Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=2)[CH:19]=[C:18]1B(O)O)(OC(C)(C)C)=O>>[Cl:26][C:23]1[CH:24]=[C:25]2[C:20]([CH:19]=[C:18]([C:2]3[CH:3]=[N:4][CH:5]=[C:6]([CH:7]=3)[C:8]#[N:9])[NH:17]2)=[CH:21][CH:22]=1
Reactant: N#Cc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(Cl)cc21
Product: N#Cc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1

Procedure:
3-Bromo-5-cyano-pyridine and N-Boc-6-chloro-indoleboronic acid are processed according to the procedure described in Example 103 to give 5-(6-chloro-1H-indol-2-yl)-nicotinonitrile, which is processed according to the procedure described in Example 114 to give 5-(6-Chloro-1-methyl-1H-indol-2-yl)-nicotinonitrile. 1H NMR (400 MHz, MeOD) δ ppm 3.81 (s, 3H), 6.81 (s, 1H), 7.14 (dd, J=8.6, 1.8 Hz, 1H), 7.56 (s, 1H), 7.61 (d, J=8.3 Hz, 1H), 8.46 (t, J=2.1 Hz, 1H), 8.98 (d, J=2.0 Hz, 1H), 9.06 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 268.0636 [(M+H)+ Calcd for C16H10ClN3 268.0636].
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9](=[O:25])[C:10]([O:23][CH3:24])=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]([F:22])(F)F)[CH:13]=1.Br[CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:33][CH:32]=1>CN(C)C=O>[CH3:7][O:8][C:9](=[O:25])[C:10]([O:23][CH3:24])=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)=[C:14]([CH2:19][F:22])[CH:13]=1
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)C(=Cc1ccc(O)c(C(F)(F)F)c1)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(=Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)c(CF)c1)OC
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
Potassium tert-butoxide (15 mg, 0.13 mmol) was added at 0° C. to a solution of 3-(4-hydroxy-3-trifluoromethyl-phenyl)-2-methoxy-acrylic acid methyl ester (35 mg, 0.126 mmol) in dry N,N-dimethylformamide (0.6 mL). The mixture was stirred for 0.5 hours and 4-(3-Bromo-propoxy)-biphenyl (example 23, Step D) (45 mg, 0.15 mmol) was added. The reaction was stirred for 6 hours at room temperature and quenched with a saturated solution of ammonium chloride (10 mL). The aqueous layer was separated and extracted with methylene chloride (5×10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The residue was chromatographed (silica gel, hexanes/ethyl acetate 8:2) to produce 3-{4-[3-(biphenyl-4-yloxy)-propoxy]-3-fluoromethyl-phenyl}-2-methoxy-acrylic acid methyl ester as a colorless oil (35 mg, 57%). 1H-NMR (CDCl3, 200.15 MHz): δ 8.00 (d, 1H, J=1.6), 7.89 (dd, 1H, J=8.6, 1.6), 7.46–7.26 (m, 7H), 7.05–6.93 (m, 4H), 4.33–4.20 (m, 4H), 3.86 (s, 3H), 3.79 (s, 3H), 2.33 (qn, 2H, J=5.9).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([I:11])=[CH:6][N:5]=1.Br[CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([NH:10][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]2)[C:7]([I:11])=[CH:6][N:5]=1
Reactant: Nc1cc(Cl)ncc1I
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(Cl)ncc2I)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
NaH (0.098 g, 3.9 mmol) was added to a solution of 2-chloro-5-iodopyridin-4-amine (0.500 g, 1.96 mmol) in DMF (12 mL) and the mixture was stirred for 30 min at r.t. The temperature was then raised to 80° C. and a solution of tert-butyl 4-(bromomethyl)-piperidine-1-carboxylate (1.093 g, 3.93 mmol) in DMF (2 mL) was added. The reaction mixture was stirred at 80° C. for 2 h, then cooled to r.t. NaH (0.050 g, 2.00 mmol) was added and the reaction mixture was heated for 1 h at 80° C. After cooling, water (40 mL) was added and the reaction mixture was partitioned between ethyl acetate and aq. NaHCO3. The organic phase was washed with brine, dried (MgSO4) and concentrated. The crude product was purified by flash silica chromatography, eluting with ethyl acetate and hexane (1/9), to give the title compound as a pink solid (0.405 g, 46%).
Reaction SMILES: S([O-])([O-])(=O)=O.[Al+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Al+3].C(=O)([O-])[O-].[Na+].[Na+].[O-:24][P:25]([O:28]P([O-])([O-])=O)(=[O:27])[O-:26].[Ca+2:33].[Ca+2]>>[P:25]([O-:28])([O-:27])([O-:26])=[O:24].[Ca+2:33].[P:25]([O-:28])([O-:27])([O-:26])=[O:24].[Ca+2:33].[Ca+2:33]
Reactant: O=P([O-])([O-])OP(=O)([O-])[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Product: O=P([O-])([O-])[O-]

Procedure:
In this method, the first reactant, 800 g of a 12% aqueous solution of aluminum sulfate was added to the reactor vessel, then the second reactant, an 18% aqueous solution of sodium carbonate, was metered into the vessel at a rate of 7 ml/minute until the pH reached 5.9. The reactants were mixed together for 20 minutes under agitation. Next, 54 grams of calcium pyrophosphate was added and the resulting slurry was mixed for 15 minutes with agitation and filtered and washed to a conductivity of about 2000 μmhos. The recovered wetcake was reslurried with 150 g of water and 200 g of a 1% FD&C Blue No. 1 aqueous solution to form a slurry of colored calcium phosphate colorant and this slurry was then mixed for approximately 1 hour.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]2)=[N:24][CH:25]=1>>[OH:32][CH:29]1[CH2:30][CH2:31][N:26]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:25][N:24]=2)[CH2:27][CH2:28]1
Reactant: Nc1ccc(N2CCC(O)CC2)nc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1ccc(N2CCC(O)CC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to example 43 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 5′-amino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol. LCMS calcd for C21H19F3N4O3 (m/e) 432, obsd 433 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:6][CH2:5][C:4](=[O:19])[NH:3]1.[H-].[Na+].Cl[CH:23]([OH:25])[CH3:24]>CN(C=O)C.O>[OH:25][CH2:23][CH2:24][N:3]1[C:4](=[O:19])[CH2:5][CH2:6][CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[C:2]1=[O:1]
Reactant: CC(O)Cl
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione (2.5 g) was dissolved in DMF (dry, 60 mL). 95% NaH (0.24 g) was added. The mixture was stirred for 30 minutes at room temperature. Then, chioroethanol (0.68 mL) was added, and the mixture was stirred over night at room temperature. The reaction mixture was diluted with 300 mL of water and extracted with ethyl acetate (3×60 mL). Organic phases were combined and washed twice with water, and once with brine, then dried over anhydrous magnesium sulfate. Rotary evaporation of solvent yielded crude product, which was purified by silica gel column chromatography (acetic ether: petroleum ether=1:1) to yield 1.1 g of pure title product. 1H NMR (CDCl3, ppm) δ 7.88-7.90 (m, 2H), 7.77-7.79 (m, 2H), 5.06 (dd, 1H, J=5.6, 12.4Hz), 4.02-4.12 (m, 2H), 3.76-3.80 (m, 2H), 2.94-3.02 (m, 1H), 2.72-2.90 (m, 2H), 2.29-2.31 (m, 1H), 2.14-2.23 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:21]=[CH:22][C:23]=2[S:24]([OH:27])(=O)=[O:25])[C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH3:20])=[O:5])[CH3:2].S(Cl)(Cl)=O.CN(C=O)C.[C:37]([NH2:41])([CH3:40])([CH3:39])[CH3:38].C(N(CC)CC)C.Cl>ClCCCl>[C:37]([NH:41][S:24]([C:23]1[CH:22]=[N:21][N:10]2[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[CH3:20])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8][C:9]=12)(=[O:25])=[O:27])([CH3:40])([CH3:39])[CH3:38]
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)O)cnn2c1Nc1ccc(F)cc1C
Reactant: CC(C)(C)N
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
6-Ethoxycarbonyl-7-(4-fluoro-2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-3-sulfonic acid (0.400 g, 1.01 mmol) obtained in step 2 was dissolved in 1,2-dichloroethane (4 mL), thionyl chloride (0.29 mL, 4.05 mmol) and DMF (0.024 mL, 0.304 mmol) were added, and the mixture was heated under reflux for 2 hr. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in methylene chloride (4 mL), tert-butylamine (0.21 mL, 2.02 mmol) and triethylamine (0.35 mL, 2.53 mmol) were added dropwise and the mixture was stirred at room temperature for 2 hr. 1 mol/L hydrochloric acid was added dropwise to the reaction mixture, and the mixture was extracted 3 times with chloroform. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.29 g, 63%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[N:9]=[C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[S:7][N:6]=1)[CH3:4].C(N(CC)CC)C.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[C:25]([NH:1][CH2:2][CH:3]([C:5]1[N:9]=[C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[S:7][N:6]=1)[CH3:4])(=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: CC(CN)c1nsc(NC(=O)OC(C)(C)C)n1
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NCC(C)c1nsc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl [3-(2-amino-1-methylethyl)-1,2,4-thiadiazol-5-yl]carbamate (0.27 mmol) was dissolved in DCM (5 mL) and triethylamine (1.4 eq) was added followed by n-butyric acid chloride (1.1 eq). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. Purification, using preparative LCMS (30–70% MeCN over 10 min followed by 100% MeCN for 5 min), afforded tert-butyl [3-(2-butyrylamino-1-methyl-ethyl)-[1,2,4]thiadiazol-5-yl]-carbamate. Deprotection was carried out in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred for 1.5 h at room temperature. The solvent was removed under reduced pressure affording the crude product which was converted to the sulfonamide using method C without any further purifications.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[S:21][C:22]([C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:32]1[C:41]([CH3:42])=[CH:40][C:39]2[C:38]([CH3:44])([CH3:43])[CH2:37][CH2:36][C:35]([CH3:46])([CH3:45])[C:34]=2[CH:33]=1>>[CH3:42][C:41]1[C:32](/[C:26](/[Si:27]([CH3:28])([CH3:29])[CH3:30])=[CH:25]/[C:22]2[S:21][C:20]([CH2:19][OH:18])=[CH:24][CH:23]=2)=[CH:33][C:34]2[C:35]([CH3:46])([CH3:45])[CH2:36][CH2:37][C:38]([CH3:44])([CH3:43])[C:39]=2[CH:40]=1
Reactant: CC(C)(C)[Si](OCc1ccc(C#C[Si](C)(C)C)s1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Product: Cc1cc2c(cc1/C(=C/c1ccc(CO)s1)[Si](C)(C)C)C(C)(C)CCC2(C)C

Procedure:
Following General Procedure A, 5-[(trimethylsilyl)ethynyl]thiophen-2-ylmethyl tert-butyldiphenylsilyl ether (Compound 13, 0.75 g, 1.8 mmol) and 2-bromo-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (0.45 g, 1.67 mmol) were coupled to give the title compound.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22]([OH:24])=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:26]=[C:27]([NH2:35])[CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=3)[CH2:11][CH:10]([C:22]3[O:24][N:35]=[C:27]([CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[N:26]=3)[CH2:9]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Reactant: NC(CN1CCOCC1)=NO
Product: CCc1ccc(C2CC(c3nc(CN4CCOCC4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 35 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2-morpholin-4-ylethanimidamide were reacted according to the General Method 1. Yield: 7 mg (8% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[C:6]([C:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=2)=[CH:7]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CC=C(c2c[nH]c3cc(Br)ccc23)CC1
Product: CN1CC=C(c2cn(C(=O)c3ccccc3)c3cc(Br)ccc23)CC1

Procedure:
(23.2 mg, 68%); from 6-bromo-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4f, 25.0 mg, 0.086 mmol) and benzoyl chloride (20 uL, 0.17 mmol); HRMS-FAB+ for C21H19N2OBr: calculated MH+ : 395.07590; found: 395.07848.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][OH:11].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.CCOC(C)=O.C(Cl)Cl>[Br:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: OCc1ccc(F)c(F)c1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1ccc(F)c(F)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 119.1 %

Procedure:
(2-Bromo-3,4-difluorophenyl)methanol (Compound AR) (2.55 g, 11.4 mmol, Eq: 1.00) was dissolved in dichloromethane (15 ml). Dess-Martin periodinane (4.85 g, 11.4 mmol, Eq: 1.00) was added. The reaction mixture was stirred for 2 hrs at room temperature. The reaction mixture was filtered over a plug of celite and washed with DCM (30 ml). Filtrate was concentrated to give a semi solid. Crude product was dissolved in EtOAc/DCM and loaded into a silica gel column (4 g). Silica gel column was flushed with EtOAc to give a light yellow solid (3 g). 1H NMR (DMSO) δ 10.13 (s, 1H), 7.74-7.82 (m, 1H), 7.70 (ddd, J=9.5, 7.3, 0.8 Hz, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH3:17])=[CH:10][C:9]=1[OH:25].Cl[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH3:34])[CH2:29]1.C(O)(C(F)(F)F)=O>C(#N)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH3:17])=[CH:10][C:9]=1[O:25][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH3:34])[CH2:29]1
Reactant: C[C@@H](NCc1ccc(Cl)c(O)c1)c1cccc(Cl)c1
Reactant: CN1CCCC(CCl)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: C[C@@H](NCc1ccc(Cl)c(OCC2CCCN(C)C2)c1)c1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 14 h
Yield: 78.6 %

Procedure:
A small vial was charged with 2 mL of acetonitrile, cesium carbonate (50 mg, 0.15 mmol), (R)-2-chloro-5-((1-(3-chlorophenyl)ethylamino)methyl)phenol 83 (30 mg, 0.10 mmol), and 3-(chloromethyl)-1-methylpiperidine (16 mg, 0.11 mmol). The vial was placed in a reaction block and it was heated to 85° C. and stirred for 14 h. The vial was allowed to cool to room temperature and the solution was filtered through a syringe filter into a well of a 24 well plate. This plate was concentrated down in a Genevac vacuum instrument. The plate was by preparatory HPLC. The desired fractions were combined and lyophilized. The final product, (1R)—N-(4-chloro-3-((1-methylpiperidin-3-yl)methoxy)benzyl)-1-(3-chlorophenyl)ethanamine 84 (32 mg, 75% yield) was isolated as a white solid of the TFA salt. 1H NMR (400 MHz, d4-methanol) δ ppm 1.44-1.56 (m, 1H) 1.72 (m, 2H) 1.99 (m, 1H) 2.07 (m, 1H) 2.40 (m, 1H) 2.91-3.00 (m, 4H) 3.55 (m, 1H) 3.67-3.74 (m, 1H) 3.93-4.01 (m, 2H) 4.10 (dd, J=9.00, 4.11 Hz, 1H) 4.18 (d, J=13.11 Hz, 1H) 4.48 (q, J=6.85 Hz, 1H) 5.50 (s, 1H) 7.00 (d, J=8.22, 1H) 7.15 (s, 1H) 7.43-7.52 (m, 3H) 7.57 (s, 1H). Mass spectrum: calculated for C22H28C12N2O 407.4. found 408.4 (M++1).
Reaction SMILES: NC1SC2C3C(CC=2C=1[C:14]([NH2:16])=[O:15])=CC=CC=3.FC(F)(F)C(O)=O.[NH2:24][C:25]1[S:29][C:28]2[C:30]3[C:35]([CH2:36][CH2:37][C:27]=2[C:26]=1[C:40]([NH2:42])=[O:41])=[CH:34][CH:33]=[C:32]([O:38][CH3:39])[CH:31]=3>>[CH3:39][O:38][C:32]1[CH:31]=[C:30]2[C:35]([CH2:36][CH2:37][C:27]3[C:26]([C:40]([NH2:42])=[O:41])=[C:25]([NH:24][C:14]([NH2:16])=[O:15])[S:29][C:28]=32)=[CH:34][CH:33]=1
Reactant: NC(=O)c1c(N)sc2c1Cc1ccccc1-2
Reactant: COc1ccc2c(c1)-c1sc(N)c(C(N)=O)c1CC2
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)-c1sc(NC(N)=O)c(C(N)=O)c1CC2

Procedure:
The title compound was prepared by the same procedure as Example 2 except 2-amino-4H-indeno[1,2-b]thiophene-3-carboxylic acid amide was replaced with 2-amino-8-methoxy-4,5-dihydro-naphtho[1,2-b]thiophene-3 carboxylic acid amide trifluoroacetate to give the above title compound as brown solid. ESMS m/z: 318 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:10])=[O:18])=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccccc1CCN
Product: COc1ccc(C(=O)NCCc2ccccc2C)cc1

Procedure:
1-Amino-2-(2-methylphenyl)ethane was reacted with 4-methoxybenzoyl chloride in the same way as in step (a) of Example 1 to afford 1-(4-methoxybenzoylamino)-2-(2-methylphenyl)ethane having a melting point of 81.8° to 82.1° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[C:35]([C:54]([CH3:62])([CH3:61])[O:55][SiH2:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[C:36]([N:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[C:45]([CH:50]4[CH2:52][CH2:51]4)[CH:46]=3)[C:41]2=[O:53])[CH:37]=[CH:38][CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O.O1CCOCC1>[C:57]([SiH2:56][O:55][C:54]([CH3:62])([CH3:61])[C:35]1[C:34]([C:6]2[CH:5]=[C:4]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[O:25])=[CH:20][N:19]=3)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=2)=[CH:39][CH:38]=[CH:37][C:36]=1[N:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([CH:50]3[CH2:52][CH2:51]3)[CH:46]=2)[C:41]1=[O:53])([CH3:60])([CH3:58])[CH3:59]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1c(Br)cccc1-n1ccc2cc(C3CC3)ccc2c1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cn1cc(-c2cccc(-n3ccc4cc(C5CC5)ccc4c3=O)c2C(C)(C)O[SiH2]C(C)(C)C)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridin-2-one (99 mg, 0.22 mmol), 2-[3-bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-6-cyclopropyl-2H-isoquinolin-1-one (120 mg, 0.248 mmol), 2 mL dioxane, and a solution of cesium carbonate in water (370 mg/420 μL) were charged into a 4 mL reaction vial fitted with a stir bar and septum. Sparged the mixture with nitrogen for 15 min. Added [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride 1:1 complex with dichloromethane (12 mg, 0.015 mmol). The reaction was sparged with nitrogen for 5 min. Sealed the vial and stirred at 90° 16 hr. Cooled to room temperature, partitioned the reaction mixture between 5 mL of 5% NaHCO3 and 10 mL of EtOAc, and separated phases. Washed the organic phase with 5 mL of water and 5 mL of brine, dried over Na2SO4 and concentrated in vacuo. Purified by C18 reverse phase flash chromatography (gradient elution, 10 to 95% acetonitrile+0.1% TFA/water+0.1% TFA). Added 1 mL of saturated NaHCO3 to the pooled product fractions and concentrated in vacuo. Extracted the remaining aqueous mixture with 2×10 mL CH2Cl2, dried over Na2SO4, and concentrated in vacuo to obtain 2-(2-(tert-Butyl-dimethyl-silanyloxymethyl)-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-6-cyclopropyl-2H-isoquinolin-1-one as a brittle amber foam. (70 mg, 0.097 mmol). MS (ESI) 718 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:10]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])[CH3:11]>ClCCl>[C:10]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:3](=[O:4])[CH2:2][Br:1])=[CH:19][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])[CH3:11]
Reactant: O=C(Br)CBr
Reactant: CC(=O)N1CCc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)N1CCc2cc(C(=O)CBr)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Bromoacetyl bromide (1.0 mL, 11.2 mmol) was slowly added to a suspension of aluminum chloride (3.7 g, 27.9 mmol) in dichloromethane (30 mL) and the reaction mixture was stirred for 20 min at rt. A solution of 1-acetylindoline (1.5 g, 9.3 mmol) in dichloromethane (10 mL) was slowly added and then the reaction mixture was heated at 55° C. for 1.5 h. The mixture was cooled and then quenched with cold water. The precipitate was filtered through a short pad of celite, washed with dichloromethane and water. The aqueous phase was extracted with dichloromethane. The combined organic extract was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to to give the product. Yield: 1.9 g (73%).
Reaction SMILES: [Cl:1][C:2]([Cl:11])=[CH:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](Cl)=[O:6].[C:12]([CH:14]([OH:28])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)#[N:13].N1C=CC=CC=1>C1C=CC=CC=1.C(OCC)C>[Cl:1][C:2]([Cl:11])=[CH:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5]([O:28][CH:14]([C:12]#[N:13])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:16]=1)=[O:6]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C=C(Cl)Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)C(C=C(Cl)Cl)C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
In 20 ml of dry benzene were dissolved 2.0 g of α-(2,2-dichlorovinyl)isovaleric acid, followed by the addition of 6.0 g of thionyl chloride. The mixture was refluxed overnight. It was then distilled to remove the low-boiling fraction, whereby α-(2,2-dichlorovinyl)isovaleroyl chloride was obtained. This α-(2,2-dichlorovinyl)isovaleroyl chloride was dissolved in 25 ml of dry benzene, followed by the addition of 2.3 g of α-cyano-3-phenoxybenzyl alcohol and, then, 2.4 g of pyridine. The mixture was stirred at room temperature overnight. The resultant reaction mixture was diluted with diethyl ether, washed with water and dilute aqueous hydrogen chloride, dried over anhydrous magnesium sulfate and distilled to remove the low-boiling fraction. Column chromatography was carried out on the residue to obtain 3.2 g of α-cyano-3-phenoxybenzyl α-(2,2-dichlorovinyl)isovalerate (Compound [1]) which was shown to have the properties given below [yield: 78% based on α-(2,2-dichlorovinyl)isovaleric acid].