Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24](B3OC(C)(C)C(C)(C)O3)[C:18]=1[CH2:19][O:20][C:21](=[O:23])[CH3:22])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:44]1[CH:45]=[C:46]([Si:52]([CH3:55])([CH3:54])[CH3:53])[C:47](=[O:51])[N:48]([CH3:50])[N:49]=1.IC1C=C([Si](C)(C)C)C(=O)N(C)N=1>>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:44]3[CH:45]=[C:46]([Si:52]([CH3:54])([CH3:53])[CH3:55])[C:47](=[O:51])[N:48]([CH3:50])[N:49]=3)[C:18]=1[CH2:19][O:20][C:21](=[O:23])[CH3:22])[N:9]=[CH:8]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: Cn1nc(Cl)cc([Si](C)(C)C)c1=O
Agent: Cn1nc(I)cc([Si](C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)OCc1c(-c2cc([Si](C)(C)C)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reaction time: 5.5 h
Yield: 71 %

Procedure:
In round bottom flask was placed 3.21 g acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester, 2.06 g sodium carbonate, 0.68 g bistriphenylphosphine palladium dichloride, and 1.99 g a 6:4 mixture of 6-chloro-2-methyl-4-trimethylsilanyl-2H-pyridazin-3-one and 6-iodo-2-methyl-4-trimethylsilanyl-2H-pyridazin-3-one followed by 130 mL of dioxane (EM DriSolv)-water (10:1). The mixture was vacuum flushed 5× argon, then set in a bath at 95° C. and stirred (mechanical). After 5.5 hours, the mixture was cooled, taken up in 350 mL of ethyl acetate and washed 1×75 mL of brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (Silicycle 120 g, 3.5×21.5 cm, 207 vol), applied in dichloromethane eluting with CH2Cl2-ethyl acetate (80:20), followed by chromatography on silica gel (Silicycle 120 g, 3.5×21.5 cm, 207 vol), applied in dichloromethane, eluting with dichloromethane-ethyl acetate (80:20) afforded 2.5418 g (71%) of product as a foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[NH2:16]>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:13]([F:12])[CH:14]=2)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: COc1ccc(N)cc1F
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2c(Cl)ncnc2Cl)cc1F
Reaction time: 0.5 h
Yield: 56 %

Procedure:
4,6-Dichloropyrimidine-5-carbonyl chloride (890 mg, 4.21 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dissolved in dichloromethane (3 ml) and TEA (587 μl, 4.21 mmol) was added. To this solution, 3-fluoro-4-methoxyaniline (594 mg, 4.21 mmol) dissolved in 3 ml dichloromethane was added dropwise and the mixture was stirred for 30 min. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The crude was purified using SP1® Purification System (0%-40%, hexane-ethyl acetate) to give 720 mg (56% yield) to the title compound as an oil.
Reaction SMILES: O=[C:2]([CH2:8][CH3:9])[CH2:3][CH2:4][C:5]([OH:7])=O.C(Cl)(=[O:15])C(C)(C)C.[NH2:17][CH:18]([P:22]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([O:24][C@@H:25]([CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:23])[CH:19]([CH3:21])[CH3:20].[Cl-].[NH4+]>C(Cl)Cl.C(N(CC)CC)C>[CH2:44]([O:43][C:41]([NH:40][CH2:39][CH2:38][CH2:37][CH2:36][C@H:25]([O:24][P:22]([CH:18]([NH:17][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][C:8](=[O:15])[CH3:9])[CH:19]([CH3:21])[CH3:20])([O:51][CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)=[O:23])[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:42])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CCC(=O)CCC(=O)O
Reactant: CC(C)C(N)P(=O)(OCc1ccccc1)O[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)CCCC(=O)NC(C(C)C)P(=O)(OCc1ccccc1)O[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.1 %

Procedure:
4-Oxohexanoic acid (56.2 μl) was dissolved in methylene chloride (1.4 ml), and the solution was added with triethylamine (98.5 μl) and pivalic chloride (58.0 μl) and stirred under an argon atmosphere at room temperature for 15 minutes. The resulting mixture was added to a methylene chloride (1.4 ml) solution of the crude benzyl (S)-2-((1-amino-2-methylpropyl)(benzyloxyphosphinoyl)oxy)-6-benzyloxycarbonylaminohexanate (140.5 mg) obtained in the step (e) of Example 24, and the mixture was further stirred at room temperature for 4 hours. Saturated aqueous ammonium chloride was added to the mixture, and then the organic substances were extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15 g, hexane:acetone=3:1) to obtain benzyl (S)-6-benzyloxycarbonylamino-2-((2-methyl-1-(5-oxohexanoylamino)propyl)(benzyloxyphosphinoyl)oxy)hexanoate (105.4 mg, 63.1%). This compound was subjected to the measurement of molecular weight and then used in the following reaction without further purification.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([CH2:11][O:12][CH2:13][CH:14]=[CH2:15])([CH2:9][CH3:10])[CH:7]=O)[CH:2]=[CH2:3].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=1.[NH:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[N:27]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:4][CH2:5][C:6]([CH2:11][O:12][CH2:13][CH:14]=[CH2:15])([CH2:9][CH3:10])[CH:7]([NH:23][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=1)[N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[N:27]1)[CH:2]=[CH2:3]
Reactant: c1ccc2[nH]nnc2c1
Reactant: C=CCOCC(C=O)(CC)COCC=C
Reactant: NC(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CCOCC(CC)(COCC=C)C(NC(=O)c1ccc(Cl)cc1)n1nnc2ccccc21

Procedure:
The product from Example 20A, 4-chlorobenzamide, benzotriazole, and p-toluenesulfonic acid were processed as described in Example 1C to provide the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][OH:10].[F:11][C:12]([F:47])([F:46])[C:13]1[CH:14]=[C:15]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)[CH2:20][C@H:19]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:17].O>CN(C)C=O>[F:45][C:42]([F:44])([F:43])[C:40]1[CH:39]=[C:15]([CH:14]=[C:13]([C:12]([F:11])([F:46])[F:47])[CH:41]=1)[C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:29]=[N:28][N:27]([CH2:8][CH2:9][OH:10])[CH:26]=2)[CH2:20][C@H:19]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:17]
Reactant: Cc1ccc(C[C@@H]2CN(Cc3cn[nH]c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C[C@@H]2CN(Cc3cnn(CCO)c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C

Procedure:
Potassium carbonate (158 mg) and 2-bromoethanol (0.045 ml) were added to a solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-pyrazolylmethyl)piperazine (300 mg) in N,N-dimethylformamide (3 ml) at room temperature with stirring. After stirring at 100° C. for 5 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by column chromatography (30 ml) on silica gel using a mixture of ethyl acetate and hexane (3:7) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]methyl]piperazine (255.2 mg).
Reaction SMILES: Cl[O-:2].[Na+].[OH-].[Na+].[C:6]([C:8]1[CH:9]=[C:10]([C:18](=[O:20])C)[CH:11]=[CH:12][C:13]=1[CH2:14][CH:15]([CH3:17])[CH3:16])#[N:7].Cl>CO>[C:6]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[CH2:14][CH:15]([CH3:16])[CH3:17])[C:18]([OH:20])=[O:2])#[N:7]
Reactant: CC(=O)c1ccc(CC(C)C)c(C#N)c1
Reactant: [O-]Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Cc1ccc(C(=O)O)cc1C#N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Subsequently, 10% aqueous sodium hypochlorite solution (370 ml) containing sodium hydroxide (8 g) and methanol (5 ml) was heated to 60° C. 3′-Cyano-4′-isobutylacetophenone (20 g) was added thereto by portions and the mixture was stirred for 1 h. The reaction mixture was cooled to room temperature and dilute hydrochloric acid was added, which was followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give 3-cyano-4-isobutylbenzoic acid (8.5 g), melting point: 118° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:14][C:15]([F:50])([F:49])[C:16]1[CH:17]=[C:18]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:19][N:20]1[CH2:25][C:24]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=2)([CH2:26][CH2:27]OS(C)(=O)=O)[CH2:23][O:22][C:21]1=[O:41].[I-].[K+].Cl>CCOCC.CN(C=O)C>[ClH:39].[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:27][CH2:26][C:24]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=3)[CH2:23][O:22][C:21](=[O:41])[N:20]([CH2:19][C:18]3[CH:17]=[C:16]([C:15]([F:49])([F:50])[F:14])[CH:44]=[C:43]([C:45]([F:47])([F:46])[F:48])[CH:42]=3)[CH2:25]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)COC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1OCC(CCN2CCC(Cc3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 27.2 %

Procedure:
This compound is prepared by the procedure described in step D of EXAMPLE 4 from 0.3 g of 4-benzylpiperidine, 0.8 g of the compound obtained in step C of EXAMPLE 4, 0.24 g of potassium iodide and 5 ml of DMF. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (96/4; v/v) as the eluent. The product obtained is taken up with a saturated solution of gaseous HCl in ether and the precipitate formed is wrung to give 0.13 g of the expected product. M.p.=124° C.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH:4]([OH:6])[CH3:5])[CH3:3].Cl[P:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:3])[CH:4]([CH3:5])[O:6][P:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7]1
Reactant: CC(O)C(C)(C)O
Reactant: ClP(Cl)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1OP(c2ccccc2)OC1(C)C

Procedure:
5 g of (+)2 methyl butane 2,3-diol, ##STR24## are mixed with 8.6 g of dichlorophenylphosphin at 0° C. under stirring in 250 ml of dry toluene, in an atmosphere. Then 10.2 g of triethylamine are added within a few minutes. After 1 hour of reaction triethylamine hydrochloride is formed; it is separated by filtration and the toluene solvent is vaporized.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9]2[N:13]([C:14]3[CH:19]=[C:18]([NH:20][CH3:21])[N:17]=[CH:16][N:15]=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:6][C:5]([NH2:23])=[CH:4][CH:3]=1.[CH:24]([NH:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[C:32](O)=[O:33])([CH3:26])[CH3:25].CN(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>[CH:24]([NH:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[C:32]([NH:23][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([NH:8][C:9]2[N:13]([C:14]3[CH:19]=[C:18]([NH:20][CH3:21])[N:17]=[CH:16][N:15]=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)[CH:6]=1)=[O:33])([CH3:26])[CH3:25]
Reactant: CC(C)NCc1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cc(-n2nc(C)cc2Nc2cc(N)ccc2C)ncn1
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: CNc1cc(-n2nc(C)cc2Nc2cc(NC(=O)c3cc(CNC(C)C)cc(C(F)(F)F)c3)ccc2C)ncn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-methyl-N1-(3-methyl-1-(6-(methylamino)pyrimidin-4-yl)-1H-pyrazol-5-yl)benzene-1,3-diamine 39 (360 mg, 1.16 mmol, 1 eq) is dissolved in dry DMF (10 mL), followed by 3-((isopropylamino)methyl)-5-(trifluoromethyl)benzoic acid (0.504 mg, 1.02 mmol, 0.9 eq), HATU (663 mg, 1.74 mmol, 1.5 eq), and DIEA (0.5 mL, 3.49 mmol, 3 eq). The reaction mixture is stirred at room temperature for about 4 hours until the reaction is complete as evidenced by the LC/MS product peak. The reaction mixture is then quenched by NaHCO3 solution and extracted with ethyl acetate. The organic layers are combined and dried over magnesium sulfate. The solvents are removed under vacuo and the residue is purified by flash column chromatography to afford 3-((isopropylamino)methyl)-N-(4-methyl-3-(3-methyl-1-(6-(methylamino)pyrimidin-4-yl)-1H-pyrazol-5-ylamino)phenyl)-5-(trifluoromethyl)benzamide. MS: m/z [M+H+]) 553.20, 1H NMR: 11.07 (s, 1H), 10.61 (s, 1H), 9.17 (bs, 1H), 8.58 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 7.95 (s, 1H), 7.69 (s, 1H), 7.39 (m, 1H), 7.24 (m, 1H), 6.88 (s, 1H), 6.16 (s, 1H), 4.36 (m, 2H), 3.34-3.48 (m, 1H), 2.87 (m, 3H), 2.49 (m, 3H), 2.22 (m, 3H), 1.33-1.34 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH:17]([CH3:20])[C:18]#[CH:19])[C:13]([O:21][CH3:22])=[C:12]([O:23][CH3:24])[CH:11]=2)=[CH:4][N:3]=1>C(N(CC)C1C=CC=CC=1)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:15]3[CH:19]=[CH:18][CH:17]([CH3:20])[O:16][C:14]=3[C:13]([O:21][CH3:22])=[C:12]([O:23][CH3:24])[CH:11]=2)=[CH:4][N:3]=1
Reactant: C#CC(C)Oc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Solvent: CCN(CC)c1ccccc1
Product: COc1cc(Cc2cnc(N)nc2N)c2c(c1OC)OC(C)C=C2
Yield: 36.5 %

Procedure:
A solution of 2,4-diamino-5-[3,4-dimethoxy-5-(1-methyl-2-propynyloxy)-benzyl]pyrimidine (4.28 g, 13.0 mmol) in N,N-diethylaniline (200 mL) was refluxed under nitrogen for 0.5 hr. The hot solution was filtered to remove dark tarry material. The filtrate was cooled and diluted with hexanes (200 mL). The precipitate (3.8 g) was recrystallized from ethanol to give title compound as off-white powder (1.56 g, 37%); mp 219°-221° dec. Anal. Calcd for C17H20N4O3 : C, 62.18; H, 6.14; N, 17.06. Found: C, 61.91; H, 6.20; N, 16.93.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16](=[O:19])[CH2:17][CH3:18].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[Cl:30]>O1CCCC1.O>[CH3:12][O:13][C:14](=[O:20])[CH:15]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[Cl:30])[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)CC(=O)OC
Reactant: Fc1ccc(CBr)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCC(=O)C(Cc1ccc(F)cc1Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of potassium tert-butoxide (1.6 g) in anhydrous tetrahydrofuran (25 mL) at 0° C. was treated with a mixture of tert-butanol (1.0 mL) and 3-oxopentanoic acid methyl ester (1.5 g). After stirring at 0° C. for 45 minutes a solution of 1-bromomethyl-2-chloro-4-fluorobenzene (2.6 g) in tetrahydrofuran (5.0 mL) was added and the resulting mixture stirred at room temperature for 3 days. The mixture was diluted with water and the tetrahydrofuran removed under reduced pressure. The mixture was extracted with ethyl acetate and the combined extracts dried over magnesium sulfate and the solvent removed under reduced pressure to afford the title compound, 3.2 g.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10](OC1C=CC([N+]([O-])=O)=CC=1)=[O:11].[NH2:22][C:23]([C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=1)([CH3:49])[CH2:24][NH:25][C:26](=[O:48])[CH2:27][N:28]1[C:32](=[O:33])[N:31]([CH2:34][C@H:35]([OH:40])[C:36]([F:39])([F:38])[F:37])[C:30]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)=[N:29]1.[OH-].[Li+].Cl>C1COCC1.O>[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([C:30]2[N:31]([CH2:34][C@H:35]([OH:40])[C:36]([F:39])([F:38])[F:37])[C:32](=[O:33])[N:28]([CH2:27][C:26]([NH:25][CH2:24][C:23]([NH:22][CH:10]=[O:11])([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=3)[CH3:49])=[O:48])[N:29]=2)=[CH:42][CH:43]=1
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: CC(N)(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)(NC=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At RT, 12 μl (68 μmol) of N,N-diisopropylethylamine and then 11 mg (65 μmol) of 4-nitrophenyl formate were added to a solution of 38 mg (62 μmol) of the compound of Example 53A in 1 ml of THF, and the mixture was stirred at RT. After 1 h, another 10 mg (62 μmol) of 4-nitrophenyl formate were added and stirring of the reaction mixture was continued overnight. Since LC/MS analysis indicated additional formation of an O-formylated byproduct, 248 μl of a 1 N solution of lithium hydroxide in water were added to the reaction mixture. After 1 h, the mixture was acidified with 1 N hydrochloric acid and separated by preparative HPLC [Method 8]. This gave 30 mg (81% of theory) of the title compound as a diastereomer mixture.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si](C)(C)C)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:11]([C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([CH:7]=1)[C:4]([NH2:6])=[O:5])#[CH:12]
Reactant: Cc1ccc(C#C[Si](C)(C)C)cc1C(N)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(C)c(C(N)=O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
To a solution of 2-methyl-5-((trimethylsilyl)ethynyl)benzamide (170) (0.190 g, 0.819 mmol) in THF (4 mL) at 0° C. was added 1.0 M solution TBAF in THF (0.5 mL). The mixture was then stirred under N2 at 0° C. for 10 minutes and then at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure then diluted with water. The resulting precipitate was collected by vacuum filtration to give the title compound (I71) (0.087 g, 67%); 1H NMR (400 MHz, d6-DMSO) δ 7.80 (s, 1H), 7.41 (m, 3H), 7.25 (d, J=7.7 Hz, 1H), 4.17 (s, 1H), 2.36 (s, 3H).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:2]=1.N1C2C(=NC=CC=2)[N:25]([CH2:32][C:33]2[CH:45]=[CH:44][C:36]3N=C(S(C)(=O)=O)S[C:35]=3[CH:34]=2)C=1.NCC1(C[OH:55])CCCCC1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:25][CH2:32][C:33]4([OH:55])[CH2:45][CH2:44][CH2:36][CH2:35][CH2:34]4)[S:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: NCC1(CO)CCCCC1
Reactant: CS(=O)(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: OC1(CNc2nc3ccc(Cn4cnc5cccnc54)cc3s2)CCCCC1
Temperature: 125 °C
Reaction time: 15 h

Procedure:
A 4:1 mixture of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole and 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfonyl)benzo[d]thiazole (80 mg) from Step 2 of Example 63 was dissolved in anhydrous DMA (2 mL), and (1-(aminomethyl)cyclohexyl)methanol (175 mg, 1.22 mmol) from Step 1 of this Example and DIEA (157 mg, 1.22 mmol) were added. The reaction vessel was sealed and the mixture was heated with stirring at 125° C. for 15 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford 1-(((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)methyl)cyclohexanol (22 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.38 (dd, J=1.1, 4.7 Hz, 1H), 8.09 (dd, J=1.3, 7.9 Hz, 1H), 7.99 (t, J=5.7 Hz, 1H), 7.68 (s, 1H), 7.20-7.33 (m, 3H), 5.49 (s, 2H), 3.33 (d, J=5.8 Hz, 2H), 3.21 (s, 1H), 1.21-1.49 (m, 12H). LCMS (ESI) m/z 408 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:9]=[C:10](N)[CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].[N:21]1C=CC=CC=1>>[C:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:21][C:16](=[O:17])[O:18][CH2:19][CH3:20])=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccncc1
Reactant: Nc1cccc(Cc2ccccc2)c1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1ccc(Cc2ccccc2)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
3-(Phenylmethyl)benzenamine (0.1 mole) and pyridine (50 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and are cooled to about 5° C. Ethyl chloroformate (0.125 mole) is added, with stirring, at about 5° C. Stirring is continued for a period of about 30 minutes at about 5° C., then for an additional 16 hours at room temperature. The mixture is then washed with 2 portion of water (50 ml), dried and the solvent is then removed to yield the desired product ethyl [N-(phenylmethyl)phenyl]carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)c1ccc(C(=O)OC(C)(C)C)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc(C(=O)O)c(Cl)c1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
To a solution of tert-butyl 2-chloro-4-isopropylbenzoate (150 mg, 0.59 mmol) in dichloromethane (10 mL) was added 2,2,2-trifluoroacetic acid (2 mL) at room temperature. The resultant reaction mixture was stirred at 30° C. for 30 minutes. Thin layer chromatography showed that starting material was consumed completely. The solution was concentrated under reduced pressure to give 2-chloro-4-isopropylbenzoic acid (100 mg, 85.5%) as a white solid which was used in the next step directly. LRMS (M+H+) m/z: calcd 199.04. found 199.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16][C:17]#N)[CH2:5]1)(=[O:3])[CH3:2].[OH-:19].[K+].[OH2:21]>>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16][C:17]([OH:21])=[O:19])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O
Reactant: CC(=O)N1CC(CCC#N)c2c(C)cc(C)cc21
Reactant: [OH-]
Agent: [K+]
Product: CC(=O)N1CC(CCC(=O)O)c2c(C)cc(C)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Acetyl-3-(2-cyanoethyl)-4,6-dimethylindoline (4.5 g) was dissolved in ETOH (150 ml), and a solution of KOH (10.4 g) in water (50 ml) was added, which was followed by refluxing for 15 hr. EtOH was evaporated under reduced pressure, and the aqueous layer was adjusted to weak acidic with 6N hydrochloric acid and extracted with CHCl3 (100 ml). The CHCl3 layer was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was dissolved in CHCl3 (20 ml) and Ac2O (1.9 g) was added, which was followed by stirring at room temperature for 1 hr. CHCl3 (100 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=50/1−10/1) to give 3.4 g of 1-acetyl-3-(2-carboxyethyl)-4,6-dimethylindoline.