Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[O-]CC.[Na+].[C:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(O)C>[C:10]([C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=1)=[C:28]1[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]1)#[N:11]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(=C(C#N)c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
To the solution of 4-(trifluoromethyl)phenylacetonitrile (2560.9 mg; 13.83 mmol; 1.06 eq.) in ethanol (50 mL), 21% sodium ethoxide (5.70 ml; 15.27 mmol; 1.17 eq.) in ethanol was added dropwise at RT. After stirred for 30 min, a solution of 1-boc-4-piperidone (2600.00 mg; 13.05 mmol; 1.00 eq.) in ethanol (10 mL) was added slowly. The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with 50 mL of saturated aqueous NH4Cl and concentrated to half volume. The aqueous solution was extracted with ether three times. The combined organic extracts were washed with brine, dried and then concentrated to give the crude product, which was purified by Biotage chromatography with EtOAc/Hexane (5-30%) to yield the desired product as light yellow solid (3200.00 mg, yield 66.9%).
Reaction SMILES: S([C:5]1[S:9][C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:7][N:6]=1)(=O)(=O)N.NC1C=CC(S(NC2SC(S(N)(=O)=O)=NN=2)(=O)=O)=CC=1.C(N(CC)CC)C.[C:59](Cl)(=[O:69])CCCCCCCCC>C(#N)C>[OH:69][CH2:59][C:5]1[S:9][C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:7][N:6]=1
Reactant: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(S(N)(=O)=O)s2)cc1
Reactant: CCCCCCCCCC(=O)Cl
Agent: Nc1ccc(S(=O)(=O)Nc2nnc(S(N)(=O)=O)s2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(CO)s2)cc1
Temperature: 0 °C
Yield: 60 %

Procedure:
N-(4-(N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl)sulfamoyl)phenyl)decanamide 139). 5-(4-Aminophenylsulfonamido)-1,3,4-thiadiazole-2-sulfonamide (7, 50 mg, 0.15 mmol) was suspended in anhydrous acetonitrile (5 mL). Triethylamine (17.1 mg, 0.17 mmol) was added with stirring at 0° C. A solution of decanoyl chloride (32.4 mg, 0.17 mmol) dissolved in anhydrous acetonitrile (1 mL) was added dropwise, and the reaction mixture was stirred at 0° C. for 2 h and overnight at room temperature. Volatiles were removed in vacuo and the residue was washed with water (5 mL). The residue was subjected to chromatography on silica gel (70-230 mesh) eluted with CH2Cl2:methanol 9:1, giving the pure product as a solid (42 mg, 0.09 mmol, 60% yield), mp 242-243° C.; 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, 3H, J=6.9 Hz), 1.24 (m, 12H), 1.56 (m, 2H), 2.32 (t, 2H, J=7.5 Hz), 7.66 (s, 4H), 7.91 (s, 2H), 10.13 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 14.1, 22.3, 25.2, 28.8, 29.0, 31.5, 36.6, 118.6, 127.0, 137.4, 142.2, 157.8, 170.8, 172.1; LRMS (LCQ, ESI−) calcd for C18H26N5O5S3 488.1, found 488.1 (M−H)−; HRMS (ESI−, m/z) calcd for C18H26N5O5S3 488.1102, found 487.1101 (M−H)−.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([O:22][CH2:23][CH2:24][O:25][C:26]3[C:27]([N:32]4[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]4)=[N:28][CH:29]=[CH:30][N:31]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1)(=[O:10])[CH3:9]>C(Cl)Cl>[N:32]1([C:27]2[C:26]([O:25][CH2:24][CH2:23][O:22][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[N:13]=[C:12]([NH:11][C:8](=[O:10])[CH3:9])[CH:21]=[CH:20]4)=[N:31][CH:30]=[CH:29][N:28]=2)[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]1
Reactant: CC(=O)Nc1ccc2cccc(OCCOc3nccnc3N3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1ccc2cccc(OCCOc3nccnc3N3CCNCC3)c2n1
Reaction time: 1 h

Procedure:
TFA (1.5 mL) was added to a solution of the product from Step 2 (112 mg, 0.22 mmol) in CH2Cl2(1.5 mL) at 0° C. and the mixture was stirred under inert atmosphere for 1 h. The reaction mixture was diluted with CH2Cl2 and washed with 2 M aqueous NaOH (×4) and brine. The organic layer was dried (MgSO4) and concentrated. The crude solid product (83 mg) was purified by column chromatography on silica using CHCl3/MeOH (9:1)+1% NH3 as eluent to give the title compound as an oil that solidified after repeated additions of pentane: yield 67 mg (75%); MS m/z 409 (M+H)+. Anal. (C21H24N6O3.0.6H2O.0.1C5H12) C, H, N.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>O>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([F:16])=[CH:18][CH:19]=3)=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1cnc2cc(Cl)ccc2c1Cl
Reactant: Nc1ccc(F)cc1
Solvent: O
Product: O=[N+]([O-])c1cnc2cc(Cl)ccc2c1Nc1ccc(F)cc1

Procedure:
1.3 g (5.3 mmol) 4,7-dichloro-3-nitro-quinoline (Example 15b) and 0.525 g (5.3 mmol) 4-fluoroaniline are stirred at rt for 1 h. The reaction mixture is poured into 150 ml of water, and the resulting crystals are filtered off. After washing with water, the solid is dissolved in ca. 170 ml of ethanol and then concentrated to ca. 30 ml. The solution is cooled in ice-water. The crystals which precipitate are filtered off and dried overnight at 70° C. (high vacuum). mp: 198-200° C.; MS: 318 (M++1); HPLC: tret=10.92 min (Grad 1).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1)[CH2:2][CH3:3].Br[CH2:18][C:19]([O:21]C(C)(C)C)=[O:20]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:18][C:19]([OH:21])=[O:20])=[CH:6][C:7]=1[C:13]([F:14])([F:15])[F:16])#[N:10]
Reactant: CCCNc1ccc(C#N)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CBr
Product: CCCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 70B using 4-(propylamino)-2-(trifluoromethyl)benzonitrile and 1,1-dimethylethyl bromoacetate: 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=8.7 Hz, 1H), 6.87 (d, J=2.6 Hz, 1H), 6.71 (dd, J=8.8, 2.6 Hz, 1H), 4.18 (s, 2H), 3.41 (t, J=7.7 Hz, 2H), 1.68 (m, 2H), 0.98 (t, J=7.5 Hz, 3H).
Reaction SMILES: CO[C:3]([C:5]#[C:6][C:7]([O:9]C)=[O:8])=[O:4].[OH:11][C:12]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][C:16]([CH3:25])([CH3:24])[O:17]2.[OH-].[Na+]>O1CCOCC1.O.OS(O)(=O)=O>[CH3:23][O:22][C:20]1[C:21]2[C:3](=[O:4])[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[O:11][C:12]=2[C:13]2[CH2:14][CH2:15][C:16]([CH3:25])([CH3:24])[O:17][C:18]=2[CH:19]=1
Reactant: COc1cc(O)c2c(c1)OC(C)(C)CC2
Reactant: COC(=O)C#CC(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2c(c3oc(C(=O)O)cc(=O)c13)CCC(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
To a solution of dimethylacetylenedicarboxylate (7.5 g) in dioxan (100 ml) containing `Triton 8` (10 drops) was added 5-hydroxy-7-methoxy-2,2-dimethylchroman (10.0 g) and the resulting mixture was warmed on a steam bath for 2 hours. A solution of sodium hydroxide (4.0 g) in water (20 ml) was added and heating was continued for 2 hours more. The organic solvent was removed and water (50 ml) was added to the residue and the mixture was acidified to give an oil which was extracted into ethylacetate. This solution was dried over MgSO4, filtered and the filtrate was evaporated to dryness. The oil so obtained was dissolved in concentrated H2SO4 (50 ml) and the solution was stirred at room temperature for 30 minutes, poured into ice and extracted with ethyl acetate. This solution was washed with water, dried (MgSO4), filtered and evaporated to dryness. The oil so produced was triturated with ethyl acetate, cooled to 0°, and the solid produced was filtered and dried. The solid was crystallised from ethanol to give 8,9-dihydro-5-methoxy-8,8-dimethyl-4-oxo-4H,10H-benzo[1,2-b: 3,4-b']dipyran-2-carboxylic acid as a white solid (3.4 g, 23%) mp 225°-6°.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[CH2:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:6]=1
Reactant: CN(C)C(=O)CBr
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1cc(I)cn1
Reaction time: 24 h
Yield: 79.8 %

Procedure:
4-iodo-1H-pyrazole (0.95 g, 4.94 mmol) and 2-bromo-N,N-dimethylacetamide (Preparation 98, 0.82 g, 4.94 mmol) were dissolved in dry DMF (10 ml). To the stirred solution was added potassium carbonate (1 g, 7.35 mmol) and the reaction mixture was stirred for 24 hours. The solid was filtered and the solution was diluted with dichloromethane (50 ml) and water (30 ml). The organic solution was collected, dried and concentrated in vacuum. The crude was purified by silica gel column chromatography eluting with neat ethyl acetate to afford the title compound as a white crystalline solid (1.1 g, 80%). 1H-NMR (500 MHz, CDCl3): δ 3 (s, 3H), 3.09 (s, 3H), 5 (s, 2H), 7.54 (s, 1H), 7.6 (s, 1H).
Reaction SMILES: Cl.[N:2]1([NH:11][C:12](=[NH:15])SC)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.Cl.[NH2:17][OH:18].[O-]CC.[K+]>C(O)C>[OH:18][NH:17][C:12]([NH:11][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)=[NH:15]
Reactant: CSC(=N)NN1CCc2ccccc21
Reactant: NO
Agent: CC[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: N=C(NO)NN1CCc2ccccc21

Procedure:
10 g of 1-(indolin-1-yl)-2-methylisothiourea hydrochloride and 11.4 g of hydroxylamine hydrochloride were suspended in 240 ml of ethanol and were heated to the boil for one hour upon the addition of 6.9 g of potassium ethoxide. Upon cooling, the potassium chloride and the excess hydroxylamine hydrochloride were filtered off with suction and the filtrate was evaporated to dryness. The evaporation residue was partitioned between concentrated aqueous ammonia solution and methylene choride. The methylene chloride solution was dried over magnesium sulphate and evaporated to dryness. 1-hydroxy-3-(indolin-1-yl)guanidine was obtained as an evaporation residue and was crystallized upon the addition of acetic acid, as the acetate from ethanol/ether having a M.Pt. of 155° - 156°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:12]([OH:14])=O)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.S(Cl)([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:12]([Cl:17])=[O:14])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1(c2cccs2)CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1(c2cccs2)CCOCC1

Procedure:
4-(2-Thienyl)tetrahydropyran-4-carboxylic acid was reacted with thionyl chloride and a catalytic amount of DMF in methylene chloride under heating to obtain 4-(2-thienyl)tetrahydropyran-4-carbonyl chloride. A THF solution of 4-(2-thienyl)tetrahydropyran-4-carbonyl chloride was added dropwise to a THF solution of hydrazine monohydrate and the whole was reacted at 0° C. to obtain 4-(2-thienyl)tetrahydropyran-4-carbohydrazide.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:23])[C:12]([O:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.[NH4+].[Cl-]>C1COCC1.CO.[Zn]>[F:1][C:2]1[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:23])[C:12]([O:14][CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(N)cc3F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-5-methyl-6-(2-morpholinoethoxy)pyrrolo[2,1-f][1,2,4]triazine (54 mg, 0.13 mmol) in a mixture of 0.8 mL of THF and 1.2 mL of MeOH were added NH4Cl (70 mg, 1.3 mmol) and Zn powder (85 mg, 1.3 mmol). The suspension was allowed to stir at room temperature for 2 h. Both HPLC analysis and LC-MS analysis indicated the completion of the reaction and the solid was thus filtered off. After concentration of the filtrate, the residue was taken into 10% MeOH in CH2Cl2. The solution was then filtered again and the filtrate was concentrated in vaco to provide the title compound (50 mg, 92%). MS(ESI+) m/z 388.4 (M+H)+.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:23]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])=[O:25]>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@H:12]([C:14](=[O:16])[NH:21][C:22]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:23]=1[C:24](=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[CH3:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reaction time: 0.67 h

Procedure:
120 g of carbobenzoxy-L-alanine are dissolved in 800 ml of absolute tetrahydrofuran, treated dropwise while cooling with ice with 70 g of thionyl chloride and stirred for 40 minutes while cooling with ice. There is then rapidly added dropwise thereto a suspension of 100 g (0.38 M) of 2-amino-5-nitro-2'-fluorobenzophenone in 400 ml of absolute tetrahydrofuran and the mixture is stirred at room temperature for 24 hours. The solution obtained is concentrated and the residue is treated with ice and 10% sodium bicarbonate solution and extracted with methylene chloride. The organic solution is dried over sodium sulphate, filtered and concentrated. The residue is dissolved in a small amount of methylene chloride and treated with ether. There is obtained (S)-benzyl-{1-[[2-(o-fluorobenzoyl)-4-nitrophenyl]carbamoyl]ethyl}carbamate. A further recrystallisation from methylene chloride/ether yields a product which melts at 158°-160° C. and shows a rotation of [α]25D =-23.4° (in methylene chloride; 1%). The mother liquors are purified on a 600 g silica gel column using methylene chloride as the eluting agent, an additional amount of the aforementioned product being obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH3:13])=[CH:6][CH:5]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH:10]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH3:13])[C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2ccc(N)cc2)cc1

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(4-nitrophenyl)-(4-methoxyphenyl)methyl]-N-[1-(3,4-difluorophenyl)ethyl]amine (3.20 g) [prepared as described in step (a) above] in methanol (60 ml), nickel chloride hexahydrate (3.82 a) and sodium borohydride (1.21 g) were reacted and purified, to afford the less polar isomer A (720 mg) as a pale yellow oil and the more polar isomer B (805 mg) as a pale yellow oil of the title compound.
Reaction SMILES: [CH:1]1([CH2:4]O)[CH2:3][CH2:2]1.[NH:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH:1]1([CH2:4][N:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: OCC1CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(CC1CC1)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 354.4 %

Procedure:
To a mixture of cyclopropylmethanol (7.15 ml, 90 mmol), di-tert-butyl hydrazine-1,2-dicarboxylate (6.30 g, 27.1 mmol) and triphenylphosphine (28.5 g, 109 mmol) in THF (100 mL) was added di-tert-butyl azodicarboxylate (25 g, 109 mmol) portion wise at ambient temperature. The mixture was stirred for 2 hours then concentrated. Solid triphenylphosphineoxide was removed by filtration. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, eluted with a gradient of 5-25% EtOAc in hexane) to provide 27.5 g (96%) of title compound. 1H NMR (300 MHz, CDCl3) δ ppm 0.15-0.26 (m, 2H), 0.42-0.54 (m, 2H), 0.91-1.09 (m, 1H), 1.47 (s, 9H), 1.48 (s, 9H), 3.31 (d, J=6.10 Hz, 2H), 6.38 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:20])[CH2:17]OC)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[O:29])[CH2:27][CH2:26]1)=[O:24].[CH:38]1(C(O)=O)[CH2:41]C[CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:17]1([C:16]([NH:15][C:11]2[CH:10]=[C:9]([O:8][C:6]3[C:5]([F:21])=[CH:4][C:3]([NH:22][C:23]([C:25]4([C:28]([NH:30][C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)=[O:29])[CH2:26][CH2:27]4)=[O:24])=[C:2]([F:1])[CH:7]=3)[CH:14]=[CH:13][N:12]=2)=[O:20])[CH2:41][CH2:38][CH2:39]1
Reactant: O=C(O)C1CCC1
Reactant: COCC(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)C1CCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a solution of N-(4-(2-chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 0.45 mmol) (as prepared in Example 9) and cyclobutanecarboxylic acid (90 mg, 0.9 mmol) in DMF (3 ml) was added HATU (513 mg, 1.35 mmol), followed by DIEA (516 mg, 4 mmol). The mixture was sparged with nitrogen and stirred overnight at 60° C. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give N-(4-(2-(cyclobutanecarboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (97 mg, yield 41.1%). 1H NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 10.42 (s, 1H), 9.80 (s, 1H), 8.18 (d, J=6.0 Hz, 1H), 8.08 (dd, J=12.4, 6.8 Hz, 1H), 7.68 (s, 1H), 7.60-7.54 (m, 3H), 7.17 (t, J=8.8 Hz, 2H), 6.73 (dd, J=5.6, 2.4 Hz, 1H), 2.18-2.02 (m, 4H), 1.92-1.83 (m, 1H), 1.76-7.69 (m, 1H), 1.62-1.55 (m, 4H); MS (ESI): m/z 525.1 [M+H]
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:20]3[C:21]([F:37])=[CH:22][C:23]([F:36])=[C:24]([NH:26][C:27](=[O:35])OC4C=CC=CC=4)[CH:25]=3)[C:13](=[O:19])[N:14]2[CH2:17][CH3:18])=[CH:9][N:8]=1)=[O:5])#[N:2].[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CS(C)=O>[C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:20]3[CH:25]=[C:24]([NH:26][C:27]([NH:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:35])[C:23]([F:36])=[CH:22][C:21]=3[F:37])[C:13](=[O:19])[N:14]2[CH2:17][CH3:18])=[CH:9][N:8]=1)=[O:5])#[N:2]
Reactant: Nc1ccccc1
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Oc3ccccc3)c(F)cc2F)cc2cnc(NC(=O)CC#N)cc21
Solvent: CS(C)=O
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2F)cc2cnc(NC(=O)CC#N)cc21
Yield: 12.4 %

Procedure:
A solution of phenyl (5-(7-(2-cyanoacetamido)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)carbamate (400 mg, 0.80 mmol) and aniline (158 mg, 1.6 mmol) in DMSO (3 mL) was heated at 60° C. overnight and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA) to afford 2-cyano-N-(3-(2,4-difluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide (50 mg, 13% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.23 (s, 1H), 8.92 (s, 1H), 8.78 (s, 1H), 8.20-8.16 (m, 2H), 8.11 (s, 1H),7.49-7.39 (m, 4H), 7.29-7.25 (m, 2H), 6.96 (t, J=7.2 Hz, 1H) 4.26-4.21 (q, J=6.8 Hz, 2H), 4.09 (s, 2H),1.30-1.26 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 503.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][OH:18].[OH-].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)[O:18][CH2:17][CH2:16][N:15]([CH3:19])[CH3:14]
Reactant: O=[N+]([O-])c1cc(Br)cc([N+](=O)[O-])c1
Reactant: CN(C)CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCOc1cc(Br)cc([N+](=O)[O-])c1
Reaction time: 20 h
Yield: 56.4 %

Procedure:
1-Bromo-3,5-dinitrobenzene (1 g, 4.1 mmol), 2-(dimethylamino)ethanol (0.54 g, 6.1 mmol), potassium hydroxide (0.45 g, 8.1 mmol), and water (0.5 mL) in DMF (5 mL) were heated at 80° C. After 20 hours, the reaction mixture was diluted with cold water and extracted with dichloromethane (2×100 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (stepwise gradient, 2% ethyl acetate in hexanes to ethyl acetate) to give 2-(3-bromo-5-nitrophenoxy)-N,N-dimethylethanamine (669 mg, 57.2% yield) as a brown oil. HPLC: Rt=1.04 min. (PHENOMENEX® Luna 5 micron C18 4.6×30 mm, 10-90% aqueous methanol containing 0.1% TFA, 2 min. gradient, flow rate=5 mL/min., detection at 254 nm). MS (ES): m/z=290.93 [M+H]+.
Reaction SMILES: [Cl-].[C:2]([C:4]1([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH2:9][CH2:8][NH2+:7][CH2:6][CH2:5]1)#[N:3].C(N(CC)CC)C.[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25]>ClCCl>[CH2:24]([S:26]([N:7]1[CH2:8][CH2:9][C:4]([CH2:10][CH:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)([C:2]#[N:3])[CH2:5][CH2:6]1)(=[O:28])=[O:27])[CH3:25]
Reactant: N#CC1(CC2CCOCC2)CC[NH2+]CC1
Reactant: CCS(=O)(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(C#N)(CC2CCOCC2)CC1
Reaction time: 1 h

Procedure:
In a dry round bottom flask was placed 4-cyano-4-(tetrahydro-2H-pyran-4-ylmethyl)piperidinium chloride (9, 1 g, 3.1 mmol), dichloromethane (50 ml) and triethylamine (2.162 ml, 15.51 mmol). To this was added dropwise ethanesulfonyl chloride (0.317 ml, 3.1 mmol). The reaction was stirred 1 hour and quenched with water (100 ml). The mixture was extracted with dichloromethane (3×50 ml) and the combined organic fractions were dried (MgSO4), filtered, and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexanes to give 1-(ethylsulfonyl)-4-(tetrahydro-2H-pyran-4-ylmethyl)piperidine-4-carbonitrile (10) as a white solid. MS 301 (M+1)