Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]([CH2:18][O:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1)=O)[CH2:9][O:10]CC1C=CC=CC=1)([CH3:4])(C)C.Cl.C(O[CH2:37][CH3:38])(=O)C.C(O[CH2:43][CH3:44])(=O)C>>[CH:38]1[C:37]2[CH:4]([CH2:1][O:5][C:6]([N:7]3[C@@H:8]([CH2:9][OH:10])[CH2:18][O:19][CH2:20][C@H:21]3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=3)=[O:31])[C:43]3[C:44](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:24]=2[CH:23]=[CH:21][CH:20]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@H](COCC(=O)c1ccc(F)c(F)c1)COCc1ccccc1
Agent: Cl
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1[C@@H](CO)COC[C@H]1c1ccc(F)c(F)c1
Reaction time: 18 h

Procedure:
To a solution of {(S)-2-benzyloxy-1-[2-(3,4-difluorophenyl)-2-oxoethoxymethyl]ethyl}carbamic acid t-butyl ester (26.8 g) in ethyl acetate (50 mL) was added a 4 N hydrochloric acid/ethyl acetate solution (100 mL), and the resultant solution was stirred at room temperature for 2.5 hours. Solvent was removed by distillation under reduced pressure, and the resultant product was twice subjected to azeotropy with toluene. The resulting residue was diluted with a mixed solvent of ether/heptane (1/1, 300 mL) to form a solid. The supernatant was decanted off, and the residue solid was dried under reduced pressure. To a solution of the residue solid in methanol (200 ml) was added 10% palladium-carbon (9.1 g, 50% water content). Under a hydrogen atmosphere, this mixture was stirred for 18 hours. The catalyst was then filtered off, and the filtrate was concentrated by distillation under reduced pressure. The resulting product was then diluted with ethyl acetate and saturated sodium bicarbonate water. The organic layer was partitioned, washed with brine, and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure. The resultant residue was diluted with tetrahydrofuran (120 mL) and saturated sodium bicarbonate water (120 mL). To this solution was added 9-fluorenylmethyl chloroformate (16.6 g) while cooling with ice. The temperature of the solution was returned to room temperature, and the solution was then stirred for 14 hours. The reaction solution was diluted with ethyl acetate and water, and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was diluted with ethyl acetate (50 mL) and heptane (5 mL). The resultant solution was then left to stand for 4 days at 4° C. The precipitated solid was collected by filtering, to thereby obtain the titled compound (7.19 g). The filtrate was purified by silica gel column chromatography (hexane/ethyl acetate 4/1→1/1), and again solidified using ethyl acetate. The titled compound (3.69 g) was collected by filtering. The physical properties of the compound were as follows.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:21][C:22]([C:24]1[CH:25]=[CH:26][C:27]2[O:31][C:30]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][C:28]=2[CH:36]=1)=[O:23]>C(#N)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:21][C:22]([C:24]3[CH:25]=[CH:26][C:27]4[O:31][C:30]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][C:28]=4[CH:36]=3)=[O:23])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc2cc(C(=O)CBr)ccc2o1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cc2cc(C(=O)CN3CCN(c4ccncc4)CC3)ccc2o1
Reaction time: 2 h

Procedure:
To a solution of 1-(4-pyridyl)piperazine (262 mg) and triethylamine (0.1 ml) in acetonitrile (10 ml) was added dropwise over 40 minutes a solution of methyl 5-(2-bromoacetyl)benzofuran-2-carboxylate in acetonitrile (5 ml). The resulting mixture was stirred for 2 hours, concentrated and purified by flash column chromatography on grade III alumina, eluting with methanol/dichloromethane (1:99 to 4:96 v/v) to give the title compound as a solid (138 mg); m.p. 173°-177° C.: NMR 2.66(4H,m), 3.8(4H,m), 3.91(3H,s), 4.00(2H,s), 6.82(2H,m), 7.8-8.5(6H,m); m/e 380 (M+H+); calculated for C21H21N3O4.0.5H2 O: C, 64.9; H, 5.7; N, 10.8. Found: C, 65.2; H, 5.7; N, 10.9%.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:14][CH2:15][CH2:16]C)=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].ICC>CS(C)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:14][CH2:15][CH3:16])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCCSc1cc2c(cc1Br)N(C(C)=O)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: CS(C)=O
Product: CCSc1cc2c(cc1Br)N(C(C)=O)CC2
Yield: 100.7 %

Procedure:
The thiol (D79) (0.35 g, 1.29 mmol) was treated with K2CO3 (0.20 g, 1.45 mmol) and iodoethane (0.31 ml, 3.88 mmol) in DMSO (15 ml) at the 50° C. as in the method of Description 80 to afford the title compound (0.39 g, 100%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]3[CH2:18][CH3:19])=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Br:20][C:21]1[CH:27]=[C:26]([CH3:28])[C:24]([NH2:25])=[C:23]([O:29][CH3:30])[CH:22]=1>C(OCC)(=O)C>[Br:20][C:21]1[CH:27]=[C:26]([CH3:28])[C:24]([NH:25][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([N:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]4[CH2:18][CH3:19])=[CH:9][CH:10]=[CH:11][C:4]=3[N:3]=2)=[C:23]([O:29][CH3:30])[CH:22]=1
Reactant: COc1cc(Br)cc(C)c1N
Reactant: CCC1CCCCN1c1cccc2nc(Cl)n(C)c12
Solvent: CCOC(C)=O
Product: CCC1CCCCN1c1cccc2nc(Nc3c(C)cc(Br)cc3OC)n(C)c12
Temperature: 110 °C
Yield: 29.9 %

Procedure:
A mixture of 2-chloro-7-(2-ethyl-1-piperidinyl)-1-methyl-1H-benzimidazole (100 mg, 0.36 mmol) and 4-bromo-2-methoxy-6-methylaniline (390 mg, 1.8 mmol) was heated at 110° C. for 12 h. The mixture was dissolved in ethyl acetate and washed with saturated sodium bicarbonate in water, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with a 15% acetone/hexanes mixture to afford 49.3 mg (30%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].C(Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: BrCc1ccccc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)CC1)O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.9 %

Procedure:
A suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (451 mg, 1.34 mmol, Intermediate 1) in DCM (12 ml) was treated with TEA (0.42 ml, 3 mmol) and benzyl bromide (0.54 ml, 4.5 mmol), and stirred at RT for 5 h. The mixture was washed with water, the pH value was adjusted to 5 with a 0.5 M HCl, then dried and concentrated. The crude residue was purified by column chromatography (eluent:DCM/MeOH 95:5) to give (E)-3-{1′-benzyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (440 mg) as a light yellow solid.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:13](=[O:32])[N:12]2[CH2:33][C:34]2[O:38][C:37]([C:39]([O:41]C)=[O:40])=[CH:36][CH:35]=2)=[CH:7][CH:6]=1)#[N:4].Cl>O1CCCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:13](=[O:32])[N:12]2[CH2:33][C:34]2[O:38][C:37]([C:39]([OH:41])=[O:40])=[CH:36][CH:35]=2)=[CH:9][CH:10]=1)#[N:4]
Reactant: COC(=O)c1ccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C3=C(C(=O)CCC3)C2c2ccc(C#N)cc2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2Cc2ccc(C(=O)O)o2)cc1

Procedure:
Aqueous sodium hydroxide solution (1.0 M, 100 μL, 100 μmol) is added to a solution of methyl 5-((4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-yl)methyl)furan-2-carboxylate (example 28, 25 mg, 45 μmol) in tetrahydrofuran (2 mL), and the mixture is at room temperature over night. Another portion of aqueous sodium hydroxide solution (4 M, 100 μL, 400 μmol) is added and stiffing was continued over night. The mixture was acidified with aqueous hydrogen chloride solution to (1 M, 100 μL, 100 μmol) and purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 11 mg; ESI mass spectrum [M+H]+=536; Retention time HPLC: 0.91 min (Z018_S04).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]([NH:19][S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([CH2:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:10][F:11].[B-].[Na+]>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]([NH:19][S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([CH2:12][C@H:13]([OH:18])[C:14]([F:17])([F:15])[F:16])[CH2:10][F:11]
Reactant: CC(C)(C)[S@@](=O)N[C@@](CF)(CC(=O)C(F)(F)F)c1cccc(F)c1F
Agent: [B-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[S@@](=O)N[C@@](CF)(C[C@H](O)C(F)(F)F)c1cccc(F)c1F
Reaction time: 0.17 h
Yield: 49.5 %

Procedure:
To a cooled (−15° C.) solution of (R)-N-((S)-2-(2,3-difluorophenyl)-1,5,5,5-tetrafluoro-4-oxopentan-2-yl)-2-methylpropane-2-sulfinamide (5.0 g, 12.84 mmol) in MeOH (20 mL) was added sodium borohydrate (0.729 g, 19.26 mmol). The resulting mixture was stirred at this temperature for 10 min. LCMS indicated reaction went to completion. The mixture was quenched with saturated NaHCO3, diluted with water and extracted with EtOAc (2×). The combined organics were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and the resulted residue was recrystallized in dichloromethane to afford (R)-N-((2S,4S)-2-(2,3-difluorophenyl)-1,5,5,5-tetrafluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (2.49 g, 6.36 mmol, 49.5% yield) as white solid. The filtrate was the undesired diastereomers and no further purification was carried out. MS m/z=392.1 [M+H]+. Calculated for C15H19F6NO2S: 391.4
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH3:10])[C:4](=O)[C@@H:5]([SH:7])[CH3:6])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH2:1]([N:3]([CH2:9][CH3:10])[CH2:4][C@@H:5]([SH:7])[CH3:6])[CH3:2]
Reactant: CCN(CC)C(=O)[C@H](C)S
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCN(CC)C[C@H](C)S
Temperature: 0 °C
Yield: 64 %

Procedure:
(S)-N,N-Diethyl-2-mercaptopropionamide (171 g) dissolved in ethyl ether (500 cc) is added dropwise to a suspension of lithium aluminium hydride (42.6 g) in ethyl ether (1500 cc) in the course of 1 hour and 20 minutes. The reaction mixture is then maintained under reflux for 2 hours and 30 minutes and then cooled to a temperature in the vicinity of 0° C. Distilled water (49.8 cc) is then added so that the temperature of the mixture does not exceed 20° C., and 5N sodium hydroxide (36.6 cc) and distilled water (166 cc) are then added. The reaction mixture is filtered, the pH of the filtrate is adjusted to 8 by adding acetic acid (70 cc). The mixture obtained is filtered again, the filtrate is dried over sodium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the vicinity of 30° C. A yellow oil is obtained, which is purified by distillation under reduced pressure (1.3 kPa). (S)-1-Diethylamino-2-propanethiol (100 g) in the form of a colourless oil [b.p.1.3 kPa=55°- 56° C.; [α]D20 =+39.6° (c=5.6, CH3OH)] is thereby obtained.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[CH2:6]2.[CH3:12][C:13]1[CH:14]=[C:15]([Mg]Br)[CH:16]=[C:17]([CH3:19])[CH:18]=1>CCOCC.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[C:5]([CH3:11])[CH2:6]3)[CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: CC1=Cc2c(Cl)cccc2C1
Reactant: Cc1cc(C)cc([Mg]Br)c1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CC1=Cc2c(cccc2-c2cc(C)cc(C)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-2-methylindene (8.9 g, 54 mmol) and NiCl2(PPh3)2 (1.8 g, 2.8 mmol) were dissolved in 150 mL of Et2O. 3,5-Dimethylphenylmagnesium bromide (10 g, 54 mmol) as a Et2O solution was added to the solution and the reaction was stirred overnight at room temperature. After overnight stirring, the reaction was slowly quenched with H2O to neutralize unreacted Grignard. The solution was subsequently treated with 100 mL of 10% HCl(aq), neutralized with saturated sodium bicarbonate aqueous solution. The organic layer was dried with magnesium sulfate and the solvent was removed by rotary evaporation. The remaining residue was loaded onto a silica gel column and eluted with hexane. Yield was 5.6 g (44%).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C(O)C>[CH3:7][N:6]1[C:2]([N:14]2[CH2:15][CH2:16][CH2:17][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1N1CCCN(C(=O)OC(C)(C)C)CC1
Yield: 68.4 %

Procedure:
To a microwave reaction vial was added 5-chloro-1-methyl-4-nitro-1H-pyrazole (500 mg, 3.10 mmol), tert-butyl 1,4-diazepane-1-carboxylate (744 mg, 3.72 mmol). Ethanol (15 mL) and diisopropylethylamine (3.23 mL, 18.57 mmol) were added and the mixture was irradiated with a microwave for 60 min at 130° C. The mixture was cooled, concentrated and purified via flash chromatography, ethyl acetate/heptane 0% to 100% to afford yellow oil tert-butyl 4-(2-methyl-4-nitro-pyrazol-3-yl)-1,4-diazepane-1-carboxylate (690 mg, 69%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:15][C:16]1[CH:17]=[C:18]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1
Reactant: O=[N+]([O-])c1cccc2ccc(Cl)nc12
Reactant: OB(O)c1cc(F)cc(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2ccc(-c3cc(F)cc(C(F)(F)F)c3)nc12
Temperature: 125 °C

Procedure:
A mixture of 2-chloro-8-nitroquinoline (0.580 g, 2.78 mmol), 3-fluoro-5-(trifluoromethyl)phenylboronic acid (0.675 g, 3.22 mmol), K3PO4 (1.1 g, 5.2 mmol), and Pd(dppf)Cl2.CH2Cl2 (0.10 g, 0.122 mmol) in DMF (3 mL) and water (1 mL) was microwave heated (125° C.×1 Hour). The mixture was filtered over celite and the celite cake was washed with ethyl acetate (30 mL). The filtrate was combined with 60 mL aqueous saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate (3×20 mL). The organic layers were combined, washed with brine, dried (MgSO4), and concentrated to yield 2-(3-fluoro-5-(trifluoromethyl)phenyl)-8-nitroquinoline. The product was used without further purification.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[S:26][C:17]=2[N:18]=[C:19]([C:21]2[O:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[O:25]1[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[S:26][C:17]=3[N:18]=2)=[CH:22][CH:23]=[N:24]1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N[C:20](N)=[O:21]>CN(C=O)C.C(Cl)Cl>[N:13]1([C:9]2[CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]3[NH:1][C:20](=[O:21])[NH:12][C:11]=3[CH:10]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: NC(N)=O
Reactant: COC(=O)c1cc(N2CCOCC2)cc(N)c1N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(N2CCOCC2)cc2[nH]c(=O)[nH]c12
Temperature: 170 °C
Yield: 62 %

Procedure:
To a solution of methyl 2,3-diamino-5-(4-morpholinyl)benzoate, prepared as described in Example 45, step a (11.0 g, 4.0 mmol) in DMF (50 mL) was added urea (720 mg, 12 mmol) and the mixture was heated to 170° C. for 4 h. When analysis by TLC showed no starting material remaining, the mixture was cooled to room temperature then diluted with DCM (200 mL), washed with water (50 mL×2) and dried over anhydrous Na2SO4, filtered and concentrated in-vacuo. The residue was then purified by chromatography on silica (eluted with EtOAc) to afford the desired product as a dark-yellow solid (690 mg, 62%). 1H NMR (300 MHz, DMSO-d6): δ ppm 3.02 (t, 4H, J=4.8 Hz), 3.74 (t, 4H, J=4.8 Hz), 3.86 (s, 3H), 6.82 (d, 1H, J=2.1 Hz), 6.99 (d, 1H, J=2.1 Hz), 10.48 (s, 1H), 10.82 (s, 1H). LC-MS: m/e=278 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[CH3:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][NH:12][CH2:11]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.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]>[Br:8][C:4]1[CH:3]=[C:2]([N:12]2[CH2:11][C@H:10]([CH3:9])[O:15][C@H:14]([CH3:16])[CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: Brc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2cccc(Br)c2)C[C@H](C)O1
Temperature: 80 °C
Yield: 65.9 %

Procedure:
A mixture of 1,3-dibromobenzene (242 μL, 2.00 mmol), cis-2,6-dimethylmorpholine (248 μL, 2.00 mmol), Pd2(dba)3 (45.8 mg, 0.0500 mmol), rac-BINAP (96.3 mg, 0.150 mmol) and NaOtBu (231 mg, 2.40 mmol) in toluene was heated at 80° C. for 11 hours under nitrogen. After cooling to room temperature, the mixture was diluted with DCM and filtered through a Celite pad. The combined filtrate and washings were concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=98:2→97: 3) to afford desired product (356 mg, 65.8%) as pale yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([O:20][CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.O.NN>CO>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:20][CH3:21])[CH:12]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3]1
Reactant: COc1cc(N2CCN(CC3CC3)CC2)ccc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc(N2CCN(CC3CC3)CC2)ccc1N
Yield: 90 %

Procedure:
A solution of 1-(cyclopropylmethyl)-4-[3-(methyloxy)-4-nitrophenyl]piperazine (1.05 g, 3.41 mmol), FeCl3 (0.165 g, 1.02 mmol), activated carbon (1.0 g), and hydrazine hydrate (1.3 mL, 41 mmol) was heated in methanol (50 mL) for 3 hours. Once the starting material was judged consumed by thin layer chromatography (10% MeOH/CH2CL2) the mixture was filtered over celite and concentrated to give 4-[4-(cyclopropylmethyl)-1-piperazinyl]-2-(methyloxy)aniline as a yellow solid (0.800 g, 3.07 mmol, 90% yield). 1H NMR (400 MHz, CDCl3) δ ppm 0.15 (q, J=4.89 Hz, 2 H), 0.52-0.60 (m, 2 H), 0.94 (d, J=6.23 Hz, 1 H), 2.35 (d, J=6.59 Hz, 2 H), 2.74 (s, 4 H), 3.07-3.15 (m, 4 H), 3.53 (s, 2 H), 3.83 (s, 3 H), 6.43 (dd, J=8.43, 2.20 Hz, 1 H), 6.53 (d, J=2.20 Hz, 1 H), 6.65 (d, J=8.06 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[C:4]([C:6]1[NH:10][C:9]([C:11]([OH:13])=O)=[CH:8][CH:7]=1)=[O:5].ClC1C=CC([N+]([O-])=O)=CC=1C(C1NC(C(Cl)=O)=CC=1)=O.C(Cl)(=O)C(Cl)=O.[N:47]1([CH2:53][CH2:54][NH2:55])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>>[N:47]1([CH2:53][CH2:54][NH:55][C:11]([C:9]2[NH:10][C:6]([C:4](=[O:5])[C:3]3[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:2]=3[Cl:1])=[CH:7][CH:8]=2)=[O:13])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1ccc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)[nH]1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)c1ccc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)[nH]1
Product: O=C(NCCN1CCOCC1)c1ccc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)[nH]1

Procedure:
5-(2-Chloro-5-nitro-benzoyl)-1H-pyrrole-2-carboxylic acid (200 mg) was converted to 5-(2-chloro-5-nitro-benzoyl)-1H-pyrrole-2-carbonyl chloride using oxalyl chloride at room temperature for one hour. It was then condensed with 2-morpholin-4-yl-ethylamine and TEA for one hour at room temperature to give 120 mg of 5-(2-chloro-5-nitro-benzoyl)-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]4[N:30]=[C:29]([C:31]5[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH3:40])=[C:33]([Br:41])[CH:32]=5)[O:28][N:27]=4)=[CH:23][CH:24]=3)[CH2:19][CH2:18]2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.C(OC1C=C(C2ON=C(C3C=CC=C4C=3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)N=2)C=CC=1OCC)C>>[NH2:7][C:8]([CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26]3[N:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH3:40])=[C:33]([Br:41])[CH:32]=4)[O:28][N:27]=3)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CCCOc1ccc(-c2nc(-c3ccc4c(c3)CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1Br
Agent: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Product: CCCOc1ccc(-c2nc(-c3ccc4c(c3)CCN4CC(N)(CO)CO)no2)cc1Br
Yield: 44 %

Procedure:
When the product of Step E was substituted for tert-butyl 5-((4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 34, Step E, the identical process afforded the title compound in 44% yield. 1H-NMR (DMSO-d6) 1.0 (tr, 3H, J=7.38 Hz); 1.75-1.79 (m, 2H); 2.99 (5, 2H); 3.2-3.4 (m, 8H); 4.13 (tr, 2H, J=6.30 Hz); 4.61 (broad s, 1H); 6.77 (d, 1H); 7.13 (tr, 1H); 7.24 (d, 1H, J=7.59 Hz), 7.31 (d, 1H, J=8.79 Hz), 8.11 (dd, 1H, J=2.13, 8.64 Hz), 8.27 (d, 1H, J=2.46 Hz).