Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCC[C@H]1C(OC(C)(C)C)=O.CCN(CC)CC.[C:20]1([CH2:26][CH2:27][S:28]([N:31]2[CH2:42][CH2:41][CH2:40][C@H:32]2[C:33]([O:35]C(C)(C)C)=[O:34])(=[O:30])=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)=O>C(Cl)Cl>[C:20]1([CH2:26][CH2:27][S:28]([N:31]2[CH2:42][CH2:41][CH2:40][C@H:32]2[C:33]([OH:35])=[O:34])(=[O:30])=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1S(=O)(=O)CCc1ccccc1
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=CO
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)CCc1ccccc1

Procedure:
PhCH2CH2SH was treated with Cl2 in a rapidly stirred mixture of CHCl3 and H2O, and then the CHCl3 layer was washed with 5% NaHSO3 and sat. NaCl, dried with MgSO4, filtered, and concentrated to give PhCH2CH2SO2Cl. This product was treated with Pro-OtBu and Et3N in CH2Cl2 to give, after aqueous workup, PhCH2CH2SO2-Pro-OtBu. This product was treated with HCO2H, and the mixture was evaporated to give PhCH2CH2SO2-Pro-OH. This product was treated with HCl.Phe-OtBu, EDAC, HOBT, and Et3N in CH2Cl2 to give, after aqueous workup and flash chromatography, PhCH2CH2SO2-Pro-Phe-OtBu. This product was treated with HCO2H, and the mixture was evaporated to give the title compound as a clear oil.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[N:9]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:11][N:12]([CH:14]=[O:15])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[B-](F)(F)(F)F.C1CC=CCCC=C1.C1CC=CCCC=C1.[Rh].CC(C)=O>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][N:12]([CH:14]=[O:15])[CH2:11][CH2:10][N:9]1[C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)C1=CN(C=O)CCN1C(=O)C(F)(F)F
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: F[B-](F)(F)F
Solvent: CC(C)=O
Solvent: C1=CCCC=CCC1
Product: CC(C)(C)NC(=O)[C@@H]1CN(C=O)CCN1C(=O)C(F)(F)F
Reaction time: 11 h
Yield: 98.9 %

Procedure:
20.6 g (67.0 mmol) of 4-formyl-1-trifluoroacetyl-1,4,5,6-tetrahydropyrazine-2-carboxylic acid tert-butylamide, 26.2 mg (64.5 μmol) of bis(1,5-cyclooctadiene)rhodium(I) tetraflouroborate and 41.8 mg (77 μmol) of 1-[1(R)-(di-tert-butylphospino)ethyl]-2-(S)-(diphenylphosphino)-ferrocene were placed in a 160 ml autoclave under argon (S/C=1000). 70 ml of acetone (degassed) was added and hydrogenation was carried out for 11 hours at 100° C. under a hydrogen pressure of 13-10 bar. After distillation of the solvent, 20.5 g (99%) of the title compound was obtained in the form of a crystalline solid. After cleavage of the protecting groups, the enantioselectivity of the hydrogenation was determined by GC analysis, giving an ee of 96.4 percent. The melting point of the title compound was: 172.0° to 173.0° C. Other data concerning the title compound was:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][C:16]1[C:23]([CH3:24])=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[CH3:25].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:15][C:16]1[C:23]([CH3:24])=[CH:22][C:19]([C:20]2[NH:6][C:4](=[O:5])[C:3]3[C:7]([O:13][CH3:14])=[CH:8][C:9]([O:11][CH3:12])=[N:10][C:2]=3[N:1]=2)=[CH:18][C:17]=1[CH3:25]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: COc1cc(OC)c(C(N)=O)c(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(O)c(C)c3)nc2n1
Temperature: 150 °C
Yield: 39.6 %

Procedure:
To a solution of 2-amino-4,6-dimethoxy-nicotinamide (1.40 g, 7.1 mmol) and 4-hydroxy-3,5-dimethylbenzaldehyde (1.07 g, 7.1 mmol) in N,N-dimethyl acetamide (20 mL), NaHSO3 (1.39 g, 7.81 mmol) and p-TSA (0.675 g, 3.55 mmol) were added and the reaction mixture was heated at 150° C. overnight. The solvent was removed under reduced pressure. The residue was diluted with water and the solid was collected and further washed with methanol. The crude product was purified by column chromatography (silica gel 230-400 mesh; 2% methanol in CH2Cl2 as eluent) to give 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one (0.92 g, 39.6%). Selected data: MS (ES) m/z: 328.07; MP 297-299° C.
Reaction SMILES: C([O-])C.[Na+].C(OCC)(=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl[C:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19][N:18]=1>CCO>[NH2:18][C:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: Clc1nsc2ccccc12
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1sc2ccccc2c1N
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
A dry 2-neck 500 mL round-bottom flask (RBF) was charged with sodium ethanolate (46.2 mL, 124 mmol), diluted with 151 mL absolute EtOH, cooled in an ice bath and treated dropwise with diethyl malonate (17.98 mL, 118 mmol) under an atmosphere of nitrogen. After stirring for 20 minutes, the ice bath was removed and 3-chlorobenzo[d]isothiazole (20.0 g, 118 mmol) was added in one portion and stirred for 24 hours. The reaction solution was quenched with water, extracted with ether and treated with excess 4 M HCl/dioxane. A pinkish-white precipitate was filtered off, suspended in water, basified with Na2CO3, extracted with ether, washed with water and brine, dried over sodium sulfate, filtered and concentrated to yellow solids (˜20 g) which were recrystallized from ethanol/water and dried in a vacuum oven at 60° C. for 3 hrs to give ethyl 3-aminobenzo[b]thiophene-2-carboxylate (19.9 g, 76% yield).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.[CH2:11]([O:18][CH2:19][C:20]([O:22]CC)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Br.[CH2:28]([N:32]1[CH2:36][CH2:35][N:34]=[C:33]1[NH2:37])[CH2:29][CH2:30][CH3:31]>>[CH2:11]([O:18][C:19]1[C:20](=[O:22])[N:34]2[CH2:35][CH2:36][N:32]([CH2:28][CH2:29][CH2:30][CH3:31])[C:33]2=[N:37][C:2]=1[C:1]([O:8][CH2:9][CH3:10])=[O:7])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCCN1CCN=C1N
Reactant: CCOC(=O)COCc1ccccc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: CCCCN1CCn2c1nc(C(=O)OCC)c(OCc1ccccc1)c2=O
Yield: 38.2 %

Procedure:
Reaction of the adduct of diethyl oxalate (5.71 g, 39.1 mmol), ethyl benzyloxyacetate (7.59 g, 39.1 mmol) and sodium hydride (1.71 g of a 60% dispersion in mineral oil, 42.7 mmol) with 1-butyl-4,5-dihydro-1H-imidazol-2-amine hydrobromide (8.68 g, 39.1 mmol) as described for intermediate 1 gave 5.55 g (38% yield) of the title ester as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 0.98 (3H, t, J=7.5 Hz, CH3), 1.31 (3H, t, J=7.1 Hz, CH3), 1.39 (2H, m, CH2), 1.56-1.63 (2H, m, CH2), 3.41 (2H, t, J=7.4 Hz, CH2), 3.69 (2H, t, J=8.9 Hz, CH2), 4.12 (2H, t, J=8.9 Hz, CH2), 4.32 (2H, q, J=7.1 Hz, OCH2), 5.09 (2H, s, OCH2), 7.3-7.4 (3H, m, aromatics), 7.49 (2H, m, aromatics). MS (ESI+) m/e 372 [M+H+].
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[F:12][C:13]1[CH:14]=[C:15](/[CH:20]=[CH:21]/[C:22](Cl)=[O:23])[CH:16]=[CH:17][C:18]=1[F:19].N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:14]=[C:15](/[CH:20]=[CH:21]/[C:22]([O:8][C@@H:6]2[CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]2[CH:9]([CH3:11])[CH3:10])=[O:23])[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: O=C(Cl)/C=C/c1ccc(F)c(F)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)/C=C/c1ccc(F)c(F)c1
Temperature: 65 °C

Procedure:
A solution of L-menthol (7.1 kg) in toluene (8.5 kg) was added over a 20 minute period to the solution of (E)-3-(3,4-difluorophenyl)-2-propenoyl chloride (prepared as in Step 2) and pyridine (0.18 kg, 2.28 mol) stirring at 65° C. The reaction mixture was stirred at 65° C. for a further 4 hours and 40 minutes after the addition was complete, then cooled to 25° C. and stirred for a 14 hours. The solution was diluted with toluene (16 kg), washed with 5% aqueous sodium chloride (6.4 kg), then 6% sodium hydrogen carbonate (6.47 kg), then water (6.1 kg). The solution was dried azeotropically by distillation of the solvent (20 L) under reduced pressure. Dimethyl sulfoxide (33.9 kg) was added and the remaining toluene was distilled off under reduced pressure, affording 47.3 kg of a solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (E)-3-(3,4-difluorophenyl)-2-propenoate (approx. 13.3 kg) in dimethyl sulfoxide.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:28]=[CH:27][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:29](O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:28]=[CH:27][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:25])([CH3:26])[C:22]([O:24][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:23])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OCc1ccccc1
Reactant: CC(C)(CCCCOc1ccc(OCCCCCn2ccnc2)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(C)(CCCCOc1ccc(OCCCCCn2ccnc2)cc1)C(=O)OCc1ccccc1
Reaction time: 120 h

Procedure:
To a mixture of 0.90 g 6-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylhexanoic acid, 10 ml dichloromethane, 0.24 ml benzyl alcohol and 30 mg dimethylaminopyridine, was added with stirring 0.46 g dicyclohexylcarbodiimide at room temperature, and stirring was continued for five days. The urea which separated out was filtered off, and the filtrate was washed with 0.1N caustic soda solution and then with water. After dehydration, the solvents were distilled off, and the residue was purified by silical gel column chromatogrpahy, affording 1.05 g of benzyl 6-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylhexanoate.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC[C@H]1[CH2:16][O:15]1.Cl.O.[CH3:19][CH:20](O)C>O>[CH2:1]([N:8]1[CH2:20][CH2:19][O:11][C@H:10]([CH2:16][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC[C@H]1CO1
Reactant: CC(C)O
Reactant: OCCNCc1ccccc1
Agent: Cl
Solvent: O
Product: OC[C@@H]1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
2-(benzylamino)ethanol 38.3 ml (270.22 mmnol) and (R)-2-(chloromethyl)oxirane 25 g (270.22 mmnol) were dissolved in H2O/IPA (26 ml+26 ml), and stirred at room temperature overnight. After that, 130 ml of Et3NOH (35%) dissolved in water was slowly dropped over 1 hour, and stirred at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was adjusted to pH 9 with 1 N HCl, followed by extraction using H2O and EA, drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:1), to give (S)-(4-benzylmorpholin-2-yl)methanol as a colorless oil (50%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:27]=[CH:26][C:14]([O:15][CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:24][CH:22]([S:19]([NH:18][CH2:17][CH:16]([O:15][C:14]1[CH:26]=[CH:27][C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][NH:2][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1)[CH3:25])(=[O:21])=[O:20])[CH3:23]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCN)cc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCNS(C)(=O)=O)cc2)cc1
Yield: 105.3 %

Procedure:
The title compound (318 mg, 100%, slow crystallizing-foam) was prepared from (2-{4-[4-(2-aminoethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]amine hydrochloride (250 mg, 0.664 mmol, prepared in example 39), methylene chloride (4.5 mL, anhydrous), triethylamine (0.09 mL, 0.664 mmol), and methanesulfonyl chloride (0.05 mL, 0.664 mmol) in a manner analogous to the procedure described in Example 40.
Reaction SMILES: [C:1]([NH2:6])([CH2:4][CH3:5])([CH3:3])[CH3:2].Cl[CH2:8][CH2:9][O:10][CH:11]([OH:13])[CH3:12]>>[C:1]([NH:6][CH2:8][CH2:9][O:10][CH:11]([OH:13])[CH3:12])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)N
Reactant: CC(O)OCCCl
Product: CCC(C)(C)NCCOC(C)O
Yield: 66.7 %

Procedure:
In the manner described in Example 8, 129.7 g of tertiaryamylamine and 92.2 g of 2-chloroethoxyethanol yielded 86.5 g of tertiaryamylaminoethoxyethanol having a b.p. of 124° C. (10 mm).
Reaction SMILES: [CH3:1][C:2]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)(=[O:7])=[O:6])=[O:3]>[Pd].O.C(O)C>[CH3:1][C:2]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)(=[O:7])=[O:6])=[O:3]
Reactant: CC(=O)NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(=O)NS(=O)(=O)c1cccc(N)c1
Yield: 70 %

Procedure:
In the same way as that described in Example 11, Step 2, using 1-(methylcarbonylaminosulphonyl)-3-nitrobenzene (2.9 g, 12 mmol), 10% palladium on carbon (0.4 g, 14% (w/w)) in water (3 ml) and ethanol (150 ml), the title compound (1.8 g, 70%) was afforded as a colourless soiid. mp 148°-150° C. 1H NMR (360 MHz, D6 -DMSO) δ 1.92 (3H, s), 5.64 (2H, brs), 6.80 (1H, dd, J=8.0 and 1.7 Hz), 6.98 (1H, d, J=7.6 Hz), 7.10 (1H, dd, J=2.0 and 2.0 Hz), 7.21 (1H, dd, J=7.9 and 7.9 Hz), 11.87 (1H, brs).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.O=S(Cl)[Cl:19]>C(Cl)(Cl)Cl>[Cl:19][CH2:2][C:3]1[N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: CCOC(=O)Cn1nc([N+](=O)[O-])cc1CO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cn1nc([N+](=O)[O-])cc1CCl
Temperature: 0 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
To a mixture of 151a (1.50 g, 6.55 mmol) in CHCl3 (60 mL) cooled at 0° C. was slowly added SOCl2 (2.34 g, 19.6 mmol) while maintaining the internal temperature below 5° C. This reaction mixture was warmed to 50° C. and stirred at this temperature for 3 h. It was then cooled to 0° C. and quenched with water. The organic layer was separated and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 151b (1.1 g, 68%) as a yellow solid. MS-ESI: [M+H]+ 247.9
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[C:8]([CH3:24])[C:6]=2[N:7]=1.[CH3:31][C:32]1[NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[N:33]=1>>[CH3:24][C:8]1[C:6]2[N:7]=[C:2]([N:33]3[C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[N:36]=[C:32]3[CH3:31])[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]=2[S:10][C:9]=1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:14][CH2:13]1
Reactant: Cc1c(CN2CCC(N3CCOCC3)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: Cc1nc2ccccc2[nH]1
Product: Cc1c(CN2CCC(N3CCOCC3)CC2)sc2c(N3CCOCC3)nc(-n3c(C)nc4ccccc43)nc12

Procedure:
Following General Procedure I for Buchwald coupling, 4-(1-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)morpholine and 2-methyl-1H-benzo[d]imidazole were reacted to give 232. LCMS: M+H+=548.3
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[CH2:10]([N:17]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:18]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2B2OC(C)(C)C(C)(C)O2)[O:20][CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:37]([N:17]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@H:18]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[C:2]2[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=2)[O:20][CH2:19]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: OCc1ccc(Br)cn1
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCc1ccc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)cn1

Procedure:
A mixture of (5-bromopyridin-2-yl)methanol (0.205 g, 1.09 mmol), (3S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-3-amine (0.13 M in isopropanol, 8.4 mL, 1.09 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (0.045 g, 0.05 mmol), and 2 M potassium carbonate (1.64 mL, 3.28 mmol) was irradiated in a microwave synthesizer at 140° C. for 20 min. The solution was filtered through a pad of celite and concentrated in vacuo. The residue was purified by column chromatography using a gradient of ethyl acetate in heptane. The crude was dissolved in chloroform and insoluble material was removed. The solvent was evaporated in vacuo yielding an oil, 0.360 g (76%); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (d, 1 H), 7.79 (dd, 1 H), 7.54 (d, 1 H), 7.24-7.34 (m, 8 H), 7.06-7.22 (m, 3 H), 6.69-6.83 (m, 2 H), 5.51 (t, 1 H), 4.64 (d, 2 H), 4.28-4.39 (m, 1 H), 3.99-4.10 (m, 1 H), 3.59-3.74 (m, 4 H), 2.86-3.11 (m, 1 H), 2.39-2.49 (m, 1 H); MS (APPI/APCI) m/z 437[M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1.[C:11](OCC)(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].N1CCCCC1>CCO>[CH2:16]([O:15][C:13]([C:12]1[C:11](=[O:18])[NH:1][C:2]2[C:7]([CH:8]=1)=[CH:6][C:5]([Br:10])=[CH:4][N:3]=2)=[O:14])[CH3:17]
Reactant: Nc1ncc(Br)cc1C=O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cc(Br)cnc2[nH]c1=O
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A mixture of 2-amino-5-bromo-pyridine-3-carbaldehyde (4.00 g, 14.2 mmol), diethyl malonate (21.6 mL, 142 mmol) and piperidine (7.00 mL, 71.0 mmol) in EtOH (70 mL) was heated to reflux overnight. The mixture was cooled to room temperature and the solid was collected by filtration to give the title compound (2.41 g, 57%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 12.65 (s, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.56 (d, J=2.4 Hz, 1H), 8.45 (s, 1H), 4.29 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]3[N:27]=[C:26]([NH:28][C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[C:25]([O:35][CH3:36])=[CH:24][N:23]=3)=[N:14]2)=[C:10]([Cl:37])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]3[N:27]=[C:26]([NH:28][C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)[C:25]([O:35][CH3:36])=[CH:24][N:23]=3)=[N:14]2)=[C:10]([Cl:37])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(Cl)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3ccccc32)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cnc(-c2nn(Cc3c(Cl)ccc(C(=O)O)c3Cl)c3ccccc23)nc1Nc1ccncc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1 g of methyl 2,4-dichloro-3-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)benzoate (2-16-1, 1.868 mmol, 1. eq.) were dissolved in 19 ml of dry THF and 2.2 ml of methanol. 4.67 ml of 2 M aqueous sodium hydroxide solution (9.34 mmol, 5 eq.) were added. The mixture was stirred for three hours at room temperature. The reaction mixture was partitioned between citric acid (pH 3) and ethyl acetate. This process dropped out a white precipitate which was filtered off and dried for three days to yield 992 mg (1.86 mmol, 99.8%) of the analytically pure target compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)([O-:3])=[O:2].[NH2:16][C@@H:17]([CH2:26][S:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][S:27][CH2:26][C@H:17]([NH:16][C:13]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][CH:6]=[CH:5][C:4]=3[N+:1]([O-:3])=[O:2])=[O:15])[CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:34][CH:33]=1
Reactant: COc1ccc(CSC[C@H](N)COC(=O)C(C)(C)C)cc1
Reactant: O=C(O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(CSC[C@@H](COC(=O)C(C)(C)C)NC(=O)c2cc3cccc([N+](=O)[O-])c3[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
7-Nitro-1H-indole-2-carboxylic acid (8.2 g, 22.7 mmol) prepared in Step A and 2,2-dimethyl-propionic acid (R)-2-amino-3-(4-methoxy-benzylsulfanyl)-propyl ester (13.2 g, 27.2 mmol) prepared in Preparation 31 were dissolved in N,N-dimethylformamide (100 mL). EDC (6.6 g, 25.0 mmol) and HOBT (4.6 g, 25.0 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. Saturated aqueous sodium bicarbonate solution was added to the mixture to quench the reaction. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The residue was purified by column chromatography to give the title compound (8.1 g, Yield 71%).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH3:2]>[Pd].C(O)C>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH3:17]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCN(CC)CCOc1ccc(N)cc1
Reaction time: 3 h
Yield: 45.7 %

Procedure:
A mixture of 4-(2-diethylaminoethoxy)-1-nitrobenzene (Method 10) (1.0 g, 4.2 mmol) and 10% palladium on charcoal catalyst (200 mg) in ethanol (30 ml) was stirred under an atmosphere of hydrogen for 3 hours. The catalyst was removed by filtration through diatomaceous earth and the filter pad was washed with methanol. The volatiles were removed from the filtrate by evaporation to give the title compound (400 mg, 46% yield) as an oil. M/z: 209 [MH]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10][CH3:11])=O.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:23][C:24]1[C:29]([CH3:30])=[C:28]([OH:31])[CH:27]=[CH:26][C:25]=1[CH2:32][CH2:33]C(OCC)=O>>[CH3:23][C:24]1[C:29]([CH3:30])=[C:11]([O:10][CH2:8][C:4]2[N:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=[CH:7][C:3]=2[C:2]([F:13])([F:12])[F:1])[CH:33]=[CH:32][C:25]=1[CH2:26][CH2:27][CH2:28][OH:31]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: COC(=O)c1[nH]ccc1C(F)(F)F
Reactant: OB(O)c1ccccc1
Product: Cc1c(CCCO)ccc(OCc2c(C(F)(F)F)ccn2-c2ccccc2)c1C

Procedure:
The title compound was prepared by (a) reacting the product prepared in Step B of Example 1 and phenylboronic acid according to the procedure described in Example 1, Step C, (b) then reacting the resulting product according to the procedure in Example 1, Step D, (c) then reacting the resulting product with ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)propanoate according to the procedure in Example 1, Step E, and Example 2.