Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](Cl)=[O:12])=[CH:3]1.Cl.[CH2:15]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([Br:38])[CH:31]=2)=[CH:26][CH:25]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:15]([N:22]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([Br:38])[CH:31]=2)=[CH:26][CH:25]=1)[C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)=[O:12])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cn1cc(C(=O)Cl)c2ccccc21
Reactant: COc1ccc(-c2ccc(CNCc3ccccc3)cc2)cc1Br
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccc(CN(Cc3ccccc3)C(=O)c3cn(C)c4ccccc34)cc2)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
1-methyl-1H-indole-3-carbonyl chloride (16.3 mmol), prepared in step 1 of Example 9, in 60 mL of methylene chloride was added under nitrogen dropwise over 15 minutes to a solution of the HCl salt of N-benzyl-N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]amine (5.0 g, 11.9 mmol), prepared in step 2 of Example 11, and triethylamine (4.6 mL, 33 mmol) in 100 mL of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature for 16 h. The reaction was extracted with 1 N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give N-benzyl-N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]-1-methyl-1H-indole-3-carboxamide (6.1 g, 95%) as a white solid, MS (ESI) m/z 539 [M+H]+. Elemental Analysis for C31H27BrN2O2: Calc'd: C, 69.02; H, 5.04; N, 5.19; Found: C, 68.55; H, 5.32; N, 4.99.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:19]([CH3:39])=[C:20]([CH:37]=[O:38])[C:21]4[O:25][C:24]([CH3:27])([CH3:26])[CH:23]([C:28]5[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=5)[C:22]=4[C:35]=3[CH3:36])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.O>C1COCC1>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:19]([CH3:39])=[C:20]([CH:37]([OH:38])[CH3:1])[C:21]4[O:25][C:24]([CH3:27])([CH3:26])[CH:23]([C:28]5[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=5)[C:22]=4[C:35]=3[CH3:36])[CH2:14][CH2:13]2)=[CH:10][CH:11]=1
Reactant: C[Mg]Br
Reactant: COc1ccc(N2CCN(c3c(C)c(C=O)c4c(c3C)C(c3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N2CCN(c3c(C)c(C(C)O)c4c(c3C)C(c3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Reaction time: 0.33 h
Yield: 1.3 %

Procedure:
To a solution of methyl magnesium bromide (THF solution 3.0 M, 1.0 mL, 3.0 mmol) in THF (5 ml) at −30° C. was added 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-7-carbaldehyde (310 mg, 640 mmol) obtained in Example 105. The reaction mixture was stirred for 20 minutes under the same temperature. The resulting mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane-ethyl acetate to obtain 19.5 mg (yield 61%) of the title compound. mp. 149–151° C.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([NH2:21])=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[NH:21][C:25]([CH:22]3[CH2:24][CH2:23]3)=[O:26])[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reactant: O=C(Cl)C1CC1
Product: O=C(Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)C1CC1

Procedure:
The title compound, MS: m/e=344.3 (M+H+), was prepared in accordance with the general method of example 18 from (R)—N2-indan-1-yl-quinoline-2,5-diamine and cyclopropane carbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.Cl.[CH3:34][C:35]1([C:41]([O:43][CH2:44][CH2:45][N:46]([CH3:48])[CH3:47])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:38]3[CH2:39][CH2:40][C:35]([CH3:34])([C:41]([O:43][CH2:44][CH2:45][N:46]([CH3:47])[CH3:48])=[O:42])[CH2:36][CH2:37]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CN(C)CCOC(=O)C1(C)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCOC(=O)C1(C)CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (3 mL) was added 2-(dimethylamino)ethyl 4-methylpiperidine-4-carboxylate hydrochloride (87 mg, 0.35 mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (38.0% MeCN up to 42.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 38.0% in 2 min); Detector, UV 254/220 nm. This resulted in 49.7 mg (41%) of the formic acid salt of 2-(dimethylamino)ethyl 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylate. LCMS (Method 28) [M+H]+=659.2, RT=1.23 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.35 (dd, 1H, J=1.2, 7.2 Hz), 8.68-8.64 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=9.2 Hz), 7.29 (dd, 1H, J=4.4, 6.8 Hz), 7.09 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 4.16 (t, 2H, J=5.6 Hz), 3.97-3.93 (m, 1H), 3.75-3.71 (m, 1H), 3.25-3.20 (m, 1H), 3.00-2.94 (m, 1H), 2.48-2.47 (m, 2H), 2.33 (s, 6H), 2.16-1.95 (m, 2H), 1.49-1.44 (m, 2H), 1.18 (s, 3H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].Cl.[NH2:22][C:23]([CH2:31][CH3:32])([CH2:29][CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:27]([O:26][C:24](=[O:25])[C:23]([CH2:31][CH3:32])([NH:22][C:14]([C:12]1[CH:11]=[CH:10][C:9]([C:17]([F:20])([F:19])[F:18])=[C:8]([O:7][CH2:6][CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[N:13]=1)=[O:16])[CH2:29][CH3:30])[CH3:28]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CCCO2)n1
Reactant: CCOC(=O)C(N)(CC)CC
Agent: Cl
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(C(F)(F)F)c(OCC2CCCO2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-((tetrahydrofuran-2-yl)methoxy)-5-(trifluoromethyl)picolinic acid and ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2) as starting materials. MS (EI): m/e=433.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl>CN(C)C=O.C(OCC)(=O)C.O>[N+:11]([C:10]1[CH:9]=[N:8][N:7]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])([O-:13])=[O:12].[N+:11]([C:10]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:7][N:8]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[CH:9]=1)([O-:13])=[O:12]
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c([N+](=O)[O-])cnn1COCC[Si](C)(C)C
Product: CCOC(=O)c1nn(COCC[Si](C)(C)C)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a 0° C. solution of 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester (6.4 g, 34.58 mmol) in dimethylformamide (80 mL) was added sodium hydride (2.07 g, 1.5 eq), and the resulting mixture was stirred from 0° C. to room temperature for one hour. To this mixture was added 2-(trimethylsilyl)ethoxy-methyl chloride (Aldrich) (9.17 mL, 1.5 eq), and the resulting mixture was stirred at room temperature for 2 days. The reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (300 mL) and water (100 mL). the organic layer was separated, washed with water (6×100 mL) and brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated to give 10 g of the crude product. Purification by column chromatography using 5% ethyl acetate in hexanes afforded 4-nitro-2-(2-trimethylsilanyl-ethoxymethyl)-2H-pyrazole-3-carboxylic acid, ethyl ester (3.82 g) as a colorless oil and 4-nitro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole-3-carboxylic acid, ethyl ester (4.055 g) as a light tan oil. (M−H)+=314.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[CH:11]=[C:10]([O:12][CH3:13])[N:9]=[N:8][C:7]=1NC(=O)C(C)(C)C)[CH2:4][CH3:5])[CH3:2].Cl[CH2:22][C:23](=O)[CH3:24].[C:26]([O-])(O)=O.[Na+]>CCO.[Cl-].[Cl-].[Zn+2]>[CH2:4]([CH:3]([C:6]1[C:7]2[N:8]([CH:22]=[C:23]([CH3:24])[CH:26]=2)[N:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[CH2:1][CH3:2])[CH3:5]
Reactant: CCC(CC)c1cc(OC)nnc1NC(=O)C(C)(C)C
Reactant: O=C([O-])O
Reactant: CC(=O)CCl
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CCO
Product: CCC(CC)c1cc(OC)nn2cc(C)cc12
Temperature: 25 °C
Yield: 10.8 %

Procedure:
A solution of N-[4-(1-ethyl-propyl)-6-methoxy-pyridazin-3-yl]-2,2-dimethyl-propionamide (5.32 g, 19.08 mmol) in EtOH (250 mL) is treated with ZnCl2 (26.0 g, 190.8 mmol) and refluxed for 48 h. The reaction is cooled to rt and concentrated. The residue is taken up with EtOAc (250 mL), and H2O (100 mL). It is washed with H2O (2×100 mL); dried with Na2SO4; filtered and concentrated. The residue is then dissolved in EtOAc (80 mL), reacted with chloroacetone (1.6 mL, 20.03 mmol.) at reflux overnight. While it is hot, NaHCO3 (8.10 g) is added and the reaction is refluxed for 1 h. It is cooled to rt and filtered through silica gel washed with EtOAc and concentrated. Purification of the crude material by chromatography gives the title compound (0.48 g, 2.07 mmol, 11%). 1H NMR (CDCl3): δ. 0.84 (t, J=7.5 Hz, 6H), 1.69-1.869 (m, 4H), 2.45 (s, 3H), 3.19-3.30 (m, 1H), 3.94 (s, 3H), 6.39 (s, 1H), 7.49 (s, 1H). ES-MS (m/z): calcd for C14H20N2O (M+H)+: 233.3; found: 234.1.
Reaction SMILES: [NH:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[NH2:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])=[CH:11][C:10]=1[CH:28]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[N:17]([CH3:26])[C:16]2=[O:27])=[CH:11][C:10]=1[CH:28]=[N:2][NH:1][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)NN
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=O)c2)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)NN=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reaction time: 2 h

Procedure:
1.0 g of ethyl hydrazinecarboxylate was added to a solution of 3.3 g of 3-[4-chloro-3-formylphenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine and 0.1 g of p-toluenesulfonic acid in 150 ml of toluene. After 2 hours, the solution was washed once with water, the organic phase was dried over sodium sulfate and evaporated down and the residue was stirred with petroleum ether. The precipitate was isolated, washed with petroleum ether and dried.
Reaction SMILES: [CH3:1][Si:2]([CH3:48])([CH3:47])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31]C(CC(OCC)=O)[CH2:29][CH2:28]2)[CH:9]=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC(I)=C2N=C(C2CC[N:69]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])CC2)C=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC(I)=C2N=C(C2CCC(CC(OCC)=O)CC2)C=1>>[CH3:46][Si:43]([CH3:45])([CH3:44])[CH2:42][CH2:41][O:40][CH2:39][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:47])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][N:69]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[CH2:29][CH2:28]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Agent: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1

Procedure:
tert-Butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate, but with tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate substituted for ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=2)=[C:27](B(O)O)[CH:28]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=2)=[C:25]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)[CH:24]=1
Reactant: OB(O)c1cc(F)ccc1OCc1cccc(F)c1
Reactant: CC(C)S(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: CC(C)S(=O)(=O)Cc1cccc(Nc2ncnc(-c3cc(F)ccc3OCc3cccc(F)c3)n2)c1

Procedure:
A suspension of crude 4-chloro-N-{3-[(prop-2-ylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (876 mg, 37% by weight) and {5-fluoro-2-[(3-fluorobenzyl)oxy]phenyl}boronic acid (264 mg) was treated as described in example 34. One obtained pure product (299 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5])[CH3:2].[H-].[Na+].Cl[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>CN(C)C=O.O.[Cu]>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: Clc1ccc2ccccc2n1
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(-c2ccc3ccccc3n2)c1C
Temperature: 20 °C
Reaction time: 0.2 h

Procedure:
2.75 g (17.9 mmol) of 3-ethoxycarbonyl-2-methyl-1H-pyrrole are added at 20° C. under an argon atmosphere to 0.756 g (18.9 mmol) of sodium hydride, at 60% by weight in liquid petroleum jelly, suspended in 12 mL of dimethylformamide. After stirring at 20° C. for 0.2 hour, 0.114 g (1.79 mmol) of copper powder and 2.93 g (17.9 mmol) of. 2-chloroquinoline are added. After stirring at 140° C. for 48 hours, the reaction mixture is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 100 mL of water and then extracted with 4 times 50 mL of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) to give 6 g of an oil, which oil is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (8/2 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa), 2.2 g of 3-ethoxycarbonyl-2-methyl-1-(quinol-2-yl)-1H-pyrrole are obtained in the form of a yellow oil. Mass spectrum (EI): m/e 280 (M+.), m/e 251, m/e 206.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].CC(C)=O.[N+:10]([C:13]1[CH:22]=[C:21]2[C:16]([NH:17][C:18](=[O:24])[C:19](=[O:23])[NH:20]2)=[CH:15][C:14]=1[S:25](Cl)(=[O:27])=[O:26])([O-:12])=[O:11].C(O)(=O)C>O>[CH2:1]([N:3]([CH2:4][CH3:5])[S:25]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:13]=1[N+:10]([O-:12])=[O:11])[NH:20][C:19](=[O:23])[C:18](=[O:24])[NH:17]2)(=[O:26])=[O:27])[CH3:2]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)Cl)cc2[nH]c1=O
Reactant: CCNCC
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CCN(CC)S(=O)(=O)c1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 59 %

Procedure:
To a solution of 10.97 g (0.015 mole) of diethylamine in 20 ml of acetone 4.58 g (0.015 mole) of 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxalinesulfonyl chloride are added a temperature between 5° C. and 10° C., under stirring, the mixture is stirred at the same temperature for 3 hours and allowed to stand for 16 hours. Then 6 ml of acetic acid and 40 ml of water are added to the mixture, the separated crystals are filtered off, washed with water and acetone, dried and recrystallized from acetonitrile. Thus 3.50 g (59%) of N,N-diethyl-1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: >360° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][N:24]=1)=[O:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.O>ClCCl>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][O:30][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:25][N:24]=1)=[O:22])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CO)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(COS(C)(=O)=O)cn1
Reaction time: 1 h
Yield: 94 %

Procedure:
Under ice cooling, methanesulfonyl chloride (4.2 mL, 54 mmol) was added to a solution of N-(2-t-butoxycarbonylaminophenyl)-5-hydroxymethylpyridine-2-carboxylic acid amide (Reference Compound No. 3-1, 16 g, 45 mmol) and triethylamine (16 mL, 110 mmol) in dichloromethane (150 mL), and then the reaction mixture was stirred for 1 hour. Water (400 mL) was added thereto, and then the whole was extracted with ethyl acetate (500 mL) five times. The organic layer was washed with water (500 mL), dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting solid was collected by filtration with hexane (80 mL) and ethyl acetate (20 mL) to give 18 g of the title reference compound as a white solid. (Yield 94%)
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:17])[NH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH:26]([CH3:28])[CH3:27]>CN(C=O)C>[CH2:25]([O:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][CH:10]([CH3:11])[CH3:5])[C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CBr
Reactant: CCOC(=O)c1c(O)c(=O)[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCC(C)C)c(=O)n(CC(C)C)c2ccccc12
Temperature: 50 °C

Procedure:
To a solution of ethyl 3-hydroxy-2-oxo-1,2-dihydroquinoline-4-carboxylate (250 mg, 1.07 mmol) in DMF (6 mL) was added cesium carbonate (908 mg, 2.79 mmol), 1-bromo-2-methylpropane (294 mg, 2.14 mmol). The reaction was heated at 50° C. for 16 h. The reaction mixture was allowed to cool to rt and washed with EtOAc. The organic phase was then washed with H2O and dried over Na2SO4 and concentrated in vacuo to give the crude product. Intermediate 28 was isolated via ISCO flash chromatography using a 40 g silica gel cartridge eluted with a 30-minute gradient from 0 to 100% EtOAc in hexane (350 mg, 1.01 mmol, 95% yield). LC-MS (ESI) m/z 346 (M+H), RT=2.30 min (Method B).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[Cl:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH:9]=[C:8](I)[CH:7]=1.CCN(CC)CC>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.CN(C=O)C>[Cl:5][C:6]1[CH:7]=[C:8](/[CH:3]=[CH:2]\[C:1]#[N:4])[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH:11]=1.[Cl:5][C:6]1[CH:7]=[C:8](/[CH:3]=[CH:2]/[C:1]#[N:4])[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH:11]=1
Reactant: C=CC#N
Reactant: COc1ccccc1Oc1cc(Cl)cc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccccc1Oc1cc(Cl)cc(/C=C/C#N)c1
Product: COc1ccccc1Oc1cc(Cl)cc(/C=C\C#N)c1
Temperature: 140 °C
Yield: 16 %
Yield: 45 %

Procedure:
Acrylonitrile (1.6 mL, 41 mmol) was added to a mixture of 9 (1.5 g, 4.1 mmol), Et3N (1.1 mL, 13 mmol), PdCl2(PPh3)2 (0.16 g 0.23 mmol), and dry DMF (15.0 mL) under a nitrogen atmosphere at room temperature. The mixture was heated at 140° C. for 3 h. The reaction mixture was quenched with water and extracted with EtOAc (3×50 mL). The organic layer was sequentially washed with brine (2×75 mL), dried over anhydrous Na2SO4, concentrated by rotary evaporation, and purified by column chromatography to give (Z)-3-(3-chloro-5-(2-methoxyphenoxy)phenyl)acrylonitrile (0.17 g, 16%) and (E)-3-(3-chloro-5-(2-methoxyphenoxy)phenyl)acrylonitrile (10) (0.52 g, 45%). 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H), 7.19-7.08 (m, 2H), 7.06-6.97 (m, 2H), 6.91 (ddt, J=15.9, 14.2, 4.6 Hz, 3H), 5.80 (dd, J=16.6, 5.2 Hz, 1H), 3.79 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>O.O1CCOCC1.C(OCC)(=O)C>[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:16]=[C:15]2[CH2:14][CH2:13][CH2:12][OH:11]
Reactant: C1=COCCC1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: OCCCc1c[nH]c2ccc(Cl)cc12
Temperature: 100 °C
Reaction time: 48 h
Yield: 64.4 %

Procedure:
A mixture of (4-chlorophenyl)hydrazine hydrochloride (5.26 g; 28.50 mmol) and 3,4-dihydro-2H-pyran (2.63 mL; 28.50 mmol) in a mixture of water (9 mL) and dioxane (36 mL) was stirred at 100° C. for 48 hours. After cooling to room temperature the mixture was diluted with ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 6% methanol in dichloromethane) to afford 3.85 g (64%) of 3-(5-Chloro-1H-indol-3-yl)propan-1-ol as an oily residue.