Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].CC(C)([O-])C.[K+].Br[CH2:24][C:25]#[N:26].Cl>C(OCC)(=O)C.CS(C)=O>[CH3:10][O:9][C:7]([C:6]1[S:5][C:4]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:3]=2[C:2]=1[O:1][CH2:24][C:25]#[N:26])=[O:8]
Reactant: COC(=O)c1sc2ccc(OC)cc2c1O
Reactant: N#CCBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2ccc(OC)cc2c1OCC#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a room temperature solution of methyl 3-hydroxy-5-methoxybenzo[b]thiophene-2-carboxylate (1.00 g, 4.2 mmol) [Connor, et al., J. Med. Chem. 35:959 (1992)]in 20 mL of DMSO is added potassium t-butoxide (494 mg, 4.41 mmol) followed by bromoacetonitrile (878 μL, 12.58 mmol). The mixture is stirred at room temperature for 1.5 hours, then poured into ethyl acetate and 1N HCl. The organic layer is washed with 1N HCl, followed by several portions of brine, and dried over MgSO4. Filtration followed by removal of solvent in vacuo and recrystallization of the residue from ethyl acetate:hexane gives 413 mg. additional crop of 112 mg can be obtained from the mother liquor, mp 159.5°-160° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>CCO.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>[F:11][C:5]1[C:4]([CH3:12])=[CH:3][C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([F:13])[CH:19]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1cc(Br)cc(C(=O)O)c1F
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: C1COCCO1
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2cccc(F)c2)cc(C(=O)O)c1F
Temperature: 85 °C
Yield: 75.2 %

Procedure:
To a solution of 5-bromo-2-fluoro-3-methyl-benzoic acid (697 mg, 2.99 mmol, 1.0 eq) and (3-fluorophenyl)boronic acid (502 mg, 3.59 mmol, 1.2 eq) in a mixture of EtOH (10 mL), dioxane (20 mL) and H2O (10 mL) were added K2CO3 (142 mg, 1.03 mmol, 2.5 eq) and Pd(PPh3)4 (345 mg, 0.30 mmol, 0.1 eq). The mixture was heated at 85° C. overnight. The reaction was quenched by addition of 1M HCl and the aqueous phase extracted with EtOAc. The organic extract was dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by chromatography to give the title compound as a solid (558 mg, 73%).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([F:17])[CH:8]=1)[CH2:3][C:4](O)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH3:1].[NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[C:9]([F:17])[CH:8]=1)[CH2:3][CH2:4][OH:5]
Reactant: NC(CC(=O)O)c1ccc(C(F)(F)F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N
Product: NC(CCO)c1ccc(C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 7.5 %
Yield: 45.3 %

Procedure:
To a stirred suspension of 93 (2.0 g, 8.0 mmol) and THF (25 mL) under N2 at 0° C. was added dropwise 1M LiAlH4 in THF (12 mL, 12 mmol), and the reaction stirred at 0° C. in an ice bath for 1.5 h. The cold reaction mixture was quenched by carefully adding the reaction mixture to a satd. solution of Rochelle's salt (50 mL) that was cooled in an ice bath and adequately vented. The resulting mixture was stirred for 18 h while warming to RT slowly as the ice bath melted. The mixture was diluted with EtOAc (50 mL) and filtered through CELITE® to remove solids which were rinsed several times with EtOAc. The phases were separated, and the aqueous phase re-extracted with EtOAc (30 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with 5% 7N NH3 in MeOH in DCM (500 mL to pre-wash column, followed by 500 mL of eluent, then 500 mL of 7.5% 7N NH3 in MeOH in DCM) to afford 0.43 g (22%) of 3-amino-3-(3-fluoro-4-(trifluoromethyl)phenyl)propan-1-ol (91a).
Reaction SMILES: C(N(C(C)C)CC)(C)C.O[C@@H:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[NH:39][CH2:38][CH2:37][CH2:36]2>ClCCl.C(OC(=O)C)C>[Cl:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[N:39]([C@H:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16])[CH2:38][CH2:37][CH2:36]2
Reactant: Clc1ccc2c(c1)CCCN2
Reactant: O=C1OCC[C@H]1O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1OCC[C@@H]1N1CCCc2cc(Cl)ccc21
Temperature: -20 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Prepared using general procedure 57. Under an N2 atmosphere at −20° C., diisopropyl ethyl amine (15.9 mL, 91.4 mmol) was added drop wise to a solution of solution of (R)-3-hydroxydihydrofuran-2(3H)-one (4.67 g, 45.7 mmol) in dichloromethane (70 mL). Then added trifluoromethanesulfonic anhydride (8.1 mL, 48.0 mmol) drop wise by maintaining internal temperature of the reaction mixture <−20° C. Upon completion of addition, the mixture was stirred at −20° C. for 1 hour. Then added at −20° C., 6-chloro-1,2,3,4-tetrahydroquinoline drop wise. The reaction was allowed to warm to RT over a period of 30 minutes and continued to stir at RT for 16 hrs. The reaction mixture was diluted with 200 mL of ethylacetate and washed with saturated sodium bicarbonate (3×50 mL). The organic layer was washed with a saturated aqueous NaCl solution (2×50 mL). The solution was dried over magnesium sulfate, filtered, and concentrated. Purification via silica gel chromatography using 5-50% ethyl acetate in hexane gave (S)-3-(6-chloro-3,4-dihyroquinolin-1(2H)-yl) dihydrofuran-2(3H)-one as a white solid (10.74 g, 93% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=252.3; tR=1.66 min. 1H NMR (400 MHz, DMSO-d6) δ 7.03-6.98 (m, 2H), 6.74 (d, J=8.9 Hz, 1H), 5.07 (t, J=10.0 Hz, 1H), 4.42 (t, J=9.5 Hz, 1H), 4.30-4.23 (m, 1H), 3.16-3.02 (m, 2H), 2.68 (t, J=6.4 Hz, 2H), 2.44-2.27 (m, 2H), 1.87-1.77 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[C:5]#[N:6].Cl[CH2:14][C:15]1[C:16]([NH:23][CH:24]([CH3:26])[CH3:25])=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>CC#N>[CH:24]([NH:23][C:16]1[C:15]([CH2:14][NH:1][C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=2)[C:5]#[N:6])=[CH:20][N:19]=[C:18]([S:21][CH3:22])[N:17]=1)([CH3:26])[CH3:25]
Reactant: CSc1ncc(CCl)c(NC(C)C)n1
Reactant: N#Cc1cc(N)cc([N+](=O)[O-])c1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(CNc2cc(C#N)cc([N+](=O)[O-])c2)c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
A solution of 3-amino-5-nitrobenzonitrile (3.59 g, 22 mmol) in CH3CN (10 mL) was added dropwise to a mixture of 5-(chloromethyl)-N-isopropyl-2-(methylthio)pyrimidin-4-amine from Example A9 (5 g, 22 mmol), sodium iodide (0.33 g, 2.2 mmol), and diisopropylethylamine (2 mL, 12 mmol) in CH3CN (100 mL) at 0° C. The resultant reaction mixture was stirred at RT overnight. The solvent was evaporated and the residue was diluted with water, and extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), concentrated and purified by silica gel chromatography to afford 3-((4-(isopropylamino)-2-(methylthio)pyrimidin-5-yl)methylamino)-5-nitrobenzonitrile (2.2 g, 28% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.87 (s, 1 H), 7.74 (s, 1 H), 7.56 (s, 1 H), 7.32 (s, 1H), 7.08 (m, 1 H), 6.63 (d, J=7.6 Hz, 1 H), 4.30 (m, 1 H), 4.15 (s, 2 H), 2.50 (s, 3 H), 1.17-1.15 (d, J=6.4 Hz, 6 H); MS (ESI) m/z: 359.2[M+H]+.
Reaction SMILES: [CH3:1][NH2:2].CO.C(OC([NH:12][C:13]1[C:21]2[CH:20]=[CH:19][S:18][C:17]=2[CH:16]=[C:15]([C:22]([O:24]CC)=O)[CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:12][C:13]1[C:21]2[CH:20]=[CH:19][S:18][C:17]=2[CH:16]=[C:15]([C:22]([NH:2][CH3:1])=[O:24])[CH:14]=1
Reactant: CCOC(=O)c1cc(NC(=O)OC(C)(C)C)c2ccsc2c1
Reactant: CN
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(N)c2ccsc2c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A 40% methylamine-methanol solution (3 ml) was added to ethyl 4-(tert-butoxycarbonylamino)benzo[b]thiophene-6-carboxylate obtained in Example 22 (Step 3) (110 mg), and the reaction solution was stirred at 90° C. overnight. Trifluoroacetic acid (0.5 ml) was added to the resultant residue, and the reaction solution was stirred at room temperature for 15 minutes. Thereafter, the solvent was evaporated under vacuum, and the residue was purified by column chromatography on silica gel (developing solvent:hexane-ethyl acetate) to obtain 4-amino-N-methylbenzo[b]thiophene-6-carboxamide.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:7][CH2:8][O:9][CH:10]([OH:12])[CH3:11].[OH-].[Na+]>CO>[C:1]([NH:5][CH2:7][CH2:8][O:9][CH:10]([OH:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC(O)OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(O)OCCNC(C)(C)C
Temperature: 150 °C

Procedure:
A solution of 45.63 g (0.625 mole) of tertiarybutylamine and 31 g (0.25 mole) of 2-chloroethoxyethanol in 100 ml of methanol was charged to a 300 ml steel autoclave and heated under autogeneous pressure for 1 hour at 150° C. The reactor was cooled and the contents removed. To the homogeneous solution was added 11 g (0.275 mole) of NaOH pellets and the reaction refluxed for 0.5-1 hour, cooled, filtered, vacuum stripped, and distilled. The yield was 31.4 g (78%).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:12]([O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O)([CH3:15])([CH3:14])[CH3:13].[BH4-].[Na+]>CC#N>[C:12]([O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH:11][CH2:10][CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(C)(C)Oc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCNCc1ccccc1OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
N-Boc-ethylenediamine (2.6 g, 16 mmol) and 8 (2.9 g, 16 mmol) were added to 250 mL of CH3CN and the reaction mixture was refluxed under argon for 4 hr. After cooling down to room temperature, the solvent was removed and the residue was redissolved in MeOH. The solvent was then evaporated and NaBH4 (3 g, 16 mmol) was added and stirred overnight. The solvent was evaporated, followed by extraction with CH2Cl2. The CH2Cl2 extract was concentrated and purified by a silica gel column using 2% methanolic NH3 (7 M NH3 in methanol/98% CH2Cl2 as eluent to yield the desired product as a pale yellow oil (97%). 1H NMR (CDCl3) δ 7.204 (dd, 1H, Ar), 7.115 (ddd, 1H, Ar), 7.007 (dd, 1H, Ar), 6.930 (ddd, 1H, Ar), 3.718 (s, 2H, —CH2—), 3.175 (d, 2H, —CH2—), 2.638 (t, 2H, —CH2—), 1.402 (s, 9H, —C(CH3)3), 1.382 (s, 9H, —C(CH3)3). Mass Spect.=323.23 (M+H)+.
Reaction SMILES: C[Si](C)(C)Cl.Br[CH2:7][C:8]([O:10][CH3:11])=[O:9].[CH:12](=[N:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>C(OC(C)C)(=O)C.[Zn]>[C:20]1([NH:19][CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C(=Nc1ccccc1)c1ccccc1
Reactant: COC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: N
Agent: [Zn]
Solvent: CC(=O)OC(C)C
Product: COC(=O)CC(Nc1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
At room temperature, a three-neck flask equipped with a reflux condenser, internal thermometer, dropping funnel and stirrer under nitrogen protective gas was initially charged with 7.6 g of zinc powder (116 mmol) in 45 ml of isopropyl acetate. After 1.83 ml of trimethylchlorosilane (14.4 mmol) had been added, the mixture was heated to 60° C. for 15 min, then allowed to cool to 55° C. and 16.3 g of undiluted methyl bromoacetate (107 mmol) were subsequently added dropwise within 5 min, and the temperature was maintained at 60° C. by external cooling. The mixture was then stirred at 50° C. for 15 min. After cooling to 5° C., 16.1 g of benzalaniline (89 mmol) dissolved in 10 ml of isopropyl acetate were added and the mixture was heated to 25° C. After the mixture had been stirred at 25° C. for 1 h, it was heated to 40° C. for a further 10 min and then cooled to 5° C. Hydrolysis was then effected using 80 ml of concentrated ammonia solution. After 40 ml of isopropyl acetate had been added, the mixture was heated to 50° C. and precipitate formed went into solution. At this temperature, excess zinc was filtered off and the organic phase removed. The organic phase was then washed at 50° C. with 20 ml of water. After the phase separation, the solvent was distilled off under reduced pressure to give a crude product in a yield of 19.7 g (87% of theory) and a purity of >95% (HPLC). After recrystallization from ethyl acetate, methyl 3-(N-phenylamino)-3-phenylpropionate having a melting point of 110° C. was obtained.
Reaction SMILES: C1(CCC[NH2:10])C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][N:24]=1)=[O:21].[CH2:32]1[C:40]2[C:35](=CC=CC=2)[CH2:34][N:33]1[C:41]([NH:43][C:44]1[CH:52]=[CH:51][C:47](C(O)=O)=CC=1)=O>>[N:43]1[CH:44]=[CH:52][CH:51]=[CH:47][C:41]=1[N:33]1[CH2:32][CH2:40][N:10]([C:27]([C:26]2[CH:30]=[CH:31][C:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13]3)=[O:21])=[N:24][CH:25]=2)=[O:29])[CH2:35][CH2:34]1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)nc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Product: O=C(Nc1ccc(C(=O)N2CCN(c3ccccn3)CC2)cn1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 1C, substituting N-(2-pyridyl)piperazine for 3-phenylpropan-1-amine and 6-(isoindoline-2-carboxamido)nicotinic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.21 (s, 1H), 8.39 (dd, J=2.3, 0.8 Hz, 1H), 8.13 (dd, J=4.9, 1.9 Hz, 1H), 8.00 (dd, J=8.6, 0.8 Hz, 1H), 7.84 (dd, J=8.6, 2.4 Hz, 1H), 7.56 (ddd, J=8.7, 6.9, 1.9 Hz, 1H), 7.34-7.39 (m, 2H), 7.29-7.34 (m, 2H), 6.85 (d, J=8.5 Hz, 1H), 6.67 (dd, J=6.7, 4.9 Hz, 1H), 4.75-4.92 (bs, 4H), 3.47-3.81 (m, 8H); MS (ESI(+)) m/e 429 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[NH:13]C(=O)C(C)(C)C)=O)C.[OH-].[K+].[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)[CH3:24]>C(O)C.[OH-].[Na+]>[C:26]1([C:23]2[CH:24]=[C:5]([C:4]([OH:20])=[O:3])[C:7]3[C:12](=[CH:11][CH:10]=[N:9][CH:8]=3)[N:13]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)C(=O)c1cnccc1NC(=O)C(C)(C)C
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(-c2ccccc2)nc2ccncc12
Temperature: 100 °C

Procedure:
[4-(2,2-Dimethyl-propionylamino)-pyridin-3-yl]-oxo-acetic acid ethyl ester (532 mg, 1.91 mmol) was taken up in ethanol (1.9 mL) and 4N KOH (1.9 mL, 4 equiv) was added. The solution was refluxed for 2-3 h at 100° C., acetophenone (0.446 mL, 2.0 equiv) was added neat, and the reaction was allowed to reflux overnight. Upon cooling to room temperature, the solution was diluted with 1N NaOH and extracted twice with ether. The product was precipitated from the aqueous layer by the addition of glacial AcOH (5-10 mL). The solids were collected by vacuum filtration, rinsed with cold water, and dried under high vacuum (white solid, 371 mg, 78%). 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1 H), 8.80 (d, J=5.6 Hz, 1 H), 8.56 (s, 1 H), 8.35-8.31 (m, 2 H), 8.03 (d, J=6.0 Hz, 1 H), 7.61-7.58 (m, 3 H). MS (LR-APCI) calcd. for C15H11N2O2 (M+H) 251.1; found 251.5.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][C:10]=1[Br:16])([CH3:4])([CH3:3])[CH3:2].BrC1C=C([F:25])C=CC=1O.BrCC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([F:25])=[CH:11][C:10]=1[Br:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Reactant: Oc1ccc(F)cc1Br
Agent: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)COc1ccc(F)cc1Br

Procedure:
Following the general method as outlined in Intermediate 1, starting from 2-bromo-4-fluorophenol and tert-butyl bromoacetate, the title compound was obtained as a white solid in quantitative yield.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]#[N:12])=[CH:8][C:7]=2[CH:13]=1)=O.[CH2:14]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[C:24]([F:27])([F:26])[F:25])[CH2:15][CH3:16].[BH4-].[Na+]>>[CH2:14]([C:17]1[CH:23]=[CH:22][C:20]([NH:21][CH2:1][C:3]2[CH:4]=[CH:5][C:6]3[O:10][C:9]([C:11]#[N:12])=[CH:8][C:7]=3[CH:13]=2)=[CH:19][C:18]=1[C:24]([F:25])([F:26])[F:27])[CH2:15][CH3:16]
Reactant: N#Cc1cc2cc(C=O)ccc2o1
Reactant: CCCc1ccc(N)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: CCCc1ccc(NCc2ccc3oc(C#N)cc3c2)cc1C(F)(F)F
Temperature: 37.5 °C
Reaction time: 0.08 h
Yield: 69.2 %

Procedure:
5-Formylbenzofuran-2-carbonitrile (168 mg, 0.98 mmol) was added to 2 mL of TFE and stirred at 35-40° C. After 5 min, the solution became clear, 4-propyl-3-(trifluoromethyl)aniline (199 mg, 0.982 mmol) was added, and a yellow precipitate formed. The mixture was vigorously stirred at the same temperature for 0.5 hr, NaBH4 (44.6 mg, 1.18 mmol) was added and the reaction was stirred at this temperature for another 0.5 hr. The mixture was then filtered, and the residue was washed with TFE (2 mL). The solvent was concentrated under reduced pressure and the crude product was purified by silica gel flash chromatography, 100% Heptane-10% Ethyl Acetate/90% Heptane, to give 5-(((4-propyl-3 (trifluoromethyl)phenyl)amino)-methyl)benzofuran-2-carbonitrile (243 mg). LCMS retention time=1.76 minutes (LC method 3); MS (m+1)=358.8. 1H NMR (400 MHz, DMSO-d6) δ 0.88 (t, J=7.3 Hz, 3H), 1.48 (sxt, J=7.5 Hz, 2H), 2.47 (br. s., 2H) 4.41 (d, J=6.0 Hz, 2H), 6.64 (t, J=6.1 Hz, 1H), 6.74 (dd, J=8.4, 2.4 Hz, 1H), 6.86 (d, J=2.5 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.59 (dd, J=8.7, 1.7 Hz, 1H), 7.71 (d, J=8.7 Hz, 1H), 7.78 (d, J=1.0 Hz, 1H), 8.09 (d, J=0.9 Hz, 1H).
Reaction SMILES: [SH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.Cl[CH2:23][CH2:24][OH:25].[H-].[Na+]>O1CCCC1.O>[OH:25][CH2:24][CH2:23][S:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1
Reactant: C[C@]12CC[C@H](S)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: OCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12CC[C@H](SCCO)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 3 h

Procedure:
To a solution of 2.0 g of 3β-mercapto-androst-5-en-17-one (Swann D. A. and Turnbull J. H., Tetrahedron, 1966, 22, 231) and 0.33 ml of 2-chloroethanol in 5.0 ml of tetrahydrofuran under nitrogen atmosphere at room temperature, 0.030 g of sodium hydride (60% dispersion in mineral oil) were added. The reaction mixture was stirred for 3 hrs, diluted with water and extracted with ethyl acetate; the organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using methylene chloride/methanol/30% ammonia solution 95/5/1 as eluant to give 1.2 g of 3β-(2-hydroxyethylthio)-androst-5-en-17-one.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)=[CH:16][C:15]=1[C:12]#[C:11][C:8]1[N:7]=[N:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=1
Reactant: C#Cc1ccc(NC(C)C)nn1
Reactant: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(I)c4)[nH]c3c2)CC1
Product: CC(C)Nc1ccc(C#Cc2cc(-c3nc4ccc(CN5CCN(C)CC5)cc4[nH]3)ccc2Cl)nn1

Procedure:
The title compound was synthesized from N-isopropyl-6-ethynylpyridazin-3-amine and 2-(4-chloro-3-iodophenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole in a manner similar to that described for in Example 1. The title compound was obtained as a khaki solid. Mp: 127-128° C.; 1H NMR (300 MHz, CDCl3) δ: 8.11-8.13 (1H, d, J=6.0 Hz), 7.82 (1H, s), 7.64 (2H, m), 7.53 (1H, s), 7.35-7.38 (1H, d, J=9.0 Hz), 7.29-7.32 (1H, d, J=9.0 Hz), 6.66-6.69 (1H, d, J=9.0 Hz), 5.22 (1H, s), 4.12-4.14 (1H, m), 3.62 (2H, s), 2.51 (8H, brs), 2.31 (3H, s), 1.25-1.31 (6H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C28H31ClN7: 500.2324. found: 500.2313.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:20](O)=[O:21])[N:16]=[CH:17]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27](=[O:38])[C@@H:28]([NH2:37])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1>>[CH3:25][O:26][C:27](=[O:38])[C@@H:28]([NH:37][C:20]([C:15]1[N:16]=[CH:17][C:18]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:9][C:8]1[CH:23]=[CH:24][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[CH:19]=2)=[O:21])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)O)ncc3c2)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Br)cc1
Product: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc2ccc(Oc3ccc(C(C)(C)C)cc3)cc2cn1
Yield: 95.4 %

Procedure:
500 mg (1.55 mmol) of 7-(4-tert-butylphenoxy)-isoquinoline-3-carboxylic acid (Example 371) was reacted with 441 mg (1.7 mmol) of (2S)-amino-3-(4-bromo-phenyl)-propionic acid methyl ester as described in general procedure A. The crude product was purified by flash column chromatography on silica using 8:2 hexane/ethyl acetate as eluent, to afford 830 mg of the title compound as a white solid.
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[CH3:36][NH:37][CH3:38].C1COCC1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH:6]([N:37]([CH3:38])[CH3:36])[C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])=[CH:16][N:17]=4)=[O:23])[CH2:26][CH2:25]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: CNC
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Temperature: 25 °C
Yield: 82 %

Procedure:
(6-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate (0.12 mmol) was dissolved in NMP (2 ml) following by addition of 2M solution of dimethylamine in THF (600 μl, 0.12 mmol) and DIEA (21 μl, 0.12 mmol). The reaction mixture was maintained at ambient temperature for 16 h. The resulting mixture was subjected to HPLC purification to provide the trifluoroacetic salt of target material (55 mg, 82%) as a colorless solid. 1H-NMR (DMSO): δ 8.43 (s, 1H), δ 8.40 (d, J=2 Hz, 1H), δ 8.06 (d, J=8.7 Hz, 1H), δ 7.96 (dd, J=2 Hz, J=8.7 Hz, 1H), δ 7.56 (bd, J=6.5 Hz, 1H), δ 7.39 (bt, J=6.5 Hz, 1H), δ 7.05-7.11 (m, 3H), δ 6.96 (s, 2H), δ 6.05 (s, 2H), δ 5.68 (bm, 1H), δ 3.85 (s, 3H), δ 2.75 (s, 6H), δ 1.42-1.45 (m, 2H), δ 1.13-1.16 (m, 2H).