Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)=[CH:22][C:4]=1[CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:36]=2[S:37][C:38]=1[C:39]([N:6]([CH2:5][C:4]1[CH:22]=[C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)[CH:24]=[CH:25][C:3]=1[O:2][CH3:1])[CH:7]1[CH2:8][CH2:9][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:12]1)=[O:40]
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccnc(C)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccnc(C)c2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 88 (160 mg, 0.36 mmol) is treated with acid chloride 6 (99 mg, 0.40 mmol) using Method D to give the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11](=[O:19])[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8]=2[CH:7]=1)[CH3:4].CN(C=O)C.[CH3:27][O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[C:33]([O:41][CH3:42])[CH:32]=1)=[O:30]>C1COCC1>[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[N:10]([S:37]([C:34]3[CH:35]=[CH:36][C:31]([C:29]([O:28][CH3:27])=[O:30])=[CH:32][C:33]=3[O:41][CH3:42])(=[O:39])=[O:38])[C:11](=[O:19])[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8]=2[CH:7]=1)[CH3:4]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CCOc1ccc2[nH]c(=O)n(-c3ccccn3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1)n(-c1ccccn1)c(=O)n2S(=O)(=O)c1ccc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
0.2 g of sodium hydride as a 60% dispersion in oil is added to a mixture of 1 g of 5-ethoxy-1,3-dihydro-3-(pyrid-2-yl)-2H-benzimidazol-2-one, 25 ml of DMF and 25 ml of THF and the mixture is stirred for 30 minutes at RT. 1 g of 4-methoxycarbonyl-2-methoxybenzenesulfonyl chloride is then added and the mixture is stirred for 3 hours at RT. The reaction mixture is concentrated under vacuum, the residue is taken up with water, extracted with AcOEt, washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 1 g of the expected product, which is used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[C:13]#[N:14].[NH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[NH2:22]>C(#N)C>[NH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[NH:22][C:6]1[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]([C:13]#[N:14])=[C:2]([Cl:1])[C:7]=1[C:8]#[N:9]
Reactant: NC1CCCCC1N
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(C#N)c1Cl
Solvent: CC#N
Product: N#Cc1c(Cl)c(Cl)c(NC2CCCCC2N)c(C#N)c1Cl
Temperature: 25 °C
Yield: 90 %

Procedure:
To the slurry of 2,4,5,6-tetrachloro-1,3-dicyanobenzene (2.0 g, 7.5 mmol) in acetonitrile (40 ml) triethylamine (5.0 ml) is added, then 1,2-diaminocyclohexane (0.86 g, 7.5 mmol) and the reaction mixture is heated under reflux for 1 h. It is cooled to ambient temperature, then deposited on ice for few hours, and the crystalline product is collected on filter. 2.32 g (89%) of the title product as pale-yellow powder are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[C:4]([N+:11]([O-])=O)[CH:3]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[Cl:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[C:4]([NH2:11])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)c2sccc2c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)c2sccc2c1

Procedure:
To the refluxing solution of 7-chloro-5-nitrobenzo[b]thiophen obtained in step 4 (4.4 g, 20 mmol) in 5% acetic acid (300 ml) and ethyl acetate (300 ml) was added portion wise iron powder (6 g, 100 mmol) and the mixture was refluxed for 4 h. The reaction mixture was cooled, filtered through celite and washed with ethyl acetate. The layers were separated and the aqueous layer was extracted in ethyl acetate. The combined organic extracts were washed with water, dried and concentrated. The residue was purified by column chromatography (silica gel, hexane:ethyl acetate/4:1) to give 7-chloro-benzo[b]thiophen-5-ylamine, 2 g. MS m/z 183 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[Br:11]Br.CCOC(C)=O.CCCCCC>CC(O)=O.CCOC(C)=O>[Br:11][C:3]1[C:4]2[S:8][CH:7]=[N:6][C:5]=2[CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: Nc1ccc2ncsc2c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1ccc2ncsc2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of 6-aminobenzothiazole (16 g, 107 mmol) in 100 mL of AcOH was added Br2 (2.0 mL, 43 mmol), dropwise and the resulting reaction mixture was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo, yielding a yellow solid which was dissolved in EtOAc and washed with aq. NaHCO3. Organic layer was dried over Na2SO4 and concentrated in vacuo, yielding an oil which was subjected to column chromatography (10-50% EtOAc/n-Hexane) to obtain 7.8 g (34 mmol, 80% ) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[O:22]=[C:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([NH:32][CH:33]=[O:34])[CH:29]=2)[NH:24]1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([NH:32][CH:33]=[O:34])[CH:29]=2)[NH:24][C:23]1=[O:22]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: O=CNc1ccc2c(c1)CC(=O)N2
Product: Cc1c(C=C2C(=O)Nc3ccc(NC=O)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 85.1 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-formamide as starting materials to give N-{3-[3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-formamide (62 mg, 85.1%) as an orange solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=S)[NH:11][NH2:12])[CH:6]=[CH:7][CH:8]=1.Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>C(O)C>[CH3:23][C:21]1[NH:12][N:11]=[C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=2)[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CSc1cccc(NC(=S)NN)c1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2cccc(SC)c2)n[nH]c1C
Temperature: 25 °C
Yield: 47 %

Procedure:
A suspension of 10.0 g (0.046 mole) of 4-(3-methylthiophenyl)-3-thiosemicarbazide and 7.72 g (0.0469 mole) of ethyl 2-chloroacetoacetate in 150 mL of absolute ethanol was stirred at room temperature for ~16 hr. Ethanolic hydrogen chloride (2N, 50 mL) was added, the mixture refluxed for 1.0 hr, the solution filtered while hot, and the filtrate evaporated under reduced pressure to give a crystalline residue which was recrystallized three times from absolute ethanol to give 6.3 g product, mp 191.5°-194° C. The sample was dried at 56° C./4 hr/0.1 mmHg then 2 hr/25° C./0.1 mmHg.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH3:11])[CH3:10])[C:5](=[O:12])[N:4]2[CH2:13][CH2:14][N:15]([CH2:18][CH:19]=[CH2:20])[C:16](=[O:17])[C:3]=12>CCO.O.[Rh](Cl)(Cl)Cl>[OH:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH3:10])[CH3:11])[C:5](=[O:12])[N:4]2[CH2:13][CH2:14][N:15]([CH:18]=[CH:19][CH3:20])[C:16](=[O:17])[C:3]=12
Reactant: C=CCN1CCn2c(c(O)c(=O)n(C(C)C)c2=O)C1=O
Agent: Cl[Rh](Cl)Cl
Solvent: CCO
Solvent: O
Product: CC=CN1CCn2c(c(O)c(=O)n(C(C)C)c2=O)C1=O
Temperature: 25 °C

Procedure:
A mixture of 9-hydroxy-7-isopropyl-2-(2-propenyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8(7H)-trione (3.0 g, 11 mmol) and rhodium trichloride hydrate (200 mg, 1 mmol) in EtOH (75 mL) was heated to reflux for 8 h. The reaction was cooled to ambient temperature and the solvent was removed in vacuo. The reddish solid was triturated in MeOH and collected by filtration to give the title compound as a solid. HPLC RT=2.90 min (Method A); ES MS (M+H)=280; 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 7.10 (d, J=4.5 Hz, 1H), 5.49 (sextet, J=6 Hz, 1H), 5.04 (septet, J=7 Hz, 1H), 3.97 (m, 2H), 3.79 (m, 2H), 1.76 (d, J=6 Hz, 3H), 1.39 (d, J=7 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]#[N:10])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>[Pt]=O.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:9][NH2:10])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C#N)CC1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)C1(CN)CC1

Procedure:
Ethyl1-cyanocyclopropane-1-carboxylate (Aldrich; 76.45 g, 550 mmol), Platinum Oxide (7.5 g) and Acetic acid (1 L) were combined then stirred at room temperature under hydrogen at 4 bar pressure for 8 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo to give the title compound as a colourless oil containing 4.5 equivalents of acetic acid. (115 g, 51%)
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][CH2:25][C:26]2[O:30][N:29]=[C:28]([C@@H:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3C(OC(C)(C)C)=O)[N:27]=2)[CH2:20][CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[NH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]1[C:28]1[N:27]=[C:26]([CH2:25][O:24][CH:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:17])[CH2:23][CH2:22]2)[O:30][N:29]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1c1noc(COC2CCN(C(=O)OCc3ccccc3)CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(OCc2nc([C@@H]3CCCCN3)no2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
Trifluoroacetic acid (25 ml) was added to a solution of tert-butyl (2S)-2-{5-[(1-[(benzyloxy)carbonyl]-4-piperidyloxy)methyl]-1,2,4-oxadiazol-3-yl}-1-piperidinecarboxylate (1.73 g) [see Preparation 94] in dichloromethane (25 ml) at 0° C. The reaction mixture was stirred for 2 hrs at room temperature, after which time the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was separated and washed with 2N aqueous hydrochloric acid and brine, the combined aqueous layers were then neutralised with saturated sodium hydrogen carbonate and the product re-extracted with ethyl acetate. The organic layer was then separated, dried over magnesium sulphate and the solvent removed under reduced pressure to afford benzyl 4-(3-[(2S)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)-1-piperidinecarboxylate (1.33 g) as a brown oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[N:13][CH:14]=2)O1.Br[C:18]1[CH:19]=[C:20]([O:25][C@@H:26]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)[CH3:27])[C:21]([NH2:24])=[N:22][CH:23]=1.[F-].[Cs+].B([O-])[O-]>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:24][C:21]1[N:22]=[CH:23][C:18]([C:9]2[CH:14]=[N:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:19][C:20]=1[O:25][C@@H:26]([C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[N:35]1[N:39]=[CH:38][CH:37]=[N:36]1)[CH3:27]
Reactant: C[C@@H](Oc1cc(Br)cnc1N)c1cc(F)ccc1-n1nccn1
Reactant: CC1(C)OB(c2ccc(O)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: CO
Product: C[C@@H](Oc1cc(-c2ccc(O)nc2)cnc1N)c1cc(F)ccc1-n1nccn1
Temperature: 120 °C

Procedure:
A mixture of the 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol (470 mg, 2.13 mmol), (R)-5-bromo-3-(1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin-2-amine of preparation 45 (510 mg, 1.35 mmol) and CsF (724 mg, 4.72 mmol) were taken up in MeOH (13 mL). The mixture was thoroughly degassed before Pd(dppf)Cl2 (55 mg, 0.067 mmol) was added and the mixture was heated in the microwave at 120° C. for 2 hr. LCMS showed the presence of starting materials. Additional portions of Pd(dppf)Cl2 (27 mg) and boronate (100 mg) were added. The mixture was degassed again and heated in the microwave at 120° C. for another 1 hr. LCMS indicated the complete consumption of bromide starting material. The mixture was filtered and the filtrate was concentrated. The residue was taken up in MeOH and purified by a reverse phase prep-HPLC to give the title compound (115 mg) as a fluffy white solid after lyophilization.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[O:14])[CH:10](C)[NH:9]2)=[CH:4][CH:3]=1.CC1C=CC(N2C(=O)C(=O)C(C3C=CC=CC=3)N2)=CC=1.CC1C=CC(N2C(=O)C(=O)C(C3C=CC(Cl)=CC=3)N2)=CC=1.CC1C=CC(N2C(=O)C(=O)C(C3C=CC=C(OC)C=3)N2)=CC=1.CC1C=CC(N2C(=O)C(=O)C(C3C=CC(OC)=CC=3)N2)=CC=1.CC1C=CC(N2C(=O)C(=O)C(C3C=CC=C([N+]([O-])=O)C=3)N2)=CC=1.CC1C=CC(N2C(=O)C(=O)C(C3C=CC(C)=CC=3)N2)=CC=1.CC1C=CC(N2C(=O)C(=O)C(OC)N2)=CC=1.CC1C=CC(N2C(=O)C(=O)C(OCC)N2)=CC=1.CC1C=CC(N2C(=O)C(=O)C(N(C)C)N2)=CC=1.CC1C=CC(N2C(=O)C(=O)C(N(CC)CC)N2)=CC=1.CC1C=CC(N2C(=O)C(=O)C(NC(=O)C)N2)=CC=1.CC1C=CC(N2C(=O)C(=O)C(C(O)=O)N2)=CC=1.CC1C=CC(N2C(=O)C(=O)C(C(OC)=O)N2)=CC=1.CC1C=CC(N2C(=O)C(=O)C(C(OCC)=O)N2)=CC=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11](=[O:14])[CH2:10][NH:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(N2NC(C)C(=O)C2=O)cc1
Agent: CC(=O)NC1NN(c2ccc(C)cc2)C(=O)C1=O
Agent: CCN(CC)C1NN(c2ccc(C)cc2)C(=O)C1=O
Agent: CCOC(=O)C1NN(c2ccc(C)cc2)C(=O)C1=O
Product: Cc1ccc(N2NCC(=O)C2=O)cc1

Procedure:
1-(4′-methylphenyl)-3-methyl-4,5-pyrazolinedione; 1-(4′-methylphenyl)-3-phenyl-4,5-pyrazolinedione; 1-(4′-methylphenyl)-3-(4′-chlorophenyl)-4,5-pyrazolinedione; 1-(4′-methylphenyl)-3-(3′-methoxyphenyl)-4,5-pyrazolinedione; 1-(4′-methylphenyl)-3-(4′-methoxyphenyl)-4,5-pyrazolinedione; 1-(4′-methylphenyl)-3-(3′-nitrophenyl)-4,5-pyrazolinedione; 1-(4′-methylphenyl)-3-(4′-methylphenyl)-4,5-pyrazolinedione; 1-(4′-methylphenyl)-3-(2′-furyl)-4,5-pyrazolinedione; 1-(4′-methylphenyl)-3-(2′-thienyl)-4,5-pyrazolinedione; 1-(4′-methylphenyl)-3-(5′-pyrazolyl)-4,5-pyrazolinedione; 1-(4′-methylphenyl)-3-methoxy-4,5-pyrazolinedione; 1-(4′-methylphenyl)-3-ethoxy-4,5-pyrazolinedione; 1-(4′-methylphenyl)-3-dimethylamino-4,5-pyrazolinedione; 1-(4-methylphenyl)-3-diethylamino-4,5-pyrazolinedione; 1-(4′-methylphenyl)-3-acetamido-4,5-pyrazolinedione; 1-(4′-methylphenyl)-3-carboxy-4,5-pyrazolinedione; 1-(4′-methylphenyl)-3-methoxycarbonyl-4,5-pyrazolinedione; 1-(4′-methylphenyl)-3-ethoxycarbonyl-4,5-pyrazolinedione;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][C:14](=O)[CH3:15])=[O:10])=[CH:4][CH:3]=1.[O-]CC.[Na+].C(O)C>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:10])[NH:11][CH2:12][CH2:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(=O)CCNC(=O)Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1=C(c2ccc(F)cc2)C(=O)NCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a solution of 2-(4-fluorophenyl)-N-(3-oxobutyl)acetamide (1.95 g, 8.7 mmol) in ethanol (120 mL) was added 20 wt % sodium ethoxide/ethanol solution (6.54 g, 19 mmol), and the mixture was stirred at 80° C. for 8 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and 1N aqueous hydrochloric acid solution were added to the residue, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×3). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane (1/10) to give the title compound (1.36 g, 76%) as a brown solid.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1>CO.[Pd]>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([N:2]([CH3:14])[CH3:1])=[O:13])=[CH:5][CH:6]=1
Reactant: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)c1ccc(N)cc1
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of N,N-dimethyl-4-nitro benzamide (23 g, 0.1185 mol) in MeOH (200 mL) was added Pd/C 10% (2.3 g) in portions and the Parr reaction vessel was purged with nitrogen for 10 min. The reaction vessel was fixed in Parr shaker at 60 psi pressure for 3 h. The reaction mixture was filtered through the Celite® pad and the filtrate was concentrated under reduced pressure to afford the title compound [18.0 g, 93%]; LC-MS (ESI): Calculated mass: 164.1; Observed mass: 165.2 [M+H]+ (RT: 0.17 min).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:6]=1[O:15][CH2:16][CH3:17])[CH2:3][OH:4].C(N(CC)CC)C.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28](Cl)=[O:29]>O1CCCC1>[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28]([NH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:7][C:6]=1[O:15][CH2:16][CH3:17])[CH2:3][OH:4])=[O:29]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CCOc1cc(C(C)(C)C)ccc1C(N)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1cc(C(C)(C)C)ccc1C(CO)NC(=O)c1c(F)cccc1F
Yield: 86.1 %

Procedure:
A mixture of 23.6 g (0.10 mole) of 2-amino-2-(2-ethoxy-4-tert-butylphenyl)ethanol, 12.2 g (0.12 moles) of triethylamine and 200 ml of tetrahydrofuran was cooled and stirred, 17.7 g (0.10 mole) of 2,6-difluorobenzoyl chloride was added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 32.5 g of N-(2,6-difluorobenzoyl)-2-amino-2-(2-ethoxy-4-tert-butylphenyl)ethanol.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][OH:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[Br:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cccc(CCO)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(CCOCc2ccccc2)c1Br
Temperature: 25 °C
Yield: 74.5 %

Procedure:
Sodium hydride (50% in oil) (1.7 g, 0.036 mol) was suspended in dry tetrahydrofuran (75 ml) in argon atmosphere. 2-(2-bromo-3-methylphenyl)-1-ethanol (7.0 g, 0.033 mol) solved in tetrahydrofuran (25 ml) was added dropwise during 30 min at room temperature. Benzyl bromide (6.2 g, 0.036 mol) was added and the reaction mixture was stirred at room temperature over night. Water (1.0 ml) was added carefully and the solvent was evaporated under reduced pressure. The residue was partitioned between water and diethyl ether and the water layer was extracted twice with diethyl ether. The ether extracts were combined, washed twice with water, and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using heptane:methylene chloride (7:3) as eluent gave 7.5 g (74.3%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]2[C:15](=[O:16])OC(C)(C)OC2=O)=[CH:4][CH:3]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]=[CH:9][CH:10]=[C:15]2[OH:16]
Reactant: CC1(C)OC(=O)C(=CNc2ccc(Cl)nc2)C(=O)O1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1ccnc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42 %

Procedure:
To the heated Dowtherm A (200 mL) at 200° C. was added 5-((6-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.5 g, 12.4 mmol) and then stirred for additional 5 min. After cooling to r.t., PE was added. The precipitate was collected, and dried in vacuo to afford 6-chloro-1,5-naphthyridin-4-ol as off-white solid in 42% yield (0.94 g). m/z 183 (M+H)+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][C:14]#[N:15]>CN(C)C=O.C(OCC)(=O)C>[N:1]1([CH2:13][C:14]#[N:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: N#CCBr
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.1 %

Procedure:
A 0° C. solution of indole (7 g, 59.8 mmol) in 200 ml of dimethylformamide is treated with NaH (60% dispersion in mineral oil; 3.1 g, 77.7 mmol). After 20 minutes, bromoacetonitrile (4.2 ml, 59.8 mmol) is added, and the resulting mixture is allowed to slowly warm to ambient temperature and stir overnight. The reaction mixture is diluted with ethyl acetate (500 ml) and washed with H2O (3×200 ml). The organic layer is dried over Na2SO4 and concentrated in vacuo. The crude residue is purified by flash chromatography (SiO2; 5% then 20% ethyl acetate in hexanes) to give 2.53 g of indol-1-yl-acetonitrile (27%).
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[CH:22]([NH:25][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4])([CH3:24])[CH3:23]
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Reactant: CC(C)N
Product: CCCCc1noc(C)c1COc1cc(C(=O)NC(C)C)[nH]n1
Yield: 89 %

Procedure:
As described for example 26d, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (97 mg, 89%) which was obtained as a colorless oil. MS: m/e=321.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][OH:19])[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.[CH3:22][C:23]([C:25]1[CH:26]=[CH:27][C:28](O)=[CH:29][CH:30]=1)=[O:24]>>[C:23]([C:25]1[CH:26]=[CH:27][C:28]([O:19][CH2:18][CH2:17][N:4]([CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=2)=[CH:29][CH:30]=1)(=[O:24])[CH3:22]
Reactant: CC(C)(C)CN(CCO)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: CC(=O)c1ccc(O)cc1
Product: CC(=O)c1ccc(OCCN(CC(C)(C)C)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-hydroxyacetophenone: 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J=8.5 Hz, 2H), 7.57 (d, J=8.8 Hz, 1H), 7.11 (app. s, 1H), 6.92 (app. bd, J=8.9 Hz, 1H), 6.86 (d, J=8.5 Hz, 2H), 4.18 (t, J=5.6 Hz, 2H), 3.96 (t, J=5.6 Hz, 2H), 3.41 (s, 2H), 2.55 (s, 3H), 1.02 (s, 9H).
Reaction SMILES: Cl.C([N:9]1[CH2:13][CH2:12][C@@H:11]([C:14]([C:27]#[N:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+].O>CO.[Pd]>[C:27]([C:14]([C@@H:11]1[CH2:12][CH2:13][NH:9][CH2:10]1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:28]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: O
Solvent: CO
Product: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a stirred solution of (S)-1-benzyl-3-(1-cyano-1,1-diphenylmethyl)pyrrolidine hydrochloride (8.55 g, 21.98 mmol) in methanol (44 mL) was added palladium on carbon (1.71 g) and ammonium formate (6.93 g, 109.9 mmol). The reaction mixture was heated to 50° C. with stirring for 3 h. The reaction was cooled to ambient temperature and water (20 mL) was added. The resulting mixture was filtered through a pad of Celite, washing with methanol (20 mL). The filtrate was collected and most of the methanol was removed in vacuo. The residue was mixed with isopropyl acetate (100 mL) and 10% aqueous sodium carbonate (50 mL). The resulting layers were separated and the aqueous layer was extracted with isopropyl acetate (50 mL). The organic layers were combined and dried over sodium sulfate (20 g). The sodium sulfate was filtered off and washed with isopropyl acetate (20 mL). The solvent was removed in vacuo to afford 5.75 g of the title intermediate as a light yellow oil (99.7% yield, 71% purity by HPLC).