Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]([C@@H:6]1[CH2:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C@H:8]([C:19]2[CH:27]=[CH:26][C:22]3[O:23][CH2:24][O:25][C:21]=3[CH:20]=2)[NH:7]1)=[O:5].[CH3:28][C:29](C)=[O:30]>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C@H:8]([C:19]2[CH:27]=[CH:26][C:22]3[O:23][CH2:24][O:25][C:21]=3[CH:20]=2)[N:7]1[C:29](=[O:30])[CH2:28][Cl:1])=[O:5]
Reactant: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)[C@H](c2ccc3c(c2)OCO3)N1
Reactant: CC(C)=O
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)[C@H](c2ccc3c(c2)OCO3)N1C(=O)CCl
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
Cis 1 -Benzo[1,3]dioxol-5 -yl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester hydrochloride (50 g) was dissolved in dichloromethane and 5% aqueous sodium bicarbonate (500 mL). The organic layer was separated and washed with deionized water (500 mL). The organic layer was added into deionized water (50 mL) and treated with sodium bicarbonate (15 g) at 25-30° C. To the resultant mixture chloroacetyl chloride (25 g) in dichloromethane (50 mL) was added at a rate sufficient to maintain the temperature of the reaction mixture between 0 and 5° C. The reaction mixture was stirred for three hours. After the completion of reaction, dichloromethane (500 mL) and DI water (1 L) were added. The organic layer was separated and washed sequentially with water followed by aqueous sodium bicarbonate solution till pH was 6.5-7.0, and finally with water. The organic layer was concentrated under reduced pressure to obtain a solid. The solid was dissolved in acetone (750 mL) and the resultant solution was concentrated to a residual volume of about 75 mL. To the concentrated solution, deionized water was slowly added at 20-25° C. and the resultant mixture cooled to 0-5° C. with continuous stirring for 0.5 hours. The solid so obtained was filtered and dried to afford cis 1-benzo[1,3]dioxol-5-yl-2-(2-chloro-acetyl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]([O:18]C)=[O:17])[N:13]=1.[OH-].[Li+]>CO.O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])[N:13]=1
Reactant: COC(=O)/C=C/c1csc(-c2c(Cl)cccc2Cl)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)/C=C/c1csc(-c2c(Cl)cccc2Cl)n1
Reaction time: 24 h
Yield: 90 %

Procedure:
To a stirred solution of (E)-methyl 3-(2-(2,6-dichlorophenyl)thiazol-4-yl)acrylate (6.3 g, 20 mmol) in MeOH (100 mL) and H2O (20 mL) was added lithium hydroxide (1.5 g, 61 mmol). The resulting mixture was stirred for 24 hours and then partially concentrated under reduced pressure. The pH of the residual aqueous mixture was adjusted to 5 by addition of 2N HCl and extracted with EtOAc (3×100 mL). The combined organic extract was washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a 0-20% gradient of MeOH in DCM to give the desired product as a white solid (5.4 g, 94% yield). LCMS (ESI) m/z: 300.0 [M+H+].
Reaction SMILES: O1[C:5]2([CH2:9][CH2:8][N:7]([C@H:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]3[O:16][CH2:17][CH2:18][C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[CH2:6]2)[O:4]CC1.S([O-])(=O)(=O)C.O>COCCOC>[ClH:25].[O:4]=[C:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[O:16][CH2:17][CH2:18][C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])[CH2:6]1
Reactant: Clc1cccc(Cl)c1CCO[C@H]1CCCC[C@@H]1N1CCC2(C1)OCCO2
Agent: CS(=O)(=O)[O-]
Solvent: COCCOC
Solvent: O
Product: Cl
Product: O=C1CCN([C@H]2CCCC[C@@H]2OCCc2c(Cl)cccc2Cl)C1
Yield: 70 %

Procedure:
(1R,2R)/(1S,2S)-2-[1,4-Dioxa-7-azaspiro[4.4]non-7-yl]-1-(2,6-dichlorophenethoxy)cyclohexane: The mesylate from (vi) in anhydrous ethylene glycol dimethyl ether (80 mL) was added quickly to the alkoxide mixture (viii) and the resulting mixture was readily refluxed for 66 hours. The cooled reaction mixture was poured into water (200 mL) and the organic solvent was evaporated in vacuo. The residual aqueous solution was diluted with more water to a volume of 700 mL, acidified to pH 0.5 with 6M HCl aqueous solution and extracted with diethyl ether (2×600 mL). The pH of the aqueous layer was adjusted to pH 5.9 and then the aqueous solution was extracted with diethyl ether (700 mL). The organic extract was dried over sodium sulfate and the solvent was evaporated in vacuo to yield 34.0 g of the title compound (70% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]=[CH:5][C:4]2[CH:8]=[CH:9][S:10][C:3]1=2.CN(C=O)C.[H-].[Na+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1>[Cu](I)I.O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:1][C:2]2[C:3]3[S:10][CH:9]=[CH:8][C:4]=3[CH:5]=[N:6][CH:7]=2)=[CH:21][CH:20]=1
Reactant: O=C1CN=Cc2ccsc21
Reactant: Clc1ccc(I)cc1
Agent: I[Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(Oc2cncc3ccsc23)cc1
Temperature: 25 °C

Procedure:
Example 145D can be processed as in Lindley (Tetrahedron, 1983, 1433). A solution of Example 145C (1.0 mmol) and DMF (2.0 mL) is treated at 0° C. with sodium hydride (1.0 mmol), slowly warmed to room temperature, treated with 1-chloro-4-iodobenzene (1.0 mmol) and copper iodide (0.1 mmol), heated at 80° C. overnight, and cooled. The solution is poured into water and extracted with diethyl ether. The extracts are combined, dried (MgSO4), filtered, and concentrated. Recrystallization from ethyl acetate/hexanes provides the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[F:49][C:50]1[CH:51]=[C:52]([CH:57]=[CH:58][CH:59]=1)[O:53][CH2:54]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:42][CH2:43][CH2:54][O:53][C:52]2[CH:57]=[CH:58][CH:59]=[C:50]([F:49])[CH:51]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OCCOc1cccc(F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCOc4cccc(F)c4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 54.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (62 mg) was added to toluene/triethylamine=10/1 (6 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (92 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-(3-fluorophenoxy)-1-ethanol (48 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (55 mg, yield 51%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=2)[CH:2]=1.Cl.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])[C:19]1=[O:32].CC#[N:35]>>[NH2:35][C:31]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=1[CH2:23][N:20]1[CH2:21][CH2:22][C@H:18]([NH:17][S:12]([C:10]2[S:11][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=2)(=[O:14])=[O:13])[C:19]1=[O:32]
Reactant: CC#N
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2cccnc2)s1
Agent: Cl
Product: N#Cc1ccc(N)c(CN2CC[C@H](NS(=O)(=O)c3ccc(-c4cccnc4)s3)C2=O)c1

Procedure:
The title compound is prepared in CH3CN instead of CH2Cl2 as described in EXAMPLE 1, Part E using 5-pyridin-3-yl-thiophene-2-sulfonyl chloride in place of benzo[b]thiophene-2-sulfonyl chloride and substituting 4-amino-[3-(3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)]-benzonitrile dihydrochloride for 3-(3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-benzonitrile hydrochloride. The crude product is obtained by diluting with ethyl acetate and washing with saturated sodium bicarbonate (aq.), water and brine. The organic layer is dried over MgSO, filtered and concentrated. The crude product is purified by column chromatography eluting with 50% EtOAc/CH2Cl2 to give a light brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15]1.O[N:29]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.N>CN(C)C=O.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:29])=[O:13])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(Br)cc2c(C3CCS(=O)(=O)C(c4ccccc4)C3)c[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C(c4ccccc4)C3)c[nH]c12
Temperature: 100 °C
Yield: 64 %

Procedure:
5-bromo-3-(1,1-dioxido-2-phenyltetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxylic acid (0.9 g, 2.007 mmol) was put in a flask and dissolved in N,N-Dimethylformamide (DMF) (2 mL). HOBt (1-hydroxybenzotriazole) (0.271 g, 2.007 mmol) and EDC (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide) (1.078 g, 5.62 mmol) were added. The mixture was stirred and 0.5N NH3 in dioxane was added (12.04 mL, 6.02 mmol). The reaction mixture was heated under microwave at 100° C. for 20 minutes. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate (3×25 mL). Organic layers were combined and washed with a saturated aqueous solution of sodium bicarbonate, dried (MgSO4) and concentrated in vacuo. The mixture was dissolved in the minimum amount of DCM and precipitated in hexane, giving 0.575 g of the title compound as a pale brown powder.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:20](=[O:22])=[O:21]>C1COCC1.O.C(OCC)(=O)C>[CH3:1][C:2]1[C:14]2[CH:13]([C:20]([OH:22])=[O:21])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1Cc1ccccc1-2
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc2c1C(C(=O)O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
A solution of 1-methylfluorene (3.8 g, 21.1 mmol) in 100 mL of THF at -78° C. was charged with n-butyl lithium (3.5M solution in hexane, 6.29 ml, 22.0 mmol). The reaction mixture was stirred for 15 min, then CO2 gaseous (5 g, 113.6 mmol) was introduced via cannula over a period of 15 min. The reaction mixture was warmed up to room temperature and stirring was continued until no color was apparent (approximately 2 hr). The slurry was diluted with water (100 mL) and ethyl acetate (50 mL). The layers were separated, the water layer was washed with ethyl acetate (3×50 mL), then acidified with conc. HCl. The precipitate was collected, washed with water and dried to give 1-methyl-9-fluorenecarboxylic acid (4.02 g, 84.8%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(CC)[NH:10][CH2:9][CH2:8][S:7]1)=[O:5])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([N:21]=[C:22]=[S:23])[CH:17]=[C:18]([Cl:20])[CH:19]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[N:10]([C:22](=[S:23])[NH:21][C:16]2[CH:17]=[C:18]([Cl:20])[CH:19]=[C:14]([Cl:13])[CH:15]=2)[CH2:9][CH2:8][S:7]1)=[O:5])[CH3:2]
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)C1(CC)NCCS1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1SCCN1C(=S)Nc1cc(Cl)cc(Cl)c1
Yield: 100.1 %

Procedure:
A mixture of 1.61 g of ethyl thiazolidine-2-carboxylic acid ethyl ester thus obtained, 2.04 g of 3,5-dichlorophenylisothiocyanate and 20 ml of toluene was heated at 90° C. for 1 hour. Then the reaction mixture was cooled and the precipitate was separated by filtration to give 3.11 g (yield 85.1%) of 3-(3,5-dichlorophenylthiocarbamoyl)thiazolidine-2-carboxylic ethyl ester. The melting point was 170.5°-171.5° C. and the results of elementary analysis were as follows: Found (calculated in parentheses): C 42.68% (42.74%), H 3.93% (3.86%), N 7.70% (7.67%), Cl 19.32% (19.41%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:16]([CH2:39][C:40](O)=[O:41])[C:17](=[O:38])[C:18]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([F:29])[CH:22]=3)[N:20]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:46](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[N:16]([CH2:39][C:40](=[O:41])[NH2:46])[C:17](=[O:38])[C:18]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([F:29])[CH:22]=3)[N:20]=2)[CH2:13][CH2:14]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccc(-c2c(-c3ccc(C#N)c(F)c3)nc(N3CCC(NC(=O)OC(C)(C)C)CC3)n(CC(=O)O)c2=O)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(-c3ccc(C#N)c(F)c3)nc(N3CCC(NC(=O)OC(C)(C)C)CC3)n(CC(N)=O)c2=O)cc1
Yield: 43.4 %

Procedure:
To a solution of [2-(4-tert-butoxycarbonylamino-piperidin-1-yl)-4-(4-cyano-3-fluoro-phenyl)-5-(4-methoxy-phenyl)-6-oxo-6H-pyrimidin-1-yl]-acetic acid (120 mg, 0.2 mmol) in DMF (5 mL) was added NH4Cl (17 mg, 0.3 mmol), HATU (95 mg, 0.25 mmol) and DIEA (25 mg, 0.4 mmol). After completion of the reaction, the solution was diluted with H2O and extracted with DCM for (3×). The combined organics were dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC to give 50 mg of the title product as a yellow solid (43%). [M+H] Calc'd for C30H33FN6O5, 577. Found, 577.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[O:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8].[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32](O)[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:38]2)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32]([O:8][C:7](=[O:9])[C:6]([O:5][C:4]2[CH:12]=[C:13]([CH3:15])[CH:14]=[C:2]([CH3:1])[CH:3]=2)([CH3:11])[CH3:10])[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:38]2)=[CH:25]1)([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: Cc1cc(C)cc(OC(C)(C)C(=O)O)c1
Product: Cc1cc(C)cc(OC(C)(C)C(=O)O[C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)C=C3C=C[C@H](C)[C@H](CC[C@@H]4C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O4)[C@H]32)c1
Yield: 81.8 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 755 mg of 2-(3,5-dimethylphenoxy)-2-methylpropionic acid and 1.0g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.10 g of the title compound as a colorless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:26])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28].C(N(CC)CC)C.[OH-].[Na+].Cl>ClC(Cl)C.O1CCOCC1>[CH3:26][N:5]1[C:6]2[C:7]([CH:8]=[CH:9][C:10]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:18][CH:17]=[C:12]4[NH:13][C:14](=[O:16])[C:15]=2[C:11]=34)=[C:2]([NH:1][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH:3]=[CH:4]1
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccccn1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCS(=O)(=O)NC1=c2ccc3c4c([nH]c(=O)c-4c2N(C)C=C1)=CCN3c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
A mixture of Example 82d (0.09 g, 0.262 mmol) in dichloroethane (2 mL) and 1,4-dioxane (4 mL) was treated with ethanesulfonyl chloride (0.075 mL, 0.786 mmol) and triethylamine (0.183 mL, 1.31 mmol). The mixture was stirred at ambient temperature overnight and then concentrated. The mixture was redissolved in 1,4-dioxane (4 mL), treated with sodium hydroxide solution (4 M aqueous) (0.655 ml, 2.62 mmol) and heated at 50° C. for 1.75 hours. The mixture was then cooled to ambient temperature and neutralized with hydrochloric acid solution (2 M aqueous). The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×60 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC(C18, acetonitrile/water (0.1% TFA), 10-60%) to provide 0.0477 g (33%) of the title compound as the TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.56 (s, 1H), 7.98 (dd, J=5.19, 1.22 Hz, 1H), 7.64 (d, J=2.44 Hz, 1H), 7.58 (s, 1H), 7.41 (m, 1H), 7.27 (d, J=8.54 Hz, 1H), 7.13 (dd, J=8.54, 2.44 Hz, 1H), 6.90 (s, 1H), 6.60 (dd, J=6.56, 5.65 Hz, 1H), 6.42 (d, J=8.85 Hz, 1H), 5.53 (s, 1H), 4.08 (s, 3H), 3.97 (s, 1H), 3.19 (q, J=7.32 Hz, 2H), 1.29 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 436.2 (M+H)+.
Reaction SMILES: C(O[C@H]1C2C(=CC(Br)=CC=2)[C@@H](NC[C@@H](O)[C@@H](N)CC2C=C(F)C=C(F)C=2)C1)C=C.[C:30]([OH:37])(=O)[CH2:31][CH2:32][CH2:33][CH:34]=[CH2:35].[CH2:38]([O:41][C@H:42]1[C:50]2[C:45](=[CH:46][C:47]([O:51][CH:52]([CH3:54])[CH3:53])=[CH:48][CH:49]=2)[C@@H:44]([NH:55][CH2:56][C@@H:57]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[C@@H:58]([NH2:63])[CH2:59][CH:60]([CH3:62])[CH3:61])[CH2:43]1)[CH:39]=[CH2:40]>>[CH2:38]([O:41][C@H:42]1[C:50]2[C:45](=[CH:46][C:47]([O:51][CH:52]([CH3:54])[CH3:53])=[CH:48][CH:49]=2)[C@@H:44]([NH:55][CH2:56][C@@H:57]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:66])[CH3:67])[C@@H:58]([NH:63][C:30](=[O:37])[CH2:31][CH2:32][CH2:33][CH:34]=[CH2:35])[CH2:59][CH:60]([CH3:61])[CH3:62])[CH2:43]1)[CH:39]=[CH2:40]
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](N)CC(C)C)c2cc(OC(C)C)ccc21
Reactant: C=CCCCC(=O)O
Agent: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c2cc(Br)ccc21
Product: C=CCCCC(=O)N[C@@H](CC(C)C)[C@@H](CN[C@H]1C[C@@H](OCC=C)c2ccc(OC(C)C)cc21)O[Si](C)(C)C(C)(C)C

Procedure:
Step EQ (1): Hex-5-enoic acid (240 mg, 2.1 mmol) and (2R,3S)-N1-((1S,3R)-3-(allyloxy)-6-isopropoxy-2,3-dihydro-1H-inden-1-yl)-2-(tert-butyldimethylsilyloxy)-5-methylhexane-1,3-diamine (1.1 g, 2.2 mmol, from Preparation BH) were coupled using a procedure analogous to Step CA (1) to afford N-((2R,3S)-1-((1S,3R)-3-(allyloxy)-6-isopropoxy-2,3-dihydro-1H-inden-1-ylamino)-2-(tert-butyldimethylsilyloxy)-5-methylhexan-3-yl)hex-5-enamide. LC-MS (M+H)+=587.47.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>C1(C)C(C)=CC=CC=1.CS(C)=O>[CH:23]1([NH:29][C:8]([C:7]2[C:2]([OH:1])=[C:3]3[C:15]([CH3:16])=[N:14][N:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[C:4]3=[N:5][CH:6]=2)=[O:10])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccn2)c1O
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CS(C)=O
Product: Cc1nn(-c2ccccn2)c2ncc(C(=O)NC3CCCCC3)c(O)c12
Temperature: 25 °C
Yield: 9.7 %

Procedure:
A mixed solution of ethyl 4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1.5 g, 5.0 mmol) and cyclohexylamine (2.2 g, 22 mmol) in xylene (5.0 mL) and dimethylsulfoxide (5.0 mL) was stirred at 130° C. for 28 hours. The solution was cooled to room temperature and water was added thereto. Subsequently, organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Purification of the residue by silica gel column chromatography (chloroform:methanol=50:1 to 20:1) gave crude crystals. The crude crystals were recrystallized from ethyl acetate/ethanol to give the title compound (0.17 g, 10% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(O)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>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.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COc1ccccc1B(O)O
Reactant: N#Cc1cccnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1ccccc1-c1ncccc1C#N
Temperature: 85 °C
Yield: 65.6 %

Procedure:
To a 250-mL, round-bottomed flask containing a large magnetic stir bar were added 2-chloro-3-cyanopyridine (1.39 g, 10.0 mmol), 2-methoxyphenylboronic acid (1.82 g, 12.0 mmol), and dichlorobis(triphenylphosphine)palladium(II) (351 mg, 0.50 mmol). Isopropyl alcohol (50 mL) and 2M sodium carbonate solution (50 mL) were added. The flask was stoppered and immersed in an oil bath heated to 80-90° C. The biphasic mixture was stirred vigorously and heated for 8 hours. After cooling to room temperature, ethyl acetate (50 mL) was added and the black mixture was transferred to a separatory funnel. The aqueous layer was removed and subsequently extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to give a brown oil. The product was crystallized from ethyl acetate/hexanes to give 1.38 g (66%) of the title compound as a tan powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:11])=[CH:5][C:4]=1[C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][NH:18]2)=[CH:14][CH:13]=1)[CH3:2].[OH-].[K+].[I:23]I>CN(C=O)C.O>[CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:11])=[CH:5][C:4]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]([I:23])=[N:17][NH:18]2)=[CH:14][CH:13]=1)[CH3:2]
Reactant: II
Reactant: CCc1cc(OC)c(F)cc1-c1ccc2cn[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(OC)c(F)cc1-c1ccc2c(I)n[nH]c2c1
Reaction time: 0.08 h
Yield: 90.7 %

Procedure:
To a solution of 6-(2-ethyl-5-fluoro-4-methoxy-phenyl)-1H-indazole (Preparation 15, 1.46 g, 5.4 mmol) in DMF (20 mL) was added KOH (1.14 g, 20.3 mmol) and the mixture was stirred for 5 minutes. A solution of iodine (2.75 g, 10.8 mmol) in DMF (5 mL) was slowly added and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (2×100 mL) and saturated sodium metabisulfite aqueous solution (100 mL), dried over MgSO4 and concentrated in vacuo to furnish the title compound (1.94 g) in a 91% yield.