Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1([CH2:9][CH2:10][NH:11][C:12](=[O:24])[O:13][CH2:14][C:15]2[O:19][N:18]=[C:17]([C:20](=[O:23])[NH:21][CH3:22])[CH:16]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:2][C:3]1([CH2:9][CH2:10][NH:11][C:12](=[O:24])[O:13][CH2:14][C:15]2[O:19][N:18]=[C:17]([C:20](=[O:23])[NH:21][CH3:22])[CH:16]=2)[CH2:4][CH2:5][N:6]([C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)[CH2:7][CH2:8]1
Reactant: CNC(=O)c1cc(COC(=O)NCCC2(C)CCNCC2)on1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNC(=O)c1cc(COC(=O)NCCC2(C)CCN(c3nccc(C(F)(F)F)n3)CC2)on1
Yield: 74.3 %

Procedure:
The process is performed according to the procedure described in Example 12 (step 12.5.). Starting with 0.30 g (0.83 mmol) of 3-methylcarbamoylisoxazol-5-ylmethyl [2-(4-methylpiperidin-4-yl)ethyl]carbamate hydrochloride, 0.23 g (1.25 mmol) of 2-chloro-4-trifluoromethylpyrimidine and 430 μL (2.49 mmol) of N,N-diisopropylethylamine, dissolved in 2.77 mL of acetonitrile, 0.29 g of expected product is obtained in the form of a powder.
Reaction SMILES: [CH3:1][O:2][NH:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][O:21][CH2:22][C:23]#[CH:24].O>C(#N)C>[CH3:1][O:2][N:3]([CH2:20][O:21][CH2:22][C:23]#[CH:24])[S:4]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)(=[O:6])=[O:5]
Reactant: CONS(=O)(=O)c1ccccc1
Reactant: C#CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C#CCOCN(OC)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
0.6 g of N-methoxybenzenesulfonamide was dissolved in 10 ml of acetonitrile, and 0.44 g of potassium carbonate and 0.34 g of chloromethylpropargyl ether were added thereto in this order. The mixture was stirred at room temperature for 4 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried, concentrated, and purified by silica gel column chromatography to obtain 0.7 g of N-methoxy-N-propargyloxymethylbenzenesulfonamide.
Reaction SMILES: Cl.[OH:2][C:3]12[CH2:36][CH2:35][C@@:34]3([CH3:37])[C:29](=[C:30]([CH3:38])[CH2:31][CH2:32][CH2:33]3)[C@H:4]1[O:5][C:6](=[O:28])[CH:7]2[CH2:8][NH:9][CH2:10][CH:11]1[C:15](=[O:16])[O:14][C@H:13]2[C:17]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C:12]12[OH:27])[CH2:21][CH2:20][CH2:19][C:18]=3[CH3:26].[CH2:39]([N:41]=[C:42]=[S:43])[CH3:40]>O1CCCC1>[CH2:39]([NH:41][C:42](=[S:43])[N:9]([CH2:10][CH:11]1[C:15](=[O:16])[O:14][C@H:13]2[C:17]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C:12]12[OH:27])[CH2:21][CH2:20][CH2:19][C:18]=3[CH3:26])[CH2:8][CH:7]1[C:6](=[O:28])[O:5][C@@H:4]2[C:29]3[C@:34]([CH3:37])([CH2:35][CH2:36][C:3]12[OH:2])[CH2:33][CH2:32][CH2:31][C:30]=3[CH3:38])[CH3:40]
Reactant: CCN=C=S
Reactant: CC1=C2[C@H]3OC(=O)C(CNCC4C(=O)O[C@H]5C6=C(C)CCC[C@]6(C)CCC45O)C3(O)CC[C@]2(C)CCC1
Agent: Cl
Solvent: C1CCOC1
Product: CCNC(=S)N(CC1C(=O)O[C@@H]2C3=C(C)CCC[C@@]3(C)CCC12O)CC1C(=O)O[C@H]2C3=C(C)CCC[C@]3(C)CCC12O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound obtained in step 1 of example 55 (200 mg, 0.389 mmole) was dissolved in dry tetrahydrofuran (10 mL) and to it ethyl isothiocyanate (54.22 mg, 0.62 mmole) was added dropwise. The reaction mixture was stirred at room temperature (25° C.) for 3 hours. Reaction mixture was concentrated and crude product was purified by column chromatography (silica gel, 20% ethyl acetate in petroleum ether) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([C:7](=O)C)[CH2:4][O:3]1.C1COCC1.Cl.[NH2:17][OH:18].C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([CH:7]=[N:17][OH:18])[CH2:4][O:3]1
Reactant: CC(=O)[C@@H]1COC(C)(C)O1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC[C@@H](C=NO)O1
Reaction time: 0.33 h
Yield: 97.5 %

Procedure:
To a solution of (S)-1-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanone (10.5 g, 72.8 mmol) in 150 (mL) THF: 60 mL water was added hydroxylamine hydrochloride (5.06 g, 72.8 mmol), and the reaction was stirred for 20 minutes. Na2CO3 (3.78 g, 35.7 mmol) was added and the reaction was stirred overnight. The reaction was extracted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated to afford (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde oxime (10.3 g, 71.0 mmol, 97.4% yield).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.[OH-].[Na+].O>C(O)C.C(O)(=O)C>[O:20]1[CH2:19][CH:18]1[CH2:16][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc2c(OCC3CO3)cccc2[nH]1

Procedure:
4.2 g of 4-hydroxy 2-ethoxycarbonyl indole and 40 ml of epichlorohydrine are dissolved by heating in an inert atmosphere in 40 ml of absolute ethanol then 0.82 g of sodium hydroxide in pellet form is added and the mixture is taken to reflux for 5 hours. Water is added to the reaction mixture and it is neutralized by the addition of acetic acid. The solvents are evaporated in vacuo then extracted with methylene chloride. The organic solution is dried over sodium sulfate and the solvent is evaporated to dryness in vacuo. The residue is chromatographed over a column of silica gel. By elution with the ether-pentane (80-20 vol/vol) mixture, the expected compound is obtained (3.5 g), m.p.: 142°-144° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:11])(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.[CH2:26](S)C.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:11][CH3:26])[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Reactant: CCS
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CCSc1nc(N)nc(-c2cc(OC)c(OC)c(OC)c2)c1C#N

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile, ethyl mercaptan and DBU in DME. EI-MS m/e (%):46 (M+, 100), 315 (52).
Reaction SMILES: [F:1][C:2]([F:17])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].C(S)CCCCCCC>ClCCl>[F:1][C:2]([F:17])([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(F)Cc1ccc(OC)cc1
Agent: CCCCCCCCS
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
To a solution of ethyl 2,2-difluoro-3-(4-methoxyphenyl)propanoate (1.72 g, 7.05 mmol) synthesized according to the method described in Synthesis, vol. 13, pp. 1917-1924 (2000) and aluminum chloride (2.82 g, 21.2 mmol) in dichloromethane (50 mL) was added dropwise 1-octanethiol (2.06 g, 14.1 mmol) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into ice water and the mixture was stirred for 30 min. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (8%-60% ethyl acetate/hexane) to give the title compound (0.90 g, yield 56%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[CH:31][C:7]([O:8][CH:9]([CH3:30])[C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:29])[CH:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[CH3:18])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CN(C)C=O.[Pd]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH:17]([CH3:18])[C:16]([O:15][CH2:14][CH2:13][O:12][C:10](=[O:11])[CH:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:32][CH:31]=2)[CH3:30])=[O:29])=[CH:21][CH:22]=1
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCOC(=O)C(C)Oc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(N)cc1)C(=O)OCCOC(=O)C(C)Oc1ccc(N)cc1
Yield: 72.1 %

Procedure:
2-(4-nitrophenoxy)propionic acid-2-[2-(4-nitrophenoxy)propionyloxy]ethyl ester 49 (50 g, 89.3 mmol) was dissolved in dry dimethylformamide (400 ml) in a pressure vessel, palladium on carbon (5%, 12.5 g) added, and the mixture stirred under an atm. of hydrogen (4 Kg) for 4 hours. The catalyst was removed by filtration and ice water (3 L) was added to the filtrate. Crude 50 was extracted into ethyl acetate, dried over Na2SO4, distilled and purified by column chromatography on silica gel using chloroform as eluant to give pure 50 (25 g, 58%) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]([N:9]([CH3:27])[CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([N:20]([CH3:26])[CH2:21][CH2:22][C:23]([OH:25])=O)=[O:19])[CH2:14][CH2:13]2)=[O:8])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:36][NH2:37]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7](=[O:8])[N:9]([CH3:27])[CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18](=[O:19])[N:20]([CH3:26])[CH2:21][CH2:22][C:23](=[O:25])[NH:37][CH3:36])[CH2:14][CH2:13]2)=[CH:28][CH:29]=1
Reactant: CN(CC[C@H]1CC[C@H](C(=O)N(C)CCC(=O)O)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)CCN(C)C(=O)[C@H]1CC[C@H](CCN(C)C(=O)Oc2ccc(Cl)cc2)CC1
Reaction time: 1.5 h

Procedure:
A solution of 0.088 g (0.20 mmol) of trans-3-[(4-{2-[(4-chloro-phenoxycarbonyl)-methyl-amino]-ethyl}-cyclohexanecarbonyl)-methyl-amino]-propionic acid in 2 mL of CH2Cl2 was treated at RT with 1 drop of DMF, followed by 0.019 mL (0.22 mmol, 1.1 eq) of oxalyl chloride and stirring was continued for 90 min. The solvent was evaporated, the residue was redissolved in 2.5 mL of CH2Cl2 and added to a solution of 0.25 mL (2.00 mmol, 10 eq) of methylamine (33% solution in EtOH) in 2 mL of CH2Cl2 at 0° C. The reaction mixture was stirred at 0° C. for 3/4 h, then partitioned between Et2O (×3)/aqueous 10% KHSO4. The organic phases were washed once with aqueous 10% NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on 20 g silica gel (CH2Cl2:MeOH 98:2 to 95:5) gave 0.042 g (48%) of pure trans-methyl-(2-{4-[methyl-(2-methylcarbamoyl-ethyl)-carbamoyl]-cyclohexyl}-ethyl)-carbamic acid 4-chloro-phenyl ester, MS: 438 (MH+, 1Cl).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH3:9][CH:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CS(O)(=O)=O>C1(C)C=CC=CC=1>[CH3:9][CH:10]([O:5][C:4](=[O:6])[CH2:3][CH2:2][C:1]([O:8][CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:9])=[O:7])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C(O)CCC(=O)O
Reactant: CCCCCCC(C)O
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCC(C)OC(=O)CCC(=O)OC(C)CCCCCC

Procedure:
A mixture of succinic acid (Alfa-Aesar, 149.00 g, 1.26 mol), 2-octanol (Alfa-Aesar, 350.00 g, 2.69 mol), toluene (625 mL), and methanesulfonic acid (Alfa-Aesar, 2.00 g, 21 mmol) was heated to reflux for 6 hours. The water liberated was collected in a Dean Stark trap. The mixture was cooled, washed with saturated sodium bicarbonate (300 mL) and brine (100 mL), and dried over magnesium sulfate. The solvent was removed under vacuum to give a yellow oil that was used without further purification (426.39 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([OH:7])=O.C[Li].[CH3:14]COC(C)=O.Cl>CCOCC>[Br:11][C:9]1[CH:8]=[C:4]([C:5](=[O:7])[CH3:14])[CH:3]=[C:2]([Br:1])[CH:10]=1
Reactant: CCOC(C)=O
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Agent: Cl
Agent: [Li]C
Solvent: CCOCC
Product: CC(=O)c1cc(Br)cc(Br)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3,5-dibromobenzoic acid (2.5 g, 8.9 mmol) in Et2O (30 mL) at 0° C. was added methyllithium (1.6M in Et2O; 12.3 mL, 19.6 mmol) dropwise. The reaction was stirred at 0° C. for 2 hours, and then worked-up with EtOAc and 10% aqueous HCl. The crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:6][CH:5]=1.C1COCC1.CN1CCCC1=O.[CH2:34]([Mg]Br)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>CCOCC>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:5]=[CH:6][C:7]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CCCCCC[Mg]Br
Solvent: CN1CCCC1=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCc1ccc(C(=O)OC)cc1
Reaction time: 0.08 h
Yield: 83 %

Procedure:
A flame-dried two-necked flask is charged under argon with 4-(4-methylbenzenesulfonyloxy)benzoic acid methyl ester (0.50 g, 1.63 mmol), Fe(acac)3 (29 mg, 0.08 mmol), THF (10 mL) and N-methylpyrrolidone (NMP, 0.95 mL). A solution of n-hexylmagnesium bromide (2M in Et2O, 1 mL, 2 mmol) is added via syringe to the resulting red solution, causing an immediate color change to dark brown and finally to violet. The resulting mixture is stirred for 5 min, the reaction is diluted with Et2O and is carefully quenched upon addition of aq. HCl (1M, ca. 10 mL). Work-up followed by flash chromatography of the crude product as described above provides 4-hexylbenzoic acid methyl ester as a colorless syrup (298 mg, 83%). The spectroscopic and analytical data are identical to those compiled above.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]([CH2:10][CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([O:14]C)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>C(O)C.O>[CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:7]([CH2:10][CH:11]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CC(Cc2ccccc2)C(=O)OC)n1Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCc1ncc(CC(Cc2ccccc2)C(=O)O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A mixture of methyl 3-[2-n-butyl-1-benzyl-1H-imidazol- 5yl]-2-benzylpropanoate (0.12 g, 0.31 mmol) in 50% aqueous ethanol (4 mL) containing potassium hydroxide (0.072 g, 1.28 mmol) was stirred at 25° C. for 18 hours. The basic solution was diluted with water (8 mL), and extracted with diethyl ether. The water solution was acidified with aqueous hydrochloric acid solution to pH 4, and the product was extracted into methylene chloride, dried, and concentrated. This crude material was dissolved in acetone and acidified with ethereal hydrochloric acid to give a precipitate. Crystallization from acetone/ether provided 0.07 g of 3-[2-n-butyl-1- benzyl-1H-imidazol-5-yl]-2-benzylpropanoic acid; mp 148°-150° C. (hydrochloride salt).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[I-:10].[Na+].CNCCNC.O>O1CCOCC1.[Cu]I>[F:8][C:7]1[C:2]([I:10])=[N:3][C:4]([CH3:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(F)c(Br)n1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(F)c(I)n1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
To a solution of 2-bromo-3-fluoro-6-methylpyridine (1000 mg, 5.26 mmol) in 1,4-dioxane (16 mL) were added sodium iodide (1580 mg, 10.52 mmol), copper (I) iodide (150 mg, 0.26 mmol), N,N′-dimethylethylenediamine (62 μL, 0.58 mmol) under argon atmosphere. The reaction solution was heated to reflux for 4 hours, cooled to room temperature, and then to the reaction solution was added water. The mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with aqueous citric acid solution and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 3-fluoro-2-iodo-6-methylpyridine (1169 mg, 94%) as a white powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24](C1C=CC=C(C2C=CN=C(C)C=2)C=1)=O)(C)(C)C.[C:41](O)([C:43](F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([C:11]4[CH:10]=[CH:9][N:21]=[C:41]([CH3:43])[CH:12]=4)[CH:15]=3)[CH2:23][C:22](=[O:39])[NH:21][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)c2)ccn1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4ccc(-c5ccccc5F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (2′-fluoro-3-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert-butyl ester (Example M65) (0.47 g, 0.87 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (305 mg, 83%).
Reaction SMILES: [I-].[NH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](Cl)=[C:8](Cl)[N+:9]([CH3:13])=[CH:10]2)=[CH:5][CH:4]=1.[CH3:16][Mg]Cl.O>O1CCCC1>[NH2:2][C:3]1[CH:12]=[C:11]2[CH:6]([CH2:7][CH2:8][N:9]([CH3:13])[CH:10]2[CH3:16])[CH2:5][CH:4]=1
Reactant: C[Mg]Cl
Reactant: C[n+]1cc2cc(N)ccc2c(Cl)c1Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: CC1C2=CC(N)=CCC2CCN1C
Temperature: -78 °C
Reaction time: 18 h

Procedure:
(±) 7-Amino-2-methyl-3,4-dichloroisoquinolinium iodide (0.50 g, 1.7 mmol) was suspended in anhydrous tetrahydrofuran (50 ml) and cooled to −78° C. The cooled solution was treated with methyl magnesium chloride (2.14 ml of a 3M solution in THF, 6.96 mmol), added as a single portion. The reaction was allowed to reach room temperature over 18 h before being poured into water (50 ml). The organic solvent was removed in vacuo and the organic product extracted into dichloromethane. Drying over magnesium sulfate and evaporation in vacuo fuinished the title compound as a pale yellow oil (0.3 g, 98%). For ease of handling the product was converted into a monohydrochloride.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:11]1[C:12]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:13][N:14]([C:16]2([CH2:22][C:23]#[N:24])[CH2:21][CH2:20][NH2+:19][CH2:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].[CH:32]1([C:35](O)=[O:36])[CH2:34][CH2:33]1.CCN(C(C)C)C(C)C.O1P(=O)OP(=O)OP1=O>CN(C=O)C.CS(C)=O>[C:23]([CH2:22][C:16]1([N:14]2[CH:15]=[C:11]([C:8]([NH2:9])=[O:10])[C:12]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:13]2)[CH2:21][CH2:20][N:19]([C:35]([CH:32]2[CH2:34][CH2:33]2)=[O:36])[CH2:18][CH2:17]1)#[N:24]
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC[NH2+]CC1
Reactant: O=C(O)C1CC1
Agent: O=C([O-])C(F)(F)F
Agent: O=[PH]1O[PH](=O)O[PH](=O)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CCN(C(=O)C2CC2)CC1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
4-[4-Carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-1) (20 mg, 0.05 mmol) was diluted with DMF (0.5 mL) and treated with cyclopropanecarboxylic acid (5 mg, 0.06 mmol), DIPEA (0.020 mL, 0.12 mmol) and 1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (0.040 mL, 0.060 mmol). The reaction mixture was heated to 40° C. and allowed to stir for 16 hours. The mixture was then cooled to ambient temperature, diluted with DMSO (1.0 mL), and purified by reverse-phase preparative HPLC (using a gradient elution of 5-95% MeCN/water, with 0.1% v/v NH4OH modifier). Desired fractions were identified, combined and concentrated in vacuo to afford the title compound, Example #34-1. 1H NMR (600 MHz, DMSO-d6): δ 9.09-9.00 (m, 1H), 8.50 (s, 1H), 7.55 (s, 1H), 7.48 (d, J=7.7 Hz, 2H), 7.26-7.17 (m, 2H), 7.15 (s, 1H), 6.80 (m, 1H), 4.09-3.90 (m, 2H), 3.18 (s, 2H), 2.47 (s, 2H), 2.35 (s, 2H), 2.07-1.97 (m, 2H), 1.95-1.87 (m, 1H), 0.74-0.62 (m, 4H).
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[NH:4][C:3]2[CH:8]=[N:9][CH:10]=[CH:11][C:2]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:8]=[N:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=C1COc2ccncc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1cc2c(cn1)NCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
4H-pyrido[4,3-b][1,4]oxazin-3-one (4.3 g, 28 mmol) was dissolved in tetrahydrofuran (140 ml) and then cooled to 0□. 1.0M Lithium aluminum hydride dissolved in tetrahydrofuran (57 ml, 57 mmol) was added thereto dropwise. After stirring for 2 hours at room temperature, 1.4 ml of water, 2.8 ml of 10% aqueous solution of sodium hydroxide, and 4.2 ml of water were added in this order under stirring. After filtering precipitates, the filtrate was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane. The fractions containing the product were collected and evaporated to obtain colorless liquid (3.5 g, 91%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>O1CCCC1>[C:22]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)(=[O:24])[CH3:23]
Reactant: NCc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-[4-(aminomethyl)phenyl]quinazoline-4-carboxylic acid (2.6 g, 9.31 mmol, 1.00 equiv), oxolane (200 mL) and acetyl acetate (20 mL). The resulting solution was stirred for 3 h at 25° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1-5:1). This resulted in 500 mg (17%) of 2-[4-(acetamidomethyl)phenyl]quinazoline-4-carboxylic acid as a light yellow solid. MS (ESI) m/z 322 ([M+H]+).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][CH2:11][NH:12]C(=O)OCC1C=CC=CC=1)=[O:8])(=[O:3])[CH3:2].C1CCCCC1>[Pd].C(O)C>[C:1]([NH:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][CH2:11][NH2:12])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCC(=O)NCCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCCCC1
Solvent: CCO
Product: CC(=O)NCCC(=O)NCCN
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
A mixture of 1.3 g of [2-[[3-(acetylamino)-1-oxo-propyl]amino] ethyl] carbamic acid, phenylmethyl ester, 25 ml of cyclohexane and 180 mg of 10% palladium on carbon in 50 ml of ethanol was heated for 1.5 hours under argon and then stirred at room temperature for 12 hours. The mixture was filtered through a pad of celite and washed with methanol. The combined filtrate and wash was evaporated, giving 670 mg of the desired compound as a white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:25][CH2:26][C:27]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(C1(C(OC)=O)CCC1)=O>>[CH:1]1([O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:19][CH2:20][N:21]([CH2:25][CH2:26][C:27]5([C:33]([O:35][CH3:36])=[O:34])[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)[CH2:22][CH2:23]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1cc(OC2CCCC2)c2c(OCC3CCNCC3)noc2c1
Reactant: COC(=O)C1(CC=O)CCOCC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CCN2CCC(COc3noc4cccc(OC5CCCC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 4-(cyclopentyloxy)-3-(piperidin-4-ylmethoxy)-1,2-benzisoxazole (EXAMPLE 24, Step 2) and methyl 4-(2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (WO 2004/043958) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.