Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:45])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:43])[C@@H:18]([NH:27][C:28]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]3)=[O:29])[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)[C:3]1=[O:44].FC(F)(F)C(O)=O>>[CH3:1][C:2]1([CH3:45])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:43])[C@@H:18]([NH:27][C:28]([C@@H:30]3[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]3)=[O:29])[CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:15][CH2:16]2)[C:3]1=[O:44]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)N[C@@H](CCc2ccccc2)C(=O)N2CCC(N3C(=O)C(C)(C)c4ccccc43)CC2)C1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)N(C2CCN(C(=O)[C@H](CCc3ccccc3)NC(=O)[C@@H]3CCCNC3)CC2)c2ccccc21
Reaction time: 0.33 h
Yield: 83.5 %

Procedure:
A mixture of (R)-tert-butyl 3-((S)-1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-ylcarbamoyl)piperidine-1-carboxylate (615 mg, 0.997 mmol, EXAMPLE 1, Alternative Method, Step 1) and trifluoroacetic acid (2 mL) was stirred for 20 min and concentrated. The residue was diluted with dichloromethane and basified by saturated sodium hydrogen carbonate aqueous solution. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by amine gel column chromatography (dichloromethane/methanol, gradient) to give the title compound (430 mg, 83%) as an amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:11]([CH3:10])(=[O:13])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)cnc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(Br)cnc1Cl
Reaction time: 8 h

Procedure:
5-Bromo-2-chloro-3-pyridinamine [commercially available] (10 g, 48.2 mmol) was dissolved in pyridine (75 ml) and methanesulfonyl chloride (7.46 ml, 96 mmol) added, and the mixture stirred overnight. Further methanesulfonyl chloride (2.1 ml) was added and the reaction stirred at room temperature for 5 h. A further portion of methanesulfonyl chloride (2.1 ml) was added and the mixture stirred at room temperature overnight. The pH was adjusted to ˜pH6 by the addition of 2M hydrochloric acid. The mixture was then extracted with dichloromethane (2×150 ml) the combined organic layers were dried using a hydrophobic frit and the solvent removed in vacuo. The residue was suspended in methanol (200 ml) and 2M sodium hydroxide (50 ml) added. The mixture was stirred for 1 h and then the solvent removed in vacuo. The residue was dissolved in water (250 ml) and extracted with dichloromethane (150 ml). The aqueous layer was then acidified and the resulting precipitate collected by filtration. The solid was air dried overnight to give the title compound as an off white solid (13.45 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16](Cl)(Cl)=[S:17]>O1CCOCC1.O>[CH3:9][S:8][C:6]1[CH:7]=[C:2]([N:1]=[C:16]=[S:17])[C:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:5]=1
Reactant: CSc1ccc(-c2ccccc2)c(N)c1
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: CSc1ccc(-c2ccccc2)c(N=C=S)c1

Procedure:
Reaction of 2-amino-4-methylthiobiphenyl (10.8 g) with thiophosgene (4.6 ml) in a mixture of dioxan (10 ml) and water (200 ml) at 10° C. and then at ambient temperature for 15 hours yielded 4-methylthio-2-biphenylylisothiocyanate as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[CH3:15][N:16]=[C:17]=[S:18]>C(O)C>[CH3:15][NH:16][C:17](=[S:18])[NH:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CN=C=S
Reactant: Nc1ccc(Cc2ccccn2)cc1
Solvent: CCO
Product: CNC(=S)Nc1ccc(Cc2ccccn2)cc1
Yield: 77.4 %

Procedure:
A solution of 2-(4-aminobenzyl)pyridine (3.8 g) and methyl isothiocyanate (2.0 g) in ethanol (100 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave a residue which was triturated with diethyl ether to give a precipitate. The precipitate was collected by filtration and dried to give 2-[4-(3-methylthioureido)benzyl]pyridine (4.11 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([CH2:8][CH3:9])[CH:7]=1.[CH3:15][CH:16]1OC(C)OC(C)O1>C(OC(=O)C)(=O)C>[CH3:2][C:3]1[NH:4][C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([CH2:8][CH3:9])[C:7]=1[CH2:15][CH3:16]
Reactant: CCOC(=O)c1[nH]c(C)cc1CC
Reactant: CC1OC(C)OC(C)O1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1[nH]c(C)c(CC)c1CC
Reaction time: 0.5 h
Yield: 20 %

Procedure:
Acetic anhydride (20 ml) was stirred into 5 ml of concentrated hydrochloric acid with cooling. 2-Methyl-4-ethyl-5-carbethoxypyrrole (0.004 mol), paraldehyde (0.008 mol), and zinc amalgam (20 mesh, 10 g) were added at 25° C. and the mixture was stirred 1/2 h. The solution was decanted into 200 ml of water, this was made alkaline with ammonia and the crude product was filtered off. It was purified by sublimation, m.p. 76°-77° C. (lit. 75° C.). Yield 20%.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:12]([O:21][CH2:22][CH3:23])(=[O:20])[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:14]>>[O:11]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:13]([OH:14])([C:12]([O:21][CH2:22][CH3:23])=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C1CCCc2ccccc21
Reactant: CCOC(=O)C(=O)C(=O)OCC
Product: CCOC(=O)C(O)(C(=O)OCC)C1CCc2ccccc2C1=O
Temperature: 100 °C
Yield: 70.4 %

Procedure:
A mixture of the required tetralone (0.01 mol) and diethyl mesoxalate (0.014 mol) was heated at 100° C. for 12 h. After cooling, the reaction mixture was purified by silica gel chromatography, eluting with cyclohexane/ethyl acetate (8/2), to give the white crystals. Yield 70.4%. ESI-MS: m/z 321.1 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([N+:29]([O-])=[O:30])=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([NH:29][OH:30])=[CH:17][CH:18]=3)[N:13]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)c3ccc([N+](=O)[O-])cc3n2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)c3ccc(NO)cc3n2)cc1

Procedure:
To a solution of [2-(4-acetamido-phenylsulfanyl)-7-nitroquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (147 mg, 3.38.10−4 mol) in methanol (5 mL) is added Pd/C 10% (40 mg) and the reaction mixture is treated with hydrogen at balloon pressure at 45° C. for 20 hours. The catalyst is filtered through a pad of celite which is then washed with dilute HCl. The combined yellow filtrate is evaporated and the resulting solid residue is crystallized from methanol to afford the desired [2-(4-acetamido-phenylsulfanyl)-7-hydroxyaminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [I-].[CH2:2]([N+:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7]([CH3:8])=[CH:6][CH:5]=1)[CH3:3].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[N+:25]([O-:27])=[O:26].C(N(C(C)C)CC)(C)C>C(#N)C>[N+:22]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:25]([O-:27])=[O:26])[C:16]=1[CH:8]=[C:7]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:2][CH3:3])[CH:5]=[CH:6]1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: CC[n+]1ccc(C)c2ccccc21
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN1C=CC(=Cc2c([N+](=O)[O-])cccc2[N+](=O)[O-])c2ccccc21
Reaction time: 8 h
Yield: 25 %

Procedure:
1-Ethyllepidinium iodide (3.0 g., 10 mmole) and 1-chloro-2,6-dinitrobenzene (2.5 g., 12 mmole) are warmed in acetonitrile (50 ml.) and diisopropylethylamine (2.6 g., 20 mmole) is added. The resulting dark mixture is aligned to cool and stand overnight. The precipitate of dye is filtered off and washed with acetonitrile and ether. On recrystallization from acetonitrile, 25% yield (0.85 g.) of purified dye is obtained with a m.p. of 45°-155° C. dec.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:16](=[O:33])[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si](C(C)(C)C)(C)C)[CH:20]=2)=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[OH:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][NH:17][C:16]([C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=1)=[O:33]
Reactant: COC(=O)c1sc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1cccc(O)c1)c1cc(-c2ccccc2)c(C(=O)O)s1

Procedure:
A mixture of 5-[3-(tert-Butyl-dimethyl-silanyloxy)-benzylcarbamoyl]-3-phenyl-thiophene-2-carboxylic acid methyl ester (180 mg, 0.37 mmol), lithium hydroxide monohydrate (310, mg, 7.47 mmol), THF (4 mL) and water (2 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 140 mg (100%). MS m/e 354.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:6]=[C:7]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([Cl:19])[CH:12]=3)[CH:8]=[N:9][CH:10]=2)[CH2:4][CH2:3]1.[CH2:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21]>C(Cl)Cl>[Cl:19][C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]([C:2]3([NH:1][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[CH2:3][CH2:4]3)[CH:10]=[N:9][CH:8]=2)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: CCS(=O)(=O)Cl
Reactant: N#Cc1ccc(-c2cncc(C3(N)CC3)c2)cc1Cl
Solvent: ClCCl
Product: CCS(=O)(=O)NC1(c2cncc(-c3ccc(C#N)c(Cl)c3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-(1-aminocyclopropyl)pyridin-3-yl)-2-chlorobenzonitrile (70 mg, 0.26 mmol) in DCM (3 mL) at room temperature was added TEA (0.109 mL, 0.779 mmol) and EtSO2Cl (74 μL, 0.779 mmol) dropwise, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, re-dissolved in DMF (3 mL) and filtered. The filtrate was purified by Xbridge Phenyl followed by Xbridge C18 eluting with 20-80% ACN-water gradient to give N-(1-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)cyclopropyl)ethanesulfonamide. HRMS: (ESI) m/z 362.0712 [(M+H)+ Calcd for C17H16ClN3O2S 362.0725]. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.3 Hz, 3H), 1.32-1.38 (m, 2H), 1.49-1.54 (m, 2H), 2.90 (q, J=7.4 Hz, 2H), 7.60 (dd, J=8.1, 1.8 Hz, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.79 (d, J=8.1 Hz, 1H), 8.01 (t, J=2.3 Hz, 1H), 8.67 (d, J=2.3 Hz, 1H), 8.72 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][N:9]=2)[CH:3]=1.Cl.[CH2:18]([NH2:21])[C:19]#[CH:20].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([NH:21][CH2:18][C:19]#[CH:20])=[O:16])[CH:11]=[CH:10][N:9]=2)[CH:3]=1
Reactant: C#CCN
Reactant: Cc1ccnc(-c2cc(C(=O)O)ccn2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNC(=O)c1ccnc(-c2cc(C)ccn2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4′-Methyl-2,2′-bipyridine-4-carboxylic acid (0.22 g, 1 mmol), propargylamine hydrochloride (0.092 g, 1 mmol), HOBt (0.15 g, 1 mmol) and DIPEA (0.21 ml) were dissolved in dry DMF (15 ml) and cooled to 0° C. DCC (0.25 g, 1.2 mmol) was dissolved in DMF (3 ml) and added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight. DCU was filtered off and solvent was removed by vacuum distillation. The remaining solid compound was dissolved in ethyl acetate and washed with NaHCO3(5%), 0.5 N HCl, brine and dried over sodium sulfate. Solvent was removed by rotary evaporator and the compound was purified by column chromatography using 2% methanol in chloroform as eluent afforded 0. 19 g (76%). FAB-MS: M.W. 251 [M+]; NMR assigned.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[CH:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: O=Cc1cccnc1
Agent: [Na+]
Agent: [OH-]
Product: N#CC(=Cc1cccnc1)c1ccc(Cl)cc1

Procedure:
This intermediate (157 g.) was prepared using the procedure described in Example 12a except using 110.0 g. (0.738 mole) of 4-chlorobenzyl cyanide, 81.0 g. (0.74 mole) of 3-pyridinecarboxaldehyde, and 40 ml. of 10% aqueous sodium hydroxide.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]3=[N:23][C:24](=[O:26])[CH3:25])[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]2=[N:23][C:24](=[O:26])[CH3:25])[CH2:12][CH2:13]1
Reactant: CC(=O)N=c1[nH]c2ccccc2n1C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)N=c1[nH]c2ccccc2n1C1CCNCC1

Procedure:
A mixture of 12 parts of N-{1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-benzimidazol-2-ylidene}acetamide and 120 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off over hyflo and the filtrate is evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and 2-propanol. The product is filtered off and recrystallized from a mixture of ethanol and 2,2'-oxybispropane, yielding 2.6 parts of N-[1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-ylidene]acetamide; mp. 164.5° C.
Reaction SMILES: [C:1]1([C@H:7]2[C:12](=[O:13])[O:11][CH2:10][CH2:9][N:8]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[F:35][C:36]([F:51])([F:50])[C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:40](Cl)=[O:41]>C1COCC1>[F:35][C:36]([F:50])([F:51])[C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:47])[F:48])[CH:45]=1)[C:40]([O:13][C@H:12]1[O:11][CH2:10][CH2:9][N:8]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:41]
Reactant: O=C1OCCN(Cc2ccccc2)[C@H]1c1ccccc1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O[C@H]1OCCN(Cc2ccccc2)[C@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.75 h
Yield: 79.7 %

Procedure:
A solution of 2.67 g (10.0 mmol) of 3-(S)-phenyl-4-benzyl-2-morpholinone (from Example 14) in 40 mL of dry THF was cooled to -78° C. The cold solution was treated with 12.5 mL of 1.0M L-Selectride®, solution in THF, maintaining the internal reaction temperature below -70° C. Alternatively, only a 6% excess of L-Selectride® may be required. The resulting solution was stirred cold for 45 minutes and the reaction was charged with 3.60 mL (20.0 mmol) of 3,5-bis(trifluoro-methyl)benzoyl chloride. The resulting yellow mixture was stirred cold for 30 minutes and the reaction was quenched with 50 mL of saturated aqueous sodium bicarbonate solution. Alternatively, acetic acid may be used for the quench. The quenched mixture was partitioned between 300 mL of ether and 50 mL of water and the layers were separated. The organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 300 mL of ether; the extract was dried and combined with the original organic layer. The combined organics were concentrated in vacuo. Flash chromatography on 150 g of silica gel using 37:3 v/v hexanes/ether as the eluant afforded 4.06 g (80%) of the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=1.O.[C:31]([OH:35])(=[O:34])[CH:32]=O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]2[C:7]=1[CH:32]([C:31]([OH:35])=[O:34])[N:10]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:18][CH:19]=1)(=[O:13])=[O:12])[CH2:9][CH2:8]2
Reactant: O=CC(=O)O
Reactant: COc1ccc(Br)cc1CCNS(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(Br)c2c1CCN(S(=O)(=O)c1ccc(Oc3ccc(F)cc3)cc1)C2C(=O)O
Reaction time: 12 h
Yield: 92.1 %

Procedure:
0.81 g (1.7 mmol) of N-[2-(5-bromo-2-methoxyphenyl)ethyl]-4-(4-fluorophenoxy)-benzenesulfonamide (crude product, 21A) is stirred with 0.32 g (3.4 mmol) of glyoxylic acid monohydrate in 10 ml of trifluoroacetic acid at room temperature. After 12 hours, the mixture is poured onto ice and extracted with dichloromethane. Drying with MgSO4 and concentration result in 0.84 g of the title compound which can be reacted further without further purification.
Reaction SMILES: CS([C:5]1[O:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[C:14]=3[CH:29]=2)=[N:8][N:9]=1)(=O)=O.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:26][C:25]([F:28])([F:27])[O:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[C:14]3[CH:29]=[C:10]([C:7]4[O:6][C:5]([N:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[N:9][N:8]=4)[CH:11]=[CH:12][C:13]=3[O:17][CH:16]=2)=[CH:19][CH:20]=1
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3occ(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Product: FC(F)(F)Oc1ccc(-c2coc3ccc(-c4nnc(N5CCNCC5)o4)cc23)cc1
Yield: 20 %

Procedure:
In the same manner as in Example 110 and using 2-(methylsulfonyl)-5-[3-[4-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole instead of 2-(2,3-dihydro-1-benzofuran-5-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole and using piperazine instead of 3-fluorobenzylalcohol, the title compound (yield 20%) was obtained as colorless crystals.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C[Si](N[Si](C)(C)C)(C)C.[C:19]([O:22][CH2:23]OC)(=O)C>FC(F)(F)S(O)(=O)=O.C(O)(C)C>[CH3:19][O:22][CH2:23][N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: COCOC(C)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC(C)O
Product: COCn1cc(C)c(=O)[nH]c1=O
Temperature: 90 °C
Yield: 86.1 %

Procedure:
A mixture of thymine (100 g, 0.79 mol), trifluoromethanesulfonic acid (2 mL, 20 mmol) and HMDS (418 mL, 1.98 mol) was heated 16 hours with stirring at 90° C. and briefly at reflux and then distilled in vacuo at 80° C. to remove the excess HMDS. The mixture was treated with trifluoromethanesulfonic acid (1.5 mL, 20 mmol) and then methoxymethyl acetate (88 mL, 0.89 mol) was added at a rate such that the reaction temperature did not exceed 95° C. The mixture was heated 20 minutes at 70° C. and then distilled in vacuo to remove the trimethysilyl acetate formed as byproduct. The reaction mixture was poured into isopropanol (800 mL) and stirred 18 hours. The solids were collected, washed with ethyl acetate and dried to give 1-methoxymethyl-5-methyl-2,4(1H,3H)-pyrimidinedione (116 g, 0.68 mol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH:15]=O)=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:29]([NH:32][CH3:33])([CH3:31])[CH3:30]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][N:32]([CH:29]([CH3:31])[CH3:30])[CH3:33])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C=O)c2cc(F)ccc2n1Cc1cccc2ccccc12
Reactant: CNC(C)C
Product: CCOC(=O)c1c(CN(C)C(C)C)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
5-Fluoro-3-formyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (from Example 76.1.) was reacted with i-propylmethyl amine as described in Example 86.1. to give 5-fluoro-3-[(isopropyl-methyl-amino)-methyl]-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a colorless solid. MS: 403.5 ([M−H]−).
Reaction SMILES: [CH:1]([N:4]=[C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:8](=[O:17])[CH:7]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[S:6]1)([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([CH:7]2[S:6][C:5](=[N:4][CH:1]([CH3:3])[CH3:2])[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:8]2=[O:17])=[CH:23][CH:22]=1
Reactant: CC(C)N=C1SC(c2ccc([N+](=O)[O-])cc2)C(=O)N1Cc1ccccn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)N=C1SC(c2ccc(N)cc2)C(=O)N1Cc1ccccn1
Reaction time: 20 h

Procedure:
A solution of 2-isopropylimino-5-(4-nitrophenyl)-3-pyridin-2-ylmethyl-thiazolidin-4-one (4.6 g, 12.4 mmol) in dry methanol (50 ml) was subjected to hydrogenation at slightly above atmospheric pressure (balloon) room temperature for 20 h using Pearlman's catalyst (1.0 g). After 20 h at room temperature, additional catalyst (0.5 g) was added and the suspension was hydrogenated for an additional 24 h. When the reaction was judged complete by LC analysis, the mixture was suction-filtered through Celite and concentrated in vacuo to afford the title compound as a yellowish-tan foam which was used without further purification: 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J=4.2 Hz, 1H), 7.61–7.57 (m, 1H), 7.21–7.16 (m, 1H), 7.18 (d, J=8.3 Hz, 2H), 7.14–7.12 (m, 1H), 6.63 (d, J=8.6 Hz, 2H), 5.15 (s, 1H), 5.08 (s, 2H), 3.85–3.60 (br m, 2H), 3.50–3.42 (m, 1H), 1.09–1.06 (m, 6H); MS (ESI) m/z=341.2 (MH+); HPLC rt 1.07 min. (3 min. grad.); Purity (83.5%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:21]2[CH2:26][C:25](C)([CH3:27])[CH2:24][C:23](C)(C)[CH2:22]2)[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](OC)=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.CC1[C:36](B(O)O)=[C:35](C)[O:34][N:33]=1.C([O-])([O-])=O.[Na+].[Na+]>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.C1COCC1.O>[C:21]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([CH3:17])=[N:33][O:34][C:35]=3[CH3:36])=[CH:11][CH:10]=2)[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:26][CH2:25][CH2:27][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1noc(C)c1B(O)O
Reactant: COC(=O)CCc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Yield: 114.7 %

Procedure:
The procedure described for 202 was followed. A round-bottomed flask was charged with 4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (9) (0.100 g, 0.28 mmol), PdCl2(PPh3)2, (0.020 g, 0.028 mmol), (3,5-dimethyl-4-isoxazolyl)boronic acid (0.079 g, 0.56 mmol), Na2CO3 (0.060 g, 0.56 mmol), and THF/H2O (5 mL, 4:1). The reaction mixture was refluxed for 10 h. Standard workup and purification by flash silica gel chromatography provided 0.120 g (78%) of the title compound 206 as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 9.28 (s, 1H), 7.28 (d, J=6.00 Hz, 2H), 7.18 (d, J=6.0 Hz, 2H), 6.94 (d, J=6.6 Hz, 2H), 6.67 (d, J=6.3 Hz, 2H), 2.37 (s, 3H), 2.23-2.22 (br, m, s, 4H), 1.52 (br s, 8H). LCMS (ESI): m/z 372 (M−H)−.