Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].[CH3:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH2:23]>>[C:24]1([C:22](=[CH2:21])[CH2:23][O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:4][C:3]2([CH3:20])[CH3:19])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=C(C)c1ccccc1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Product: C=C(CON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C)c1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 1.0 g (3.6 mmol) of 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine and 10 g (85 mmol) of α-methylstyrene under a nitrogen atmosphere is heated at 120° C. for 36 hours. The reaction mixture is concentrated in vacuo and the title compound is isolated as a pale yellow oil after column chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([C:34]([CH3:38])([CH3:37])[C:35]#[N:36])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([C:34]([CH3:38])([CH3:37])[C:35]#[N:36])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC(C)(C#N)S(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CC(C)(C#N)S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-((2-bromophenyl)sulfonyl)-2-methylpropanenitrile. MS (ESI): mass calcd. for C20H17FN4O2S, 396.11; m/z found, 397.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.18 (d, J=8.0, 1H), 8.12 (d, J=1.2, 1H), 7.94 (m, 1H), 7.88-7.82 (m, 2H), 7.54 (d, J=7.6, 1H), 7.37 (dd, J=12.4, 1.4, 1H), 7.29 (dd, J=8.1, 1.6, 1H), 1.50 (s, 6H).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[CH:5]=[C:6]([OH:19])[C:7](=[CH:17][CH:18]=1)[CH:8]=[N:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[NH2:16])[CH3:2].[OH:22][C:23]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:24]=1[CH:25]=O>C(O)C>[CH2:20]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]([OH:19])[C:7](=[CH:17][CH:18]=1)[CH:8]=[N:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[N:16]=[CH:25][C:24]1[C:23](=[CH:30][C:29]([OH:31])=[CH:28][CH:27]=1)[OH:22])[CH3:21]
Reactant: CCN(CC)c1ccc(C=N[C@@H]2CCCC[C@H]2N)c(O)c1
Reactant: O=Cc1ccc(O)cc1O
Solvent: CCO
Product: CCN(CC)c1ccc(C=N[C@@H]2CCCC[C@H]2N=Cc2ccc(O)cc2O)c(O)c1
Temperature: 60 °C

Procedure:
To a suspension of 2.5 g (8.64 mmol) of (R,R)-N-mono[4-(diethylamino)salicylidene]-1,2-cyclohexanediamine in 200 ml of ethanol is added dropwise at room temperature over the course of 45 minutes a solution of 1.19 g (8.64 mmol) of 2,4-dihydroxybenzaldehyde. The suspension is heated at 60° C. for 4 h. After cooling to room temperature the resultant brownish orange solution is concentrated to dryness. The crude product (3.5 g) is resolved by column chromatography (ethyl acetate/methanol 9:1). Yield: 570 mg (16%), yellowish orange solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=1
Reactant: COC(=O)CCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(N)cc1
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
Methyl 3-(4-nitrophenyl)propanoate (450 mg, 2.151 mmol) was dissolved in MeOH (10 ml) and then Pd/C 5% (458 mg, 0.215 mmol) was added. The solution was shaken under hydrogen atmosphere at 35 psi for 30 minutes on a Parr apparatus. The catalyst was filtered off and the solvent removed under vacuum to give methyl 3-(4-aminophenyl)propanoate (350 mg, 1.953 mmol, 91% yield).
Reaction SMILES: O[C:2]1[CH:10]=CC=C[C:3]=1C([O-])=O.C[O:12][C:13](=[O:28])[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:15]=1[OH:27]>>[CH2:10]([O:27][C:15]1[CH:16]=[CH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:19][C:14]=1[C:13]([OH:12])=[O:28])[CH:2]=[CH2:3]
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)ccc1O
Reactant: O=C([O-])c1ccccc1O
Product: C=CCOc1ccc(-c2ccc(F)cc2)cc1C(=O)O

Procedure:
When the 2-hydroxy-benzoate compounds obtained from Example 9 are used in place of methyl-2-hydroxy-5-(4'-fluorophenyl)-benzoate in the above example, there are obtained the corresponding allyloxy-benzoic acid compounds.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Cl:23])[C:16]=2[CH3:24])[C:11](=[O:25])[NH:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[K+].IC>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Cl:23])[C:16]=2[CH3:24])[C:11](=[O:25])[N:10]1[CH3:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1c(N2C(=O)NC(CNC(=O)OC(C)(C)C)C2=O)ccc(C#N)c1Cl
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1c(N2C(=O)C(CNC(=O)OC(C)(C)C)N(C)C2=O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
To a solution of the hydantoin 13A (1.00 g, 2.64 mmol) in DMF (10 mL) was added KHMDS (530 mg, 2.64 mmol) followed by iodomethane (0.16 mL, 2.64 mmol) and the resulting solution was stirred at rt for 2 h. The solution was then diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, CH2Cl2/CH3OH, 100:0 to 80:20 gradient) to afford the title compound (608 mg) as a white foam. 1H NMR (CDCl3) δ 1.41, 1.43 (s, 9H), 2.26, 2.28 (s, 3H), 3.11, 3.12 (s, 3H), 3.60-3.86 (m, 2H), 4.08-4.12 (m, 1H), 4.77, 4.83 (br s, 1H), 7.16, 7.20 (d, J=8.3 Hz, 1H), 7.60, 7.61 (d, J=8.3 Hz, 1H); HPLC a) column: Phenominex C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 3.05 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.86, 2.96 min retention time (98%); HPLC c) column: Daicel Chiralcel OD 4.6×250 mm, Isocratic 25% isopropanol/hexanes, 30 min, 1 mL/min, UV detection at 220 nm, 14.40 min retention time (97%); MS (ES) m/z 391 [M−H]−.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([N+:14]([O-])=O)[CH:8]=2)=[N:3]1>CO.CCOC(C)=O.[Ni]>[CH3:1][N:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:11])=[CH:12][CH:13]=2)[NH:3]1
Reactant: Cn1nnc(-c2ccc(N)c([N+](=O)[O-])c2)n1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1NN=C(c2ccc(N)c(N)c2)N1
Yield: 98.4 %

Procedure:
4-(2-Methyl-2H-tetrazol-5-yl)-2-nitroaniline (8-3) (242 mg, 1.1 mmol) in MeOH-EtOAc (1:1, 200 mL) was hydrogenized (H2 pressure 50 psi) in the presence of Raney-Ni (35 mg) overnight. After this time, the reaction solution color was changed from yellow to colorless. LCMS indicated that the starting material was completely disappeared but the product peak was weak. The catalyst was filtered and washed with MeOH (2×20 mL). The collected MeOH-EtOAc solution was concentrated to afford the desired pure product (8-4) (208 mg, 100%) according to 1H NMR. 1H NMR (500 MHz, DMSO-d6): δ7.26 (d, J=2.0 Hz, 1H), 7.12 (dd, J=8.0, 2.0 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), (s, 2H), 4.93 (s, 2H), 4.72 s, 2H), 4.34 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][S:3]([C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O.O>[Cl:1][CH2:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:20][C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(CCl)c1ccc(F)cc1
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc(S(=O)(=O)CCl)cc2)cc1
Temperature: 95 °C

Procedure:
A mixture of 1-chloromethanesulfonyl-4-fluoro-benzene (0.5 g, 2.4 mmol) from Step A, 4-methyl-phenol (0.21 mL, 2.0 mmol) and K2CO3 (0.55 g, 4.0 mmol) in dry DMA (10 mL) was heated at 95° C. overnight. The reaction mixture was diluted with EtOAc and water. After the usual work-up, crude product was purified by chromatography (silica gel, 25% EtOAc/hexanes). MS 319 (M+H)+.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+].Br[C:50]1[CH:51]=[N:52][C:53]2[C:58]([CH:59]=1)=[N:57][CH:56]=[CH:55][C:54]=2[Cl:60].[NH:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1>ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:60][C:54]1[CH:55]=[CH:56][N:57]=[C:58]2[C:53]=1[N:52]=[CH:51][C:50]([N:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1)=[CH:59]2
Reactant: Clc1ccnc2cc(Br)cnc12
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Clc1ccnc2cc(N3CCOCC3)cnc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 31.7 %

Procedure:
A round bottom flask under nitrogen atmosphere was charged with Pd2(dba)3 (578 mg, 0.63 mmol), Xantphos (1.1 g, 1.89 mmol), and sodium tert-butoxide (364 mg, 3.79 mmol). This was purged with Argon followed by addition of 3-bromo-8-chloro-1,5-naphthyridine (615 mg, 2.53 mmol), morpholine (0.22 mL, 2.53 mmol), and toluene (1M, 2.53 mL). This was then placed in a preheated oil bath at 80° C. After 2.5 hours, reaction was stopped, cooled to room temp and diluted with Dichloromethane. This was passed over a celite cake and filtrate concentrated to afford brown oil; which was purified by ISCO silica gel chromatography (40 g, 1% MeOH/DCM over 50 mins) to afford 8-chloro-3-morpholino-1,5-naphthyridine (200 mg, 32% yield). MS[M+H]=250.2. Calc'd for C12H12ClN3O=249.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[NH:12][CH:13]=[C:14]([CH3:16])[N:15]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])/[C:10](/[C:11]1[NH:12][CH:13]=[C:14]([CH3:16])[N:15]=1)=[CH:20]\[N:21]([CH3:23])[CH3:22]
Reactant: Cc1c[nH]c(CC(=O)c2ccc(Cl)cc2Cl)n1
Reactant: COC(OC)N(C)C
Product: Cc1c[nH]c(/C(=C/N(C)C)C(=O)c2ccc(Cl)cc2Cl)n1
Temperature: 72.5 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1-(2,4-dichlorophenyl)-2-(4-methylimidazol-2-yl)ethan-1-one (0.33 M) and N,N-dimethylformamide-dimethyl acetal (DMFDMA) (25 ml) was stirred for 2.5 h at 70-75° C. The DMFDMA was then removed under reduced pressure and dried under high vacuum for several hours giving a light orange solid in quantitative yield. The enaminone product (2Z)-1-(2,4-dichlorophenyl)-3-(dimethylamino)-2-(4-methylimidazol-2-yl)prop-2-en-1-one was typically used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.C(O[CH:12]=[C:13]([CH3:16])[CH:14]=O)C>C(O)C.O>[CH3:16][C:13]1[CH:12]=[N:1][C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=2[CH:14]=1
Reactant: NC1=CC(=O)CCC1
Reactant: CCOC=C(C)C=O
Solvent: O
Solvent: CCO
Product: Cc1cnc2c(c1)C(=O)CCC2
Yield: 48.4 %

Procedure:
A mixture of 3-aminocyclohex-2-enone (11.1 g., 0.1m) and 3-ethoxy-2-methylacrolein (11.4 g, 0.1m) was heated at 120° for 16 hours in a flask equipped for downward distillation. The ethanol-water distillate (6.5 ml.) was discarded and the residual oil distilled at 0.2 mm Hg to give 3-methyl-7,8-dihydro-5(6H)quinolone as a colourless oil b.p. 78°-80° (7.8 g, 48%) which solidified on standing and was recrystallized from 40- 60° petroleum ether as colourless needles m.p. 45°. Found: C, 74.81; H, 6.97; N, 8.91%. C10H11NO requires: C, 74.51; H, 6.88; N, 8.69%.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.C(Cl)Cl>[NH2:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5]
Reactant: CON(C)C(=O)c1cc(F)ccc1N
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1ccc(F)cc1C(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 3.5 h

Procedure:
To a −78° C. solution of 2-amino-5-fluoro-N-methoxy-N-methylbenzamide in THF (100 mL) was added 1M phenylmagnesium bromide in THF (124.12 mL, 124.12 mmol). The reaction was stirred from −78° C. to ambient temperature over 3.5 h and then cooled again to −78° C. Additional 1M phenylmagnesium bromide in THF (62.06 mL, 62.06 mmol) was added and the reaction stirred at −78° C. for another hour. The reaction was then diluted with CH2Cl2 (500 mL) and quenched with saturated ammonium chloride solution (300 mL). The layers were separated and the organic one washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by normal phase chromatography (3-8% MeOH/CH2Cl2) yielded (2-amino-5-fluorophenyl)(phenyl)methanone as a yellow solid. 1H NMR (CDCl3, 400 MHz) 7.63 (m, 2H, ArH); 7.55 (m, 1H, ArH); 7.47 (m, 2H, ArH); 7.15 (m, 1H, ArH); 7.08 (m, 1H, ArH); 6.70 (m, 1H, ArH); 5.91 (s, NH2); MS (Electrospray): m/z 216.1 (M+H).
Reaction SMILES: [CH:1]#[N:2].[CH:3](=[N:10][C:11]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[C:1]([CH:3]([NH:10][C:11]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: CCOC(=O)C1(N=Cc2ccccc2)CC1
Reactant: C#N
Solvent: CCO
Product: CCOC(=O)C1(NC(C#N)c2ccccc2)CC1
Temperature: 25 °C
Yield: 100 %

Procedure:
Liquid HCN (2.4 ml; 0.062 M) was added to a solution of ethyl N-benzylidene-1-aminocyclopropane carboxylate (5.61 g, obtained as described in Example 1) in ethanol (25 ml) at room temperature. The solution was stirred at room temperature for forty eight hours; subsequently the excess ethanol was evaporated. The desired product was obtained in a yield of 100% (6.3 g).
Reaction SMILES: O.[OH-].[Li+].C([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[O:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([O:27][CH3:28])=[O:26])[C:16]=2[CH:32]=1)(=O)CCCCC.CO.O1CCCC1>O.C(O)(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[NH2:11][C:12]1[CH:13]=[CH:14][C:15]2[O:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([O:27][CH3:28])=[O:26])[C:16]=2[CH:32]=1
Reactant: CCCCCC(=O)Nc1ccc2c(c1)N(Cc1cccc(C(=O)OC)c1)CCO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN2CCOc3ccc(N)cc32)c1
Yield: 58.5 %

Procedure:
Lithium hydroxide monohydrate (0.2 g.) in water (5 ml.) was added to a stirred solution of methyl 3-(6-hexanamido-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)benzoate (ca. 400 mg.) in 1:1 v/v methanol: tetrahydrofuran (10 ml.). When TLC (solvent system 80:20:2 v/v/v toluene:ethyl acetate:acetic acid) indicated complete disappearance of ester, the mixture was diluted with water, filtered to remove any solids, and carefully acidified with 1N hydrochloric acid. The precipitate was isolated by filtration and recrystallized from a mixture of methanol and water to give the title compound (0.176 g., 46% overall yield from amino ester (X)) as an off-white solid, m.p. 167°-171° C. (hemihydrate).
Reaction SMILES: C(OC([N:8]1[CH2:27][CH2:26][N:11]2[C:12](=[O:25])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([S:19][CH3:20])=[CH:15][C:14]=3[C:21]([F:24])([F:23])[F:22])=O)(C)(C)C.[ClH:28]>CCOCC.O>[ClH:28].[CH3:20][S:19][C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:25])[N:11]3[CH2:26][CH2:27][NH:8][CH2:9][C@H:10]32)=[C:14]([C:21]([F:23])([F:22])[F:24])[CH:15]=1
Reactant: CSc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CSc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCNC[C@@H]21
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-methylthio-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (34 mg, 0.08 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to yield 21 mg of a white solid. MS (ESI) 303 (M−Cl).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[O:12][CH3:13])([O-])=O>[Pt]>[NH2:1][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[O:12][CH3:13]
Reactant: COc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Product: COc1c(N)cc(Cl)cc1Cl
Yield: 95.5 %

Procedure:
2-Amino-4,6-dichloroanisole was prepared by same method as described in Step 2 of Preparation 2c except using 2-nitro-4,6-dichloroanisole (13.32 g) and 10%Pt(S)/C (1.33 g). Workup gave crude 2-amino-4,6-dichloroanisole (11 g, 95%) which was used in the next step without purification. 1H NMR (300 MHz, CDCl3) δ6.73 (d, J=2.4 Hz, 1 H), 6.62 (d, J=2.4 Hz, 1 H), 3.82 (s, 3 H).
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][N:28]=[C:29]=[O:30]>ClCCl>[CH3:27][NH:28][C:29]([N:12]1[CH2:11][CH2:10][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[CH:16][CH:15]=2)[CH2:8][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:30]
Reactant: Clc1ccccc1-c1ccc(CN2CCNC(c3ccccc3)C2)cc1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N1CCN(Cc2ccc(-c3ccccc3Cl)cc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound could be made in the following manner: 100 mg of 3-phenyl-1-(2′-chloro-biphenyl-4-ylmethyl)-piperazine would be dissolved in dichloromethane, 1.1 equiv. methylisocyanate would be added. The reaction would be stirred at room temperature under nitrogen overnight. Aminomethylpolystyrene (loading 1.6 mmol/g) could be added and the reaction would be shaken for further 6 h. The polymer could be separated by filtration and rinsed with dichloromethane. The filtrate could be concentrated in vacuo to afford the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].[CH3:34][C:35]1[CH:36]=[N:37][C:38]([C:41]2([NH2:44])[CH2:43][CH2:42]2)=[N:39][CH:40]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:30]=[C:26]([C:27](=[O:28])[NH:44][C:41]2([C:38]3[N:37]=[CH:36][C:35]([CH3:34])=[CH:40][N:39]=3)[CH2:42][CH2:43]2)[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Reactant: Cc1cnc(C2(N)CC2)nc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)cn5)CC4)c(OC)cc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.089 mmol, 1 eq), 1-(5-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.06 g, 0.11 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.027 g, 0.26 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.025 g (48%). 1H NMR (400 MHz, CD3OD): δ 8.58 (d, J=0.8 Hz, 2H), 7.97-7.94 (m, 2H), 7.90 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 3H), 7.19 (s, 1H), 4.10 (s, 3H), 2.96 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H), 1.82-1.79 (m, 2H), 1.55-1.52 (m, 2H). 19F NMR (376.57 MHz, CD3OD) δ−77.67 (TFA), −112.34, −122.75 LCMS: (ES+) m/z=583.2 (M+H)+
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1.C(OCC)(=O)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH:22]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:10][CH:11]=2)=[CH:25][CH:24]=1)=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(CCOc2ccc(C=O)cc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(CCOc2ccc(C=O)cc2)cc1
Yield: 34.3 %

Procedure:
6.75 g (64 mmole) triethylamine was added to 5 g (14,6 mmole) 4-[2-(4-aminophenyl)ethoxy]benzaldehyde x HCl (containing some ethyl acetate) in dichloromethane. 3.65 g (32 mmole) methanesulfonyl chloride was slowly added at 0° C., and the mixture was stirred over the weekend. A yellow precipitate was filtered off and the filtrate was washed with water. The organic phase was dried (sodium sulfate), filtered and the solvent was evaporated. The residue contained some triethylamine and therefore it was dissolved in dichloromethane and washed with 2 M hydrochloric acid and brine, dried and filtered and the solvent was evaporated to give 1.6 g (yield 34%) of N-{4-[2-(4-formylphenoxy)ethyl]phenyl}methanesulfonamide as a yellow powder.
Reaction SMILES: [C:1]([CH2:3][CH2:4][PH:5](=[O:10])[CH2:6][CH2:7][C:8]#[N:9])#[N:2].[CH3:11][C:12]([CH3:14])=[O:13].CN(C)C(=NC)N(C)C>C(N(CC)CC)C>[CH3:11][C:12]([P:5](=[O:10])([CH2:6][CH2:7][C:8]#[N:9])[CH2:4][CH2:3][C:1]#[N:2])([OH:13])[CH3:14]
Reactant: N#CCC[PH](=O)CCC#N
Reactant: CC(C)=O
Agent: CN=C(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)(O)P(=O)(CCC#N)CCC#N
Yield: 88 %

Procedure:
To a mixture of 0.1 mol of bis(2-cyanoethyl)phosphine oxide and 0.1 mol of acetone was added 1.0 gram of either triethyl amine or pentamethyl guanidine. The mixture was heated for 2 hours at steam bath temperatures. The resulting solid was filtered and recrystallized from acetone to give an 88% yield of product, m.p. 124°-125° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CC([O-])(C)C.[Na+].C(Cl)(Cl)Cl>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2[C-](N(C)C)C=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:3][CH:4]=1
Reactant: C1COCCN1
Reactant: COc1ccc(Br)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(N2CCOCC2)cc1
Yield: 66.2 %

Procedure:
According to General Procedure B, a mixture of 4-bromoanisole (63 μL, 0.50 mmol), morpholine (52 μL, 0.60 mmol), NaOt-Bu (67 mg, 0.70 mmol), Pd2(dba)3.CHCl3 (10 mg, 0.01 mmol), and 12f (8 mg, 0.02 mmol) in PhMe (2.5 mL) was heated, cooled and filtered. Evaporation of the solvent under reduced pressure and column chromatography of the pre-adsorbed crude material (2:50:48 Et3N/Et2O/hexane, silica gel) gave 52e (64 mg, 67%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 6.92-6.84 (m, 4H), 3.86 (t, 4H, J=4.8 Hz), 3.77 (s, 3H), 3.06 (t, 4H, J=4.8 Hz); 13C NMR (75.5 MHz, CDCl3) δ 153.9, 145.5, 117.7, 114.4, 66.9, 55.5, 50.7.