Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]#[CH:4].C([Mg]Cl)#C.C(=O)C1C=CC=CC=1.Br[C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1/[C:26](=[CH:34]/[C:35]1[NH:36][CH:37]=[CH:38][C:39]=1[O:40][CH3:41])/[C:27](=[O:33])[NH:28]2>[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]#[C:4][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1/[C:26](=[CH:34]/[C:35]1[NH:36][CH:37]=[CH:38][C:39]=1[O:40][CH3:41])/[C:27](=[O:33])[NH:28]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(O)c1ccccc1
Agent: [Cu]I
Agent: C#C[Mg]Cl
Solvent: CN(C)C=O
Solvent: O=Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccccc3)c21

Procedure:
Using Method D above, 3-hydroxy-3-phenyl-1-propyne (0.1 g, 0.78 mmol) (prepared by the addition of ethynylmagnesium chloride (Aldrich) to benzaldehyde (Aldrich) through Method A above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (0.1 g, 0.31 mmol) (Starting Material 1) using DPPFPdCl2 (12.6 mg) (Aldrich) and CuI (3 mg) (Aldrich) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h, yielding rac-(Z)-1,3-dihydro-4-(3-hydroxy-3-phenyl-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 42 mg, 38%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([N:26]([CH2:33][CH3:34])[CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[C:23]([CH3:35])=[C:22]([C:36](=[O:48])[NH:37][CH2:38][C:39]4[C:40](=[O:47])[NH:41][C:42]([CH3:46])=[CH:43][C:44]=4[CH3:45])[CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:15]=[CH:16][C:17]([C:20]3[CH:25]=[C:24]([N:26]([CH2:33][CH3:34])[CH:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[C:23]([CH3:35])=[C:22]([CH:21]=3)[C:36]([NH:37][CH2:38][C:39]3[C:40](=[O:47])[NH:41][C:42]([CH3:46])=[CH:43][C:44]=3[CH3:45])=[O:48])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: CCN(c1cc(-c2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(c1cc(-c2ccc(N3CCC(N)CC3)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 903.1 %

Procedure:
To a stirred solution of tert-butyl(1-(5-(3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl) carbamoyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)pyridin-2-yl)piperidin-4-yl)carbamate (0.39 g, 0.058 mmol) in DCM (4 mL) at 0° C., TFA (2 mL) was added and reaction was stirred for 1 h at room temperature. After completion, reaction was concentrated to dryness. The residue was then basified with aqueous sat. bicarbonate solution (30 mL) till pH 8 and aqueous layer extracted with 20% methanol in DCM (50 mL×4). Combined organic phase was dried over Na2SO4 and solvent removed under reduced pressure to afford the title compound (0.3 g, 90.63%) which was used as such for next reaction.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([O:20][CH2:21][CH3:22])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[F:19])=[C:5]([OH:26])[CH:4]=1)#[N:2].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][O:26][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:25]=[CH:24][C:6]=1[CH2:7][NH:8][C:9](=[O:23])[CH:10]([O:20][CH2:21][CH3:22])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[F:19])[CH3:33]
Reactant: CCOC(=O)CBr
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1O)c1ccc(OC)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C#N)ccc1CNC(=O)C(OCC)c1ccc(OC)cc1F

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-2-hydroxy-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide (example 110.3) was alkylated with ethyl bromoacetate/cesium carbonate in DMF to give (RS)-(5-cyano-2-{[2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetylamino]-methyl}-phenoxy)-acetic acid ethyl ester as a colorless solid. MS 443.4 ([M−H])
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][CH:20]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(Cl)(O[C:32](=[O:38])OC(Cl)(Cl)Cl)Cl.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:42]=1[C:48]1[N:49]=[N:50][NH:51][C:52]=1[C:53]#[N:54]>ClCCl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:53]([C:52]1[N:51]([C:32]([N:4]([C:5]2[CH:6]=[C:7]([CH:18]=[CH:19][CH:20]=2)[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH:1]([CH3:3])[CH3:2])=[O:38])[N:50]=[N:49][C:48]=1[C:42]1[C:43]([F:47])=[CH:44][CH:45]=[CH:46][C:41]=1[F:40])#[N:54]
Reactant: N#Cc1[nH]nnc1-c1c(F)cccc1F
Reactant: CC(C)Nc1cccc(C(=O)OCc2ccccc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)n1nnc(-c2c(F)cccc2F)c1C#N)c1cccc(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of benzyl 3-(isopropylamino)benzoate (5) in dry dichloromethane (0.4 M) under Ar at 0° C. was added triethylamine (1.5 equiv) followed by triphosgene (1.5 equiv). The resulting mixture was stirred at rt for 15 min and was concentrated in vacuo. The residue was suspended in dry toluene (0.4 M), DMAP (1.0 equiv) and 4-(2,6-difluorophenyl)-1H-1,2,3-triazole-5-carbonitrile (2) (1.0 equiv) were added and the resulting suspension was heated to reflux for 1 h, then cooled to rt, diluted with AcOEt and washed with water, 10% HCl and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Hexanes/AcOEt as eluant). Benzyl 3-(5-cyano-4-(2,6-difluorophenyl)-N-isopropyl-1H-1,2,3-triazole-1-carboxamido)benzoate (6) was obtained as a pale yellow foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24](Br)=[CH:23][C:10]=1[CH2:11][N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29]>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]([C:33]2[CH:34]=[CH:35][C:30]([CH:28]=[O:29])=[CH:31][CH:32]=2)=[CH:23][C:10]=1[CH2:11][N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCCCCCCC(=O)N(C)Cc1cc(Br)ccc1OCc1ccccc1
Product: CCCCCCCC(=O)N(C)Cc1cc(-c2ccc(C=O)cc2)ccc1OCc1ccccc1

Procedure:
In a manner similar to that of Example 1(e), by reacting 8 g (18.5 mmol) of N-(2-benzyloxy-5-bromo benzyl)-N-methyloctanamide and 3.6 g (24 mmol) of 4-formylbenzene boronic acid, and after purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (8/2), 5.8 g (69%) of the expected product are obtained in the form of a white solid.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH3:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[O:9])[C:4](=[O:23])O1.C=O.[CH3:27][NH2:28].[CH3:29]O>>[CH3:22][N:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=1)[C:8]([C:7]1[CH2:27][N:28]([CH3:29])[C:4](=[O:23])[C:5]=1[OH:6])=[O:9]
Reactant: CO
Reactant: CN
Reactant: CN(Cc1ccc(C(F)(F)F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Agent: C=O
Product: CN1CC(C(=O)N(C)Cc2ccc(C(F)(F)F)cc2)=C(O)C1=O
Yield: 64 %

Procedure:
Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methyl-N-(4-trifluoromethylbenzyl)-acetamide (0.50 g, 1.45 mmol) with the paraformaldehyde-methylamine adduct in methanol using a procedure similar to the one described in the preparation of compound 44 (method 44B) gave 0.31 g (64% yield) of the title compound as white crystals; mp 126–128° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm); 3.07 (3H, s, NCH3), 3.13 (3H, s, NCH3), 4.18 (2H, s, NCH2), 4.74 (2H, s, NCH2), 7.41 (2H, d, J=8.1 Hz, aromatics), 7.64 (2H, d, J=8.1 Hz, aromatics), 10.56 (1H, broad, OH). Anal. Calcd for C15H15F3N2O3: C, 54.88; H, 4.61; N, 8.53. Found: C, 54.93; H, 4.57; N, 8.44.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH2:15][OH:16])[C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.CNCCO>>[OH:16][CH2:15][CH2:14][N:3]([CH3:1])[C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCN(CCO)C(=O)OCc1ccccc1
Agent: CNCCO
Product: CN(CCO)C(=O)OCc1ccccc1
Yield: 93 %

Procedure:
A similar procedure to that described for INTERMEDIATE 47 utilizing 2-(methylamino)ethanol (2.3 g, 30.62 mmol) as starting material was followed, with subsequent purification by column chromatography (ISCO, silica gel column, eluting with 60→100% EtOAc/hexanes for 14 minutes) to give the title product (5.96 g, yield: 93%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([CH3:14])[CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([CH3:14])[CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1
Reactant: CC1CCNc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1CCNc2cc(N)ccc21
Yield: 93.2 %

Procedure:
A solution of 7-nitro-1,2,3,4-tetrahydro-4-methylquinoline (36 mg, 0.172 mmol) in ethyl acetate (3 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (4 mg) at rt for 2 h. Filtration over Celite™ afforded 26 mg (85%) of 7-amino-1,2,3,4-tetrahydro-4-methylquinoline (structure 61A of Scheme XLVIII, where R1-3 =H, R4 =methyl) that was used without further purification for the next step. The title compound was prepared by General Method 13 (EXAMPLE 147) from 7-amino-1,2,3,4-tetrahydro-4-methylquinoline (26 mg, 0.145 mmol), ZnCl2 (30 mg, 0.218 mmol) and ethyl 4,4,4-trifluoroacetoacetate (21 mL, 0.145 mol) to afford 0.8 mg (2%) of 1,2,3,4-tetrahydro-4-methyl-6-trifluoromethyl-8-pyridono[5,6-g]quinoline (Compound 425). Data for Compound 425: 1H NMR (400 MHz, DMSO-d6) 11.65 (bs, 1H), 7.20 (s, 1H), 6.96 (s, 1H), 6.37 (s, 2H), 3.25 (m, 2H), 2.90 (m, 1H), 1.84 (m, 1H), 1.59 (m, 1H), 1.20 (d, J=6.9, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33].CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])=[O:33])=[CH:18][CH:17]=1
Reactant: COc1ccccc1N=C=O
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 45 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml), and 2-methoxyphenyl isocyanate (27 μl) was then added to the solution. The mixture was heated under reflux overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 34 mg (yield 45%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].C(N(CCCC)CCCC)CCC.[C:26]([O-:29])(=[O:28])C.[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C=O)C>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:2]([CH:3]=1)[C:26]([OH:29])=[O:28])=[O:6]
Reactant: COC(=O)c1ccc(C)c(Br)c1
Reactant: CC(=O)[O-]
Agent: [Pd+2]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)c1ccc(C)c(C(=O)O)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A pressure vessel was charged with methyl 3-bromo-4-methylbenzoate (5.0 g, 22 mmol), DMF (20 ml), water (1.25 ml) and tributylamine (8 ml, 34 mmol). Cesium acetate (2.1 g, 11 mmol) was then added and the flask was purged with N2. Palladium acetate (0.25 g, 1.0 mmol) and triphenylphosphine (2.9 g, 11 mmol) were added and the flask was purged with CO gas. The reaction mixture was then heated at 90° C. under 20 psi of CO gas with vigorous stirring overnight. The reaction mixture was diluted with 50 mL of toluene and extracted with saturated NaHCO3 (3×50 ml). The combined aqueous layer was washed with EtOAc (10 mL), then acidified using 2 N HCl to pH 5. The volume was reduced to about 50 mL and the resulting precipitate was collected by filtration, washed with water and dried to give 5-(methoxycarbonyl)-2-methylbenzoic acid as a white solid. MS (ESI, pos. ion) m/z: 193.1 (M−1).
Reaction SMILES: C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.[CH3:15][O+:16]([CH3:18])C.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:43]2C(=O)[CH2:47][CH2:46][CH2:45][C:44]=2[OH:50])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]>ClCCl>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:43]2[C:44](=[O:50])[CH2:45][CH2:46][CH2:47][C:15]=2[O:16][CH3:18])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]([F:40])([F:42])[F:41])[CH:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]
Reactant: C[O+](C)C
Reactant: N#Cc1ccc(C(NC(=O)Nc2ccc(F)c(C(F)(F)F)c2)C2=C(O)CCCC2=O)cc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC1=C(C(NC(=O)Nc2ccc(F)c(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CCC1

Procedure:
N,N-Diisopropylethylamine (450 μL, 2.59 mmol) and trimethyloxonium tetrafluoroborate (331 mg, 2.24 mmol) are added to a mixture of 1-((4-cyanophenyl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea (intermediate 44, 500 mg, 1.12 mmol) in dichloromethane (4.0 mL), and the mixture is stirred at room temperature for 20 min Dichloromethane (20 mL) is added, and the phases are separated. The organic layer is washed three times with water and concentrated under reduced pressure. Yield: 567 mg; ESI mass spectrum [M+H]+=462; Retention time HPLC: 1.09 min (Z018_S04).
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH3:7][CH:8]([CH3:12])[CH:9]([OH:11])[CH3:10].C(N(C(C)C)CC)(C)C.Cl>ClCCl>[CH3:10][CH:9]([O:11][C:1](=[O:5])[CH:2]=[CH:3][CH3:4])[CH:8]([CH3:12])[CH3:7]
Reactant: C/C=C/C(=O)Cl
Reactant: CC(C)C(C)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC=CC(=O)OC(C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
Crotonoyl chloride (21.35 g) in dichloromethane (100 mL) was charged into a 2-L reaction flask and cooled to 0° C. 3-Methyl-butan-2-ol (18 g) was added followed by diisopropylethylamine (31.7 g). The reaction mixture was aged at 0-10° C. for about 30 minutes and poured into dilute hydrochloric acid (33 g in 170 g water). Hexanes were added and the aqueous and organic layers were split. The organic layer was separated and subsequently purified via liquid chromatography to provide but-2-enoic acid 1,2-dimethyl-propyl ester (25.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:19]=2)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1
Reactant: FC(F)(F)c1cc(I)cc(Cl)n1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(Nc2cc(Cl)nc(C(F)(F)F)c2)cc1
Yield: 23 %

Procedure:
Following General Procedure B1, 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (0.244 g, 0.80 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.156 g, 0.87 mmol) to afford the title compound (0.066 g, 33%) as a colorless oil. MW=358.74. 1H NMR (CDCl3, 500 MHz) δ 7.37-7.31 (m, 2H), 7.17-7.12 (m, 2H), 7.00 (d, J=2.0 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 6.43 (s, 1H), 4.19 (q, J=7.2 Hz, 2H), 3.64 (s, 2H), 1.32-1.25 (m, 3H); APCI MS m/z 359 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[O:26]1[C:31]2[CH:32]=[CH:33][C:34]([CH:36]([OH:40])[CH2:37][NH:38][CH3:39])=[CH:35][C:30]=2[O:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:38]([CH2:37][CH:36]([C:34]4[CH:33]=[CH:32][C:31]5[O:26][CH2:27][CH2:28][O:29][C:30]=5[CH:35]=4)[OH:40])[CH3:39])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ccc2c(c1)OCCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CN(C)CC(O)c2ccc3c(c2)OCCO3)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.253 mmol), 1-(1,4-benzodioxan-6-yl)-2-(methylamino)ethanol (Preparation 13, 79 mg, 0.38 mmol), and diisopropylethylamine (66 μL, 0.38 mmol) in dry DMF (5.5 mL) was stirred at room temperature for 18 hours. The solution was then diluted with water (20 mL). The resulting precipitate was collected by filtration and the collected solid was dried in vacuo at 60° C. to provide the titled compound (105 mg) as an off white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:23])([F:22])[O:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:46]=[C:47]([N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)[CH2:48][NH:49][C:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:54][CH:53]=1)=[O:51]>CN(C=O)C.O>[O:46]=[C:47]([N:64]1[CH2:69][CH2:68][N:67]([C:15](=[O:17])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12][C:11]([F:10])([F:23])[F:22])[CH2:66][CH2:65]1)[CH2:48][NH:49][C:50]([C:52]1[CH:53]=[CH:54][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:56][CH:57]=1)=[O:51]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccccc1OC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2OC(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 2-trifluoromethoxy-benzoic acid (53.09 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 45 mg (34.1% yield) of biphenyl-4-carboxylicacid {2-oxo-2-[4-(2-trifluoromethoxy-benzoyl)-piperazin-1-yl]-ethyl}-amide, LC-MS purity: 99.18%, 1H NMR: (DMSO) δ 8.7 (s, 1H), 8.0 (s, 2H), 7.8 (s, 4H), 7.4 (s, 7H), 4.2 (d, 2H), 3.8-3.4 (m, 6H), 3.2 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[S:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][CH2:29]Br)([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.CCOCC>C1COCC1>[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][CH2:29][N:18]1[CH2:19][CH2:20][CH:15]([N:3]([CH2:1][CH3:2])[S:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:16][CH2:17]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CCN(C1CCNCC1)S(=O)(=O)c1ccc(OC)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C1CCN(CCNC(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
A mixture of N-ethyl-4-methoxy-N-piperidin-4-yl-benzenesulfonamide (Example A4., 1.19 g, 4 mmol), (2-bromo-ethyl)-carbamic acid tert-butyl ester (1.12 g, 5.0 mmol) and DIPEA (650 mg, 5 mmol) in THF (30 mL) is heated at reflux for 15 h. The solution is poured into Et2O (150 mL) and extracted with sat. aq. Na2CO3 (2×50 mL) and sat. aq. NaCl (30 mL), dried (Na2SO4), filtered and evaporated. The residue is purified by reversed phase MPLC to provide the title compound.
Reaction SMILES: C(C1CN(CC(NC2C=CC=C([N+]([O-])=O)C=2)=O)CCN1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])C1C=CC=CC=1.[CH2:37]([CH:44]1[CH2:49][NH:48][CH2:47][CH2:46][N:45]1[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C.ClC(OCC1C=CC=CC=1)=O>C(Cl)Cl>[CH2:37]([CH:44]1[CH2:49][N:48]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:47][CH2:46][N:45]1[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1Cc1ccccc1
Reactant: O=C(CN1CCN(C(=O)OCc2ccccc2)C(Cc2ccccc2)C1)Nc1cccc([N+](=O)[O-])c1
Agent: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)CC1Cc1ccccc1
Reaction time: 2 h

Procedure:
Benzyl 2-benzyl-4-{2-[(3-nitrophenyl)amino]-2-oxoethyl}piperazine-1-carboxylate. To a solution of 3.0 g (10.9 mmol) of (RS)-tert-butyl 2-benzylpiperazine-1-carboxylate in 30 mL of methylene chloride at 0° C. was added 2.3 mL (16.5 mmol) of triethylamine and 1.7 mL (11.9 mmol) of benzyl chloroformate. The resultant mixture was stirred at ambient temperature for 16 h and an additional 0.4 mL (2.8 mmol) of benzyl chloroformate was added. After stirring for a further 2 h, the reaction was partitioned between methylene chloride and water. The organic layer was washed sequentially with dilute hydrochloric acid, saturated sodium bicarbonate solution, and brine, dried over magnesium sulfate, and concentrated in vacuo to give 4-benzyl 1-tert-butyl 2-benzylpiperazine-1,4-dicarboxylate. The tert butyl carbamate was deprotected as described in Example 1, Step A to give 2.9 g of the free amine. A portion (1.5 g, 4.8 mmol), of this material was coupled with 1.6 g (7.5 mmol) of alpha-chloro-3-nitroacetanilide as described in Example 1, Step A, to give 1.3 g of the title compound as an off-white foamy solid. 1H NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 7.99 (d, 1H, J=8 Hz), 7.96 (d, 1H, J=8 Hz), 5.58 (t, 1H, J=8 Hz), 7.36–7.05 (m, 10H), 5.00 (bs, 2H), 4.38–4.31 (m, 1H), 3.99 (d, 1H, J=16 Hz), 3.48 (td, 1H, J=16,2 Hz), 3.22–2.95 (m, 5H), 2.80 (d, 1H, J=14 Hz), 2.33–2.20 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2[N:19]1[CH2:23][CH2:22][C@@H:21]([CH2:24][NH:25]C(=O)OCC2C=CC=CC=2)[CH2:20]1>[Pd].CO>[NH2:25][CH2:24][C@@H:21]1[CH2:22][CH2:23][N:19]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:6]=2)[CH2:20]1
Reactant: O=C(NC[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1
Reaction time: 8 h
Yield: 83.1 %

Procedure:
Under an N2 atmosphere, a mixture of benzyl ((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate (0.770 g, 1.6 mmol) and MeOH (5 mL) was added to Pd/C (77 mg, 10% weight Pd on carbon) weighed into a 100 mL flask. After the atmosphere in the flask was evacuated and purged with N2 three times, the reaction mixture was vigorously stirred under an H2 atmosphere at ambient pressure overnight and then filtered through a pad of Celite, concentrated, and dried to obtain 2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol (0.45 g, 81%). LC/MS: m/z 459.5 (M+H)+ at 2.81 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).