Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:46])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([N:43]([CH3:45])[CH3:44])[N:37]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:45][N:43]([CH3:44])[C:38]1[N:37]=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:46])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:41]=[C:40]([CH3:42])[N:39]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nc(N(C)C)n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)nc(N(C)C)n1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (116 mg, 0.4 mmol) and 3-[3-(2-dimethylamino-6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K49) (171 mg, 0.48 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (114 mg).
Reaction SMILES: BrC(Br)C.Br[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([F:15])[CH:8]=1.I[C:17]1[N:18]=[CH:19][N:20]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=1>C1COCC1.[Zn]>[F:15][C:9]1[CH:8]=[C:7]([CH2:6][C:17]2[N:18]=[CH:19][N:20]([C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:21]=2)[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccc(CBr)cc1F
Agent: CC(Br)Br
Agent: [Zn]
Solvent: C1CCOC1
Product: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F
Reaction time: 1 h

Procedure:
Zinc (0.301 g, 4.63 mmol) and dibromoethane (0.040 mL, 0.463 mmol) were stirred in anhydrous THF (2 mL) under Ar for 1.5 h. A solution of 4-bromomethyl-2-fluoro-benzonitrile (as described in Example 1, Step D) (0.546 g, 2.55 mmol) in anhydrous THF (1 mL) was added dropwise and stirred for 1 h. A mixture of 4-iodo-1-trityl-1H-imidazole (0.808 g, 1.85 mmol) and NiCl2 (PPh3)2 (0.120 g, 0.183 mmol) were added together to the reaction. After stirring overnight under Ar, the reaction was quenched with NH4Cl (9 mL), stirred for 2 h, extracted with CH2Cl2 (3×), dried (MgSO4), concentrated and purified using SiO2 chromatography (0.5% MeOH/CH2Cl2 w/NH4OH) to give the title compound.
Reaction SMILES: C1C=C([O:7]O)C(C(O)=O)=C(C(O)=O)C=1.[CH3:15][C:16]([C:19]1[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]2[S:28][C:29]([S:32][CH3:33])=[N:30][N:31]=2)[CH:22]=[C:21]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:20]=1[OH:38])([CH3:18])[CH3:17].[OH2:39]>CO>[CH3:35][C:34]([C:21]1[CH:22]=[C:23](/[CH:25]=[CH:26]/[C:27]2[S:28][C:29]([S:32]([CH3:33])(=[O:7])=[O:39])=[N:30][N:31]=2)[CH:24]=[C:19]([C:16]([CH3:15])([CH3:17])[CH3:18])[C:20]=1[OH:38])([CH3:37])[CH3:36]
Reactant: O
Reactant: CSc1nnc(/C=C/c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Solvent: CO
Product: CC(C)(C)c1cc(/C=C/c2nnc(S(C)(=O)=O)s2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
Monoperoxyphthalic acid, magnesium salt hexahydrate (1.4 g of a 80% pure solid, 0.0056 mole) is added portionwise to a 0° C. solution of (E)-2,6-bis(1,1-dimethylethyl)-4-[2-[5-(methylthio)-1,3,4-thiadiazol-2-yl]ethenyl]-phenol (1.0 g, 0.0028 mole) in methanol (15 ml) and water (7 ml). After the addition is complete the solution is allowed to warm to room temperature and stir for two hours. The mixture is then warmed on a steam bath for 45 minutes before cooling and concentrating in vacuo. The residue is dissolved in ether and washed with saturated aqueous NaHCO3, saturated aqueous NaCl, and dried over MgSO 4. Filtration and concentration in vacuo gives a residue which is purified by flash chromatography (SiO2) using a 15% ethyl acetate/hexane eluent, followed by recrystallization from ethyl acetate/hexane to give 0.22 g (1.1 g theor., 22%) (E)-2,6-bis(1,1-dimethylethyl)-4-[2- [5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl]ethenyl]phenol, mp 235° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[N:14]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[CH2:27]([N:29]([CH2:30][CH3:31])[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[N:14]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1)[CH3:28]
Reactant: CCNCC
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(I)cc4)no3)cc2C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)c1ccc(-c2noc(-c3cc(C)n(Cc4ccc(C)cc4)n3)n2)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 19 %

Procedure:
A mixture of 3-(4-iodophenyl)-5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazole (Example 13, 250 mg, 0.55 mmol), diethylamine (113 μl, 1.1 mmol), sodium tert-butylat (74 mg, 0.77 mmol), palladium(II) acetate (25 mg, 0.11 mmol), 2-(dicyclohexylphosphino)-1,1′-biphenyl (19 mg, 0.06 mmol) and toluene (3 ml) was stirred at 80° C. for 15 h. The reaction mixture was cooled and water (100 mL) and ethyl acetate (100 mL) was added. The layers were separated and the organic layer was washed with water and brine and then dried with magnesium sulfate. The solvent was evaporated and the residue was purified, first using preparative HPLC, then via flash chromatography (silica, cyclohexane/ethyl acetate, 10:1→1:1) to afford the title compound as a white solid (42 mg, 19%): 1H NMR (400 MHz, CDCl3) 8.03 (d, 2H), 7.12 (d, 2H), 7.07 (d, 2H), 6.78 (s, 1H), 6.71 (d, 2H), 5.40 (s, 2H), 3.41 (quart, 4H), 2.32 (s, 3H), 2.25 (s, 3H), 1.20 (t, 6H); ES-MS m/z 402 (MH)+, HPLC RT (Method E) 2.68 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4].[CH3:14][C:15]([O-:17])=[O:16].[Na+].O>CC(CC)=O>[C:15]([O:17][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4])(=[O:16])[CH3:14]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(=O)OCC(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 48 h
Yield: 87.5 %

Procedure:
2-Bromo-1-(3-nitrophenyl)ethanone (25 g) was dissolved in methylethyl ketone (150 mL). NaOAc (12.5 g) was added and the mixture stirred for 48 hours. Water (100 mL) was added and the reaction mixture extracted with DCM. The DCM layer was dried over Na2SO4 and concentrated to give the title compound (20 g, 87%).
Reaction SMILES: [CH2:1]1[CH2:9][O:8][C:7]2[C:3](=[CH:4][S:5][CH:6]=2)[O:2]1.C([Li])CCC.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])[C:4]1[S:5][CH:6]=[C:7]2[O:8][CH2:9][CH2:1][O:2][C:3]=12)[CH2:25][CH2:26][CH3:27]
Reactant: c1scc2c1OCCO2
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1scc2c1OCCO2
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
The synthesis described herein is depicted schematically in FIG. 4. 2.0 g (14 mmol) of 3,4-ethylenedioxythiophene in 150 ml dry THF was treated dropwise with 10 ml (16.2 mmol) of 1.6 M n-butyl lithium at −78° C. under argon. After stirring for 0.5 h and warming to −40° C., 5.95 g (18.8 mmol) tributylstannyl chloride was added to the solution and it was warmed to room temperature. The solvent was removed by rotary evaporation after stirring for 8 h. The residue was dissolved in hexanes and filtered. The filtrate was dried in vacuum to afford 6.0 g 2-(tributylstannyl)-3,4-ethylenedioxythiophene as a yellow liquid. The compound was used for next step reaction as obtained, no further purifications. 1H NMR (250 MHZ, CDCl3): d (ppm) 6.56 (s, 1H); 4.16 (s, 4H); 1.61-1.49 (m, 6H); 1.39-1.22 (m, 6H); 1.09 (t, 9H); 0.90 (q, 6H). 13C NMR (125 MHZ, CDCl3): d (ppm) 147.88, 142.65, 109.08, 105.99, 64.86, 64.80, 29.08, 27.40, 13.79, 10.71. (M+H)+ found: 431, caled for C18H32O2SSn: 430.11
Reaction SMILES: [Cl:1][C:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[I:16]I>C(Cl)(Cl)Cl>[I-:16].[Cl:1][C:2]1[C:15]2[C:6](=[S+:7][C:8]3[C:13]([N:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: II
Reactant: Clc1cccc2c1Nc1ccccc1S2
Solvent: ClC(Cl)Cl
Product: Clc1cccc2[s+]c3ccccc3nc12
Product: [I-]
Temperature: 5 °C
Reaction time: 8 h

Procedure:
1-Chlorophenothiazine (664 mg, 2.84 mmol) was dissolved in CHCl3 (50 mL) and cooled to 5° C. The solution was stirred as a solution of I2 (2.16 g, 8.51 mmol) dissolved in CHCl3 (10 mL) was added dropwise. The mixture was stirred at 5° C. overnight and allowed to warm to RT. The solvent was evaporated to dryness. The residue was stirred in Et2O and was filtered off and washed with Et2O until the filtrate was colorless. The dark solid was dried under vacuum and used without purification.
Reaction SMILES: COC1C=CC([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=CC=1.C(Br)CC>CC(C)=O>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[O:13][CH2:12][CH2:11][CH2:10][NH2:9]
Reactant: COc1ccc(NCCCOc2ccc3ccccc3c2)cc1
Solvent: CCCBr
Solvent: CC(C)=O
Product: NCCCOc1ccc2ccccc2c1

Procedure:
A mixture of N-(4-methoxyphenyl)-[3-(naphthalen-2-yloxy)propyl]amine (0.5 gm, 0.002 mole) and propyl bromide (0.54ml, 0.003 mole) was taken in dry acetone (40 ml). It was refluxed for 12 hrs and the progress of reaction checked by TLC. Reaction mixture was filtered and the filtrate was concentrated to get oily compound which was further crystallized by benzene hexane mixture to get N-(4-methoxyphenyl)-N-propyl[3-(naphthalen-2-yloxy)propylamine, yellow solid, m.p. 127° C., (yield 0.67 gm, 95.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:6]([C@@H:12]([NH2:14])[CH3:13])=[N:7]2.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:6]([C@@H:12]([NH:14][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][NH:27]3)[CH3:13])=[N:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C[C@H](N)c1nc2cccc(Cl)c2cc1-c1cccc(F)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(Cl)c2cc1-c1cccc(F)c1

Procedure:
Prepared according to Procedure H using (1S)-1-(5-chloro-3-(3-fluorophenyl)-quinolin-2-yl)ethanamine (0.050 g, 0.166 mmol), 6-chloropurine (0.031 g, 0.20 mmol, 1.2 eq) and DIEA (0.33 mmol, 2.0 eq) in n-butanol (3 mL). N-((S)-1-(5-chloro-3-(3-fluorophenyl)quinolin-2-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=5 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 9.22 (s, 1 H), 8.63 (s, 1 H), 8.44-8.47 (m, 3 H), 8.42 (s, 1 H), 8.34 (s, 1 H), 7.87-7.94 (m, 2 H), 7.56 (t, 1 H), 1.79 (d, 3 H), Mass Spectrum (ESI) m/e=419 (M+1).
Reaction SMILES: [C:1]([CH:4]1[CH2:6][CH:5]1[C:7]1[C:17]([F:18])=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([F:19])[C:8]=1[F:20])([OH:3])=[O:2].Cl(O)(=O)(=O)=O.C(OCC)(=O)C.O.C(O[C:37]([CH3:40])([CH3:39])[CH3:38])(=O)C>>[C:37]([O:2][C:1]([CH:4]1[CH2:6][CH:5]1[C:7]1[C:17]([F:18])=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([F:19])[C:8]=1[F:20])=[O:3])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc(F)c(C2CC2C(=O)O)c(F)c1F
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(F)c(C2CC2C(=O)OC(C)(C)C)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
In 10 ml of tert-butyl acetate was dissolved 1.00 g of ethyl 4-(2-carboxycyclopropyl)-2,3,5-trifluorobenzoate. To the resulting solution was added 0.2 ml of a 70% aqueous perchloric acid solution. The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture were added 40 ml of ethyl acetate and 20 ml of water in this order. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: n-hexane/toluene=1/1) to obtain 0.81 g (yield: 68.1%) of ethyl 4-(2-tert-butoxycarbonylcyclopropyl)-2,3,5trifluorobenzoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[OH-].[Na+].C=O.C[CH2:18][OH:19]>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:18][OH:19])[CH:6]=[CH:5]2
Reactant: CCO
Reactant: Cc1ccc2cc(F)ccc2n1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCc1ccc2cc(F)ccc2n1
Temperature: 85 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
6-Fluoro-2-methylquinoline (1.00 g, 6.20 mmol) and sodium hydroxide were each added sequentially to the mixture of HCHO in water. Then 2 mL of EtOH were added to the mixture. The resulting solution was stirred at about 85° C. overnight. The organic layer was extracted with EA (3×10 mL), collected and dried with anhydrous Na2SO4, filtered and concentrated to afford a pink oil. The crude material was purified by chromatography on silica-gel (eluent: PE/EA=6/1) and then further purified by combi-flash chromatography (NH4HCO3/H2O, MeOH/H2O=40%-60%) to give 360 mg of the title product (yield: 30.3%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[C:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)[C:3]=1[C:4]([OH:6])=O.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1>ClCCCl>[Cl:1][C:2]1[C:3]2[C:4](=[O:6])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)[NH:17][C:7]=2[C:8]([N+:14]([O-:16])=[O:15])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1c(Cl)c([N+](=O)[O-])cc([N+](=O)[O-])c1Nc1ccc(OCc2ccccc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)c1ccccc1
Product: O=c1c2cc(OCc3ccccc3)ccc2[nH]c2c([N+](=O)[O-])cc([N+](=O)[O-])c(Cl)c12

Procedure:
A mixture of 9.7 g of 2-chloro-3,5-dinitro-6-[[4-(phenylmethoxy)phenyl]amino]benzoic acid, 200 ml of 1,2-dichloroethane, 20 ml of phosphorus oxychloride, and 1.0 ml of N,N-dimethylaniline was heated under reflux for 30 minutes. Upon cooling, a solid formed which was collected and washed with 1,2-dichloroethane providing the title compound, mp 217°-220° C.
Reaction SMILES: [OH:1][C@@:2]([CH3:24])([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][CH:7]=1)=[O:4].B(Br)(Br)Br.O.CCOC(C)=O>C(Cl)Cl>[OH:1][C@@:2]([CH3:24])([CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)=[O:4]
Reactant: COc1ccc(NC(=O)[C@@](C)(O)COc2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: C[C@](O)(COc1ccc(O)cc1)C(=O)Nc1ccc(O)cc1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
(S)-2-hydroxy-3-(4-methoxyphenoxy)-N-(4-methoxyphenyl)-2-methylpropanamide (6d) (0.20 g, 0.60 mmol) was dissolved in dry CH2Cl2 (30 mL). BBr3 (4 mL of 1.0 M CH2Cl2 solution) was added dropwise with stirring via a syringe at room temperature. The reaction solution was allowed to stir overnight at room temperature. The mixture was cooled to 0° C. in a ice bath and hydrolyzed by adding water (25 mL). EtOAc (50 mL) was added to partition the solution. The organic layer was separated; the aqueous layer was extracted with EtOAc (2×10 mL). The organic layers were combined, washed with brine and dried over anhydrous MgSO4. The solvent was removed under vacuum. The residue was purified by flash column chromatography using silica-gel with hexanes/EtOAc (3/7 v/v) to afford a white solid product, (S)-2-hydroxy-3-(4-hydroxyphenoxy)-N-(4-hydroxyphenyl)-2-methylpropanamide (6f), 0.13 g, 67.2% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([OH:13])[CH:10]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)=[O:21])[CH2:16][CH2:15]3)[CH2:9]2)=[C:4]([N+:29]([O-:31])=[O:30])[CH:3]=1.CCN(CC)CC.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH:10]3[CH2:9][N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[N+:29]([O-:31])=[O:30])[CH2:12][CH:11]3[O:13][C:39](=[O:41])[CH3:40])[CH2:19][CH2:18]2)=[O:21])=[CH:23][CH:24]=1
Reactant: O=C(c1ccc(Cl)cc1)N1CCN(C2CN(c3ccc(Cl)cc3[N+](=O)[O-])CC2O)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1CN(c2ccc(Cl)cc2[N+](=O)[O-])CC1N1CCN(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To a solution of {4-[1-(4-chloro-2-nitro-phenyl)-4-hydroxy-pyrrolidin-3-yl]-piperazin-1-yl}-(4-chloro-phenyl)-methanone (300 mg, 0.64 mmol) in CH2Cl2 (5 mL) at 0° C., was added Et3N (0.2 mL, 1.42 mmol) and acetyl chloride (112 mg, 1.42 mmol). The mixture was stirred at RT for overnight. The organic phase was washed with Saturated NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (Ethyl acetate) to give the desired product (160 mg, 50% yield) as a yellow oil. MS: (ESI), M/Z, 507(M+1). Retention time: 2.59 min (FA-polar).
Reaction SMILES: [OH-:1].[K+].[CH2:3]([C:5]1[N:6]([CH3:22])[C:7]2[C:12]([C:13]=1[C:14](=[O:19])C(F)(F)F)=[CH:11][CH:10]=[C:9]([O:20][CH3:21])[CH:8]=2)[CH3:4]>O.CCO>[CH2:3]([C:5]1[N:6]([CH3:22])[C:7]2[C:12]([C:13]=1[C:14]([OH:19])=[O:1])=[CH:11][CH:10]=[C:9]([O:20][CH3:21])[CH:8]=2)[CH3:4]
Reactant: [OH-]
Reactant: CCc1c(C(=O)C(F)(F)F)c2ccc(OC)cc2n1C
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCc1c(C(=O)O)c2ccc(OC)cc2n1C
Yield: 65.8 %

Procedure:
KOH (1.9 g, 33.49 mmole) in 20 ml H2O was added to a solution of 1-(2-ethyl-6-methoxy-1-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone 73d (2.42 g, 8.47 mmole) in 20 ml EtOH. The reaction mixture was heated to reflux for 8 h and concentrated. The residue was dissolved in H2O acidified with 1N HCl to pH ˜1 and filtrated. The solid was purified by flash column chromatography (2-5% CH3OH in CH2Cl2) to give yellow color solid (1.3 g, 72%). 1H NMR (CDCl3) δ11.88 (1H, bs), 7.82 (1H, d, J=8.7 Hz), 7.04 (1H, s), 6.77 (1H, d, J=8.7 Hz), 3.80 (3H, s), 3.70 (3H, s), 3.51 (2H, q, J=7.4 Hz), 1.15 (3H, t, J=7.4 Hz). ESIMS (MH+): 234.05.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][Si](C(C)C)(C(C)C)C(C)C)=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[C:8]2=[O:34])=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:32][CH3:33])[C:9]=3[CH:8]2[OH:34])=[CH:35][CH:36]=1
Reactant: COc1c2c(c(O[Si](C(C)C)(C(C)C)C(C)C)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2O

Procedure:
To a solution of 13 (0.699 g, 1.38 mmol) in 14 mL of a 1:1 solution of dry MeOH: CH2Cl2 under a N2 atmosphere was added sodium borohydride (NaBH4, 156 mg, 4.13 mmol). The reaction mixture was dried after 5 hours and the residue was loaded onto a silica column. The product was eluted with a 10% EtOAc-Hex to provide the product 20. 1H NMR (300 MHz, CDCl3) δ 1.10 (d, 9H, J=8 Hz), 1.16 (d, 9H, J=7 Hz), 1.52 (septet, 3H, J=8 Hz), 3.72 (d, 1H, J=11 Hz), 4.11 (s, 3H), 4.23 (d, 1H, J=15 Hz), 4.85 (d, 1H, J=15 Hz), 5.79 (d, 11H, J=11 Hz), 6.97 (t, 2H, J=9 Hz), 7.27 (dd, 2H, J=6, 9 Hz), 7.43 (dd, 1H, J=4, 8 Hz), 8.43 (dd, 1H, J=2, 8 Hz), 8.81 (dd, 1H, J=2,4 Hz); 13C NMR (75 MHz, CDCl3) δ 14.8. 18.2,41.3, 61.6, 78.6, 115.3, 115.6, 116.6, 122.3, 126.0, 126.8, 130.1, 130.2, 131.1, 132.8, 143.1, 143.8, 148.3, 162.1 (d, J=244 Hz), 165.2; EI MS (m/z) 511.5 [MH+], 533.4 [M+Na].
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[O:5]1[CH2:9][CH2:8][C@H:7]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:6]1.N1C=CC=CC=1.[CH3:22][N:23]1[CH:27]=[C:26]([C:28]2[CH:33]=[C:32]([O:34][C:35]3[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=3)[CH:31]=[CH:30][N:29]=2)[CH:25]=[N:24]1>C(Cl)Cl.O>[CH3:22][N:23]1[CH:27]=[C:26]([C:28]2[CH:33]=[C:32]([O:34][C:35]3[CH:36]=[CH:37][C:38]([NH:41][C:11]([N:12]4[CH2:13][CH2:14][N:10]([C@H:7]5[CH2:8][CH2:9][O:5][CH2:6]5)[C:1]4=[O:2])=[O:15])=[N:39][CH:40]=3)[CH:31]=[CH:30][N:29]=2)[CH:25]=[N:24]1
Reactant: O=C1NCCN1[C@H]1CCOC1
Reactant: O=C(Cl)Cl
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN([C@H]5CCOC5)C4=O)nc3)ccn2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
A 0° C. solution of phosgene (20% in toluene, 0.092 mL, 0.174 mmol) in DCM (2 mL) was treated slowly with a solution of Example B6 (26 mg, 0.166 mmol) and pyridine (0.027 mL, 0.331 mmol) in DCM (2 mL), stirred at 0° C. for 0.5 h, then concentrated to dryness. The residue was dissolved in DCM (2 mL), treated with pyridine (0.0400 mL, 0.495 mmol), cooled to 0° C., treated slowly with a solution of Example A2 (36 mg, 0.165 mmol) in DCM (2 mL), warmed to RT and stirred for 1.5 h. The mixture was diluted with water, extracted with DCM and the organic layer was washed with water, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford (S)—N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide (33 mg, 45%). 1H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1 H), 8.38 (d, J=5.8 Hz, 1 H), 8.27 (s, 1 H), 8.23 (d, J=2.9 Hz, 1 H), 8.07 (d, J=9.0 Hz, 1 H), 7.97 (s, 1 H), 7.72 (dd, J=9.0, 2.9 Hz, 1 H), 7.25 (s, 1 H), 6.71 (d, J=5.5 Hz, 1 H), 4.57-4.49 (m, 1 H), 3.91-3.86 (m, 1 H), 3.84 (s, 3 H), 3.83-3.76 (m, 3 H), 3.70-3.57 (m, 2 H), 3.51-3.43 (m, 2 H), 2.19-2.09 (m, 1 H), 2.02-1.91 (m, 1 H); MS (ESI) m/z: 450.1 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][C:26]([CH2:29][NH:30][CH3:31])=[CH:25][CH:24]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].CCN(CC)CC>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:24]=[CH:25][C:26]([CH2:29][N:30]([CH3:31])[S:33]([CH3:32])(=[O:35])=[O:34])=[CH:27][CH:28]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: CNCc1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CN(C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.8 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((methylamino)-methyl)biphenyl-3-yl)cyclopropane carboxamide (30 mg, 0.070 mmol), methanesulfonyl chloride (7.8 μL, 0.14 mmol) and Et3N (30 μL, 0.22 mmol) were dissolved in N,N-dimethylformamide (1.0 mL) and allowed to stir at 25° C. for 16 hours. The crude reaction was purified by reverse phase HPLC to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((N-methylmethylsulfonamido) methyl)biphenyl-3-yl)cyclopropanecarboxamide (22 mg, 64%). ESI-MS m/z calc. 492.2. found 493.3 (M+1)+; retention time 3.45 minutes.