Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C>C1COCC1>[CH2:11]([C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[C:8]=[O:9])[CH3:12]
Reactant: CCC(C(=O)Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=C=O)c1ccccc1
Reaction time: 1 h
Yield: 70 %

Procedure:
A THF solution of 2-phenyl butyryl chloride (55 g, 0.3 mol) was added dropwise to a mixture of triethyl amine (91 g, 0.9 mol) in THF under nitrogen atmosphere. After one hour, precipitated triethyl amine hydrochloride was filtered. Filtrate was distilled under reduced pressure and EPK was obtained (60–70° C./4 mmHg). Amount obtained was 30 g (yield was 70%).
Reaction SMILES: [CH2:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N(OC(C)(C)C)=[O:14].ON1C(=O)C2=CC=CC=C2C1=O.C1(=NO)CCCCCCCCCCC1.[N+](C1CCCCCCCCCCC1)([O-])=O>C(O)(=O)C>[C:1]1(=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCCCCCCCCCC1
Reactant: CC(C)(C)ON=O
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=[N+]([O-])C1CCCCCCCCCCC1
Agent: ON=C1CCCCCCCCCCC1
Solvent: CC(=O)O
Product: O=C1CCCCCCCCCCC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Cyclododecane (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that cyclododecanone oxime, nitrocyclododecane, and cyclododecanone were formed in yields of 41%, 4%, and 9%, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:14]([C:15]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][N:19]4C3CCCCO3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:31][C:32](=[O:34])[CH3:33].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:14]([C:15]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][NH:19]4)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:31][C:32](=[O:34])[CH3:33]
Reactant: CC(=O)Nc1ccc(Nc2ncccc2-c2nc(C)nc3c2ncn3C2CCCCO2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Nc2ncccc2-c2nc(C)nc3[nH]cnc23)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A mixture of N-(2-chloro-4-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)acetamide (100 mg, 0.209 mmol) in DCM (3 mL) was cooled to 0° C., treated with trifluoroacetic acid (3 mL, 40.4 mmol), and the yellow solution was stirred at 0° C. for 1 h. The mixture was concentrated in vacuo, the residue was treated with 2 M NH3 in MeOH and concentrated in vacuo. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 2% to 10% 2M NH3-MeOH in DCM, to give N-(2-chloro-4-(3-(2-methyl-9H-purin-6-yl)pyridin-2-ylamino)phenyl)acetamide (70 mg, 0.178 mmol, 58.3% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 13.62 (s, 1H); 13.01 (s, 1H); 9.80 (s, 1H); 9.47 (s, 1H); 8.38-8.43 (m, 1H); 8.31 (d, J=1.57 Hz, 1H); 7.54-7.60 (m, 1H); 7.47-7.52 (m, 1H); 7.07 (dd, J=7.82, 4.69 Hz, 1H); 2.88 (s, 3H); 2.07 (s, 3H). m/z (ESI, +ve ion) 394 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(=O)C)=C(C)[NH:15][C:16]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[CH2:1]([O:8][C:9](=[O:10])/[CH:11]=[C:16](\[NH2:15])/[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C1=C(C)NC(C)=C(C(=O)OCc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccccc1
Yield: 67 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetylacetone and 75 mmols of β-aminocrotonic acid benzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-acetyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid benzyl ester of melting point 152° C (from ethanol).
Reaction SMILES: ClCC([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=O.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O.CCOC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[NH:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[CH:5]=[CH:6]1
Reactant: O=C(CCl)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: c1cnc2[nH]ccc2c1
Reaction time: 16 h

Procedure:
A stirred solution of 2-chloro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone (12.5 g) in TFA at room temperature is treated with triethylsilane (72 mL, 7 eq.), stirred for 16 h, diluted with EtOAc and saturated sodium carbonate to pH 8. The phases are separated and the organic phase is dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, 10% EtOAc in ether as eluent) to give the title pyrrolo[2,3-b]pyridine compound, identified by NMR and mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C1COCC1>[C:17]([O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26](=[O:27])[NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:29])([CH3:18])([CH3:19])[CH3:20]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#Cc1ccc(N)c(Nc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(C#N)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.9 %

Procedure:
A mixture of 4-amino-3-phenylaminobenzonitrile (490 mg, 2.34 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (490 mg, 2.57 mol), HOAt (380 mg, 2.79 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (540 mg, 2.81 mol) and 4-methylmorpholine (560 μL, 5.15 mmol) in THF (5 mL) was stirred at RT for 48 h under an argon atmosphere. The crude reaction mixture was then partitioned between EtOAc and a saturated solution of NaHCO3. The aqueous phase was further extracted with EtOAc and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% EtOAc in DCM) affording [(S)-1-(4-Cyano-2-phenylaminophenylcarbamoyl)ethyl]carbamic acid tertbutyl ester as a cream foam (800 mg, 89%). LCMS: RT 3.62 min [M+H]+ 381.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[CH:8][CH:7]=1)[CH3:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([S:16]([CH3:15])(=[O:18])=[O:17])[CH3:13])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(NC)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Cc1ccc(N(C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a stirred solution of (4-methylamino-phenyl)-acetic acid ethyl ester (Preparation 269, 418 mg, 2.16 mmol) in pyridine (4 mL) was added methanesulfonyl chloride (0.25 mL, 3.24 mmol) and the mixture stirred at room temperature for 3 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried (Na2SO4) and evaporated in vacuo to afford the title compound as a gum in 78% yield, 460 mg.
Reaction SMILES: [CH3:1][CH:2]([NH:6][CH2:7][C:8]1[S:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH3:5].Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:38]([S:35]([N:32]1[CH2:31][CH2:30][CH:29]([C:20]2[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=[C:17]([C:11]4[S:12][C:8]([CH2:7][NH:6][CH:2]([CH3:1])[CH2:3][CH2:4][CH3:5])=[CH:9][CH:10]=4)[CH:18]=3)[NH:22][CH:21]=2)[CH2:34][CH2:33]1)(=[O:37])=[O:36])[CH3:39]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CCCC(C)NCc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCC(C)NCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Yield: 60 %

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (1-methylbutyl)amine (29 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 43 mg of crude (5-{[(1-methylbutyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(1-methylbutyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 35.2 mg of the title compound (60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25](CC3C=CC(OC)=CC=3OC)[C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[N:15]([CH3:42])[CH2:14][CH2:13]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[N:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:23])=[O:24])=[CH:19][CH:20]=2)[N:15]([CH3:42])[CH2:14][CH2:13]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)N(C)CCN3c2ccc(C(F)(F)F)cc2Cl)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(F)(F)F)cc2Cl)c2ccc(S(=O)(=O)Nc3ncns3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-4-methyl-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide (0.046 g, 0.072 mmol) was dissolved in 1 mL of DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The solution was concentrated, dissolved in acetonitrile and loaded onto an ion exchange column (pre-wetted with acetonitrile). The column was flushed several times with acetonitrile, then the product was liberated by flushing the column several times with about 1M HCl solution in MeOH/EtOAc (made by adding acetyl chloride to a MeOH/EtOAc mixture). The second filtrate was concentrated to afford 1-(2-chloro-4-(trifluoromethyl)phenyl)-4-methyl-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide as a light pink solid. 1H NMR (400 MHz, DMSO-d6) δ=8.41 (s, 1 H), 8.02 (d, J=1.8 Hz, 1 H), 7.82 (dd, J=1.8, 8.7 Hz, 1 H), 7.67 (d, J=8.1 Hz, 1 H), 6.91 (qd, J=2.2, 4.4 Hz, 2 H), 6.03 (d, J=8.9 Hz, 1 H), 3.71 (t, J=4.8 Hz, 2 H), 3.40 (t, J=4.8 Hz, 2 H), 2.91 (s, 3H). m/z (ESI) 489.8 (M+H)+.
Reaction SMILES: CI.[CH2:3]([O:10]C1C=CC(CCl)=CC=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]([CH:27]1[C:32](=[O:33])[NH:31][CH2:30][CH2:29][N:28]1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])(=O)C1C=CC=CC=1>>[C:3]([C:27]1([CH3:19])[C:32](=[O:33])[NH:31][CH2:30][CH2:29][N:28]1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1C(=O)c1ccccc1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Solvent: CI
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1(C)C(=O)c1ccccc1

Procedure:
When in the procedure of Example 3a, methyl iodide is substituted for p-benzyloxybenzyl chloride and 27d is substituted for 2, the title compound is obtained.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:6]2[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=2[N:4]([CH3:16])[C:3]1=[O:17].C([NH:25][C@H:26]([C:28](O)=[O:29])[CH3:27])(OC(C)(C)C)=O>>[NH2:25][C@H:26]([C:28]([C:2]1([NH2:1])[N:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:6]2[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=2[N:4]([CH3:16])[C:3]1=[O:17])=[O:29])[CH3:27]
Reactant: CC(C)C1=NC(N)C(=O)N(C)c2ccccc21
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)C1=NC(N)(C(=O)[C@H](C)N)C(=O)N(C)c2ccccc21

Procedure:
Following General Procedure D using 3-amino-2,3-dihydro-5-isopropyl-1-methyl-1H-1,4-benzodiazepin-2-one and N-Boc alanine (Novabiochem), the title compound was prepared as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:3]1[C:14](=[O:18])[C:15](Cl)=[O:16].[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=3)[CH2:29][CH2:28]2)[CH:21]=1.C(N(CC)CC)C>ClCCl.CC(C)=O>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:3]1[C:14](=[O:18])[C:15]([NH:39][C:36]1[CH:35]=[CH:34][C:33]([N:30]2[CH2:31][CH2:32][N:27]([C:22]3[CH:21]=[C:20]([CH3:19])[CH:25]=[C:24]([CH3:26])[N:23]=3)[CH2:28][CH2:29]2)=[CH:38][CH:37]=1)=[O:16]
Reactant: Cc1cc(-c2ccccc2)c(C(=O)C(=O)Cl)n1C
Reactant: Cc1cc(C)nc(N2CCN(c3ccc(N)cc3)CC2)c1
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(N2CCN(c3ccc(NC(=O)C(=O)c4c(-c5ccccc5)cc(C)n4C)cc3)CC2)c1
Temperature: 47.5 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A solution of (1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-oxo-acetyl chloride (46 g, 0.176 mol) in dry dichloromethane (300 mL) was added to a solution of 4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine (40 g, 0.140 mol) and triethylamine (14.2 g, 0.140 mol) in dry dichloromethane (300 mL) over 15 min. After stirring for 1 h the reaction mixture was quenched into water (200 mL) and the organic phase separated. The aqueous layer was extracted with dichloromethane (2×50 mL) and the combined organic layers were washed successively with water (2×200 mL), brine (2×100 mL), dried over anhydrous sodium sulfate and concentrated to give a solid. This was dissolved in acetone (580 mL) and silica gel was added (72.5 g, 100-200 mesh). The mixture was stirred at room temperature for 1 h, filtered and the solids washed with acetone (75 mL). The silica treatment was repeated a second time. The filtrate was concentrated to ˜300 mL (˜4 vols), activated carbon (8 g) was added and heated at reflux for 15 min. The mixture was cooled to 45-50° C. and filtered over celite, washing with acetone (75 mL). The solution was again concentrated to ˜300 mL and petroleum ether (725 mL, 10 vols) was added, slowly, at reflux. The resulting suspension was cooled to room temperature, stirred for 15 min, then cooled to 0° C. and stirred for 1 h. The solid was filtered off, washed with petroleum ether (150 mL) and dried under vacuum to afford 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide (53.5 g, 74%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][P:4](Cl)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Na].[K].[S-:12][C:13]#[N:14].[NH4+]>>[CH2:1]([O:3][P:4]([N:14]=[C:13]=[S:12])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cl)OCC
Reactant: N#C[S-]
Agent: [K]
Agent: [NH4+]
Agent: [Na]
Product: CCOP(=O)(N=C=S)OCC
Reaction time: 3 h

Procedure:
One molar equivalent of diethoxyphosphoryl chloride of formula (II) is reacted with 1.0 to 1.2 molar equivalent of sodium-, potassium- or ammonium thiocyanate at a temperature range of 5° C to 30° C and, preferably, 15° C to 25° C for a period of time ranging from 2 to 4 hours to yield diethoxyphosphinyl isothiocyanate of formula (III). The reaction is slightly exothermic, but is easily controlled by a cooling bath.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[CH:12]2.[OH-].[Na+].CN([CH:21]=[O:22])C>O>[F:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: Fc1cccc2cc[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2c(F)cccc12
Reaction time: 1 h

Procedure:
Phosphoryl chloride (2.0 ml) was added to DMF (3 ml) under nitrogen at 0° and to this mixture was added 7-fluoroindole (2.1 g) in dry DMF (4 ml). The mixture was stirred for 1h, 5N sodium hydroxide solution (50 ml) was added, and stirring was continued at 50° for 1h. The mixture was then diluted with water (200 ml) and extracted with ethyl acetate (2×200 ml). The combined, dried organic extracts were evaporated in vacuo to give the title compound (2.07 g), m.p. 203°-205°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=[O:9])[CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>CC(N(C)C)=O>[C:8]([C:4]1[CH:3]=[C:2]([O:18][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[NH2:11])[CH:7]=[CH:6][N:5]=1)(=[O:9])[NH2:10]
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1cccc(O)c1
Solvent: CC(=O)N(C)C
Product: NC(=O)c1cc(Oc2cccc(N)c2)ccn1

Procedure:
Entry 12: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(2-carbamoyl-4-pyridyloxy)aniline afford the urea.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C(C3C(C)=NC(C)=CC=3)O)[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([C:49]2[N:53]([CH3:54])[CH:52]=[N:51][CH:50]=2)=[O:48])=[CH:43][CH:42]=1.C(=O)=O.CC(C)=O>C1COCC1>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:47]([C:44]3[CH:43]=[CH:42][C:41]([Cl:40])=[CH:46][CH:45]=3)([C:49]3[N:53]([CH3:54])[CH:52]=[N:51][CH:50]=3)[OH:48])[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1nc2ccc(C(O)(c3ccc(Cl)cc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 4.6 mL, 11.5 mmol) was added drop-wise by syringe to a solution of 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (5.0 g, 11.6 mmol, Intermediate 47: step d) in dry THF (58 mL) in a dry ice-acetone bath. After 1 min, a solution of (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (2.6 g, 11.6 mmol, Intermediate 1: step b) in dry THF (58 mL) was added drop-wise via syringe. An additional 10 mL of THF was used to complete the quantitative addition. The reaction mixture was stirred for 5 minutes in the dry ice-acetone bath then placed into an ice-water bath. After 10 minutes, the ice-water bath was removed and the mixture was allowed to warm to ambient temperature. The reaction was quenched with saturated aqueous ammonium chloride and the mixture was partitioned between water and DCM. The layers were separated and the aqueous phase was further extracted with DCM. The organic phase was dried (Na2SO4), filtered, and concentrated. Crude product was purified by flash column chromatography (silica gel, 0-3% MeOH-DCM) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J=2.1 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.53 (dd, J=8.8, 2.1 Hz, 1H), 7.51-7.47 (m, 2H), 7.40-7.36 (m, 2H), 7.28-7.32 (m, 4H), 7.23-7.21 (m, 1H), 6.29 (d, J=1.2 Hz, 1H), 5.06 (s, 1H), 4.32 (s, 2H), 4.07 (s, 2H), 3.33 (s, 3H). MS m/e 572.0 (M+H).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[O:16][C:17]=2[CH3:18])=[N:9][CH:10]=1.[CH2:24]([O:26][C:27](=[O:40])[CH2:28][C:29]1[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:31][NH:32][CH:33]=1)[CH3:25].O>CN(C)C=O>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:15]1[O:16][C:17]([CH3:18])=[C:13]([CH2:12][O:11][C:8]2[N:9]=[CH:10][C:5]([CH2:4][N:32]3[CH:33]=[C:29]([CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:40])[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:31]3)=[CH:6][CH:7]=2)[N:14]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cn1
Reactant: CCOC(=O)Cc1c[nH]nc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 5-chloromethyl-2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]pyridine (533 mg) and ethyl(3-phenyl-1H-pyrazol-4-yl)acetate (403 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl [1-[6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (581 mg, yield: 67%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10](O)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCCC1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCCCC1CCCCC1

Procedure:
4-cyclohexylbutyric acid (Aldrich) is reduced with excess lithium aluminum hydride in ether to yield 4-cyclohexyl-1-butanol (D. S. Hiers and R. Adams, J. Am. Chem. Soc., 48 2385 (1926)) which is cloro-methylated with hydrogen chloride and formaldehyde to yield the desired compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:21]12[CH2:28][NH:27][CH2:26][C:25]=1[CH2:24][NH:23][CH2:22]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:23]4[CH2:24][C:25]5[CH2:26][NH:27][CH2:28][C:21]=5[CH2:22]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1NCC2=C1CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
0.28 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.16 g of 3,7-diazabicyclo-[3.3.0]oct-1(5)-ene and 0.3 ml of 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) were suspended in 20 ml of acetonitrile and refluxed in 100° C. oil bath for 5 hours. The reaction mixture was kept overnight at room temperature. The produced precipitate was filtered and was washed with ethanol-ethylether (1:1) solvent. 0.3 g of the title compound was obtained (yield 80%).