Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].I[CH:8]([CH3:10])[CH3:9].[I:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=1.Cl>CN(C=O)C>[I:11][C:12]1[CH:13]=[C:14]([CH3:20])[C:15]([O:19][CH:8]([CH3:10])[CH3:9])=[CH:16][C:17]=1[CH3:18]
Reactant: Cc1cc(I)c(C)cc1O
Reactant: CC(C)I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OC(C)C)c(C)cc1I
Temperature: 50 °C
Yield: 42 %

Procedure:
K2CO3 (1.23 g, 8.87 mmol) followed by 2-iodopropane (806 μL, 8.06 mmol) were added to a solution of 4-iodo-2,5-dimethyl-phenol (1.00 g, 4.03 mmol) in DMF (40 mL) and the solution was heated at 50° C. for 24 h. The mixture was then acidified with 1% aq HCl before it was extracted with EtOAc (3×100 mL). The combined organics were washed with 1N NaOH (3×200 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0-10% ethyl acetate/hexanes) to provide 1-iodo-4-isopropoxy-2,5-dimethylbenzene (42%) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].Cl.[NH2:20][C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[C:25]([CH3:34])[CH:24]=1)[CH3:22].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(N(CC)CC)C.CN(C)C=O>[CH3:34][C:25]1[CH:24]=[C:23]([C@H:21]([NH:20][C:12](=[O:14])[CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([C:3]([CH3:4])([CH3:5])[C:2]([F:1])([F:18])[F:17])=[CH:16][CH:15]=2)[CH3:22])[CH:28]=[CH:27][C:26]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: Cc1cc([C@@H](C)N)ccc1NS(C)(=O)=O
Reactant: CC(C)(c1ccc(OCC(=O)O)cc1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc([C@@H](C)NC(=O)COc2ccc(C(C)(C)C(F)(F)F)cc2)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
To a N,N-dimethylformamide (DMF) (3 ml) solution of [4-(2,2,2-trifluoro-1,1-dimethylethyl)phenoxy]acetic acid (131 mg, 0.5 mmol) and N-{4-[(1R)-1-aminoethyl]-2-methylphenyl}methanesulfonamide hydrochloride (132 mg, 0.5 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (144 mg, 0.75 mmol), 1-hydroxybenzotriazole (HOBt) monohydrate (85 mg, 0.55 mmol) and triethylamine (0.21 ml) were added and the mixture was stirred for 2 hours at ambient temperature. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with ethyl acetate. The organic layer was then washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=1/1 to furnish 92 mg (39% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1COCC1.[Cl:9][CH2:10][C:11]([NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])=[O:12]>CN(C=O)C>[ClH:9].[CH3:1][N:2]([CH3:3])[CH2:10][C:11]([NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])=[O:12]
Reactant: CNC
Reactant: O=C(CCl)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)CC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
Dimethylamine/THF (2M, 6.1 mL, 12.3 mmol) was added to a stirred solution of 2-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (1.0 g, 3.1 mmol) in DMF (30 mL). The resulting solution was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with CH2Cl2 (15 mL). The mixture was filtered, and the solid was dissolved in H2O (10 mL). 4N HCl (1.5 mL) was added and stirred for 30 minutes. The resulting solution was concentrated, and the residue was evaporated with ethanol (3×10 mL). The residue was slurried with ether (15 mL) and ethanol (5 mL). The mixture was filtered to give 2-dimethylamino-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide hydrochloride (0.7 g, 54%) as a white solid: mp 273-275° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.33-2.65 (m, 2H), 2.81 (s, 6H, 2CH3), 2.87-3.01 (m, 1H), 4.02 (s, 2H, CH2), 4.36 (d, J=17.4 Hz, 1H), 4.43 (d, J=4.6 Hz, 2H, CH2), 4.55 (d, J=17.4 Hz, 1H), 5.12-5.19 (dd, J=5.0 and 13.1 Hz, 1H, CH), 7.48-7.67 (m, 3H, Ar), 9.41 (t, J=5.7 Hz, 1H, NH), 10.08 (s, 1H, NH), 11.04 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.60, 31.16, 39.06, 43.05, 46.19, 51.55, 57.07, 121.95, 128.32, 130.87, 131.72, 133.59, 140.25, 164.43, 167.93, 170.94, 172.84; Anal. calcd. for C18H23N4O4Cl+0.34H2O: C, 53.92; H, 5.95; N, 13.94; Cl, 8.84. Found: C, 54.06; H, 6.08; N, 13.72; Cl, 9.06.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)[CH3:3].[NH2:19][C:20]1[N:25]=[C:24]([NH2:26])[C:23]([C:27]#[N:28])=[C:22](Cl)[N:21]=1.CCN(CC)CC>C(#N)C>[NH2:19][C:20]1[N:25]=[C:24]([NH2:26])[C:23]([C:27]#[N:28])=[C:22]([NH:1][CH:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[N:14]2[CH2:17][CH:16]([OH:18])[CH2:15]2)[CH3:3])[N:21]=1
Reactant: CC(N)c1nc2ccn(C)c2cc1N1CC(O)C1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CC(O)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 4.3 %

Procedure:
To a 10 mL vial were added 1-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)azetidin-3-ol (75 mg, 0.304 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (62.0 mg, 0.365 mmol) and Et3N (0.085 mL, 0.61 mmol) in acetonitrile (2 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The crude product was purified by preparative HPLC eluting with 20-40% ACN in water (with 0.05% ammonium bicarbonate). The fractions containing the desired product were combined and lyophilized to give the title compound as a pale yellow solid (5 mg, 5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30-1.40 (m, 4 H), 3.47-3.58 (m, 1 H), 3.67-3.75 (m, 1 H), 3.75-3.80 (m, 4 H), 4.05-4.14 (m, 1 H), 4.20-4.33 (m, 1 H), 4.51-4.63 (m, 1 H), 5.40-5.53 (m, 1H), 5.57-5.68 (m, 1 H), 6.38-6.53 (m, 3 H), 6.54-6.66 (m, 2 H), 6.76-6.86 (m, 1 H), 7.10-7.20 (m, 1 H), 7.36-7.46 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H21N9O, 380; found 380.
Reaction SMILES: [C-]#N.[K+].[F:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].[C:13]([O:17][CH2:18]C)(=[O:16])[CH:14]=[CH2:15].O>CN(C)C=O>[CH3:18][O:17][C:13](=[O:16])[CH2:14][CH2:15][C:8]([C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([F:4])[CH:6]=1)=[O:9]
Reactant: O=Cc1cccc(F)c1
Reactant: C=CC(=O)OCC
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)c1cccc(F)c1
Temperature: 45 °C

Procedure:
To a stirred suspension of potassium cyanide (3.25 g) in N,N-dimethylformamide (30 cm3), being maintained at a temperature of 45° C., was added 3-fluorobenzaldehyde (25.0 g). Ethyl acrylate (18.46 cm3) was then added and the resultant mixture was stirred at 40° C. for 2 h. Water (200 cm3) was added and the aqueous mixture was extracted with diethyl ether (2×125 cm3). The organic extracts were washed with water (100 cm3) and saturated aqueous sodium chloride solution (100 cm3) before being dried (Na2SO4) and the solvent was removed under reduced pressure to yield the title compound (25.27 g) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58])=[CH:48][C:47]=1[CH3:59].C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:59][C:47]1[CH:48]=[C:49]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58])[CH:50]=[CH:51][C:46]=1[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOCCOc1ccc(OB([O-])[O-])c(C)c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 2-methyl-4-(2-propoxyethoxy)phenyl borate (165 mg) and potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 14 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=4/1) and recrystallized from ethanol to give 7-[2-methyl-4-(2-propoxyethoxy)phenyl]-N[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 121) (184 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:26])[C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH2:27]([OH:29])[CH3:28].[H-].[Na+]>O1CCOCC1>[CH2:27]([O:29][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:26])[C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1)[CH3:28]
Reactant: CCO
Reactant: CCNC(=O)C(C)c1ccc(C2CCN(c3ccnc(Cl)n3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCNC(=O)C(C)c1ccc(C2CCN(c3ccnc(OCC)n3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 80 mg (0.22 mmol) 2-{4-[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-yl]-phenyl}-N-ethyl-propionamide (XII.1) and 25 μL (0.43 mmol) ethanol in 1 mL 1,4-dioxane are added 26 mg (0.64 mmol) sodium hydride (60%) at 0° C. The mixture is stirred for 12 h at rt. After that time, the mixture is directly purified by HPLC (XBridge 10 μM; water, 0.3% NH4OH/MeOH) to yield the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C.C(OCC)(=O)C.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([Cl:14])=[CH:16][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: Nc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
Tert butyl-2-oxo-1-pyrrolidinecarboxylate (190 mg, 1.02 mmol), 4-chloroaniline (64 mg, 0.5 mmol) and acetic acid (184 mg) were mixed in dichloroethane (5 mL). Sodium triacetoxyborohydride (326.5 mg) was added and the reaction mixture kept on stirring at room temperature for overnight. After addition of aq. NaHCO3 the reaction mixture was diluted by addition of ethyl acetate. Two layers were separated. The organic layer was dried over Na2SO4, filtered, concentrated. The residue was purified by flash chromatography (0-15% ethyl acetate in petroleum spirit, 40-60) to give the subtitled product (140 mg).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH3:23])[CH:16]=4)[C:4]=2[C:3]=1[CH3:24])[CH:12]=[CH:11][CH:10]=[CH:9]3.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH3:21])[C:18]([O:22][C:25](=[O:27])[CH3:26])=[C:17]([CH3:23])[CH:16]=4)[C:4]=2[C:3]=1[CH3:24])[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.8 %

Procedure:
To a solution of 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenol (24.0 g, 72.2 mmol) in pyridine (200 mL) at 0° C. under nitrogen was added dropwise acetic anhydride (8.9 mL, 93.9 mmol) over a period of 10 min. After 45 min at 0° C., the reaction mixture was placed in the freezer for 18 h, then removed and stirred for 2 h in an ice bath that was allowed to warm to room temperature. The reaction mixture was poured onto water (1 L) and acidified with 10% hydrochloric acid to a pH of 1. The resulting mixture was extracted with diethyl ether (1 L), which was washed with 10% hydrochloric acid (1 L), twice with water (1 L), brine (700 mL), and dried (MgSO4). Concentration under reduced pressure and chromatography with petroleum ether:ethyl acetate (97:3) gave the title compound as a cream solid (22.4 g, 79%): NMR (CDCl3) δ 8.26 (s, 1 H), 7.87 (d, 1 H), 7.58 (d, 1 H), 7.44-7.40 (m, 1 H), 7.33-7.29 (m, 1 H), 7.07 (s, 2 H), 2.42 (s, 3 H), 2.41 (s, 3 H), 2.23 (s, 6 H), 1.67 (s, 3 H). MS(EI), [M+] 374. Anal. Calc. for C24H22O2S: C, 76.97, H, 5.92, N, 0.00. Found: C, 76.17, H, 5.75, N, 0.22.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][OH:12].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: OCCOc1ccc(I)cc1

Procedure:
A suspension of 11 g (50 mmol) 4-iodophenol, 3.88 mL (55 mmol) 2-bromoethanol and 8.3 g (60 mmol) K2CO3 in 60 mL acetone is refluxed for 24 h. The solvent is eliminated i.vac., the residue is combined with water, exhaustively extracted with EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography on silica gel (cyc/EtOAc 7:3).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][C:27]=2[Cl:28])[NH:24][CH:23]=[C:22]3[C:29]([OH:31])=[O:30])=[CH:15][CH:14]=1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[Cl:28][C:27]1[CH:26]=[C:25]2[C:21]([C:22]([C:29]([OH:31])=[O:30])=[CH:23][NH:24]2)=[CH:20][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCCN4)cc3)cc12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 92.3 %

Procedure:
To a suspension of 5-{4-[1-(tert-butoxycarbonyl)pyrrolidin-2-yl]phenyl}-6-chloro-1H-indole-3-carboxylic acid (140 mg, 0.318 mmol) in ethyl acetate (10 mL) was added hydrogen chloride in ethyl acetate (4N HCl in EtOAc, 10 mL) under nitrogen. The suspension was stirred for 4.5 hours at room temperature. The mixture was concentrated to afford the desired product (100 mg, 83.5% yield). MS (ES+) 341 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.10 (s, 1H), 7.95 (s, 1H), 7.66 (s, 1H), 7.62 (d, 2H), 7.52 (d, 2H), 4.60 (s, 1H), 3.35 (s, 4H), 2.49 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:16][CH2:17][CH3:18])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([O:14]C)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CCO.O>[CH:1]1([CH2:4][N:5]([CH2:16][CH2:17][CH3:18])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=[O:13])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)OC)ncn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
A solution of methyl 6-[(cyclopropylmethyl)(propyl)amino]pyrimidine-4-carboxylate (5.10 g; 20.5 mmol) in THF/EtOH/H2O (3/2/1, total volume 400 mL) was treated with an aqueous solution (1N) LiOH (60 mL; 60 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvents were concentrated under vacuum and then water (200 mL) was added. The aqueous layer was washed with DCM then acidified to pH 5 by addition of 1N HCl solution (60 mL). The aqueous layer was extracted with DCM (3 times) and the combined organic layers were dried over MgSO4, filtered and concentrated under vacuum to give the title compound as a yellow solid (3.71 g, 77.1%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[C:26]([CH3:27])=[CH:25][C:24]([OH:28])=[CH:23][C:22]=1[CH3:29])[C:3]([NH:5][C@@H:6]([C:8](=[O:19])[NH:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:7])=[O:4].CC1C=C(C)[N:33]([C:37](N)=[NH:38])N=1.C(N(CC)CC)C>C(O)C>[NH3:1].[NH:1]([C@@H:2]([CH2:20][C:21]1[C:22]([CH3:29])=[CH:23][C:24]([OH:28])=[CH:25][C:26]=1[CH3:27])[C:3]([NH:5][C@@H:6]([C:8](=[O:19])[NH:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:7])=[O:4])[C:37]([NH2:38])=[NH:33]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: Cc1cc(O)cc(C)c1C[C@H](N)C(=O)N[C@H](C)C(=O)NCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)cc(C)c1C[C@H](NC(=N)N)C(=O)N[C@H](C)C(=O)NCCCc1ccccc1
Product: N
Reaction time: 24 h

Procedure:
(S)-2-Amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-N-[(R)-1-(3-phenyl-propylcarbamoyl)-ethyl]-propionamide (J. Med. Chem. 1994, 37, 888) (449 mg, 1.0 mmol) and 3,5-dimethylpyrazole-1-carboxamidine (240 mg, 1.2 mmol) were heated in ethanol at 60° C. After 24 hours, triethylamine (167 μl, 1.2 mmol) was added. The reaction was heated for a further 24 hours. The solvent was evaporated and the crude material was redissolved in dichloromethane containing 2% methanol. The resulting solution was washed with a solution of citric acid followed by sodium bicarbonate solution. The organic phase was washed with brine then dried over MgSO4. The organics were filtered and evaporated leaving a small amount of a crude gum. The gum was purified using an ISCO chromatography system on a 12 g silica column using gradient elution from 95:5:0.5 to 80:20:5 DCM:MeOH:NH3 to afford the title compound as a solid in 5% yield, 20 mg. 1H NMR (400 MHz, MeOH-d4) δ : 1.18 (d, 3H), 1.75-1.82 (m, 2H), 2.21 (s, 1H), 2.49 (s, 1H), 2.58-2.63 (m, 2H), 2.95-3.02 (m, 1H), 3.10-3.24 (m, 3H), 3.28-3.32 (m, 1H), 4.18-4.22 (m, 1H), 4.35-4.40 (m, 1H), 6.51 (s, 2H), 7.08-7.28 (m, 5H). LRMS m/z 440 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:32][C:33]([NH:35][C@@H:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C@H:39]([O:46][C:47]3[CH:48]=[CH:49][C:50]4[N:51]([C:53]([N:56]5[CH2:61][CH2:60][CH2:59][CH2:58][C@@H:57]5[CH3:62])=[N:54][N:55]=4)[CH:52]=3)[CH2:38][CH2:37]2)=[O:34])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[C:12]([O:28][CH2:29][CH2:30][OH:31])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:63][S:64](Cl)(=[O:66])=[O:65].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:32][C:33]([NH:35][C@@H:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C@H:39]([O:46][C:47]3[CH:48]=[CH:49][C:50]4[N:51]([C:53]([N:56]5[CH2:61][CH2:60][CH2:59][CH2:58][C@@H:57]5[CH3:62])=[N:54][N:55]=4)[CH:52]=3)[CH2:38][CH2:37]2)=[O:34])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:20])[CH3:21])=[C:12]([CH:11]=2)[O:28][CH2:29][CH2:30][O:31][S:64]([CH3:63])(=[O:66])=[O:65])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)[Si](OCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1OCCO)(C(C)C)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[Si](OCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1OCCOS(C)(=O)=O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A mixture of Intermediate 55eB (26.0 mg, 0.30 mmol), methanesulfonyl chloride (70.0 μL, 0.90 mmol) and DIPEA (208 μL, 1.20 mmol) in DCM (8 mL) was stirred at RT for 1 h. The reaction mixture was partitioned between DCM and water. The organic layer was washed with brine, separated through a phase separating cartridge and concentrated in vacuo to afford the title compound (275 mg, 97%). LCMS (Method 3): Rt 5.23 min, m/z 943 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(O)C.[CH2:23]([NH2:34])[C:24]1[CH:33]=[CH:32][C:29]([O:30][CH3:31])=[C:26]([O:27][CH3:28])[CH:25]=1>>[Cl:1][C:2]1[C:3]([NH:34][CH2:23][C:24]2[CH:33]=[CH:32][C:29]([O:30][CH3:31])=[C:26]([O:27][CH3:28])[CH:25]=2)=[N:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)c(Cl)nc1-c1cccc(F)c1
Reactant: COc1ccc(CN)cc1OC
Solvent: CCO
Product: COC(=O)c1cc(Cl)c(NCc2ccc(OC)c(OC)c2)nc1-c1cccc(F)c1
Yield: 82.5 %

Procedure:
A solution of methyl 5,6-dichloro-2-(3-fluorophenyl)nicotinate (55 mg, 0.18 mmol) in ethanol (1 mL, 20 mmol) was treated with veratrylamine (82 μL, 0.55 mmol) and refluxed for 30 minutes. The reaction mixture was concentrated and purified by flash column chromatography using ethyl acetate in hexanes (0-30%) to give the desired product (64 mg, 81%). LCMS calculated for C22H21ClFN2O4 (M+H)+: m/z=431.1. found: 430.9.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[N:7]=1.CC(C)([O-])C.[K+].[CH3:21][NH:22][C:23]([C:25]1[CH:30]=[C:29](Cl)[CH:28]=[CH:27][N:26]=1)=[O:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[NH2:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:29]3[CH:28]=[CH:27][N:26]=[C:25]([C:23]([NH:22][CH3:21])=[O:24])[CH:30]=3)=[CH:12][CH:13]=2)[N:7]=1
Reactant: Nc1nncc(-c2ccc(O)cc2)n1
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(Oc2ccc(-c3cnnc(N)n3)cc2)ccn1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
3.71 g (19.73 mmol) of 4-(3-amino-[1,2,4]triazin-5-yl)-phenol can be dissolved in 80 mL of anhydrous DMF under argon atmosphere. 2.44 g (21.71 mmol, 1.1 equivalent) of solid potassium tert-butoxide can be added to the solution. The resulting mixture can be heated to about 100° C. and stirred at that temperature for 15 min. Then a solution of 3.7 g (21.71 mmol, 1.1 equivalent) of 4-chloro-pyridine-2-carboxylic acid methylamide in 10 mL of anhydrous DMF can be added, followed by 3.28 g (23.68 mmol, 1.2 eq.) of anhydrous K2CO3. The reaction mixture can be heated at 140° C. for 30 hrs. The progress of the reaction can be monitored by LC/MS. Then it can be allowed to cool down to ambient temperature. The resulting mixture can be poured into 500 mL of water and 100 mL of ethyl acetate. The aqueous layer can be extracted with a number of solvents, such as ethyl acetate, methylene chloride or ether. The combined extracts can be washed 3 times with 100 mL of water, then with brine and dried over anhydrous sodium sulfate. Solvent can be removed in vacuum to give crude 4-[4-(3-amino-[1,2,4]triazin-5-yl)-phenoxy]-N-methylpyridine-2-carboxamide. The product can be than purified using silica gel column chromatography. Those having ordinary skill in the art can determine which solvent system can be used as an eluents in the chromatographic purification.