Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][N:14]1[C@@H:19](/[CH:20]=[CH:21]/[C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][C:15]1=[O:31]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][N:14]1[C:15](=[O:31])[CH2:16][CH2:17][CH2:18][C@@H:19]1/[CH:20]=[CH:21]/[CH:22]([OH:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)CCCC=CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCCC=CCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.8 %

Procedure:
Sodium borohydride (2.0 mg, 0.053 mmol), followed by MeOH (0.1 mL), was added to a solution of 7-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-enoic acid methyl ester (10 mg, 0.026 mmol) in CH2Cl2 (0.5 mL) at 0° C. The mixture was allowed to warm to rt. After 10 min at rt, the reaction was quenched with aqueous HCl (1.0 M, 1 mL) and extracted with EtOAc (3×5 mL). The combined organic phase was washed with brine (10 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 9.9 mg (98%) of the title compound.
Reaction SMILES: [C:1]1([CH:11]=[C:12]([CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(O)C.[C].[Pd]>[C:1]1([CH2:11][CH:12]([CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(=Cc1cccc2ccccc12)CCCOC1CCCCO1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(CCCOC1CCCCO1)Cc1cccc2ccccc12
Yield: 99.2 %

Procedure:
3.37 g of ethyl 3-(1-naphthyl)-2-[3-(2-tetrahydropyranyloxy)propyl]-2-propenoate was dissolved in 5 ml of ethanol and hydrogenated under atmospheric pressure by means of 10% palladium carbon. The reaction, mixture was subjected to filtration, the solvent of the filtrate was distilled off under reduced pressure to obtain 3.36 g of ethyl (2RS)-2-(1-naphthylmethyl)-5-(2-tetrahydropyranyloxy)pentanoate as oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:3]=1[CH2:4][C:5]([O:18][CH2:19][CH3:20])([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[F:17])[C:6]([NH2:8])=[O:7].I[CH2:28][C:29]([NH2:31])=[O:30].C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O.O>[C:29]([CH2:28][NH:1][C:2]1[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:3]=1[CH2:4][C:5]([O:18][CH2:19][CH3:20])([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[F:17])[C:6]([NH2:8])=[O:7])(=[O:30])[NH2:31]
Reactant: CCOC(Cc1ccc(C#N)cc1N)(C(N)=O)c1ccc(OC)cc1F
Reactant: NC(=O)CI
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(Cc1ccc(C#N)cc1NCC(N)=O)(C(N)=O)c1ccc(OC)cc1F
Temperature: 110 °C
Reaction time: 50 h
Yield: 24.4 %

Procedure:
To a stirred solution of (RS)-(2-amino-4-cyano-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide (470 mg) in DMF (8 ml) were added iodoacetamide (376 mg) and N-ethyldiisopropylamine (0.34 ml). After 50 hrs stirring at 110° C. under argon atmosphere. The mixture was diluted with EtOAc and water. The organic phase was separated and washed with water and brine, dried ovef MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (CH2Cl2=>CH2Cl2/MeOH 4:1) to give (RS)-[2-(carbamoylmethyl-amino)-4-cyano-benzyl]-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide (133 mg) as an off-white solid. MS 415.1([M+H]+)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1.O[C:15]([C:18](O)([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[CH3:16][C:15]1([CH3:17])[C:18]([CH3:20])([CH3:19])[O:10][B:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=2)[O:11]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(O)C(C)(C)O
Product: CC1(C)OB(c2cccc(C(F)(F)F)c2)OC1(C)C
Yield: 47 %

Procedure:
The title compound (47%, oil) was prepared from 3-trifluoromethylphenylboronic acid and pinacol.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].CN(C)C.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].CN(C1C=CC=CN=1)C.[Cl-].[NH4+]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCCCCCCCCCCBr
Agent: CN(C)C
Agent: CN(C)c1ccccn1
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
15-Bromo-pentadecan-1-ol (2.3 g, 7.49 mmol) dissolved in methylene chloride (23 mL) was mixed with trimethylamine (2.1 mL, 14.98 mmol), t-butyldimethylsilyl chloride (2.03 g, 13.48 mmol), and dimethylaminopyridine (457.6 mg, 3.74 mmol). The mixture was stirred for one hour at room temperature. Subsequently, aqueous saturated ammonium chloride solution was added to the reaction mixture for separation into a methylene chloride layer (200 mL) and an aqueous layer (200 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by means of silica gel column flash chromatography (hexane/ethyl acetate=99/1), to thereby afford 2.98 g (7.07 mmol) of 15-bromo-1-(t-butyldimethylsiloxy)pentadecane.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:27][C:28]1[CH:37]=[CH:36][C:31]2[NH:32][C:33](=[O:35])[NH:34][C:30]=2[CH:29]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:27][C:28]3[CH:37]=[CH:36][C:31]4[NH:32][C:33](=[O:35])[NH:34][C:30]=4[CH:29]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2[nH]c(=O)[nH]c2c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.6 %

Procedure:
A mixture of 2.5 g (9.6 mmol) of [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b), 1.1 ml (8 mmol) of triethylamine, 1.2 g (8 mmol) of 5-amino-1,3-dihydro-benzimidazol-2-one [J. Amer. Chem. Soc., 80, 1657. (1958)] 3.03 g (8 mmol) of HBTU and 80 ml of dimethylformamide is stirred at room temperature for 24 hours. The reaction mixture is concentrated, then 100 ml of 8% sodium hydrogencarbonate solution is added. The precipitated product is filtered off and recrystallized from methanol to yield 1.51 g (48%) of the title compound. Melting Point: >260° C. (methanol)
Reaction SMILES: [OH-].[K+:2].[OH:3][CH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]([O:13]CC)=[O:12])=[CH:7][CH:6]=1>C1COCC1>[OH:3][CH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[K+:2]
Reactant: CCOC(=O)c1ccc(CO)nc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])c1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
An aqueous solution of potassium hydroxide (40.4 mmol, 8 mL, 5 N, 2.0 eq.) was added to a solution of ethyl 6-(hydroxymethyl)pyridine-3-carboxylate (3.7 g; 20.4 mmol; 1.0 eq.) (J. Med. Chem. 2004, 47, 5230-5234) in THF (80 mL). The resulting reaction mixture was stirred at rt for 3 h. The precipitate was collected by filtration and dried on under vacuum to give the title compound as a white powder (3.6 g, 92%).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][NH:16][C:17]([NH:23][CH2:24][CH2:25]N(C)C)=[N:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:13][CH:14]=2)[N:9]=1)[NH2:3]>O>[NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][NH:16][C:17]([NH:23][CH2:24][CH3:25])=[N:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:13][CH:14]=2)[N:9]=1)[NH2:3]
Reactant: CN(C)CCNC(=NS(C)(=O)=O)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Solvent: O
Product: CCNC(=NS(C)(=O)=O)NCc1ccc(-c2csc(N=C(N)N)n2)o1

Procedure:
Anal. Calcd. for C13H19N7O3S2.2HCl.1/3H2O: C 33.62, H 4.70, N 21.11, Cl 15.27, H2O 1.29 Found: C 33.75, H 4.53, N 21.05, Cl 15.06, H2O 1.18. ##STR91## 2-(Diaminomethyleneamino)-4-[5-{3-(2-dimethylaminoethyl)-2-mesylguanidino}methylfuran-2-yl]thiazole.
Reaction SMILES: C([C:3]1[N:4](CC2C=CC=CC=2)[C:5]2[C:10]([C:11]=1[C:12](=O)[C:13]([NH2:15])=[O:14])=[C:9](OC)[CH:8]=[CH:7][CH:6]=2)C.C(Cl)(=O)C(Cl)=O.C(C1N(CC2C=CC=CC=2)C2C(C=1)=C(OC)C=CC=2)C>C(Cl)Cl>[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]([CH2:12][C:13]([NH2:15])=[O:14])=[CH:3]1
Reactant: CCc1c(C(=O)C(N)=O)c2c(OC)cccc2n1Cc1ccccc1
Agent: CCc1cc2c(OC)cccc2n1Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)Cc1c[nH]c2ccccc12
Reaction time: 3 h

Procedure:
2-Ethyl-4-methoxy-alpha-oxo-1-(phenylmethyl)-1H-indole-3-acetamide. Oxalyl chloride (0.87 mL, 10 mmol) was added to 2.6 g (9.8 mmol) of 2-ethyl-4-methoxy-1-(phenylmethyl)-1H-indole in 25 mL of methylene chloride, the mixture stirred for 3 hours and concentrated at reduced pressure. The residue was redissolved in 25 mL of methylene chloride, anhydrous ammonia bubbled in for 0.25 hours and the mixture concentrated. The residue was stirred with ethyl acetate/water and the insoluble material filtered. The ethyl acetate from the filtrate was washed with brine, dried (MgSO4) and concentrated. The residue was washed with ether and combined with the filtered material above to give 1.19 g (36% yield) of 2-ethyl-4-methoxy-alpha-oxo-1-phenylmethyl)-1H-indole-3-acetamide, mp, 193°-199° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([O:8][CH2:9][CH2:10][C:11]([NH:27][C:28](=[O:30])[CH3:29])([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17])(=[O:7])[CH3:6]>ClCCCl.C(Cl)(=O)CCCCCCC>[C:5]([O:8][CH2:9][CH2:10][C:11]([NH:27][C:28](=[O:30])[CH3:29])([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:9](=[O:8])[CH2:10][CH2:11][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:25][CH:26]=1)[CH2:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17])(=[O:7])[CH3:6]
Reactant: CC(=O)NC(CCCOC(C)=O)(CCOC(C)=O)CCc1ccccc1
Agent: CCCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCCCCCC(=O)c1ccc(CCC(CCCOC(C)=O)(CCOC(C)=O)NC(C)=O)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 148.5 %

Procedure:
To a suspension of anhydrous aluminum chloride (1.4 g) in 1,2-dichloroetane (20 ml), octanoyl chloride was carefully added at room temperature and the suspension was stirred until anhydrous aluminum chloride was entirely dissolved. To the reaction solution, a solution of 3-acetamido-6-acetoxy-3-(2-phenylethyl)hexyl acetate (780 mg) in 1,2-dichloroethane (10 ml) was dropwise added at room temperature over 10 minutes. The reaction temperature raised to 70° C. and the mixture was stirred for 30 minutes. After cooling, the reaction solution was poured into ice-water and extracted with chloroform. The chloroform layer was washed with water and a saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled away. The residue obtained was purified by silica gel chromatography (eluent; hexane-ethyl acetate=1:1) to give the subject compound (780 mg) as a yellowish oily substance.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][C:7]([CH3:10])=[CH:6][N:5]=1)(O)=[O:2].ClC(OCC)=O.[NH3:17]>O1CCOCC1.C(N(CCCC)CCCC)CCC>[C:1]([C:4]1[CH:9]=[N:8][C:7]([CH3:10])=[CH:6][N:5]=1)(=[O:2])[NH2:17]
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: N
Agent: CCOC(=O)Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: C1COCCO1
Product: Cc1cnc(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Carboxy-5-methylpyrazine (9.7 g) in dry dioxan (114 ml) and tributylamine (17.7 ml) was treated with ethyl chloroformate (7.5 ml), keeping the temperature at 0°-5° C. After ten minutes, dioxan (190 ml) saturated with ammonia was added. The mixture was stirred for 3 hours at room temperature, then dioxan was distilled off, and the residue was taken up in saturated aqueous sodium bicarbonate (20 ml). The mixture was filtered and the product washed with water to give 2-carbamoyl-5-methylpyrazine (9.2 g), m.p. 204°- 206° C. This amide (7 g) in glacial acetic acid (30 ml) and 35% hydrogen peroxide (20 ml.) was heated with stirring at 70° C for 7 hours. The reaction mixture was cooled, the product which separated was filtered and washed with water to give 2-carbamoyl-5-methylpyrazine 4-oxide (5.5 g), m.p. 206°-208° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]([C:8](=O)[CH:9]([CH3:11])[CH3:10])[CH:7]=1.[NH2:14]O.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CCO.CC(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:13][N:14]=[C:8]([CH:9]([CH3:11])[CH3:10])[C:6]=2[CH:7]=1
Reactant: CC(C)C(=O)c1cc(Br)ccc1O
Reactant: NO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: CC(C)c1noc2ccc(Br)cc12
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 14.8 %

Procedure:
1-(5-Bromo-2-hydroxyphenyl)-2-methylpropan-1-one (0.82 g, 3.37 mmol) was dissolved in EtOH (10 mL) then hydroxylamine (50% solution in water, 0.267 g, 4.05 mmol) was added followed by HOAc (1 drop). The mixture was heated to about 80° C. for about 2 h. The mixture was cooled then evaporated under reduced pressure to give an oil. Acetic anhydride (2 mL, 20 mmol) was added and the mixture was stirred for about 45 min at ambient temperature. The mixture was concentrated under reduced pressure then pyridine (7 mL) was added and then the mixture was heated to about 145° C. for about 3 h. The mixture was cooled, treated with 1 N HCl, and extracted with EtOAc. The organic extract was dried over MgSO4, filtered and evaporated to a residue that was then dissolved in DME (4 mL). Cesium carbonate (1.09 g, 3.35 mmol) was added and the mixture was heated at about 150° C. for about 30 min in the microwave. The mixture was evaporated and then purified by flash chromatography with 9:1 heptane/EtOAc to give the title compound (0.12 g, 15%): LC/MS (Table 1, Method a) Rt=3.33 min; MS m/z: 340.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:30])[CH:10]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=2)[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.CCN=C=NCCCN(C)C.[CH:42]1[CH:43]=[CH:44][C:45]2[N:50](O)N=[N:48][C:46]=2[CH:47]=1.C1(N)C=CC=CC=1N>CN(C=O)C>[NH2:48][C:46]1[CH:47]=[CH:42][CH:43]=[CH:44][C:45]=1[NH:50][C:25]([C:24]1[CH:23]=[CH:22][C:21]([CH:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[O:12])[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:30])=[CH:29][CH:28]=1)=[O:27]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(C(C(=O)Nc2cccc(Cl)c2)C(=O)Nc2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(C(C(=O)Nc2cccc(Cl)c2)C(=O)Nc2cccc(Cl)c2)cc1
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a solution of 4-(2-[(3-chlorophenyl)amino]-1-{[(3-chlorophenyl)amino]carbonyl}-2-oxoethyl)benzoic acid (61 mg, 0.14 mmol) in DMF (3 mL) at room temperature was added EDCI (31 mg, 0.16 mmol) and HOBT (22 mg, 0.16 mmol). The solution was stirred for 30 min and 1,2-phenylenediamine (45 mg, 0.42 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 18 h and purified directly by reverse phase HPLC (20% to 80% MeCN in water) to give 2-(4-{[(2-aminophenyl)amino]carbonyl}phenyl)-N,N′-bis(3-chlorophenyl)malonamide (46 mg, TFA salt, 52%) as a white solid: 1H NMR (600 MHz, CD3OD) δ 8.06 (d, J=8.2 Hz, 2H), 7.79 (t, J=2.1 Hz, 2H), 7.70 (d, J=8.2 Hz, 2H), 7.44 (dd, J=8.2, 1.2 Hz, 2H), 7.36 (d, J=7.9 Hz, 1H), 7.33-7.24 (m, 5H), 7.11 (dd, J=7.9, 0.8 Hz, 2H); ESIMS calcd 533.1 (M++H), found 533.0 (M++H).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)C=CC=[CH:3][CH:2]=1.C(O)(=O)C.[C-]#[N:22].[K+]>C(OCCO)C.O>[CH3:3][CH2:2][CH2:1][CH2:7][CH2:8][CH2:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:22]
Reactant: [C-]#N
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCCO
Product: CCCCCCCCCCCC#N
Temperature: 105 °C
Reaction time: 0.25 h

Procedure:
To the chalcone, 187, (17.95 g, 54.7) mmol) in 2-ethoxyethanol (150 mL) at 55° C. was added acetic acid (4 mL) followed by slow addition of potassium cyanide (5.3 g, 81 mmol) in water. The solution was stirred at 105° C. for 0.25 hour. The solution was cooled and treated with water (25 mL). The mixture was filtered to collect the solid. The solid was washed repeatedly with 70% ethanol (50 mL), air dried, and then dried in vacuo to give the nitrile 12.7 g (68%) as a yellow solid. The nitrile was identified by 1H NMR, IR, MS, and microanalysis.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:12]=[N:11][NH:10][C:9](=[O:13])[C:8]=1Cl)(=[O:3])[CH3:2].C(O)=O.C([O-])=O.[NH4+]>[Pd].C(O)C>[C:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:12]=[N:11][NH:10][C:9](=[O:13])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccccc1Oc1cn[nH]c(=O)c1Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O=CO
Solvent: CCO
Product: CC(=O)c1ccccc1Oc1cn[nH]c(=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.9 %

Procedure:
A suspension of 5-(2-acetyl-phenoxy)-4-chloro-2H-pyridazin-3-one (6 g, 0.0227 mol) and palladium on carbon (2.5 g) in ethanol (180 mL) was heated to reflux and then treated with formic acid (1.2 g, 0.023 mol). The reaction stirred for 10 min at reflux and then ammonium formate (1.43 g, 0.023 mol) was added. The reaction stirred at reflux for another 10 min. At this time, a second portion of ammonium formate (0.3 g, 0.0048 mol) was added. After 5 min, the reaction was cooled to 25° C. and filtered. The filtrate was concentrated in vacuo to afford 5-(2-acetyl-phenoxy)-2H-pyridazin-3-one (4.7 g, 90%); ESI-MS 231 [M+H+].
Reaction SMILES: CC([N:5]([C:9]1[S:10][C:11]([Cl:21])=[C:12]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][C:15]=2[Cl:20])[CH:13]=1)C(=O)[O-])(C)C.Cl>CO>[Cl:21][C:11]1[S:10][C:9]([NH2:5])=[CH:13][C:12]=1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][C:15]=1[Cl:20]
Reactant: Cn1ncc(Cl)c1-c1cc(N(C(=O)[O-])C(C)(C)C)sc1Cl
Agent: Cl
Solvent: CO
Product: Cn1ncc(Cl)c1-c1cc(N)sc1Cl
Reaction time: 12 h
Yield: 118.9 %

Procedure:
To a solution of 1,1-dimethylethyl[5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbamate (1.3 g, 3.73 mmol) in methanol (18.66 ml) at 25° C. was added HCl (18.66 ml, 74.7 mmol)[4M in dioxane]. After 12 h, additional HCl (18.66 ml, 74.7 mmol)[4M in dioxane] was added and the solution stirred 12 h. The reaction mixture was concentrated to a dark foam affording the HCl salt of [5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]amine (1.1 g, 99% yield): LCMS (ES) m/e 248, 250 (M, M+2)+.
Reaction SMILES: [F:1][C:2]1([C:12](OC)=[O:13])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.CO.[BH4-].[Li+].[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1([CH2:12][OH:13])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2
Reactant: COC(=O)C1(F)C2CC3CC(C2)CC1C3
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCC1(F)C2CC3CC(C2)CC1C3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
To a stirred solution of methyl 2-fluoroadamantane-2-carboxylate (0.90 g, 4.20 mmol) (Zhurnal Organicheskoi Khimii, 1981, 17, 1642) in tetrahydrofuran (40 mL) was added methanol (0.24 mL, 5.90 mmol), followed by the addition of lithium borohydride solution (2.0 M in tetrahydrofuran, 5.3 mL, 10.60 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes, at ambient temperature for 30 minutes and then at reflux for 1 hour. The reaction mixture was cooled to ambient temperature and poured in small portions into a cooled to 0° C. saturated ammonium chloride solution (25 mL) with stirring. The mixture was stirred at ambient temperature for 1 hour and extracted with ethyl acetate (3×70 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford (2-fluoroadamantan-2-yl)methanol (0.69 g, 88%) as colorless solid: MS (ES+) m/z 223.2 (M+39).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([NH:9]C(=O)C(C)(C)C)=[N:7][CH:8]=1)#[CH:2]>[OH-].[Na+]>[NH2:9][C:6]1[CH:5]=[C:4]([CH3:16])[C:3]([C:1]#[CH:2])=[CH:8][N:7]=1
Reactant: C#Cc1cnc(NC(=O)C(C)(C)C)cc1C
Agent: [Na+]
Agent: [OH-]
Product: C#Cc1cnc(N)cc1C
Temperature: 90 °C

Procedure:
A suspension of 5-ethynyl-4-methyl-2-(trimethylacetylamino)-pyridine (50 mg, 0.23 mmol) in 2N sodium hydroxide (1.0 mL) was heated at 90° C. for 18 h. The reaction mixture was cooled to room temperature, extracted with chloroform, dried (Na2SO4), and evaporated to give a tan solid. The title compound was purified by silica gel chromatography using 1% methanol/methylene chloride as eluant.
Reaction SMILES: Cl.[C:2]([C:4]1[C:5]([NH:31][CH2:32][CH:33]2[O:38][CH2:37][CH2:36][N:35]([CH3:39])[CH2:34]2)=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH:28]([F:30])[F:29])=[C:20]([CH:23](OC)[O:24]C)[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3].C([O-])(O)=O.[Na+]>C1COCC1>[C:2]([C:4]1[C:5]([NH:31][CH2:32][CH:33]2[O:38][CH2:37][CH2:36][N:35]([CH3:39])[CH2:34]2)=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH:28]([F:30])[F:29])=[C:20]([CH:23]=[O:24])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3]
Reactant: COC(OC)c1nc2c(cc1C(F)F)CCCN2C(=O)Nc1cc(NCC2CN(C)CCO2)c(C#N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCOC(CNc2cc(NC(=O)N3CCCc4cc(C(F)F)c(C=O)nc43)ncc2C#N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrochloric acid (4 M, 3.5 ml) was added to a solution of (racemic) N-(5-cyano-4-(((4-methylmorpholin-2-yl)methyl)amino)pyridin-2-yl)-6-(difluoromethyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 232B, 55 mg, 0.103 mmol) in THF (2 ml) at room temperature. After stirring for 2 h at room temperature, sat. aq. NaHCO3 was added and the mixture extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated. The residue was triturated and sonicated with DCM to give the title compound. (UPLC-MS 3) tR 0.79 min; MS m/z [M+H]+ 486.4.