Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:5]([C:21](O)=[O:22])=[N:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9].[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:21]([C:5]2[C:4]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)=[CH:3][C:2]([CH3:1])=[C:7]([C:8]([N:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH2:17][CH2:18][CH2:19][CH2:20]4)[CH2:12][CH2:11]3)=[O:9])[N:6]=2)=[O:22])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 1, 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with piperazine-1-carboxylic acid tert-butyl ester, Et3N and HATU in DMF to give the title compound as light yellow solid. MS: 630.3 (MH+).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:18][O:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[F:20][C:21]1([F:30])[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>C(#N)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:18][O:17][CH2:16][CH2:15][N:14]2[C:27]([CH:24]2[CH2:25][CH2:26][C:21]([F:30])([F:20])[CH2:22][CH2:23]2)=[O:28])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)C2COCCN2)no1
Reactant: O=C(O)C1CCC(F)(F)CC1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)c1cc(NC(=O)C2COCCN2C(=O)C2CCC(F)(F)CC2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cold (0° C.) solution of morpholine-3-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (50 mg; 0.115 mmol), 4,4-difluorocyclohexanecarboxylic acid (18.9 mg, 0.115 mmol) and N,N-diisopropylethylamine (0.052 mL; 0.3 mmol) in anhydrous acetonitrile (2 mL) is added phosphorous oxychloride (0.01 mL; 0.115 mmol). The reaction mixture is left stirring at room temperature for 18 hours. After this time, the reaction mixture is quenched with saturated NH4Cl aqueous solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by preparative LC-MS provides the title compound, m/z 400 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6](=[O:13])[C:5]2=O.[OH-:15].[K+].[F:17][C:18]([F:30])([F:29])[C:19]1[CH:20]=[C:21]([C:25](=O)[CH2:26][CH3:27])[CH:22]=[CH:23][CH:24]=1>CCO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[N:7]=[C:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:29])[F:30])[CH:20]=1)[C:26]([CH3:27])=[C:5]2[C:6]([OH:13])=[O:15]
Reactant: COc1cc2c(cc1Br)C(=O)C(=O)N2
Reactant: CCC(=O)c1cccc(C(F)(F)F)c1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)O)c2cc1Br
Yield: 44.2 %

Procedure:
A solution of 5-bromo-6-(methyloxy)-1H-indole-2,3-dione (75 g, 293 mmol), KOH (98.5 g, 1760 mmol) in EtOH (500 mL) and H2O (150 mL) was stirred followed by the addition of 1-[3-(trifluoromethyl)phenyl]-1-propanone (59 g, 293 mmol) in one portion. After refluxing for 16 h, the mixture was evaporated to remove EtOH and pH adjusted to 3 with 2N HCl. Following filtration to yield the crude product, the material was refluxed in EtOH (1 L) for 1 h, filtered and dried to yield 6-bromo-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (57 g, 44% yield) as an off white solid. MS (m/z) 440 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[CH:14][C:15]([OH:17])=O)[CH:6]=[CH:7][CH:8]=1.[C:18]1([C:24]([CH:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)O)=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([N:36]=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:18]1([C:24]2[N:36]=[C:15]([CH2:14][C:10]3[CH2:11][CH2:12][CH2:13][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[O:17][C:26]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cccc(C2CCCC2=CC(=O)O)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cccc(C2=C(Cc3nc(-c4ccccc4)c(-c4ccccc4)o3)CCC2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of [2-(3-methoxyphenyl)-cyclopentylidene]acetic acid (4.0 g) in methylene chloride (80 ml) were added benzoin (3.7 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodimide (4.1 ml) and 4-dimethylaminopyridine (2.1 g). The resulting mixture was stirred at room temperature for 12 hours and then partitioned between ethyl acetate and 1N-hydrochloric acid. The organic layer was separated, washed successively with 1N-hydrochloric acid, saturated sodium bicarbonate aqueous solution, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue and ammonium acetate (6.6 g) were dissolved in acetic acid (40 ml) and refluxed for 4 hours. The reaction mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed by silica gel to give 2-[(4,5-diphenyloxazol-2-yl)methyl]-1-(3-methoxyphenyl)cyclopentene (4.1 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19](O)=O)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[CH3:22][NH:23][C:24]1[C:25]([NH2:30])=[CH:26][CH:27]=[CH:28][CH:29]=1.C(OP(C#N)(OCC)=O)C.C(N(CC)CC)C>COCCOC>[CH2:17]([S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:4]=[C:3]([C:19]3[N:23]([CH3:22])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[N:30]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH2:9][CH2:10]1)(=[O:16])=[O:15])[CH3:18]
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Reactant: CNc1ccccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3nc4ccccc4n3C)n2)CC1
Temperature: 150 °C
Yield: 62.1 %

Procedure:
A mixture of 3-amino-6-(4-ethylsulfonylpiperazin-1-yl)pyrazine-2-carboxylic acid (100 mg, 0.3171 mmol), N-methylbenzene-1,2-diamine (42.61 mg, 39.64 μL, 0.3488 mmol), diethoxyphosphorylformonitrile (56.89 mg, 51.72 μL, 0.3488 mmol) and triethylamine (64.17 mg, 88.39 μL, 0.6342 mmol) in DME (3.000 mL) was heated in the microwave at 150° C. for 20 mins. The reaction mixture was allowed to cool and concentrated in vacuo. The resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a yellow solid (79 mg, 60% Yield).
Reaction SMILES: C(OC(=O)[C:5](=[CH:11][NH:12][C:13]1[N:17]([CH2:18][CH3:19])[N:16]=[CH:15][CH:14]=1)[C:6]([O:8]CC)=O)C.[CH2:21]([OH:23])[CH3:22].[C:24]1([O:30]C2C=CC=CC=2)C=CC=CC=1>>[CH2:21]([O:23][C:24]([C:15]1[C:14]2[C:13](=[N:12][CH:11]=[CH:5][C:6]=2[OH:8])[N:17]([CH2:18][CH3:19])[N:16]=1)=[O:30])[CH3:22]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)C(=CNc1ccnn1CC)C(=O)OCC
Reactant: CCO
Product: CCOC(=O)c1nn(CC)c2nccc(O)c12

Procedure:
253 g of [[(1-ethyl-5-pyrazolyl)amino]methylene]malonic acid diethyl ester (0.09 mol) is dissolved in 770 g of diphenyl ether. The reaction mixture is heated to 235°-250° (bath temperature) and allowed to react at this temperature for 1 to 2 hours, while the resulting ethanol is continuously distilled off. The remaining alcohol is removed by means of a water aspirator. The diphenyl ether is separated by distillation with a fractionating column in vacuo. The 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridinecarboxylic acid ethyl ester is obtained at b.p.0.05 115°-120°, yield 195 q = 92% of theory, m.p. 86°-87°. The compound is recrystallized from ligroin (90° to 100°), and has a melting point of 87°-89°.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:7]([O-])([OH:9])=[O:8]>O>[N+:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O-:9])=[O:8]
Reactant: c1ccccc1
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=[N+]([O-])c1ccccc1

Procedure:
Benzene (25 ml) was taken in a 50 ml two-necked round-bottomed flask equipped with a Dean-Stark apparatus. Fuming nitric acid (17 ml) was added dropwise into the reaction mixture and the reaction mixture was heated to reflux where upon the required amount of liberated water is collected in the Dean-Stark apparatus which usually takes 2 hrs. Later on, the catalyst was filtered and the reaction mixture was concentrated to obtain nitrobenzene.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([Br:20])[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(=N)O[C:25]([CH3:28])([CH3:27])[CH3:26].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([Br:20])[C:17]([O:19][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: O=C(NCCCC[C@H](Br)C(=O)O)OCc1ccccc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C(Br)CCCCNC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
(S)-6-{[(Benzyl-oxy)carbonyl]amino}-2-bromohexanoic acid, 10.0 g (0.029 mole), was dissolved in chloroform, 20 mL. To this was added a solution of t-butyl trichloroacetimidate, 12.7 g (0.058 mole), dissolved in chloroform, 50 mL, drop-wise over 30 minutes. The mixture was allowed to stir an additional 5 minutes and boron trifluoride etherate, 100 μL, was added. The reaction mixture was allowed to stir overnight. Sodium bicarbonate, 5 g, was added. After stirring 10 minutes, hexanes, 50 mL, was added and the mixture filtered to remove the solids present. The filtrate was evaporated and the residue purified by flash chromatography, ethyl acetate-hexanes, to give a clear-colorless oil. The yield was 8.5 g, 73% based on starting (S)-6-{[(benzyloxy)carbonyl]amino}-2-bromohexanoic acid. NMR is consistent with structure.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:23][C:24]#[N:25].CC#N>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:23][C:24]#[N:25])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#CCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Yield: 999.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (6.0 g, 2.7 mmol), NaHCO3 (2.5 g, 3.0 m-mol) chloroacetonitrile (2.5 g, 3.3 mmol) and CH3CN (150 mol) was stirred at reflux under N2 for 18 hours. The cooled reaction was poured into H2O and the aqueous solution was extracted with EtOAc. The EtOAc extract was washed with H2O washed with brine, dried with MgSO4 and concentrated to yield 7.0 g of a tan solid. A 1.3 g sample was recrystallized from EtOAc to yield 0.65 g of a beige solid, m.p. 154°-156° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Br:8])[S:5][C:6]=1[CH3:7].[C:9](OC=O)(=[O:11])C>>[Br:8][C:4]1[S:5][C:6]([CH3:7])=[C:2]([NH:1][CH:9]=[O:11])[N:3]=1
Reactant: Cc1sc(Br)nc1N
Reactant: CC(=O)OC=O
Product: Cc1sc(Br)nc1NC=O

Procedure:
4-Amino-2-bromo-5-methylthiazole is treated with formic-acetic anhydride (prepared as described in Example 12b) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]([NH:16][CH2:17][C:18]#[CH:19])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(CC)C(C)C)(C)C>ClCCl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]#[C:18][CH2:17][NH:16][C:9](=[O:10])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:4][CH:3]=1
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: Clc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
To a solution of 1-chloro-4-iodobenzene (6.40 g, 26.8 mmol) and N-boc propargylamine (5.00 g, 32.2 mmol) in dichloromethane (117 mL) was added copper (I) iodide (0.204 g, 1.07 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.754 g, 1.07 mmol). The solution was degassed with argon for 10 minutes, then N,N-diisopropylethylamine (14.3 mL, 81.9 mmol) was added and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated, then the residue was diluted with EA and water. The layers were separated and the aqueous layer was extracted twice more with EA. The combined organic layers were dried over anhydrous sodium sulfate, filtered, then concentrated. The residue was purified using column chromatography on silica gel (80 g Analogix column, gradient hexanes to 20% EA in hexanes over 20 minutes) to give the product (5.97 g, 84%). LCMS: (AA) ES+ 210, 212 (Boc group fragmentation). 1H NMR (400 MHz, d6-DMSO) δ: 7.47-7.39 (m, 4H), 7.35 (s, 1H), 3.97 (d, J=5.6 Hz, 2H), 1.39 (s, 9H).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:13]([O:21][CH3:22])[CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH3:23][O:24][C:25]1[CH:32]=[C:31]([CH2:33][CH:34]=O)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C([BH3-])#N.[Na+].CC(O)=O>CO.CCOC(C)=O>[CH3:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:13]([O:21][CH3:22])[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:34][CH2:33][C:31]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([O:24][CH3:23])[CH:32]=2)[CH2:17][CH2:16]1
Reactant: COC(CN1CCNCC1)c1ccc2c(c1C)COC2=O
Reactant: COc1cc(CC=O)ccc1C#N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(CCN2CCN(CC(OC)c3ccc4c(c3C)COC4=O)CC2)ccc1C#N
Reaction time: 12 h

Procedure:
4-Methyl-5-[1-(methyloxy)-2-piperazin-1-ylethyl]-2-benzofuran-1(3H)-one hydrochloride (50 mg, 0.17 mmol), 2-(methyloxy)-4-(2-oxoethyl)benzonitrile (60 mg, 0.34 mmol), sodium cyanoborohydride (108 mg, 1.72 mmol) and a stir bar were added to a 25 mL flask and few drops of AcOH. The resulting mixture was then dissolved in MeOH (3 mL) and stirred for 12 h; analysis by LC indicated that reaction had gone to completion. The reaction mixture was treated with EtOAc (20 mL) and washed with aq. NaHCO3, aq. NaCl. The organic phase was then dried over Na2SO4, filtered and concentrated to dryness; the resulting residue was then dissolved in MeOH (3.5 mL), filtered and shot into Mass-directed HPLC for separation to give the desired product. LC-MS (IE, m/z): 481 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[NH:19][C:20]([C:22]5[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=5)=[CH:21][C:14]=34)=[CH:11][N:10]([CH2:32][CH3:33])[N:9]=2)=[CH:4][CH:3]=1.[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>>[CH3:35][CH2:34][NH:36][C:37]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[C:14]=3[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH3:30])[CH3:31])=[CH:24][CH:23]=3)[NH:19]4)=[CH:11][N:10]([CH2:32][CH3:33])[N:9]=2)=[CH:6][CH:7]=1)=[O:38]
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN(C)C)cc4)cc23)c(-c2ccc(N)cc2)n1
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc(-c2nn(CC)cc2-c2ccnc3[nH]c(-c4ccc(CN(C)C)cc4)cc23)cc1

Procedure:
Following the procedure described in Example 48 using 4-[3-(4-aminophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[4-(dimethylaminomethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine and ethyl isocyanate provided the title compound. ESMS (M+H)+: 508.4
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10].C(N(CC)CC)C.[C:25]1([C:31](Cl)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCCCCCC>O1CCCC1>[CH3:7][N:6]1[C:2]([NH:1][C:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[C:3]([NH:8][C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 6.5 h
Yield: 80.7 %

Procedure:
To a suspension of 5-amino-1-methyl-4-phenoxycarbonylaminopyrazole (153.8 g) in tetrahydrofuran (1 L) were added triethylamine (67 g) and triphenylmethyl chloride (185 g) at room temperature. The mixture was stirred for 6.5 hours. To the reaction mixture was added heptane (2.6 L) and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and washed with heptane-diisopropyl ether (1:1). The crude solid was suspended in water (3 L) and the suspension was stirred for 1 hour. The solid was collected by filtration and dried to give 1-methyl-4-phenoxycarbonylamino-5-triphenylmethylaminopyrazole (253.6 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:14][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)cccc1-c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(-c2ccccc2)c1CBr
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A stirred solution of 3-chloro-2-methyl-[1,1'-biphenyl] (13.5 g, 0.067 mole) and N-bromosuccinimide (11.8 g, 0.067 mole) in 125 ml of carbon tetrachloride was irradiated and heated to reflux for 61/2 hours with a 250 watt brooder lamp. The light/heat source was turned off and the reaction mixture stirred at room temperature for approximately 64 hours. The reaction mixture was again irradiated and heated for two hours with the brooder lamp. The mixture was cooled, a solid precipitate filtered off, and the filter cake washed with two 50 ml portions of carbon tetrachloride. The filtrate was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give 2-bromomethyl-3-chloro-[1,1'-biphenyl] as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]2[C:4](=[C:5]([C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br-:29].[K+]>CS(C)=O.C1COCC1>[Br:29][C:10]1[C:9]2[C:4](=[C:5]([C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1
Reactant: Cc1cc(C)c(-c2cccc3c(OS(=O)(=O)C(F)(F)F)cc(C)nc23)c(C)c1
Reactant: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1cc(C)c(-c2cccc3c(Br)cc(C)nc23)c(C)c1
Temperature: 120 °C
Yield: 105.2 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 2-methyl-8-(2,4,6-trimethyl-phenyl)-quinolin-4-yl ester (426 mg, 1 mmol) and potassium bromide (KBr) (809 mg, 1.1 mmol) in a mixture of 1 ml of dry DMSO and 3 ml of dry THF was heated in 120° C. oil bath for 3 hours. The mixture was quenched with water, extracted with ethyl acetate. The organic layer was dried and concentrated to give 358 mg of the title compound as an off-white solid. 1H NMR (CDCl3) δ 8.16 (m,1H), 7.59 (m,1H), 7.56(s,1H), 7.48(m,1H), 6.97(s,1H), 2.53(s,3H), 2.37(s,3H), 1.87(,6H) ppm.
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:27][C:28]1[C:29]([F:51])=[CH:30][C:31]([Cl:50])=[C:32]([CH:49]=1)[O:33][C:34]1[CH:35]=[CH:36][C:37]2[N:38]([CH:40]=[C:41]([NH:43][C:44]([CH:46]3[CH2:48][CH2:47]3)=[O:45])[N:42]=2)[N:39]=1>CN(C)C=O.CN1CCCC1=O>[Cl:50][C:31]1[C:32]([O:33][C:34]2[CH:35]=[CH:36][C:37]3[N:38]([CH:40]=[C:41]([NH:43][C:44]([CH:46]4[CH2:47][CH2:48]4)=[O:45])[N:42]=3)[N:39]=2)=[CH:49][C:28]([NH:27][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][CH:15]=[C:7]([C:3]3([C:1]#[N:2])[CH2:4][CH2:5][CH2:6]3)[CH:8]=2)=[C:29]([F:51])[CH:30]=1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c(Cl)cc1F
Reactant: N#CC1(c2cccc(C(=O)O)c2)CCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(NC(=O)C6CC6)cn5n4)c(Cl)cc3F)c2)CCC1
Yield: 67.8 %

Procedure:
Using 3-(1-cyanocyclobutyl)benzoic acid (110 mg, 0.56 mmol), oxalyl chloride (60 μL, 0.70 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(5-amino-2-chloro-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (170 mg, 0.46 mmol) and N-methylpyrrolidone (3.0 mL) as starting materials and in the same manner as in Example 335, the title compound (170 mg, 68%) was obtained as a white powder.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](C(N)CCBr)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:21]([O:20][C:18](=[O:19])[NH:10][CH2:9][CH2:8][CH2:7][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)([CH3:22])([CH3:23])[CH3:24]
Reactant: c1ccc(C2(c3cccs3)CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)C(N)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCN1CCC(c2ccccc2)(c2cccs2)CC1
Yield: 20 %

Procedure:
A solution of 4-phenyl-4-(thiophen-2-yl)piperidine and 3-Boc-aminopropylbromide (1.0 g, 4.4 mmol) with 1 g of K2CO3 in 20 ml of dioxane was stirred at reflux for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic solution was dried over Na2SO4 and concentrated in vacuo to yield an oil which was subjected to column chromatography over silica gel (EtOAc) to provide 0.43 g (1.1 mmol, 20% for two steps) of 3-(4-phenyl-4-(thiophene-2-yl)piperidin-1-yl)-propylcarbamic acid tert-butyl ester as colorless oil. The ester in 5 ml of CH2Cl2 was added with 1 ml of CF3CO2H and resulting solution was stirred for 1 h at 25° C. The reaction mixture was concentrated in vacuo to yield oily mixture, which was dissolved in EtOAc and washed with aqueous NaHCO3. Concentration of the reaction mixture provided the desired product as an oil (0.29 g, 0.96 mmol, 88%) which was used in the next step without further purification.