Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=1[CH3:28])[CH2:10][C:9]2([CH3:30])[CH3:29])=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:29][C:9]1([CH3:30])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[CH3:28])[CH2:10]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(N3CCOCC3)ccc1C)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Temperature: 60 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
To a stirred mixture solution of 4,4-dimethyl-2-(2-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.2 g, 7.8 mmol) in methanol (50 mL) and tetrahydrofuran (50 mL) was added 30% sodium hydroxide in water (10 mL). The reaction mixture was stirred at 60° C. for 3 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4-dimethyl-2-(2-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2.4 g, 80%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=381.1.
Reaction SMILES: [F:1][CH2:2][C:3]1([S:6]([NH:9][C:10]([C@@:12]23[CH2:27][C@H:26]2[CH:25]=[CH:24][CH2:23][CH2:22][CH:21]([CH3:28])[CH2:20][C@@H:19]([CH3:29])[C@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:17](=[O:38])[N:16]2[CH2:39][C@H:40]([OH:42])[CH2:41][C@H:15]2[C:14](=[O:43])[NH:13]3)=[O:11])(=[O:8])=[O:7])[CH2:5][CH2:4]1.Cl[C:45]1[C:54]2[C:49](=[CH:50][C:51]([O:55][CH3:56])=[CH:52][CH:53]=2)[N:48]=[C:47]([C:57]2[CH:62]=[CH:61][C:60]([O:63][CH:64]([CH3:66])[CH3:65])=[CH:59][CH:58]=2)[CH:46]=1.CC([O-])(C)C.[K+]>CS(C)=O>[F:1][CH2:2][C:3]1([S:6]([NH:9][C:10]([C@@:12]23[CH2:27][C@H:26]2[CH:25]=[CH:24][CH2:23][CH2:22][CH:21]([CH3:28])[CH2:20][C@@H:19]([CH3:29])[C@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])[C:17](=[O:38])[N:16]2[CH2:39][C@H:40]([O:42][C:45]4[C:54]5[C:49](=[CH:50][C:51]([O:55][CH3:56])=[CH:52][CH:53]=5)[N:48]=[C:47]([C:57]5[CH:62]=[CH:61][C:60]([O:63][CH:64]([CH3:66])[CH3:65])=[CH:59][CH:58]=5)[CH:46]=4)[CH2:41][C@H:15]2[C:14](=[O:43])[NH:13]3)=[O:11])(=[O:7])=[O:8])[CH2:5][CH2:4]1
Reactant: COc1ccc2c(Cl)cc(-c3ccc(OC(C)C)cc3)nc2c1
Reactant: CC1CCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(CF)CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Agent: CC(C)(C)[O-]
Agent: CC1CC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(CF)CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Agent: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(CF)CC6)C[C@H]5/C=C\CCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)cc(-c3ccc(OC(C)C)cc3)nc2c1
Solvent: CS(C)=O
Product: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(CF)CC6)C[C@H]5C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)cc(-c3ccc(OC(C)C)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-hydroxy-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate (150 mg, 0.238 mmole) and 4-chloro-2-(4-isopropoxyphenyl)-7-methoxyquinoline (93 mg, 0.284 mmole) in DMSO (8 mL) was added t-BuOK (133 mg, 1.19 mmol, 1 M solution in THF, 1.2 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mass was quenched with aqueous citric acid solution and extracted with ethyl acetate (10 mL×2). The combined organic layer was washed with water, brine solution, dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by HPLC to get 130 mg (60%) of desired compound tert-butyl (2R,6S,7R,13aS,14aR,16aS,Z)-14a-(1-(fluoromethyl)cyclopropylsulfonylcarbamoyl)-2-(2-(4-isopropoxyphenyl)-7-methoxyquinolin-4-yloxy)-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate as white solid. MS: MS m/z 921.5 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:16][CH3:17])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[C:12][CH:13]2[CH2:15][CH2:14]2)[CH:7]=1.[Si]([O:25][CH2:26][CH:27]([F:43])[CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)(C(C)(C)C)(C)C.[F-].[K+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:13]1([C:12]#[C:11][C:10]2[CH:9]=[N:8][N:6]3[CH:7]=[C:2]([C:32]4[CH:31]=[N:30][N:29]([CH2:28][CH:27]([F:43])[CH2:26][OH:25])[CH:33]=4)[CH:3]=[C:4]([O:16][CH3:17])[C:5]=23)[CH2:15][CH2:14]1
Reactant: CC1(C)OB(c2cnn(CC(F)CO[Si](C)(C)C(C)(C)C)c2)OC1(C)C
Reactant: COc1cc(Br)cn2ncc(C#CC3CC3)c12
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(-c2cnn(CC(F)CO)c2)cn2ncc(C#CC3CC3)c12
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
6-bromo-3-(cyclopropylethynyl)-4-methoxypyrazolo[1,5-a]pyridine (36.0 mg, 0.124 mmol), 1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2-fluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (95.0 mg, 0.247 mmol), tris(dibenzylideneacetone)dipalladium (11.3 mg, 0.012 mmol), potassium fluoride (38.1 mg, 0.655 mmol), and tri-t-butylphosphonium tetrafluoroborate (7.2 mg, 0.025 mmol) were suspended in 1.3 mL of DMF and sparged with Ar for 10 minutes. The mixture was heated to 100° C. for 1 h, then allowed to cool to ambient temperature. Tetra-n-butylammonium fluoride (247 μl 0.247 mmol, 1M in THF) was added and the mixture was allowed to stir for 30 minutes, then additional tetra-n-butylammonium fluoride (247 μl, 0.247 mmol, 1M in THF) was added and the mixture was stirred for 30 minutes more. The reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA (20-100%). The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to give a yellow solid that was slightly impure. The residue was purified by column chromatography on silica gel (methanol/ethylacetate gradient) to give 3-{4-[3-(cyclopropylethynyl)-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-1H-pyrazol-1-yl}-2-fluoropropan-1-ol. 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H); 8.36 (s, 1H); 8.09 (s, 1H); 7.94 (s, 1H); 6.92 (s, 1H); 5.15 (t, 1H); 4.78-4.93 (m, 1H); 4.34-4.46 (m, 2H); 3.96 (s, 3H); 3.50-3.72 (m, 2H); 1.48-1.54 (m, 1H); 0.80-0.87 (m, 2H); 0.66-0.70 (m, 2H). LRMS (ESI) calculated for C19H20FN4O2 [M+H]+, 355.1; found 355.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:20]3[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=3)([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[C:3]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38].CB1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+].O.[NH4+].[Cl-]>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.O1CCOCC1.COCCOC>[CH2:29]([N:26]([CH2:27][CH3:28])[C:4]1[C:3]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:2]([CH3:37])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:20]3[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=3)([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=1)[CH3:30].[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]
Reactant: CCN(CC)c1nc2ccc(C(O)(c3ccncc3)c3cncn3C)cc2c(Cl)c1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)c1nc2ccc(C(O)(c3ccncc3)c3cncn3C)cc2c(C)c1-c1ccccc1
Temperature: 90 °C

Procedure:
A sealed tube containing [4-chloro-2-(diethylamino)-3-phenylquinolin-6-yl](1-methyl-1H-imidazol-5-yl)pyridin-4-ylmethanol•TFA (21 mg, 0.029 mmol, Example 99), Pd(PPh3)4 (5.0 mg, 0.0043 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.010 mL, 0.072 mmol), 2.0 M K2CO3 in water (0.050 mL, 0.10 mmol), and 1,2-dimethoxyethane (1.2 mL) was bubbled with N2 for 3 min. After heating at 90° C. for 17 hours, more Pd(PPh3)4 (5.0 mg, 0.0043 mmol), 2.0 M K2CO3 in water (0.040 mL, 0.080 mmol), and 1,4-dioxane (1 mL) were added. The mixture was heated at 130° C. for 16 hours. NH4Cl (aqueous) was added, the organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered, concentrated, and purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to give the title compound. 1H NMR (400 MHz, MeOH-d4) δ 9.06 (s, 1H), 8.79 (d, J=6.57 Hz, 2H), 8.25 (d, J=2.02 Hz, 1H), 8.14 (d, J=9.09 Hz, 1H), 7.94 (d, J=6.57 Hz, 2H), 7.88 (dd, J=2.02, 9.09 Hz, 1H), 7.51-7.64 (m, 3H), 7.40 (d, J=6.57 Hz, 2H), 7.20 (s, 1H), 3.69 (s, 3H), 3.46 (q, J=7.07 Hz, 4H), 2.41 (s, 3H), 1.04 (t, J=7.07 Hz, 6H); MS m/e 478.0 [M+H]+.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH2:11][CH3:12])[N:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:26]=[CH:25][C:24]([C:27]([C:34]3[N:38]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:37]4[CH:47]=[CH:48][CH:49]=[CH:50][C:36]=4[N:35]=3)=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.C1COCC1>[CH2:11]([N:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:2]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([C:34]3[N:38]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:37]4[CH:47]=[CH:48][CH:49]=[CH:50][C:36]=4[N:35]=3)=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=2)=[N:3]1)[CH3:12]
Reactant: CCOC(=O)C=C(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1nc2ccccc2n1COCC[Si](C)(C)C
Reactant: CCn1nc(Br)c2ncccc21
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
Product: CCOC(=O)C=C(c1ccc(-c2nn(CC)c3cccnc23)cc1)c1nc2ccccc2n1COCC[Si](C)(C)C
Temperature: 150 °C
Yield: 88.9 %

Procedure:
A mixture of 3-bromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine (300 mg), ethyl 3-{4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}-3-(1-[{2-(trimethylsilyl)ethoxy}methyl]-1H-benzo[d]imidazol-2-yl)acrylate (1456 mg), Pd(PPh3)4 (77 mg), 2 M Na2CO3 aqueous solution (1.991 mL) and THF (4 mL) was heated at 150° C. for 30 min under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give the title compound (670 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:24][CH2:25][N:26]3[C:30](=[O:31])[CH2:29][S:28][C:27]3=[O:32])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[CH:33]1([CH:36]=O)[CH2:35][CH2:34]1.N1CCCCC1.ClCCl>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:24][CH2:25][N:26]3[C:30](=[O:31])[C:29](=[CH:36][CH:33]4[CH2:35][CH2:34]4)[S:28][C:27]3=[O:32])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2CCN1C(=O)CSC1=O
Reactant: O=CC1CC1
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CO
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2CCN1C(=O)SC(=CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
Into a 50-mL scaled tube, was placed a solution of 3-[2-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-1,3-thiazolidine-2,4-dione (100 mg, 0.22 mmol, 1.00 equiv) in methanol (20 mL), cyclopropanecarbaldehyde (47 mg, 0.67 mmol, 2.99 equiv), piperidine (9.5 mg, 0.11 mmol, 0.50 equiv), dichloromethane (5 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 28 mg (24%) of 3-[2-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-5-(cyclopropylmethylidene)-1,3-thiazolidine-2,4-dione as a white solid. LC-MS (ES, m/z): 499 (M+H)+
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].CC(C[AlH]CC(C)C)C.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](OC)=[O:27])=[CH:21][CH:20]=1)#[N:18]>C1COCC1.CCOC(C)=O>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH:5][C:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]#[N:18])=[CH:20][CH:21]=1)=[O:27]
Reactant: CC(C)(C)CCN
Reactant: COC(=O)Cc1ccc(C#N)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)CCNC(=O)Cc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
Dissolve 3,3-dimethylbutylamine (0.8 mL, 6.4 mmol) in anhydrous THF (2 mL) under nitrogen. Cool the solution at 0° C. and add DIBAL-H (6.2 mL, 6.2 mmol, 1M solution in toluene). Allow the mixture to warm up to room temperature and stir for 2 h. Add this complex to a solution of methyl (4-cyanophenyl)acetate (192 mg, 1.1 mmol) in THF (4 mL) and stir at room temperature overnight. Dilute with EtOAc and quench with 5% KHSO4. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (7:3) to obtain the desired intermediate (160 mg, 60%). MS (ES+) m/z: 245 (M+H)+.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].N12CCCN=C1CCCCC2.[CH:28]([C:30]([CH2:32][CH3:33])=[O:31])=[CH2:29]>O1CCCC1>[CH2:1]([C:5]1([CH2:29][CH2:28][C:30](=[O:31])[CH2:32][CH3:33])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: C=CC(=O)CC
Reactant: CCCCC1Cc2cc(OC)ccc2C1=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC1(CCC(=O)CC)Cc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.8 %

Procedure:
A solution of crude 2-butyl-5-methoxy-1-indanone (218 mg, 1 mmol) in tetrahydrofuran (THF, 2 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.030 mL, 0.2 mmol) and ethyl vinyl ketone (EVK, 0.200 mL, 2 mmol). The resulting solution was stirred under a nitrogen atmosphere at room temperature for 16 hours, followed by heating in an oil bath at 60° C. for 24 hours. Evaporation of the solvent under vacuum left a residue that was shown by NMR to be approximately a 1:1 mixture of starting material and product. The residue was purified by preparative layer chromatography on three 0.1×20×20 cm silica gel GF plates using 5% EtOAc in CH2Cl2 as developing solvent. The product band was eluted with EtOAc to provide 2-butyl-5-methoxy-2-(3-oxo-pentyl)-1-indanone (84 mg) as an oil.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[C:21]2[N:27]([CH3:39])[C:28](=[O:38])[C:29]([C:31]4[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=4)=[CH:30][C:20]3=2)[N:16]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1.O>C(O)(C(F)(F)F)=O>[NH2:10][CH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[C:21]2[N:27]([CH3:39])[C:28](=[O:38])[C:29]([C:31]4[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=4)=[CH:30][C:20]3=2)[N:16]=1
Reactant: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4csc(CNC(=O)OCc5ccccc5)n4)ccc3n(C)c21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CSc1ccccc1
Product: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4csc(CN)n4)ccc3n(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of compound A {4-[3-(4-bromophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]thiazol-2-ylmethyl}carbamic acid benzyl ester (200 mg, 0.32 mmol) and thioanisole (308 μl, 2.60 mmol) in 2 ml of TFA is left to stir overnight at ambient temperature. H2O is added, the mixture is extracted with EtOAc, the organic phases are washed with H2O and the product is dried over MgSO4, filtered and concentrated. Purification is carried out by chromatography on a silica column, elution being carried out with 100% EtOAc and then with an EtOAc/5% MeOH mixture then with an EtOAc/5% MeOH/1% TEA mixture. The residue is taken up in a 1/1 EtOAc/Et2O mixture and the product is filtered and washed with a minimum amount of Et2O.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].Br[CH2:15][C:16]1[CH:20]=[CH:19][O:18][N:17]=1.[H-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]([N:5]([CH2:15][C:16]1[CH:20]=[CH:19][O:18][N:17]=1)[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: BrCc1ccon1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1N(Cc1ccon1)C(=O)CCl

Procedure:
A mixture of 6.1 g N-chloroacetyl-2,6-dimethylaniline and 5 g 3-bromomethylisoxazole (prepared as in Example 6 above) in 200 ml dry dimethylformamide was treated with 1.5 g sodium hydride as in Example 3 above. After workup, the solid product was purified by column and high-pressure liquid chromatography to yield a pure product, m.p. 78°-81° C. This product is shown as Compound 2 in Table I. C14H15ClN2O2 : calc., %C 60.32, %H 5.39, %N 10.05; found, %C 60.72, %H 5.71, %N 8.85.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:64][C:65]1[S:66][CH:67]=[CH:68][N:69]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:18]([CH3:22])([CH3:23])[C:19]([NH:64][C:65]4[S:66][CH:67]=[CH:68][N:69]=4)=[O:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1nccs1
Reactant: CC(C)(C(=O)O)C(Cc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)Nc1nccs1)C(Cc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
To a stirred solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-4-phenylbutanoic acid (10 mg, 0.025 mmol) and diisopropylethylamine (0.05 mL) in anhydrous DMF (0.2 mL) was added HATU (25 mg, 0.066 mmol) at rt under argon. After stirring at rt for 10 min, 2-aminothiazole (15 mg, 0.15 mmol) was added. The reaction mixture was stirred at rt for 2.5 hr, 40° C. for 1 hr, and 80° C. for 30 min. Purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) gave 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethyl-4-phenyl-N-(thiazol-2-yl)butanamide (Example 138, 7 mg, 0.01 mmol, 40% yield) as a white solid. MS found: (M+H)+=485. 1H-NMR (400 MHz, CDCl3) δ ppm 8.00 (1H, s) 7.53-7.58 (3H, m) 7.44 (1H, d, J=8.65 Hz) 7.35 (1H, d, J=3.56 Hz) 7.23 (1H, d, J=7.63 Hz) 7.11-7.15 (2H, m) 6.89-6.99 (7H, m) 3.63 (1H, dd, J=10.43, 4.32 Hz) 2.97-3.08 (2H, m) 1.37 (3H, s) 1.18 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[OH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:36](=[O:37])[C:35]3[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][OH:23])=[CH:40][CH:39]=3)[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: O=C(O)c1ccc(CCCCCCCCO)cc1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCCCCCO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 154 %

Procedure:
A solution of Intermediate 7 (182 mg, 0.6 mmol), 4-(8-hydroxyoctyl)benzoic acid (100 mg, 0.4 mmol, e.g. preparable according to K. Fukai JP11174621), (1H-1,2,3-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP, 208 mg, 0.4 mmol, e.g. available from Aldrich) and N,N-diisopropylethylamine (0.276 ml, 1.6 mmol) in dry N,N-dimethylformamide (3 ml) was allowed to stir at room temperature for 4 hours. The solvent was evaporated and the residue partitioned between chloroform (10 ml) and saturated aqueous sodium bicarbonate solution (10 ml); the organic fraction was collected by passing through a hydrophobic frit and evaporated. The residue was dissolved in chloroform (20 ml), and the solution passed through a 10 g aminopropyl SPE cartridge under gravity. The cartridge was further eluted with 10% methanol in chloroform, and product containing fractions evaporated to give the title compound (330 mg). LCMS showed MH+=536; TRET=2.92 min.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].Cl[C@@H:20]([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C.CCOC(C)=O.[Li+].[Cl-]>[O:7]=[C:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:12])[N:2]1[O:1][C@H:20]([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: C[C@H](Cl)C(=O)OC(C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](ON1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 72 h
Yield: 84.7 %

Procedure:
To a slurry of N-hydroxyphthalimide (3.71 g, 22.1 mmol) and potassium carbonate (4.58 g, 33.1 mmol) in DMF (55 mL) was added (S)-tert-butyl 2-chloropropanoate (4.30 g, 24.3 mmol). After 72 h of stirring, the slurry was heated to 40° C. for an additional 16 h, at which point it was diluted with EtOAc/LiCl (5% aq) and the layers were separated. The aqueous layer was extracted with EtOAc (2×) and the combined organic layers were washed with LiCl (5% aq), brine, dried over Na2SO4 and concentrated in vacuo, affording the title compound (5.45 g, 85%) as an off-white solid. LCMS: Rt=0.88 min, m/z=313.9 (M+23) Method 2m_acidic.