Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[S:4].[OH:7][CH2:8][C:9](O)=O>O>[NH2:6][N:5]1[C:3]([SH:4])=[N:2][N:1]=[C:9]1[CH2:8][OH:7]
Reactant: NNC(=S)NN
Reactant: O=C(O)CO
Solvent: O
Product: Nn1c(S)nnc1CO
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
A mixture of 10.6 g (0.1 mole) of thiocarbohydrazide and 25.0 g (0.33 mole) of hydroxyacetic acid were heated and stirred at 130° C. for 20 minutes. The mixture is cooled to room temperature and diluted with 25 ml of water. It is then cooled for 24 hours at 11° C., yielding 7.0 g of crystals. The latter are recrystallized from chloroform/methanol, affording 4.5 g of solvated product. The product is dried in vacuo, affording 2.0 g of pale yellow crystals of 4-amino-5-mercapto-4H-1,2,4-triazole-3-methanol. m.p. 150.5°-151.5° C. When the reaction is repeated, using a longer heating time, (1 hour at 125° C.), and is followed by recrystallization from methanol/water, a higher yield of the same product is obtained (80% ).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:32]=[CH:31][C:21]3[NH:22][C:23]([CH2:25][C:26]([O:28]CC)=O)=[N:24][C:20]=3[CH:19]=2)[CH2:14][CH2:13]1.[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:39]=1[C:40]#[N:41]>C1COCC1>[NH2:41][C:40]1[C:39]2[C:34](=[CH:35][N:36]=[CH:37][CH:38]=2)[NH:33][C:26](=[O:28])[C:25]=1[C:23]1[NH:22][C:21]2[CH:31]=[CH:32][C:18]([N:15]3[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]3)=[CH:19][C:20]=2[N:24]=1
Reactant: N#Cc1ccncc1N
Reactant: CCOC(=O)Cc1nc2cc(N3CCN(C)CC3)ccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc3[nH]c(-c4c(N)c5ccncc5[nH]c4=O)nc3c2)CC1
Reaction time: 8 h

Procedure:
LiHMDS (3.6 eq) was added to ethyl [5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]acetate (1.0 eq) and 3-aminopyridine-4-carbonitrile (1.0 eq) in THF at 0° C. The reaction was stirred overnight. The resulting mixture was quenched with an aqueous saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a green solid. The crude material was washed successively with CH2Cl2 and MeOH and then was purified by reverse phase HPLC to provide the desired product. LC/MS m/z 376.3 (MH+), Rt 1.70 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:30][Si](C)(C)C>C(Cl)Cl.CN(C)C=O.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH2:30])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(N)=O)cc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67.7 %

Procedure:
A mixture of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (400 mg, 1.07 mmol) in methylene chloride (4 mL) cooled to 0° C. was treated with N,N-dimethylformamide (2 drops) followed by oxalyl chloride (100 μL, 1.18 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 1 h. The resulting reaction mixture was then treated dropwise with 1,1,1,3,3,3-hexamethyldisilazane (680 μL, 3.21 mmol) and subsequently stirred at 25° C. for 15 h. The reaction mixture was then diluted with methylene chloride (20 mL) and methanol (20 mL). The organic layer was washed with a 5% aqueous sulfuric acid solution (1×40 mL) and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (271 mg, 68%) as a white foam. The white foam was used without further purification: mp 60-63° C.; EI-HRMS m/e calcd for C15H20BrNO3S (M+) 373.0347, found 373.0348.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8](O)=[O:9].C(Cl)(=O)C([Cl:18])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8]([Cl:18])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(C(=O)Cl)c1

Procedure:
A mixture of 5-methoxy-2-nitrobenzoic acid (15.8 g, 0.08 mol), oxalyl chloride (25 g, 0.197 mol) and N,N-dimethylformamide (2 drops) is stirred at reflux for 4 hours, cooled, stirred at room temperature under nitrogen for several days and concentrated in vacuo to give the title product as a yellow oil which is identified by 1HNMR spectral analysis.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.[CH2:15]([NH2:28])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27].[OH-:29].[K+]>C(Cl)CCl>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:28][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([O:29][C:2]([F:1])([F:13])[F:14])=[CH:5][CH:6]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: NCCCCCCCCCCCCN
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: ClCCCl
Product: O=C(NCCCCCCCCCCCCNC(=O)c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1

Procedure:
m.p. 158°-159° C., 11.3 g., was prepared as in Example 1 using 24.8 g. of 4-trifluoromethoxybenzoyl chloride in 150 ml. of ethylene dichloride, 10.0 g. of 1,12-dodecanediamine, 60 ml. of 10% aqueous potassium hydroxide solution, 350 ml. of ethylene dichloride and recrystallization twice from ethanol and once from isopropyl alcohol.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Mg].II.BrC1SC2C=CC=CC=2C=1.CON(C)[C:27](=[O:32])[CH2:28][CH:29]([CH3:31])[CH3:30]>O1CCCC1>[S:6]1[CH:7]=[CH:8][C:4]2[CH:3]=[C:2]([C:27](=[O:32])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH:10]=[CH:9][C:5]1=2
Reactant: Brc1ccc2sccc2c1
Reactant: CON(C)C(=O)CC(C)C
Agent: Brc1cc2ccccc2s1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)CC(=O)c1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A few drops of a solution of 5-bromobenzo[b]thiophene (2 g; prepared in a manner similar to that described in Example 21) in tetrahydrofuran (10 ml) was added under nitrogen to a mixture of magnesium turnings (0.24 g), tetrahydrofuran (2 ml) and a few small crystals of iodine, heat was applied to initiate the reaction, then the remainder of the bromobenzo[b]thiophene solution was added at reflux temperature over 10 minutes. When the addition was complete, the mixture was heated under reflux for 1 hour, then a solution of N-methoxy-N,3-dimethylbutyramide (1.43 g) in tetrahydrofuran (10 ml) was added. The mixture was heated under reflux for 1 hour, cooled to ambient temperature, then quenched by the addition of 2M hydrochloric acid (25 ml) and stirred at ambient temperature for 5 minutes. The majority of the tetrahydrofuran was removed in vacuo, then water (25 ml) was added to the residue and the product was extracted into ethyl acetate (2×25 ml). The extracts were washed with water (25 ml) and saturated aqueous sodium chloride solution (25 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography over silica using petroleum ether (b.p. 60-80° C.) followed by a 95:5 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluants. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-5-yl)-3-methylbutan-1-one (1.25 g) as an off-white solid which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6](OC)=O)#[N:2].[CH3:13][C:14]([CH3:16])=[O:15].[CH3:17][O-:18].[Na+]>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[CH2:6][C:17](=[O:18])[CH2:13][C:14](=[O:15])[CH3:16])#[N:2]
Reactant: C[O-]
Reactant: COC(=O)c1ccnc(C#N)c1
Reactant: CC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(=O)Cc1ccnc(C#N)c1
Temperature: 35 °C
Yield: 51 %

Procedure:
To a solution of methyl 2-cyanoisonicotinate (20.0 g, 0.126 mol) in 250 mL THF was added acetone (30.6 mL, 0.42 mol). The solution was warmed to 35° C. and sodium methoxide (7.15 g, 0.132 mol) was added portionwise over 20 minutes. The mixture was heated at reflux for 16 hours. The solvent was removed in vacuo and the residue was dissolved in water, acidified to pH=6 with acetic acid. The aqueous phase was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to yield 13.0 g (58% yield) of product as a brown solid, which was used in next step without purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C@@H:16]([CH2:61][OH:62])[C:17]([NH:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH:58]=[CH:59][CH:60]=1)[CH2:26][O:27][CH2:28][C@H:29]([NH:34][C:35](=[O:57])[CH2:36][N:37]1[CH:41]=[C:40]([CH2:42][O:43][C:44]2[CH:56]=[CH:55][C:47]3[N:48]=[C:49]([S:51](=[O:54])(=[O:53])[NH2:52])[S:50][C:46]=3[CH:45]=2)[N:39]=[N:38]1)[C:30]([O:32]C)=[O:31])=[O:18])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C@@H:16]([CH2:61][OH:62])[C:17]([NH:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH:58]=[CH:59][CH:60]=1)[CH2:26][O:27][CH2:28][C@H:29]([NH:34][C:35](=[O:57])[CH2:36][N:37]1[CH:41]=[C:40]([CH2:42][O:43][C:44]2[CH:56]=[CH:55][C:47]3[N:48]=[C:49]([S:51](=[O:53])(=[O:54])[NH2:52])[S:50][C:46]=3[CH:45]=2)[N:39]=[N:38]1)[C:30]([OH:32])=[O:31])=[O:18]
Reactant: COC(=O)[C@H](COCc1cccc(OCCNC(=O)[C@H](CO)NC(=O)OC(C)(C)C)c1)NC(=O)Cn1cc(COc2ccc3nc(S(N)(=O)=O)sc3c2)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CO)C(=O)NCCOc1cccc(COC[C@H](NC(=O)Cn2cc(COc3ccc4nc(S(N)(=O)=O)sc4c3)nn2)C(=O)O)c1
Reaction time: 0.5 h

Procedure:
To a 10 mL vial with magnetic stir bar was added DCM (0.5 mL) and TFA (0.5 mL). To this, compound 70 was added and let to react for 30 min. After the completion of the reaction, solvents were removed in vacuo, THF was added (0.2 mL) followed by aq. LiOH (0.4 mL) and the reaction stirred for 30 min. After completion of the reaction, THF was removed and the crude residue was purified by HPLC to afford VM3163 (33%) as a colorless solid. LCMS for C27H32N8O10S2, calc'd: 692.17. found: 693.0 (M+H).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([O:10]C)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:13][S:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:25][CH:26]([OH:29])[CH2:27][OH:28].[CH2:30](Cl)Cl>CCOCC>[C:1]1([CH3:12])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[OH:29][CH:26]([CH2:27][OH:28])[CH2:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH2:16][CH2:15][S+:14]([CH3:30])[CH3:13]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CSCCOc1ccccc1OCC(O)CO
Reactant: ClCCl
Solvent: CCOCC
Product: C[S+](C)CCOc1ccccc1OCC(O)CO
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.1 %

Procedure:
A 7 g quantity of methyl p-toluenesulfonate was added to 2.58 g of 2-{2-(2,3-dihydroxypropoxy)phenoxy}ethyl methyl sulfide and 5 ml of methylene chloride and the mixture was stirred at room temperature for 24 hours. Ether was added to the reaction mixture. The oily product precipitated was separated and purified with ethanol-ether, affording 4.01 g of 2-{2-(2,3-dihydroxypropoxy)phenoxy}ethyldimethylsulfonium p-toluenesulfonate in 90.1% yield.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)(=[O:3])[CH3:2].[Cl:21]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:8]([Cl:21])=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccc2c(c1)NC(=O)C1CCCC21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(=O)OCCc1cc2c(cc1Cl)C1CCCC1C(=O)N2
Yield: 82.3 %

Procedure:
A solution of 400 mg (1.5 mmol) of 7-acetoxyethyl-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one and 193 mg (1.5 mmol) of N-chlorosuccinimide in 40 ml of DMF is heated for 6 days to 100° C. The batch is poured onto ice water and extracted with ethyl acetate. The organic phase is washed with 10% sulfuric acid and water, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 380 mg of product.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[C:1]1([CH:7]([CH3:11])[C:8]([Cl:20])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C(=O)O)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C(=O)Cl)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-phenylpropionic acid (0.36 mL; 2.6 mmol) and a catalytic amount of dry dimethylformamide (ca. 10 μL) in 3.0 mL of dry methylene chloride under nitrogen at room temperature was added oxalyl chloride (0.34 mL; 3.9 mmol) dropwise. After 30 minutes, the mixture was concentrated in vacuo and used immediately for Step 2.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:22]#[N:23])[CH:17]=[CH:18][C:19]=1[Cl:20].[CH2:33]([O:35][C:36](=[O:39])[CH2:37]Br)[CH3:34]>O1CCCC1.O>[C:22]([C:21]([C:16]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=1)([CH2:24][CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:37][C:36]([O:35][CH2:33][CH3:34])=[O:39])#[N:23]
Reactant: CCOC(=O)CBr
Reactant: N#CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC(C#N)(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diisopropylamine (25.9 ml, 1 mol. equiv.) in tetrahydrofuran (200 ml) at −78° C. under nitrogen was added n-butyllithium (73.9 ml of a 2.5M solution, 1 mol. equiv.). The solution was allowed to warm to room temperature over two hours. A solution of 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butanenitrile (PREPARATION 17) (58 g, 158 mmol) in tetrahydrofuran (200 ml) was then added and the solution was stirred for one hour. A solution of ethyl-2-bromoacetate (20.5 ml, 1 mol. equiv.) in tetrahydrofuran (50 ml) was then added and the reaction was heated to reflux for two hours. Water (10 ml) was then added and the solution was concentrated under reduced pressure. Water (300 ml) and brine (300 ml) were added and the mixture was extracted with ethyl acetate (2×300 ml). The combined organic layers were washed with water (2×300 ml), dried over anhydrous magnesium sulphate, filtered and the solvent was removed under reduced pressure. Chromatography using silica gel, eluting with diethyl ether:hexane using gradient elution (4:1 to 1:1 by volume), gave the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH2:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1.O>N1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:16]([CH:13]3[CH2:15][CH2:14]3)=[O:17])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cc2ccc(Br)cc2cn1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a cold solution (below 0° C.) of 7-bromoisoquinolin-3-amine (20 g, 0.09 mol) in pyridine (150 mL) was added cyclopropanecarbonyl chloride (11.2 g, 0.108 mol) dropwise. The mixture was stirred at room temperature overnight. After water (500 mL) was added, the reaction mixture was stirred for 30 min. Solid was collected by filtration and washed with water to give the desired product (21 g, 80.4%). LCMS (ESI): RT (min)=1.009, M+H+=290.7, method=A. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.10 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.67 (d, J=8.8 Hz, 1H), 2.02-2.10 (m, 1H), 0.84-0.79 (m, 4H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[CH2:32][C:33](O)=[O:34]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:33](=[O:34])[CH2:32][C@H:27]5[CH2:28][CH2:29][CH2:30][CH2:31][O:26]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C[C@H]1CCCCO1
Agent: Cl
Product: O=C(C[C@H]1CCCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (20.9 mg, 65.4%), MS (ISP) m/z=457.3[(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.070 mmol) and (R)-2-(tetrahydro-2H-pyran-2-yl)acetic acid
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.P(C#N)(OCC)(OCC)=O.[NH2:23][CH:24]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]([C:35](=[O:52])[C:36]2[CH:41]=[CH:40][C:39]([NH:42][C:43](=[O:51])[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[CH3:50])=[CH:38][CH:37]=2)[CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>CN(C)C=O>[NH2:8][CH2:9][C:10]([NH:23][CH:24]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]([C:35](=[O:52])[C:36]2[CH:41]=[CH:40][C:39]([NH:42][C:43](=[O:51])[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[CH3:50])=[CH:38][CH:37]=2)[CH2:27][CH2:26][CH2:25]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N)c3ccccc32)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC(=O)CN)c3ccccc32)cc1
Reaction time: 0.5 h
Yield: 8 %

Procedure:
To a solution of t-butoxycarbonylglycine (0.84 g) in dimethylformamide (20 ml) are added diethyl cyanophosphate (0.73 ml) and 5-amino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.74 g), and further thereto is added triethylamine (1.8 ml) under ice-cooling. The mixture is stirred for 30 minutes, and then stirred at room temperature overnight. The reaction solution is concentrated and water is added to the resulting residue. The precipitated crystal is collected by filtration, washed with water, and recrystallized from ethyl acetate to give 5-(2-aminoacetylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (E) (0.16 g). Separately, the filtrate is concentrated and purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1), and recrystallized from diethyl ether to give 5-[2-(t-butoxycarbonylamino)acetylamino]-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (F) (0.19 g).
Reaction SMILES: [OH-:1].[K+].C(P(C(C)(C)C)C1C=CC=CC=1[C:14]1[C:19](C(C)C)=[CH:18][C:17](C(C)C)=[CH:16][C:15]=1[CH:26](C)C)(C)(C)C>C1(C)C=CC=CC=1.CCOC(C)=O.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]>[CH2:26]([O:1][CH2:26][C:15]1[CH:14]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:14]=1
Reactant: [OH-]
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 1.25 h

Procedure:
Method C) Compound 10 was dissolved in toluene (8 mml/mmol) and to the solution was added potassium hydroxide (2 eq, 11.7N) and the solution was degassed. To the solution was added properly substituted benzyl bromide (1.1 eq), 2-di-t-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.06 eq) and tris-(dibenzylideneaceton)-dipalladium(0) (0.03 eq). The mixture was stirred at 60° C. for 1.25 hrs. The mixture was cooled to room temperature, diluted with EtOAc and washed with 5% NaHCO3 solution (10 ml/mmol). The organic layers were dried on MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give compound 12 in yields varying from 30-80%.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=2[S:5][CH2:4][C:3]1=[O:13].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl.S(Cl)(Cl)(=O)=O>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=2[S:5][CH:4]([C:17]2[CH:18]=[CH:19][C:14]([OH:20])=[CH:15][CH:16]=2)[C:3]1=[O:13]
Reactant: Oc1ccccc1
Reactant: Cc1ccc2c(c1)SCC(=O)N2C
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: Cc1ccc2c(c1)SC(c1ccc(O)cc1)C(=O)N2C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
To a stirred solution of 3,4-dihydro-4,7-dimethyl-3-oxo-2H-1,4-benzothiazine (11.0 g) in methylene chloride (50 ml), sulfuryl chloride (4.8 ml) is added under ice-cooling. After the addition, the mixture is stirred for 15 minutes under ice-cooling. Phenol (7.0 g) is added to the mixture, and the mixture is stirred for 45 minutes and concentrated in vacuo. Ether is added to the residue and the separated crystals are collected by filtration to give 11.3 g (69.4%) of the titled compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[C:4](F)[C:3]=1[F:11].[C:12](=[O:15])([O-])[O-].[K+].[K+].[OH:18][C:19]1[N:23]([CH3:24])[N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1>CN(C=O)C>[CH3:24][N:23]1[C:19]([O:18][C:6]2[C:7]([F:8])=[C:2]([CH3:1])[C:3]([F:11])=[C:4]([O:15][C:12]3[N:23]([CH3:19])[N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[N:5]=2)=[CH:20][C:21]([C:25]([F:28])([F:27])[F:26])=[N:22]1
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: Cc1c(F)c(F)nc(F)c1F
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(F)c(Oc2cc(C(F)(F)F)nn2C)nc(Oc2cc(C(F)(F)F)nn2C)c1F
Temperature: 80 °C
Yield: 79.2 %

Procedure:
A mixture of 4-methyl-2,3,5,6-tetrafluoropyridine (4 g, 24 mmol), potassium carbonate (3.7 g, 26.5 mmol) and 5-hydroxy-1-methyl-3-trifluoromethylpyrazole (4.4 g, 26.5 mmol) in anhydrous DMF (20 ml) is heated to 80° C. overnight. After cooling, the solvent is removed under reduced pressure. Pentane/ethyl acetate (1/2 by volume) is added to the residue and the mixture is washed twice with water. After drying of the organic layer, the solvent is removed and both products are purified by flash chromatography: One obtains 2-(1-methyl-3-trifluoromethylpyrazol.-5-yloxy)-4-methyl-3,5,6-trifluoropyridine (silica gel, pentane/ethyl acetate 1/1 by volume) (1.6 g, 21%) and 2,6-bis(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-3,5-difluoro-4-methylpyridine (silica gel, pentane/ethyl acetate 1/1) (4.8 g, 43% yield, m.p. 101° C.).
Reaction SMILES: [NH2:1][C:2](=C)/[CH:3]=[CH:4]/[C:5](/[NH:8][C:9]1[C:18]2[CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:15](=[O:28])[NH:14][C:13]=2[N:12]=[CH:11][CH:10]=1)=[CH:6]/[CH3:7].[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[C:33]([C:40]([F:43])([F:42])[F:41])[CH:32]=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[C:18]4[CH2:17][N:16]([CH2:19][C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=5)[C:15](=[O:28])[NH:14][C:13]=4[N:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=2)=[O:39])=[C:33]([C:40]([F:41])([F:42])[F:43])[CH:32]=1
Reactant: C=C(N)/C=C/C(=C/C)Nc1ccnc2c1CN(Cc1ccc(OC)cc1)C(=O)N2
Reactant: O=C=Nc1ccc(F)cc1C(F)(F)F
Product: COc1ccc(CN2Cc3c(Nc4ccc(NC(=O)Nc5ccc(F)cc5C(F)(F)F)cc4)ccnc3NC2=O)cc1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 63 using 5-[(Z)-4-amino-1-eth-(E)-ylidene-penta-2,4-dienylamino]-3-(4-methoxy-benzyl)-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one and 4-fluoro-1-isocyanato-2-trifluoromethyl-benzene. LC-MS (M+H=581, obsd.=581).