Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([S:22](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:24])=[O:23])=[CH:17]2.[O:37]1[CH:41]=[CH:40][N:39]=[C:38]1[NH2:42].S1C=CN=C1N>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([S:22]([NH:42][C:38]1[O:37][CH:41]=[CH:40][N:39]=1)(=[O:23])=[O:24])=[CH:17]2
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)cccc2c1
Reactant: Nc1ncco1
Agent: Nc1nccs1
Solvent: ClCCl
Product: O=S(=O)(Nc1ncco1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)cccc2c1

Procedure:
This product was prepared as described in EXAMPLE 41, using perfluorophenyl 5-(2-chloro-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonate and oxazole-2-amine instead of perfluorophenyl 5-bromonaphthalene-2-sulfonate and thiazole-2-amine. The residue was taken up in minimal CH2Cl2 and absorbed onto a 5 g loading cartridge and passed through a silica gel column (12 g) using a gradient from 5% to 100% EtOAc to Heptanes and then triturated with an IPA/DCM/Heptanes mixture to give desired product 5-(2-chloro-4-(trifluoromethyl)phenyl)-N-(oxazol-2-yl)naphthalene-2-sulfonamide (0.010 g, 0.022 mmol) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.88 (d, J=1.76 Hz, 2H) 7.09 (d, J=1.76 Hz, 1H) 7.45-7.60 (m, 3H) 7.62-7.78 (m, 2H) 7.82-7.96 (m, 2H) 8.08 (d, J=8.61 Hz, 1H) 8.60 (d, J=1.76 Hz, 1H); m/z (ESI, +ve ion) 453.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6](/[CH:7]=[CH:8]/[C:9]([O:11]CC2C=CC=CC=2)=[O:10])=[N:5][C:4]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:3]1>[Pd].O1CCOCC1>[CH3:1][N:2]1[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[N:5][C:4]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:3]1
Reactant: Cn1nc(N2CCCC2)nc1/C=C/C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Product: Cn1nc(N2CCCC2)nc1CCC(=O)O
Reaction time: 8 h
Yield: 96.7 %

Procedure:
(E)-Benzyl 3-(1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)acrylate was stirred with palladium on carbon (10 wt %, 140 mg) in dioxane (60 ml) under hydrogen for 2 h. Additional palladium on carbon (10 wt %, 250 mg) was added and the mixture was stirred overnight under hydrogen. The mixture was filtered over Celite and concentrated to give the product (1.95 g, 96.7%) as a white solid. MS: m/z=225.2 (M+H+).
Reaction SMILES: C([S-])=S.[Na+].[C:5]([S-:8])(=[S:7])[CH3:6].[Na+].C(S[CH:13]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])=[CH:23][CH:22]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=S>>[C:5]([S:8][CH:13]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])=[CH:23][CH:22]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[S:7])[CH3:6]
Reactant: CCOC(=O)C(CCc1ccc(-c2ccccc2Cl)cc1)SC=S
Reactant: CC(=S)[S-]
Agent: S=C[S-]
Agent: [Na+]
Product: CCOC(=O)C(CCc1ccc(-c2ccccc2Cl)cc1)SC(C)=S

Procedure:
When sodium dithioformate is used in the above procedure in place of sodium dithioactate then the product prepared is ethyl α-thioformylthio-γ-(2'-chloro-4-biphenylyl)butyrate.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C@@:13]2([C:25]#[N:26])[CH2:15][C@H:14]2[CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C>[C:7]1([C@@:13]2([CH2:25][NH2:26])[CH2:15][C@H:14]2[CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#C[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NC[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
To 19.4 mL IM lithium aluminum hydride (19.4 mmol) in diethyl ether at 0° C. was added (1R,2R)-1-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropanecarbonitrile (5.10 g, 19.4 mmol), accessed via the method of Preparation 3B, dissolved in 20 mL diethyl ether. After complete addition, the reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was diluted with 360 mL diethyl ether and quenched with successive addition of 0.6 mL water, 0.6 mL 15% NaOH, and 3.0 mL water. The reaction mixture was filtered and the filtrate was concentrated to a clear oil. The oil was purified by flash chromatography (SiO2, 3→7% CH3OH/EtOAc with 1% NH4OH) to give the title product (3.03 g, 11.3 mmol, 59%) as a single diastereomer. 1H NMR (300 MHz, CDCl3) δ 7.35-7.21 (m, 10H), 4.35-4.25 (m, 2H), 3.22-3.18 (m, 1H), 3.00-2.94 (m, 2H), 2.43 (d, J=13.5 Hz, 1H), 1.36 (m, 1H), 0.91 (m, 1H), 0.78 (m, 1H). ES-LCMS m/z 268.4 (M+H).
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[CH3:15][O:16][C:17]1[C:18]([NH:23][C:24](=O)[CH2:25][O:26][CH2:27][CH3:28])=[C:19]([CH3:22])[S:20][CH:21]=1.[OH-].[K+]>C1(C)C=CC=CC=1>[CH2:27]([O:26][CH2:25][CH2:24][NH:23][C:18]1[C:17]([O:16][CH3:15])=[CH:21][S:20][C:19]=1[CH3:22])[CH3:28]
Reactant: CCOCC(=O)Nc1c(OC)csc1C
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOCCNc1c(OC)csc1C
Reaction time: 1.5 h

Procedure:
To 70 ml (0.245 mol) of sodium bis(2-methoxyethoxy)aluminium hydride (70% solution in toluene) and 30 ml of dry toluene is added dropwise with stirring a solution of 9.4 g (0.041 mol) of N-(4-methoxy-2-methyl-thien-3-yl)-ethoxyacetamide in 125 ml of dry toluene. After the exothermic reaction has subsided, stirring is continued for a further 90 minutes and the reaction solution then cautiously added in small portions at -10° to 100 ml of 20% KOH solution.
Reaction SMILES: [BrH:1].C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][NH:16][CH:17]2[C:20]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[CH2:22][CH2:21]2)=[CH:12][C:11]=1[O:30][CH3:31])C1C=CC=CC=1.[CH2:32]=O.[Na].Cl.Br>CO>[BrH:1].[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1([CH:17]2[C:18]3[C:13](=[CH:12][C:11]([O:30][CH3:31])=[C:10]([OH:9])[CH:19]=3)[CH2:14][CH2:15][N:16]2[CH3:32])[CH2:22][CH2:21]1
Reactant: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3Cl)CC1)NCC2
Reactant: C=O
Agent: Br
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COc1cc2c(cc1O)C(C1(c3ccccc3Cl)CC1)N(C)CC2
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A mixture of 7-benzyloxy-1-[1-(2-chlorophenyl)cyclopropyl]-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (5 g prepared as described in Example RC14), methanol (100 ml) and 37% aqueous formaldehyde solution (5 ml) was cooled to 10° C. Sodium borohyride (2.5 g) was added and the mixture stirred at ambient temperature for 2 hours. The methanol was evaporated in vacuo and the residue partitioned between dilute aqueous sodium hydroxide solution (100 ml) and ether (2×100 ml). The organic layer yielded an oil which was dissolved in methanol (25 ml) and concentrated hydrochloric acid (25 ml) and heated under reflux for 2 hours. The solvent was removed in vacuo and the residue dissolved in hot ethanol, decolorised, filtered and the solvent evaporated. The resulting solid was washed in ether, dried and then partitioned between ethyl acetate and concentrated aqueous ammonia solution. The organic layer yielded an oil which was dissolved in methanol. 48% Aqueous hydrobromic acid was added and the mixture heated under reflux for 2 hours. The solvents were removed by evaporation to yield a solid which was recrystallised from ethanol. The solid residue was washed with ether and dried in vacuo at 50° C. to give 1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide, m.p. 150°-153° C. Yield 2.95 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:3]=1.S1C=CC=C1B(O)O.O.C(Cl)[Cl:23]>>[Cl:23][C:9]1[S:10][CH:11]=[CH:12][C:8]=1[C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1
Reactant: Clc1ccnc(-c2ccsc2)c1
Reactant: ClCCl
Agent: OB(O)c1cccs1
Solvent: O
Product: Clc1ccnc(-c2ccsc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-2-thiophen-3-yl-pyridine (410 mg, 2.1 mmol), prepared as described in Example 26, Step A, using 2-thiopheneboronic acid, in CH2Cl2 (10 mL), was added SO2Cl2 (1 M in CH2Cl2, 3 mL). The resulting mixture was stirred at room temperature for 8 h, then was poured into water and extracted with CH2Cl2. The organic layer was dried and concentrated to yield a residue. The residue was purified by preparative TLC (hexanes/EtOAc) to yield 2-(2-chloro-thiophen-3-yl)-4-chloro-pyridine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23](C5NN=CC=5)=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC1(C2C=CC(C3C(=O)C4C(=C(Br)C=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[CH3:77][C:78]1[C:82](B(O)O)=[C:81]([CH3:86])[O:80][N:79]=1>>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([C:82]5[C:78]([CH3:77])=[N:79][O:80][C:81]=5[CH3:86])[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Reactant: Cc1noc(C)c1B(O)O
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Product: Cc1noc(C)c1-c1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Yield: 31 %

Procedure:
Following the procedure of (1-{-4-[4-oxo-2-phenyl-7-(2H-pyrazol-3-yl)-4H-chromen-3-yl]phenyl}cyclobutyl)-carbamic acid tert-butyl ester, {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted with 3,5-dimethylisoxazole-4-boronic acid to give the title compound (16 mg, 31%). LCMS (Method G): RT=4.34 min, [M+H]+=563.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])=[O:2].[O-:26][Mn](=O)(=O)=O.[K+]>C1COCC1.O>[C:18]([C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:24]([CH3:25])=[C:3]([CH:4]=3)[C:1]([OH:26])=[O:2])=[O:7])[CH2:9][CH2:10]2)=[CH:21][CH:20]=1)#[N:19]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a stirred mixture of 4-(1-(3-formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 39.2, 600 mg, 1.81 mmol, 1.00 equiv) in THF (5 mL) was added dropwise a solution of KMnO4 (1 g) in water (10 mL). The resulting mixture was stirred overnight at 60° C. in an oil bath. After cooling to ambient temperature, the solids were removed by filtration and the pH of the filtrate was adjusted to ≧10 with sodium hydroxide (aqueous, 1 M). The resulting mixture was washed with 20 mL of ethyl acetate. Aqueous 1 M HCl was then employed to adjust the pH of the aqueous layer to ˜4. The resulting aqueous phase was extracted with 2×100 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 500 mg (80%) of the title compound as light yellow oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=[C:12]([C:24](OCC)=[O:25])[C:11]3=[O:29])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:36][C:24]([C:12]2[C:11](=[O:29])[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:9]=3)[N:14]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:13]=2)=[O:25])=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1cn(C2CCNCC2)c2ccc(CN3CCOCC3)cc2c1=O
Reactant: NCc1ccc(Cl)cc1
Product: O=C(NCc1ccc(Cl)cc1)c1cn(C2CCNCC2)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 180 °C

Procedure:
A flask containing crude ethyl 6-(4-morpholinylmethyl)-4-oxo-1-(4-piperidinyl)-1,4-dihydro-3-quinolinecarboxylate (0.14 g) is treated with 4-chlorobenzylamine (1.0 mL). The reaction is tightly capped and heated to 180° C. for 2 hours. The reaction is cooled to room temperature and flash column chromatographed on silica eluting with 2% to 10% methanol saturated with ammonia in dichloromethane and then by recrystallization from acetonitrile to afford 0.10 g of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[CH3:16][N:17]1[CH2:21][CH2:20][CH:19]([N:22]2[CH:26]=[C:25]([NH2:27])[CH:24]=[N:23]2)[CH2:18]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:27][C:25]1[CH:24]=[N:23][N:22]([CH:19]2[CH2:20][CH2:21][N:17]([CH3:16])[CH2:18]2)[CH:26]=1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN1CCC(n2cc(N)cn2)C1
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1cnn(C2CCN(C)C2)c1
Yield: 86.9 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (285 mg, 1.0 mmol) was reacted with 1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-amine (0.28 g, 1.68 mmol) to afford the desired product (360 mg, 87%) as a light yellow solid. ESI MS m/z 414 [C19H20BrN5O+H]+
Reaction SMILES: [CH:1]([N:4]([CH3:31])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16]C(=O)OCC3C=CC=CC=3)[C:12]2=[O:27])[C@H:7]([CH2:28][CH2:29][CH3:30])[CH2:6]1)([CH3:3])[CH3:2].Br.CC(O)=O.CCOCC.O.C=O>CCOC(C)=O>[NH2:16][C@H:13]1[CH2:14][CH2:15][N:11]([C@H:8]2[CH2:9][CH2:10][C@@H:5]([N:4]([CH:1]([CH3:2])[CH3:3])[CH3:31])[CH2:6][C@H:7]2[CH2:28][CH2:29][CH3:30])[C:12]1=[O:27]
Reactant: CCC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: Br
Agent: C=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
The entirety of benzyl (S)-1-[(1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl]-2-oxopyrrolidin-3-ylcarbamate prepared in Step 2 (assumed 8.2 mmol) was wet with 3 mL of EtOAc and then charged with 30% HBr/AcOH (30 mL). The reaction vessel warms and a vigorous gas evolution occurs. The mixture was stirred for 25 min at RT and then the flask was placed in a cool water bath before the addition of 150 mL of 1:1 Et2O/H2O. This mixture was mixed and separated, and the aqueous phase was extracted once with Et2O. The aqueous phase was basified to pH 14 through the addition of solid NaOH (the temperature of this exothermic process was controlled through the intermittent use of an external ice bath) and the resulting mixture was extracted with EtOAc (75 mL, then 2×35 mL). The organic extracts were combined, washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give an orange oil, contaminated with some powdery white solid (presumed to be formaldehyde-related). The mixture was dissolved in a minimal volume of EtOAc, filtered, and concentrated to provide (S)-3-amino-1-[(1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl]pyrrolidin-2-one (2.31 g; 1H-NMR shows 30% EtOAc, indicating an estimated 7.0 mmol of product from Steps 1 to 3). MS found: (M+H)+=296.6.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14](Cl)=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])([O-:3])=[O:2].[F-:21].[K+]>CN(C)C=O>[N+:1]([C:4]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([F:21])=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])([O-:3])=[O:2]
Reactant: [F-]
Reactant: CCOC(=O)COc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 122 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
A suspension of ethyl 2,4-dinitro-5-chlorophenoxyacetate (2.0 g) and potassium fluoride (0.76 g) in N,N-dimethylformamide (10 g) was stirred at a temperature of 122° C. for 1.5 hours. After cooling, the reaction mixture was diluted with ice water (200 ml) and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution in order, dried over anhydrous magnesium sulfate and concentrated to give ethyl 2,4-dinitro-5-fluorophenoxyacetate (1.4 g; yield, 74.0%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[C:16](Br)=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[CH3:29][Sn](C)(C)C>Cl[Pd](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>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[C:16]([CH3:29])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Br)cn2Cc2ccccc2)c1OC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)c1nc(C#N)c2c(c(C)cn2Cc2ccccc2)c1OC(C)=O

Procedure:
Prepared in analogy to a Stille methylation step in the Example 103(b) from 4-acetoxy-1-benzyl-3-bromo-7-cyano-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, tetramethyl tin, and Pd(PPh3)2Cl2. The title compound, ESI MS (m/z): 378 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH2:10][CH2:11]2)(=[O:22])=[O:23])=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2cccc(OC)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3cccc(OC)c3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl) 1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)piperidine-4-carboxylic acid ethyl ester (2.4 g, 5.36 mmol) dissolve in methanol (30 mL), 10 N sodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 710 mg (32%). white solid mp 199° C., MS: 419.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[C@H:20]([N:24]1[CH:28]=[C:27]([CH2:29][N:30]2C(=O)C3=CC=CC=C3C2=O)[N:26]=[C:25]1[C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[NH2:30][CH2:29][C:27]1[N:26]=[C:25]([C:41]2[CH:42]=[CH:43][C:44]([CH3:47])=[CH:45][CH:46]=2)[N:24]([C@@H:20]([C:9]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=3)[N:10]=2)[CH:21]([CH3:23])[CH3:22])[CH:28]=1
Reactant: Cc1ccc(-c2nc(CN3C(=O)c4ccccc4C3=O)cn2[C@@H](c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc(CN)cn2[C@@H](c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.2 %

Procedure:
To N-{1-[(R)-1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-2-p-tolyl-1H-imidazol-4-ylmethyl}-phthalimide (3.50 g, 5.5 mMol) in EtOH (100 mL) was added hydrazine monohydrate (1.1 mL, 22.7 mMol). The reaction was stirred at RT for 72 h, filtered through a pad of Celite® to remove the insoluble precipitate, rinsed with EtOH and evaporated to dryness. Purification by flash chromatography on silica gel [5-10% (5% NH4OH in MeOH)/CH2Cl2] gave the title compound (2.71 g, 96%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=8.6 Hz, 1 H), 7.80 (d, J=2.0 Hz, 1 H), 7.40-7.51 (m, 6 H), 7.15-7.22 (m, 3 H), 6.43 (d, J=7.1 Hz, 2 H), 5.78 (d, J=16.3 Hz, 1 H), 4.84 (d, J=10.5 Hz, 1 H), 3.87 (d, J=16.3 Hz, 1 H), 3.83 (2d, 2H), 3.00 (m, 1 H), 2.60 (br s, 2H), 2.54 (s, 3 H), 0.90 (d, J=6.7 Hz, 3 H), 0.31 (d, J=6.7 Hz, 3 H); MS (ES) m/e 512.2 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:19])[CH2:15][C:16]([OH:18])=O)([CH3:3])[CH3:2].[CH2:20]([NH:27][CH:28]([CH3:30])[CH3:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C>C(N(CC)CC)C.CO.C(OCC)(=O)C>[CH2:20]([N:27]([CH:28]([CH3:30])[CH3:29])[C:16](=[O:18])[CH2:15][C:14]([NH:13][C:5]1[C:6]([CH:10]([CH3:11])[CH3:12])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:2])[CH3:3])=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CC(=O)O
Reactant: CC(C)NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CC(=O)N(Cc1ccccc1)C(C)C
Temperature: -5 °C
Reaction time: 8 h

Procedure:
A 2 liter flask equipped with a stirrer and nitrogen inlet was charged with N-(2,6-diisopropyl-phenyl)-malonamic acid (100 g, 0.380 moles) and N-benzylisopropylamine (82 mL, 74 g, 0.5 moles). The resulting solution was stirred in an ice-acetone bath until cooled to −5° C., then EDAC (80 g, 0.42 moles) was added, followed by triethylamine (75 mL, 54 g, 0.54 moles). The mixture was stirred and allowed to come to room temperature, then left overnight. TLC (ethyl acetate:methanol, 95:5) showed unreacted acid still present. Another 8 g of EDAC and 15 mL of triethylamine were added, and the mixture was stirred at room temperature 4 h longer. TLC showed no change, and the reaction was worked up by washing, first with 2N HCl (500 mL), then 2N NaOH (acidification of the basic wash precipitated ˜13 g of the unreacted malonamic acid). After the acid and base washes, the organic solution was washed with water (500 mL), then brine (250 mL). It was then dried over magnesium sulfate, filtered and concentrated to a thick oil. The crude product was taken up in a small volume of warm heptane and filtered through ˜500 g of silica gel, which was rinsed with 10% ethyl acetate in heptane until all the desired product had come through. This left a thin layer of polar impurities at the top of the silica gel, and gave a nearly pure solution of the product. Most of the solvent was removed on the Rotavap, to remove the ethyl acetate, and then the oil was dissolved in warm heptane (1 liter). The solution was allowed to cool, seeded with a few crystals of the form A polymorph, and stirred at room temperature until precipitation of product was complete. The suspension was further stirred for 24 h, then chilled to 0° C. and filtered with suction. The collected product was air dried at room temperature to give 98 g of the Form A polymorph of N-benzyl-N′-(2,6-diisopropyl-phenyl)-N-isopropyl-malonamide. Melting point was 102.3° C., as determined by DSC, as described above.
Reaction SMILES: C1(SC2C3C=CC=CC=3SC=2I)C=CC=CC=1.[C:18]1([Se:24][C:25]2[C:26]3[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=3[S:28][C:29]=2I)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:23]1[C:18]2[Se:24][C:25]3[C:26]4[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=4[S:28][C:29]=3[C:19]=2[CH:20]=[CH:21][CH:22]=1
Reactant: Ic1sc2ccccc2c1[Se]c1ccccc1
Agent: Ic1sc2ccccc2c1Sc1ccccc1
Product: c1ccc2c(c1)sc1c3ccccc3[se]c21
Yield: 85 %

Procedure:
Except that 3-(phenylsulfenyl)-2-iodobenzo[b]thiophene was replaced with 3-(phenylselenenyl)-2-iodobenzo[b]thiophene, the reaction was implemented in the same way as in Example 3. Purification was implemented by column chromatography (silica gel, CHCl3, Rf: 0.9), so that a yellow solid was produced (yield: 85%).