl2 to 39:1-CH2Cl2:acetone) to yield Compound 3 (2.34 g, 62%) as an off-white foam: confirmed by LCMS (APCI): calculated for C31H21BrN2 (M+): 501; Found: 501.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:30][N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1.CO.C(O)(=O)C.[BH3-]C#N.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)[CH2:13][CH2:12]3)[C:9]=2[CH:10]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCNCC2)c(=O)[nH]1
Reactant: CN1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCN(C3CCN(C)CC3)CC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 24 %

Procedure:
To a stirred solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(piperidin-4-yl)-1H-indazole-4-carboxamide (1 equiv.) and 1-methylpiperidin-4-one (1.5 equiv.) in methanol (5 mL per 0.3 mmol), acetic acid (1 equiv.) was added and reaction stirred at room temperature for 5 h. Then NaBH3CN (1 equiv.) was added and the reaction stirred overnight. On completion, the solvent was removed under reduced pressure and the residue purified by column chromatography (24% yield). LCMS: 555.15 (M+1)+; HPLC: 92.59% (@ 254 nm) (Rt; 4.143); 1H NMR (DMSO-d6, 400 MHz) δ 11.52 (s, 1H), 8.60 (t, 1H, J=5.2 Hz), 8.35 (s, 1H), 8.24 (s, 1H), 7.68 (s, 1H), 5.88 (s, 1H), 4.63-4.68 (m, 1H), 4.32 (d, 2H, J=4.8 Hz), 2.97 (d, 2H, J=11.6 Hz), 2.79 (d, 2H, J=10.8 Hz), 2.22-2.40 (m, 3H), 2.19 (s, 3H), 2.13 (s, 3H), 2.11 (s, 3H), 1.99-2.08 (m, 2H), 1.81-1.88 (m, 4H), 1.69 (d, 2H, J=11.2 Hz), 1.43-1.48 (m, 2H).
Reaction SMILES: CS([C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[CH:16][N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=4)[C:14]=3[CH:29]=2)=[N:7][N:6]=1)(=O)=O.[CH3:30][NH2:31].O1CCCC1>CN1CCCC1=O>[CH3:30][NH:31][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[CH:16][N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=4)[C:14]=3[CH:29]=2)=[N:7][N:6]=1
Reactant: CN
Reactant: CS(=O)(=O)c1nnc(-c2ccc3ncn(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CNc1nnc(-c2ccc3ncn(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Yield: 79 %

Procedure:
In the same manner as in Example 433 and using 6-[5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl]-1-[3-(trifluoromethoxy)phenyl]-1H-benzimidazole instead of 6-[5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl]-1-[4-(trifluoromethoxy)phenyl]-1H-benzimidazole, using 2M methylamine-tetrahydrofuran solution instead of sodium methoxide, and using 1-methyl-2-pyrrolidone instead of N,N-dimethylformamide, the title compound (yield 79%) was obtained as colorless crystals.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]([OH:10])=[O:9])=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[NH:3]1.OS(O)(=O)=O.O=S(Cl)Cl.[CH2:28](O)[CH3:29]>>[O:1]=[C:2]1[NH:7][C:6]([C:8]([O:10][CH2:28][CH3:29])=[O:9])=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[NH:3]1
Reactant: CCO
Reactant: O=C(O)c1[nH]c(=O)[nH]c(=O)c1Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1[nH]c(=O)[nH]c(=O)c1Oc1ccccc1

Procedure:
The required starting compound may also be prepared as follows: 1.8 g of 2,6-dioxo-5-phenoxy-1,2,3,6-tetrahydro-pyrimidine-4-carboxylic acid (preparation described in: Khim Geterotsikl. Soedin., 1974, p1527) are emulsified in 65 ml of ethanol, 0.92 ml of conc. H2SO4 and 0.92 ml of SOCl2 are subsequently added and the mixture is heated at reflux for 12 hrs. Subsequently, the mixture is concentrated on a rotary evaporator and the seperated solid is filtered off under suction and chromatographed on silica gel (eluent: CH2Cl2 /ether: 3/1). There are obtained 520 mg of ethyl 2,6-dioxo-5-phenoxy-1,2,3,6-tetrahydro-pyrimidine-4-carboxylate as a solid. MS: M=276.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:8][CH:7]=2.Cl.[NH:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][S:17]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=1)[C:3]([CH2:2][N:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)=[C:12]2[C:13]([O:15][CH3:16])=[O:14])(=[O:19])=[O:18]
Reactant: O=C1CCNCC1
Reactant: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1c(CN2CCC(=O)CC2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Yield: 50.7 %

Procedure:
Methyl 3-(bromomethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2 g, 3.98 mmol), 4-piperidone HCl salt (0.648 g, 4.78 mmol), N,N-diisopropylethylamine (1.53 mL, 8.76 mmol) in acetonitrile (13.27 mL) was heated to 50° C. overnight. The solvent was removed under reduced pressure. The residue was diluted with Na2CO3 and extracted with methylene chloride (four times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 40 g silica, 5-100% ethyl acetate/hexanes) to afford methyl 6-(methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.051 g, 51% yield). MS (m/z) 521.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C(#N)CC>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=2)[O:7][CH:12]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: NC(=O)c1ccc(O)cc1
Solvent: CCC#N
Product: COC(=O)Cc1coc(-c2ccc(O)cc2)n1
Temperature: 98 °C
Yield: 411.2 %

Procedure:
A solution of 4-hydroxybenzamide (10 g, 7.3 mmol, 1 eq) and methyl 4-chloro-3-oxobutanoate (15 g, 11 mmol, 5 eq) in propionitrile (300 ml) is stirred at reflux (98° C.) during 3 days. After concentration under reduced pressure, the residue is purified over silicagel (eluent: dichloromethane/methanol/ammonia 90:9:1) to yield 7 g of methyl[2-(4-hydroxyphenyl)-1,3-oxazol-4-yl]acetate i50.