Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[N:7]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[NH:16][C:17]2[C:22]([C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][N:27]4C3CCCCO3)=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:8]1.[C:38]12([CH2:48][S:49]([OH:52])(=[O:51])=[O:50])[C:45]([CH3:47])([CH3:46])[CH:42]([CH2:43][CH2:44]1)[CH2:41][C:39]2=[O:40].N#N>C(Cl)Cl.CO>[C:38]12([CH2:48][S:49]([OH:52])(=[O:50])=[O:51])[C:45]([CH3:47])([CH3:46])[CH:42]([CH2:43][CH2:44]1)[CH2:41][C:39]2=[O:40].[N:31]1[C:23]([C:22]2[C:17]([NH:16][C:13]3[C:14]4[CH:15]=[N:7][NH:8][C:9]=4[CH:10]=[CH:11][CH:12]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:24]2[C:28]([NH:27][CH:26]=[N:25]2)=[N:29][CH:30]=1
Reactant: c1cnc(Nc2cccc3nn(C4CCCCO4)cc23)c(-c2ncnc3c2ncn3C2CCCCO2)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: N#N
Solvent: ClCCl
Solvent: CO
Product: c1cnc(Nc2cccc3[nH]ncc23)c(-c2ncnc3[nH]cnc23)c1
Temperature: 40 °C
Reaction time: 16 h
Yield: 174.5 %

Procedure:
A solution of 2-(tetrahydro-2H-pyran-2-yl)-N-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)-2H-indazol-4-amine (34.8 mg, 70 μmol) in DCM/MeOH (4 mL; 1:1) was treated with (+/−)-10-camphorsulfonic acid (8 mg, 0.5 equiv.) and the mixture stirred for 16 h. About 50% monodeprotection was observed in a clean reaction. An additional 20 mg of CSA was added (1.7 equiv. total). After 1 h, virtually complete monodeprotection observed and about 10% dideprotection. After 3 h, about 27% conversion to fully deprotected compound was observed in a clean reaction by LCMS. An additional 8 mg CSA was added (2.2 equiv. total) and the temperature of the reaction mixture was increased to 40° C. After a further 3 h, deprotection was essentially complete by LCMS. The volume of the reaction mixture was reduced by about 50% under a stream of N2 in order to remove DCM, and the solution was triturated with Et2O resulting in the formation of a precipitate which was collected by filtration washing with Et2O and dried under vacuum to give N-(3-(9H-purin-6-yl)pyridin-2-yl)-1H-indazol-4-amine (+/−)-10-camphorsulfonate salt (33.7 mg, 86% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 13.17 (br. s., 1H); 9.89 (d, 1H); 9.33 (s, 1H); 8.76 (s, 1H); 8.41-8.46 (m, 1H); 8.31 (s, 1H); 8.24 (d, 1H); 7.35 (t, 1H); 7.21 (d, 1H); 7.14 (t, 1H); 2.88 (d, 1H); 2.63-2.73 (m, 1H); 2.34-2.42 (d, 1H); 2.18-2.29 (m, 1H); 1.90-1.97 (m, 1H); 1.74-1.90 (m, 2H); 1.27 (m, 2H); 1.05 (s, 3H); 0.75 (s, 3H). m/z (ESI, +ve) 329.0 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li:14])CCC>>[CH-:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li+:14]
Reactant: C1=Cc2ccccc2C1
Reactant: [Li]CCCC
Product: [Li+]
Product: c1ccc2[cH-]ccc2c1
Temperature: 38 °C
Yield: 99 %

Procedure:
Under N2 a mixture of 51.6 g (0.115 mole) of technical grade indene (92.5% by GC analysis, pre-purified by a neutral alumina column), 186.3 g of dry diethyl ether and 8.0 g of dried (over 4 Å molecular sieve) toluene was placed in a 1-L flask. The flask was equipped with an agitator, a condenser and thermometer. To the mixture a total of 172 mL (0.4316 mole) of n-butyllithium (2.5 M in hexanes) was added dropwise in 2 portions. The pot temperature was allowed to raise to reflux (38° C.) during the addition. When 150 mL of butyllithium were added, the addition was stopped and the analysis (NMR) of the mixture indicated that 22 mL more of butyllithium were needed to finish the reaction. After feeding the calculated amount of butyllithium, the final analysis of the reaction mixture showed 99% conversion and 99% yield of lithium-indenide (Li-Ind). The mixture was used as such for the next reaction.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=1.[OH:15][C:16]([CH3:31])([CH3:30])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[O:28][CH3:29]>C(Cl)Cl.CO>[Cl:7][C:8]1[CH:13]=[CH:12][N:11]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:16]([OH:15])([CH3:31])[CH3:30])=[C:20]([O:28][CH3:29])[CH:21]=2)[C:10](=[O:14])[CH:9]=1
Reactant: COc1cc(B(O)O)ccc1OCC(C)(C)O
Reactant: O=c1cc(Cl)cc[nH]1
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(-n2ccc(Cl)cc2=O)ccc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 21 h
Yield: 62.8 %

Procedure:
Pyridine (1.2 mL, 15.4 mmol) was added to a stirred solution of commercially available 4-chloropyridin-2(1H)-one (100 mg, 0.77 mmol), 4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acid Part C (278 mg, 1.16 mmol), and copper (II) acetate, monohydrate (154 mg, 0.77 mmol) in CH2Cl2 (7 mL) and MeOH (0.7 mL). The reaction mixture stirred at RT under the presence of air overnight (21 hours). The reaction mixture was diluted with CH2Cl2, washed with IN HCl, sat. NaHCO3, dried (Na2SO4), and concentrated. The crude product was purified using preparative HPLC (C18 column/10:90:0.1 to 90:10:0.1 MeOH—H2O-TFA) to afford the desired product 4-chloro-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridin-2(1H)-one 9D (169 mg, 0.49 mmol, 62.8% yield) as a brown gum. LC/MS 324 (M+H)+, tR 0.75 min (method 5)
Reaction SMILES: C(O[C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25][CH3:26])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][O:21]2)=[C:8]([NH2:27])[N:7]=1)CCC.FC(F)(F)C(O)=O.[CH2:35]([NH:39]C1N=C2C(N=C(OC)N2)=C(N)N=1)[CH2:36][CH2:37][CH3:38].BrCCCBr>>[CH2:35]([NH:39][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25][CH3:26])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][O:21]2)=[C:8]([NH2:27])[N:7]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCNCC3CCCO3)c2n1
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: BrCCCBr
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCNCC3CCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 15 from N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt, 1,3-dibromopropane, and 2-(tetrahydro-2H-pyran-4-ylethyl)amine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)[CH:11]=2)=[CH:4][C:3]=1[NH:27][C:28]([N:30]1[C:34]2[N:35]=[CH:36][N:37]=[C:38](Cl)[C:33]=2[CH:32]=[CH:31]1)=[O:29].[NH2:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44]([NH2:46])=[O:45]>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)[CH:11]=2)=[CH:4][C:3]=1[NH:27][C:28]([N:30]1[C:34]2[N:35]=[CH:36][N:37]=[C:38]([NH:40][C:41]3[CH:49]=[CH:48][CH:47]=[C:43]([C:44](=[O:45])[NH2:46])[CH:42]=3)[C:33]=2[CH:32]=[CH:31]1)=[O:29]
Reactant: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(NC(=O)n4ccc5c(Cl)ncnc54)c3)cc(C(F)(F)F)c2)cn1
Reactant: NC(=O)c1cccc(N)c1
Solvent: CC(=O)O
Product: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(NC(=O)n4ccc5c(Nc6cccc(C(N)=O)c6)ncnc54)c3)cc(C(F)(F)F)c2)cn1
Temperature: 80 °C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
4-Chloro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoylamino]-phenyl}-amide, (50 mg, 0.09 mmol), prepared as in reference 3, in glacial acetic acid (2 mL) is mixed with 3-aminobenzamide (24.5 mg, 0.18 mmol) and shaken at 80° C. for 24 hours. The resulting mixture is directly purified by preparative HPLC-MS to give 4-(3-carbamoyl-phenylamino)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoylamino]-phenyl}-amide (42.9 mg, yield 73%); 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 10.65 (s, 1H), 9.96 (s, 1H), 9.68 (s, 1H), 8.59 (d, J=13.1 Hz, 1H), 8.51 (s, 1H), 8.50 (s, 1H), 8.45 (s, 1H), 8.41 (s, 1H), 8.19 (d, J=10.1 Hz, 2H), 8.09 (d, J=7.9 Hz, 1H), 7.94 (s, 1H), 7.83 (d, J=3.9 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.57 (d, J=4.7 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.08 (d, J=3.9 Hz, 1H), 2.43 (s, 3H), 2.34 (s, 3H); ESIMS m/z 654.1 (M++1).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[CH3:15][CH:16]([NH2:22])[CH2:17][CH:18]([CH3:21])[CH2:19][CH3:20]>>[Cl:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2]([NH:22][CH:16]([CH3:15])[CH2:17][CH:18]([CH3:21])[CH2:19][CH3:20])=[N:3][S:4](=[O:14])(=[O:13])[C:5]=2[CH:11]=1
Reactant: CCC(C)CC(C)N
Reactant: O=S1(=O)N=C(Cl)Nc2ccc(Cl)cc21
Product: CCC(C)CC(C)NC1=NS(=O)(=O)c2cc(Cl)ccc2N1

Procedure:
Starting from 3,7-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (500 mg; 1.99 mmol) and 1,3-dimethylpentylamine (1 g; 8.68 mmol) and with the use of same procedure as in example 21 230 mg (35.1%) of the title compound was prepared; m.p. >220° C.; 1H-NMR (DMSO-d6) ppm; 10.41 (s, 1H, NH), 7.68 (d, 1H, H-8), 7.60 (dd, 1H, H-5), 7.2 (d, 1H, H-7), 7.0 (br, 1H, NH), 3.95 (m, 1H, CH), 1.5 (m, 8H), 0.9 (m, 6H, 2×CH3); MS:EI/70eV: 329 (M+), 301, 258, 231, 190, 126, 69, 44. Analysis: C14H20ClN3O2S requires C, 50.98; H, 6.11; N, 12.74; (found C, 51.23; H, 6.42; N, 12.53).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[Br:10]Br.S(=O)(=O)(O)[O-].[Na+]>ClCCCl.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([Br:10])[C:5]([F:8])=[CH:4][C:3]=1[F:9]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: BrBr
Agent: [Fe]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Fc1cc(F)c(Br)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
Iron powder (16.49 g, 291 mmol) is added to 1-bromo-2,4-difluorobenzene (110 mL, 968 mmol) in 1,2-dichloroethane (968 mL) in a 3-neck flask at ambient temperature under a stream of nitrogen. A solution of bromine (59.7 mL, 1.16 mol) in 1,2-dichloroethane (968 mL) is added dropwise over 1 hour and the reaction mixture is stirred at ambient temperature for 18 h. The reaction mixture is cooled to 0° C. and a saturated aqueous solution of sodium bisulfate (1.11 L, 533 mmol) is added portionwise and the mixture is separated. The aqueous phase is extracted with dichloromethane. The organic layer is washed with a saturated aqueous solution of sodium bicarbonate, water, and brine. The organic layer is dried over sodium sulfate, and the solvent is removed under reduced pressure to give a residue purified with a pad of silica using diethyl ether to give the title compound (229 g, 76%). 1H NMR (400 MHz, CDCl3) δ 7.70 (dd, J=4.6, 6.8 Hz, 1H), 6.95-6.92 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[C:10]3[CH:17]=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:4][N:3]=1.[CH3:18][C:19]1[CH:28]=[CH:27][C:26]2[C:25]([NH:29][C:30]3[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=3[CH3:40])=[N:24][CH:23]=[CH:22][C:21]=2[C:20]=1[NH2:41].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:41][C:20]2[C:21]3[CH:22]=[CH:23][N:24]=[C:25]([NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:33]=[CH:32][C:31]=4[CH3:40])[C:26]=3[CH:27]=[CH:28][C:19]=2[CH3:18])[C:5]([C:9]2[C:10]3[CH:17]=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(C(F)(F)F)cc1Nc1nccc2c(N)c(C)ccc12
Reactant: Clc1ncc(-c2ncnc3[nH]ccc23)c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(C(F)(F)F)cc1Nc1nccc2c(Nc3nc(Cl)ncc3-c3ncnc4[nH]ccc34)c(C)ccc12
Temperature: 70 °C

Procedure:
A mixture of 4-(2,4-dichloropyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine (89 mg, 335 μmol) and 6-methyl-N1-(2-methyl-5-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine (111 mg, 335 μmol) in DMSO (2 mL) was treated with DIPEA (0.3 mL). The mixture was heated to 70° C. in an oil bath for 2 days. Additional quantities of 4-(2,4-dichloropyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine (3×20 mg) were added during the course of the reaction. The reaction mixture was cooled to rt and poured onto 50 g of ice with 20 mL of NaHCO3. The resulting suspension was extracted with EtOAc (3×50 mL). The EtOAc solution was washed with brine then dried over Na2SO4 and concentrated. The residue was purified via prep LCMS on silica [4% 1M NH3-MeOH in DCM-EtOAc (5-1)]. The residue was further purified by trituation in MeOH to give the title compound as a light yellow solid. MS (ESI, pos. ion) m/z: 561.2 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11]C([O-])=O.N1CCCCC1>N1C=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][C:10]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)C=Cc1ccc(O)cc1
Temperature: 105 °C
Yield: 80.1 %

Procedure:
To 20 g of p-hydroxybenzaldehyde and 32.5 g of monoethyl malonate were added 6 ml of pyridine and 0.2 ml of piperidine, then the mixture thus obtained was heated at 100 to 110° C. for 10 hours under stirring. The reaction mixture was then cooled, extracted with chloroform, and the chloroform layer was washed with a saturated aqueous solution of potassium hydrogen sulfite and water in this order, the chloroform extract was dried with magnesium sulfate. The solvent was removed by evaporation and the residue thus obtained was crystallized from isopropyl ether-n-hexane to yield 25.2 g of ethyl 4-hydroxycinnamate. Light yellow indefinite form crystals. Melting point: 70°-71° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=O.[C:18]([O-])(=O)[CH3:19].[NH4+:22]>CO>[CH3:11][C:2]1[CH:3]=[CH:4][C:5]([C:18]2[CH:19]=[C:14]([C:15]([OH:17])=[O:16])[CH:13]=[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[N:22]=2)=[CH:10][CH:1]=1
Reactant: [NH4+]
Reactant: CC(=O)[O-]
Reactant: O=C(O)C=CC(=O)c1ccc2ccccc2c1
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)cc(-c3ccc4ccccc4c3)n2)cc1

Procedure:
A mixture of 2.92 g (0.01 mole) of the appropriate pyridinium salt, 2.26 g (0.01 mole) of β-(2-naphthoyl)acrylic acid and 8.5 g of ammonium acetate in 20 ml of methanol is heated at reflux for 6 hr. The mixture is concentrated and the residue is diluted with water and extracted with methylene chloride. The organic layer is concentrated and the residue is chromatographed on silica gel using 5% methanol-1% acetic acid-94% methylene chloride. The product is recrystallized from ethanol yielding 1.14 g (33.6%) of the titled crystals with a melting point of 272°-274° C. The C:H:N ratio is 81.32:5.01:4.16.
Reaction SMILES: BrC1C=CC(Cl)=CC=1C#CC(OCC)(OCC)OCC.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[C:24]([C:46]#[C:47][C:48](OCC)([O:52]CC)[O:49][CH2:50][CH3:51])[CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO.O.CCOC(C)=O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[C:24]([C:46]#[C:47][C:48]([O:49][CH2:50][CH3:51])=[O:52])[CH:23]=1
Reactant: CCOC(=O)C1(c2ccc(Cl)cc2C#CC(OCC)(OCC)OCC)CCN(C(=O)OC(C)(C)C)CC1
Agent: CCOC(C#Cc1cc(Cl)ccc1Br)(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C#Cc1cc(Cl)ccc1C1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
In a separate round-bottomed flask, 1-bromo-4-chloro-2-(3,3,3-triethoxyprop-1-ynyl)benzene (487 mg, 1.3 μmol) and [Pd(PtBu3)Br]2 (105 mg, 135 μmol) were mixed. The reaction vessel was evacuated under vacuum and backfilled with argon. Toluene (5 mL) was added, and the mixture was heated to 50° C. for 5 minutes and then transferred by syringe to the enolate solution. The aryl bromide-Pd flask was rinsed with toluene (1 mL) and added to the reaction mixture. The resulting mixture was heated at 50° C. under nitrogen. After 90 minutes, the reaction was cooled to 23° C., diluted with EtOAc (100 mL), and washed with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (eluant: 4-6% EtOAc/hexane+1% TEA) affording the desired coupled product 1-tert-butyl ethyl 4-(4-chloro-2-(3,3,3-triethoxyprop-1-ynyl)phenyl)piperidine-1,4-dicarboxylate. A solution of the 1-tert-butyl ethyl 4-(4-chloro-2-(3,3,3-triethoxyprop-1-ynyl)phenyl)piperidine-1,4-dicarboxylate in EtOH (10 mL) and water (2 mL) was treated with p-toluenesulfonic acid monohydrate (69.3 mg, 364 μmol). The reaction was stirred at 23° C. for 30 minutes, and then diluted with EtOAc (100 mL) and washed with saturated NaHCO3 solution (2×50 mL) and brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 12-16% EtOAc/hexane), affording 155 mg of 1-tert-butyl ethyl 4-(4-chloro-2-(3-ethoxy-3-oxoprop-1-ynyl)phenyl)piperidine-1,4-dicarboxylate. MS m/e=486.1 (M+Na)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH:33]([N:36]([CH:39]([CH3:41])[CH3:40])[CH2:37][CH3:38])([CH3:35])C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:10][C:5]3[CH:6]=[CH:40][C:39]([N:36]4[CH:33]=[CH:35][CH:38]=[CH:37]4)=[CH:41][CH:4]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc(-n4cccc4)cc3)C2)c1
Reaction time: 8 h
Yield: 185.8 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (44.4 mg, 0.10 mmol) in CH3CN (5 ml) was added 1-[4-Bromomethyl) phenyl]-H-pyrrole) (35.1 mg, 0.15 mmol) and diisopropylethylamine (35 μl, 0.20 mmol). The reaction was microwaved at 150° C. for 1 hour, then continued at room temperature overnight, then diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (56 mg, 94%). Calcd for C37H41F3N2O2 (M+H) 602.73, Found 603.5
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]1[C:29](=[O:30])[CH2:28][CH:27]([CH2:31]OS(C)(=O)=O)[CH2:26]1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:31][CH:27]2[CH2:28][C:29](=[O:30])[N:25]([C:19]3[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=3[F:17])[CH2:26]2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)OCC1CC(=O)N(c2ccc(F)cc2F)C1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(CC2CC(=O)N(c3ccc(F)cc3F)C2)c1
Temperature: 57.5 °C
Yield: 88.3 %

Procedure:
A mixture of 1H-Pyrazole-4-carboxylic acid ethyl ester (0.100 g, 0.713 mmol), potassium carbonate (0.019 g, 1.42 mmol), Methanesulfonic acid 1-(2,4-difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl ester (0.32 g, 1.07 mmol) were taken in DMF (2 ml). The reaction mixture was heated at 55-60° C. for 20 hour. The mixture was cooled to room temperature and then to this reaction mixture water (20 ml) was added and extracted with ethyl acetate (3×25 ml), organic layers were combined and washed with brine (25 ml), dried over Na2SO4 and evaporated to dryness to obtain 1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.22 g, 91%) as a brownish sticky mass.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8]/[CH:9]=[C:10](\[CH3:14])/[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:12][C:11](=[O:13])/[C:10](/[CH3:14])=[CH:9]/[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C/C(=C\C=C(c1ccccc1)c1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C/C(=C\C=C(c1ccccc1)c1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid (1.85 g) and 4-nitrophenol (1.12 g) in dichloromethane (25 mL), stirred at 0°-5° C. in an ice-water bath, was treated with 1,3-dicyclohexylcarbodiimide (1.44 g). The mixture was stirred at 0°-5° C. for 30 minutes, then at room temperature for 1 hour. After the precipitated dicyclohexylurea was filtered off, the concentrated filtrate was passed through a short column of silica gel (~25 g) made up in dichloromethane-hexane (3:2). The appropriate fractions were combined and evaporated to give 2.4 g of (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid 4-nitrophenyl ester. Crystallization of the material from 2-propanol furnished 1.64 g of (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid 4-nitrophenyl ester mp 139°-141° C. Anal. Calculated for C24H19NO4 : C, 74.79; H, 4.97; N, 3.63 Found: C, 74.83; H, 5.05 ; N, 3.68.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])=[C:12](Br)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:30][S:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)(C)C>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.O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])=[C:12]([C:35]3[CH:36]=[CH:37][C:32]([S:31][CH3:30])=[CH:33][CH:34]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: C[C@H](CCOc1c(Br)cnn(-c2ccc(F)c(F)c2)c1=O)O[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CSc1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2OCC[C@@H](C)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, a mixture of the product from Example 545C (0.98 g, 2 mmol), 4-(methylthio)benzeneboronic acid (0.4 g, 2.4 mmol), K3PO4 (1.2 g, 6 mmol), PdCl2(PPh3)2 (28 mg, 0.04 mmol), isopropanol (9 mL), and water (1 mL) was stirred at 70° C. for 4 hours. The reaction mixture was then cooled to room temperature, water (30 mL) was added and stirring was continued for 2 hours. The crude black precipitate was collected by filtration then washed with water (10 mL) and hexane (10 mL). This title intermediate was used without further purification in the following oxidation/deprotection step.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1>>[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:7]([C:3]4[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=4)=[O:9])[CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: Cn1cccc1C(=O)O
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: Cn1cccc1C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 9, making variations only as required to use 1-methyl-1H-pyrrole-2-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)-amide, the title compound was obtained as a white powder (51.8% yield). 1H NMR (500 MHz, CDCl3) δ 8.07, 8.01, 7.00, 6.75, 6.40, 6.12, 4.00-3.80, 3.58, 1.52, 0.76, 0.48, 0.10. MS (ES+) m/z 383 (M+1).