Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=O)=[CH:11][CH:12]=2)[C@H:7]([N:17]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:6][C@@H:5]1[CH3:36])(=[O:3])[CH3:2].[NH3:37]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:37])=[O:16])=[CH:11][CH:12]=2)[C@H:7]([N:17]([C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:28][CH:29]=2)[C:18](=[O:23])[C:19]([F:20])([F:22])[F:21])[CH2:6][C@@H:5]1[CH3:36])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](N(C(=O)C(F)(F)F)c2ccc(N3CCOCC3)cc2)C[C@@H]1C
Reactant: N
Product: CC(=O)N1c2ccc(C(N)=O)cc2[C@H](N(C(=O)C(F)(F)F)c2ccc(N3CCOCC3)cc2)C[C@@H]1C
Yield: 100 %

Procedure:
[Step 4] Reactions and treatments were carried out in the same manner as in Example 118, using 83.5 mg of (2S,4R)-1-acetyl-2-methyl-4-[2,2,2-trifluoro-N-(4-morpholinophenyl)acetamido]-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of (2S,4R)-1-acetyl-2-methyl-4-(4-morpholinophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, and using aqueous ammonia instead of monomethylamine. Thus, 86.9 mg (100%) of (2S,4R)-1-acetyl-2-methyl-4-[2,2,2-trifluoro-N-(4-morpholinophenyl)acetamido]-1,2,3,4-tetrahydroquinoline-6-carboxamide was obtained as a pale yellow amorphous substance.
Reaction SMILES: [CH3:1][CH:2]1[N:7]=[CH:6][C:5]2[S:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.[CH3:11][I:12]>C(#N)C>[I-:12].[CH3:1][CH:2]1[N+:7]([CH3:11])=[CH:6][C:5]2[S:8][CH:9]=[CH:10][C:4]=2[CH2:3]1
Reactant: CI
Reactant: CC1Cc2ccsc2C=N1
Solvent: CC#N
Product: CC1Cc2ccsc2C=[N+]1C
Product: [I-]
Reaction time: 0.5 h

Procedure:
A solution of 4.0 g (26.5 mmol) 5-methyl-4,5-dihydro-thieno[2,3-c]-pyridine in 250 ml acetonitrile is combined at RT with 16.5 ml (264.5 mmol) methyl iodide and stirred for 30 min. The precipitate formed is filtered off and washed with acetonitrile.
Reaction SMILES: [C:1](OCC)(=[O:4])[CH2:2][CH3:3].[C:8]([I:12])(=[O:11])[CH2:9][CH3:10].C(I)C.C(I)(=[O:18])C.CI>>[C:8]([O:11][C:1](=[O:4])[CH2:2][CH3:3])(=[O:18])[CH2:9][CH3:10].[C:8]([I:12])(=[O:11])[CH2:9][CH3:10]
Reactant: CC(=O)I
Reactant: CCOC(=O)CC
Agent: CCC(=O)I
Solvent: CI
Solvent: CCI
Product: CCC(=O)OC(=O)CC

Procedure:
Examples 1-5 are repeated but using ethyl propionate, propionyl iodide and ethyl iodide in place of methyl acetate, acetyl iodide and methyl iodide, respectively. Propionic anhydride is produced in corresponding manner, with propionyl iodide also being produced in the procedures of runs 2-5.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[N+:8]([O-])([O-])=O.[Na+].S(=O)(=O)(O)O.[C:18]1([N:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[OH:27][CH2:26][CH2:25][N:24]([C:18]1[CH:23]=[CH:22][C:21]([N:8]=[N:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:20][CH:19]=1)[CH2:28][CH2:29][OH:30]
Reactant: OCCN(CCO)c1ccccc1
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1ccncc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: OCCN(CCO)c1ccc(N=Nc2ccncc2)cc1

Procedure:
4-[[4-[N,N-Bis(hydroxylethyl)amino]phenyl]azo]pyridine (1) was prepared according to procedures described in Lin et al., J. Am. Chem. Soc., 118: 8034 (1996). Specifically, pyridin-4-amine was reacted with a mixture of sodium nitrate and sulfuric acid, followed by reaction with 2,2′-(phenylazanediyl)diethanol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.Cl.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:28](Cl)=[O:29]>CCOCC>[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:28]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:29]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1F
Reactant: C1CCNCC1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)N2CCCCC2)cc1F
Temperature: 25 °C

Procedure:
To a chilled solution of 35 ml. of piperidine, 2.5 ml. of triethylamine and 0.6 g. of dimethylaminopyridine in 100 ml. of diethyl ether is added (1/2 hour) a solution of 8.3 g. of 3-fluoro-4-hexadecylaminobenzoyl chloride hydrochloride in 50 ml. of ether. The solution is warmed to room temperature and maintained there for two hours. The solution is heated to reflux for an additional 2 hours at which time the reaction is complete. The solution is cooled, extracted twice with water and dried. The solvent is removed in vacuo and the solid is recrystallized from diethyl ether to yield 3-fluoro-4-(hexadecylamino)benzoylpiperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>O1CCCC1>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[CH:7]=2)=[CH:10][C:11]=1[Cl:16]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc(N)c(Cl)c2)ccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(Oc2ccnc(NC(=O)Oc3ccccc3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (707 mg) as disclosed in WO 02/32872 was dissolved in tetrahydrofuran (15 ml) under a nitrogen atmosphere, and then triethylamine (0.523 ml) and phenyl chloroformate (0.470 ml) were added dropwise thereto while cooling in an ice bath, followed by raising the temperature gradually to room temperature while stirring. After 6 hrs, the reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=3:2) to provide a crude product of 4-(4-amino-3-chlorophenoxy)-2-phenoxycarbonylaminopyridine (920 mg). The crude product was dissolved in N,N-dimethylformamide (9 ml), and then 2 M solution of ethylamine in tetrahydrofuran (4.5 ml) was added thereto, followed by stirring at room temperature for 23 hrs. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2). Fractions containing the target compound were concentrated to give a residue, to which hexane-ethyl acetate (5:1) was added to precipitate crystals. The crystals were filtered, and dried under aeration to provide the titled compound (298 mg, 32%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[CH:22]([C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29](B(O)O)[CH:30]=1)([CH3:24])[CH3:23].[C:36]1([CH2:42][CH2:43][SH:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH:22]([C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])([CH3:21])[CH:11]=[C:10]3[CH2:12][S:44][CH2:43][CH2:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=1)([CH3:24])[CH3:23]
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: COc1ccc(C(C)C)cc1B(O)O
Reactant: SCCc1ccccc1
Product: COc1ccc(C(C)C)cc1-c1ccc2c(c1)C(CSCCc1ccccc1)=CC(C)(C)N2

Procedure:
Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester was coupled with 5-isopropyl-2-methoxyphenylboronic acid. Bromination and coupling reaction with 2-phenylethanethiol gave 30 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[O:30][CH3:31])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O:35]CC)=[O:34].[OH-].[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[O:30][CH3:31])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4OC)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1CCNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate (31.0 g, 56.9 mmol) in 3:1 THF/EtOH (200 ml) was added sodium hydroxide (120 ml, 120 mmol), and the reaction was allowed to stir overnight at ambient temperature, at which point it was complete as determined by thin layer chromatography. The reaction was concentrated to about 25% volume, taken up in 100 ml of EtOH and 100 ml of water, and acidified with 10 ml of concentrated HCl with stirring. The product initially oiled out, but became a solid. The solids were collected by filtration and washed with 200 ml of water to yield 6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (24.7 g, 47.8 mmol) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH:3]=C.[CH2:7]([O:9][CH:10]([O:14][CH2:15][CH3:16])[CH2:11][CH2:12][NH2:13])[CH3:8].[C:17]([O-])(O)=[O:18].[Na+]>C(Cl)Cl>[CH2:2]([O:3][C:17](=[O:18])[NH:13][CH2:12][CH2:11][CH:10]([O:14][CH2:15][CH3:16])[O:9][CH2:7][CH3:8])[CH:1]=[CH2:5]
Reactant: CCOC(CCN)OCC
Reactant: O=C([O-])O
Reactant: C=CCC(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOC(=O)NCCC(OCC)OCC

Procedure:
But-3-enoyl chloride (930 uL, 8.84 mmol) was added slowly to a rapidly stirring mixture of 3,3-diethoxy-propylamine (1.0 g, 6.80 mmol) and NaHCO3 (2 mL of 0.6 M NaHCO3 in water) in DCM (100 mL). The reaction was stirred at room temperature overnight, then partitioned between water and DCM. The organic layer was washed several times with water and concentrated to give the crude sub-title compound that was used without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:26])[C@@H:9]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])([CH3:6])([CH3:5])[CH3:4].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([N:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:9]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:26])(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: COc1ccc(S(=O)(=O)N[C@H](CC(C)C)C(=O)OC(C)(C)C)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](CC(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of sodium hydride (0.68 g, 14.1 mmol) in dimethylformamide (60.0 mL), is added N-[4-methoxybenzenesulfonyl]-(D)-leucine t-butyl ester (5.02 g, 14.06 mmol) in dimethylformamide (10.0 mL). After stirring at room temperature for 20 minutes, benzyl bromide (1.67 mL, 14.06 mmol) is added, and the reaction is stirred overnight at room temperature. The reaction is then partitioned between ethyl acetate and acidic water (pH=5), the organic layer is dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (10% ethyl acetate/hexane) to give t-butyl 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-methylpentanoate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.Br[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(CC)CC)C.O>ClCCl>[OH:7][CH:4]1[CH2:5][CH2:6][N:1]([CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:2][CH2:3]1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(CN1CCC(O)CC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To piperidin-4-ol (HCl salt, 9.0 g) was added a solution of benzyl 2-bromoacetate (15.0 g, 65.7 mmol) in dichloromethane (100 mL). The mixture was cooled to 0° C. and triethylamine (27.6 mL, 0.200 mol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. Water (100 mL) was added and the resulting mixture was extracted with dichloromethane (100 mL×3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=20:1 to 10:1) to afford benzyl 2-(4-hydroxypiperidin-1-yl)acetate (8.3 g, 51% yield).
Reaction SMILES: N(C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].Cl.[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH:35]=O.[BH-](O[C:47]([CH3:49])=O)(OC(C)=O)OC(C)=O.[Na+].O>ClCCCl>[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH2:35][N:7]([CH2:35][C:31]1[N:30]([CH3:29])[CH:47]=[CH:49][N:32]=1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:8]([OH:10])=[O:9]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Cn1ccnc1C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: Cn1ccnc1CN(CCCCCC(=O)O)Cc1nccn1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 160 %

Procedure:
A solution of Fmoc-Lys-OH.HCl (1.822 g, 4.5 mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (1.10 g, 10 mmol) in DCE (50 mL) was stirred at 75° C. for 30 min under nitrogen. The reaction mixture was cooled to 0° C., and treated with NaBH(OAc)3 (3.165 g, 15 mmol). The reaction mixture was stirred at room temperature for overnight and decomposed with water. The reaction mixture was extracted with DCM, the organic layer dried and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel to afford (S)-2-4(9H-fluoren-9-yl)methoxy)carbonylamino)-6-(bis((1-methyl-1H-imidazol-2-yl)methyl)amino)hexanoic acid (2.30 g, 92%). MS (ESI), 557 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].C[O-].[Na+].F[B-](F)(F)F.[CH2:15]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH:31]=[N+](C)C)=[C:23]1[O:35][CH2:36][CH3:37])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[CH2:15]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](/[CH:31]=[C:3](\[C:1]#[N:2])/[C:4]([NH2:6])=[O:5])=[C:23]1[O:35][CH2:36][CH3:37])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N#CCC(N)=O
Reactant: CCOc1c(C=[N+](C)C)c2ccccc2n1Cc1ccccc1
Agent: C[O-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CO
Product: CCOc1c(/C=C(\C#N)C(N)=O)c2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 59.6 %

Procedure:
To a mixture of cyanoacetamide (4.60 g, 54.7 mmol) and NaOMe (0.5 M solution in MeOH, 80 mL, 4 mmol) was added a solution of (N-[(1-benzyl-2-ethoxy-1H-indol-3-yl)methylene]-N-methylmethanaminium tetrafluoroborate (v-a, 27.6 mmol) in MeOH (120 mL). The reaction was stirred at RT under an atmosphere of Ar. After 15 h, the reaction was cooled to 0° C. and was quenched by the addition of water. The insoluble product was filtered, triturated in MeOH and refiltered to yield a yellow solid (2E)-3-(1-benzyl-2-ethoxy-1H-indol-3-yl)-2-cyanoacrylamide (vi-a, 5.68 g, 60%). NH4OAc QC conditions. DAD Retention Time =1.78 min. M+H=346.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:9]1[O:10][C:11]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=2[C:13](=[O:15])[CH:14]=1)(=O)[NH2:7]>CN(C)C=O>[C:6]([C:9]1[O:10][C:11]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=2[C:13](=[O:15])[CH:14]=1)#[N:7]
Reactant: Cc1ccc2c(=O)cc(C(N)=O)oc2c1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(=O)cc(C#N)oc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
26.41 g (17.22 mmoles) of phosphorus oxychloride is added to 100 ml dimethylformamide at 0° C. and stirred at 0° C. for 15 minutes at room temperature for 30 minutes 7.0 g (34.45 mmoles) 2-carbamyl-7-methyl-4-oxo-4H-1-benzopyran is added and the mixture stirred at room temperature overnight, then poured into ice water and is allowed to stand for 1 hour at room temperature. The resulting precipitate is filtered off, redissolved in ethyl acetate, decolorized with carbon, filtered and the filtrate concentrated in vacuo to give 4.5 g of 2-cyano-7-methyl-4-oxo-4H1-benzopyran as a crystalline solid having an m.p. of 155°-56° C.
Reaction SMILES: N[C@@H:2]([CH3:32])[CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=23)=[O:11])[C:6]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH:29]([F:31])[F:30])=[N:5]1.[CH2:33]=O.[BH3-][C:36]#[N:37].[Na+]>CO>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH:29]([F:31])[F:30])=[C:21]([C:6]2[C:7]([NH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[N:17][C:16]=34)=[O:11])=[CH:8][N:4]([CH2:3][C@@H:2]([N:37]([CH3:36])[CH3:33])[CH3:32])[N:5]=2)[CH:26]=1
Reactant: C[C@H](N)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: C=O
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: C[C@@H](Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1)N(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-[1-[(2S)-2-aminopropyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (170 mg, 0.37 mmol) in MeOH (15 mL) was added 37% formaldehyde solution (16.6 mg, 0.55 mmol), NaBH3CN (23.3 mg, 0.37 mmol). The resulting solution was stirred at room temperature for 12 h and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 10% MeOH in DCM. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 10 mM NH4CO3 and MeCN (20.0% MeCN up to 35.0% in 8 min); Detector, 254/220. This resulted in 29 mg (16%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-(dimethylamino)propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as an off-white solid. LCMS (Method 10) [M+H]+=490.1, RT=0.84 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.66 (m, 2H), 8.34 (s, 1H), 7.61 (dd, 1H, J=2.7, 8.7 Hz), 7.60 (d, 1H, J=2.1 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.5, 7.2 Hz), 6.99 (t, 1H, J=73.5 Hz), 4.22 (dd, 1H, J=7.2, 13.8 Hz), 4.02 (dd, 1H, J=6.9, 13.8 Hz), 3.20-3.18 (m, 1H), 2.22 (s, 6H), 0.88 (d, 3H, J=6.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1
Reactant: C1CNCCN1
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: c1ccncc1
Product: Nc1c(F)c(N2CCNCC2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 84.8 %

Procedure:
A mixture of 0.42 g of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.39 g of anhydrous piperazine and 10 ml of pyridine was heated under reflux for 2.5 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was washed with ethanol and then dissolved in water and a 1N aqueous solution of sodium hydroxide. The solution was neutralized with a 10% aqueous solution of acetic acid. The crystals which precipitated were collected by filtration, washed with water, and dried to give 0.44 g of 5-amino-1-cyclopropyl-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as pale yellow needles. m.p. 214°-216° C.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:18]=[N:17][CH:16]=[CH:15][C:9]=3/[C:10](=[N:13]/[OH:14])/[C:11](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:19]([OH:22])(=[O:21])C>C(OCC)(=O)C.O>[OH:14][N:13]1[C:10]2[C:9]3[CH:15]=[CH:16][N:17]=[CH:18][C:8]=3[NH:7][C:6]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:11]=2[N:13]=[C:10]1[C:9]1[CH:15]=[CH:16][N:17]=[CH:18][C:8]=1[NH:7][C:19](=[O:21])[O:22][C:5]([CH3:11])([CH3:6])[CH3:4]
Reactant: O=c1/c(=N\O)c2ccncc2[nH]c2ncccc12
Reactant: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cnccc1-c1nc2c(n1O)-c1ccncc1Nc1ncccc1-2
Temperature: 80 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture of (6Z)-5H-dipyrido[2,3-b:4′,3′-f]azepine-5,6(11H)-dione 6-oxime (80.0 mg, 0.333 mmol), tert-butyl-(4fprmylpyridin-3yl)carbamate lammonium acetate (0.513 g, 6.66 mmol), water (0.12 mL) and acetic acid (0.76 mL) was stirred at 80° C. for 3 h. The solution was diluted with ethyl acetate and water, the organic solution was washed with brine, dried over MgSO4 and concentrated. The crude residue was purified by preparative LCMS to yield the desired product (102 mg, 69%). LCMS for C23H22N7O3(M+H)+: m/z=444.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[C:20]([NH:22][O:23]C3CCCCO3)=[O:21])[C:13](=[O:35])[CH:12]=2)=[CH:7][CH:6]=1.Cl>O1CCOCC1.CO>[OH:23][NH:22][C:20](=[O:21])[C:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:18][CH2:17][N:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=2)=[CH:12][C:13]1=[O:35]
Reactant: CC(CCn1ccc(-c2ccc(CCCO)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(CCn1ccc(-c2ccc(CCCO)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To 4-{4-[4-(3-hydroxypropyl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (213 mg, 0.420 mmol) was added 4 N hydrogen chloride in dioxane (5.0 mL) and methanol (0.50 mL). The reaction was stirred for 30 minutes and then evaporated to dryness. The residue was dissolved in minimal dichloromethane (2.0 mL) and diluted with ether to produce a precipitate. The suspension was stirred overnight at room temperature. The resulting solid was allowed to settle and the liquid was decanted off. The solid was rinsed twice with ether and dried on a vacuum pump to give the title compound as a white solid (164 mg, 92.4%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].[H][H]>O1CCOCC1.[Pd]>[CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: CCc1nc(C)cc(=O)n1CCOc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CCc1nc(C)cc(=O)n1CCOc1ccc(N)cc1
Yield: 69.3 %

Procedure:
A solution of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]nitrobenzene (1.0 g, 3.3 mmol) (obtained from preparation 20) in 1,4-dioxane (20 ml) was reduced with hydrogen in the presence of 10% palladium on charcoal (100 mg) at 30 psi for 16 h. The mixture was filtered through a bed of celite and washed with dioxane and evaporated to dryness under reduced pressure to yield the title compound (625 mg, 70%).