Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[O:2].[CH2:18]([N:20](CC)[CH2:21][CH3:22])[CH3:19].ClC(OCC)=O.C(NCC)C>ClCCl.CCOCC.O>[CH2:18]([N:20]([CH2:21][CH3:22])[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:3]=1[CH:1]=[O:2])[CH3:19]
Reactant: CCN(CC)CC
Reactant: O=Cc1c(O)cccc1OCCCCC(=O)O
Agent: CCOC(=O)Cl
Solvent: CCNCC
Solvent: CCOCC
Solvent: O
Product: CCN(CC)C(=O)CCCCOc1cccc(O)c1C=O
Reaction time: 0.08 h

Procedure:
5-(2-Formyl-3-hydroxyphenoxy)pentanoic acid (595 mg, 2.5 mM) was dissolved in dry dichloromethane (7.5 ml) under nitrogen with stirring and immersed in a cooling bath kept at -10° C. To this solution was added dropwise from a syringe triethylamine (0.35 ml, 2.5 mM). After 5 minutes was then similarly added ethyl chloroformate (0.25 ml, 2.5 mM). After 15 minutes was then similarly added diethylamine (0.26 ml, 2.5 mM). The reaction mixture was stirred at -10° C. (10 minutes) and then allowed to warm to 10°-15° C. After diluting with ether (50 ml) and water the aqueous layer was removed and the organic phase washed with dilute sodium bicarbonate solution and then quickly extracted with 2 N sodium hydroxide solution (1×25 ml). The layers were separated and the aqueous phase immediately acidified with dilute hydrochloric acid and extracted with ether/ethyl acetate. The combined extracts were washed with dilute sodium bicarbonate solution, water, dried (sodium sulphate) and evaporated. The oily residue was chromatographed on a short column of kieselgel G (40 g) eluting with chloroform-methanol (95:5) to give N,N-diethyl 5-(2-formyl-3-hydroxyphenoxy)pentanamide as a colourless oil, homogeneous by chromatography (chloroform:methanol, 95:5; Rf 0.35) and having NMR, IR and UV spectra consistent with the assigned structure.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]3([OH:24])[CH2:23][CH2:22][S:21][CH2:20][CH2:19]3)=[CH:11][C:10]=2[CH3:25])[CH:6]=[CH:7][CH:8]=1.[F:26][C:27]1[CH:32]=[C:31](O)[CH:30]=[CH:29][C:28]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[F:26][C:27]1[CH:32]=[C:31]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[C:10]([CH3:25])=[CH:11][C:12]([O:16][CH2:17][C:18]4([OH:24])[CH2:23][CH2:22][S:21][CH2:20][CH2:19]4)=[CH:13][C:14]=3[CH3:15])[CH:6]=[CH:7][CH:8]=2)[CH:30]=[CH:29][C:28]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Reactant: Cc1cc(OCC2(O)CCSCC2)cc(C)c1-c1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(OCC4(O)CCSCC4)cc3C)c2)cc1F
Yield: 89.4 %

Procedure:
To a solution of 4-({[3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-yl]oxy}methyl)tetrahydro-2H-thiopyran-4-ol (0.90 g, 2.51 mmol), ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate (0.56 g, 2.64 mmol) and tributylphosphine (0.86 mL, 3.26 mmol) in tetrahydrofuran (20 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.85 g, 3.26 mmol) at room temperature with stirring, and the mixture was stirred for 10 hrs. The resulting precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) to give the title compound (1.24 g, yield 89%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)=[O:19])=[CH:13][C:11]=3[CH:12]=2)=[CH:6][C:5]([B:28]2[O:32]C(C)(C)C(C)(C)[O:29]2)=[CH:4][N:3]=1.Cl>O1CCCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([B:28]([OH:29])[OH:32])=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)=[O:19])=[CH:13][C:11]=2[CH:12]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc3sc(-c4cc(B5OC(C)(C)C(C)(C)O5)cnc4N)cc3c2)c1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Nc2ccc3sc(-c4cc(B(O)O)cnc4N)cc3c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the solution of 1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-1-benzothien-5-yl}-3-(3-methylphenyl)urea (500 mg, 1 mmol, 1 eq) in tetrahydrofuran (6 mL) at room temperature was added dropwise aqueous HCl (3N, 6 mL) and the reaction was stirred at room temperature for 4 hours. The reaction mixture was filtered directly through a Buchner funnel, rinsed with isopropanol, followed by i-PrOH—H2O (1:1) to give {6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]pyridin-3-yl}boronic acid as a white solid in amount of 384 mg.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]3[CH2:12][CH2:11][C:10](=[CH:13][C:14]#[N:15])[C:8]3=2)[O:3][CH2:2]1.N.C(O)C>CO.[Co]>[CH2:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]3[CH2:12][CH2:11][C:10](=[CH:13][CH2:14][NH2:15])[C:8]3=2)[O:3][CH2:2]1
Reactant: N#CC=C1CCc2cnc3c(c21)CCO3
Agent: [Co]
Agent: N
Solvent: CO
Solvent: CCO
Product: NCC=C1CCc2cnc3c(c21)CCO3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1,2,6,7-tetrahydro-8H-cyclopenta[d]furo[2,3-b]pyridine-8-ylideneacetonitrile (84.9 mg, 0.428 mmol) in methanol (3 mL) were added Raney cobalt (400 mg) and 2M ammonia/ethanol solution (1.5 mL), and the mixture was stirred at room temperature for 4 hr under a hydrogen atmosphere. The catalyst was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound. The obtained title compound was used for the reaction in Example 19 without purification.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10](COCC[Si](C)(C)C)[C:9]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]#[C:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=4)=[CH:24][CH:23]=3)=[N:8][C:7]=2[N:6]([CH2:43][CH2:44][CH3:45])[C:5]1=[O:46])[CH2:2][CH3:3].Cl>C(O)C>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]#[C:31][C:32]4[CH:33]=[CH:34][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:36][CH:37]=4)=[CH:24][CH:23]=3)=[N:8][C:7]=2[N:6]([CH2:43][CH2:44][CH3:45])[C:5]1=[O:46])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2c(nc(-c3ccc(OCC#Cc4ccc(OC(F)(F)F)cc4)cc3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Agent: Cl
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(-c3ccc(OCC#Cc4ccc(OC(F)(F)F)cc4)cc3)nc2n(CCC)c1=O
Temperature: 85 °C
Yield: 131.2 %

Procedure:
A mixture of 1,3-dipropyl-8-{4-[3-(4-trifluoromethoxy-phenyl)-prop-2-ynyloxy]-phenyl}-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.053 g, 0.055 mmol), 2N HCl (2 ml), ethanol (2 ml) was heated at 85° C. for 2 hours. The mixture was cooled and the solvent was evaporated. The residue was washed with n-pentane to obtain 1,3-dipropyl-8-{4-[3-(4-trifluoromethoxy-phenyl)-prop-2-ynyloxy]-phenyl}-3,7-dihydro-purine-2,6-dione (0.038 g, 88%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8]([C:10]1[CH:11]=[N:12][C:13](Cl)=[CH:14][C:15]=1[C:16]1[C:17]([CH3:22])=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:9].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>ClCCl>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8]([C:10]1[CH:11]=[N:12][C:13]([N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[CH:14][C:15]=1[C:16]1[C:17]([CH3:22])=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:9]
Reactant: Cc1ncccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: Cc1ncccc1-c1cc(N2CCN(C)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
2-Methyl-6′-(4-methyl-piperazin-1-yl)-[3,4′]bipyridinyl-3′-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide of formula I-1 is prepared as follows: A mixture of 6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide and 1-methylpiperazine is heated at about 120° C. for 2 h. After cooling to room temperature the mixture is diluted with dichloromethane and washed with water. The aqueous layer is worked up in conventional manner to give the compound 2-methyl-6′-(4-methyl-piperazin-1-yl)-[3,4′]bipyridinyl-3′-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide of formula I-1.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+].II.CO>C1COCC1>[CH3:1][NH:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CNC(=O)COc1cccc2ccccc12
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCCOc1cccc2ccccc12
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 11.9 %

Procedure:
At 0° C., a solution of N-methyl-2-(1-naphthyloxy)acetamide (17.4 g, 81.1 mmol) in THF (100 ml) was added dropwise to a suspension of sodium borohydride (7.35 g, 195 mmol) in THF (100 ml). The reaction mixture was stirred for 15 min at this temperature. A solution of iodine (20.6 g, 81 mmol) in THF (200 ml) was added dropwise. The reaction mixture was heated to 70° C. for 16 hours. It was cooled to 0° C. Methanol (250 ml) was added dropwise. The solvents were removed in vacuo. The residue was dissolved in a mixture of tert-butyl methyl ether (200 ml) and a 20% aqueous solution of sodium hydroxide (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2×100 ml). The combined organic layers were dried over magnesium sulphate. The crude product was purified by flash chromatography on silica (200 g), using DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 1.94 g of N-methyl-N-[2-(1-naphthyloxy)ethyl]amine.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:19]([O-])=O)=[C:13]([CH:18]=1)[C:14]([NH:16][CH3:17])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S1C=CC=C1.COCCO.[H][H]>CO.[Pd]>[NH2:19][C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:18][C:13]=1[C:14]([NH:16][CH3:17])=[O:15]
Reactant: [H][H]
Reactant: CNC(=O)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: COCCO
Solvent: CO
Solvent: c1ccsc1
Product: CNC(=O)c1cc(C(=O)c2ccccc2)ccc1N
Yield: 79.3 %

Procedure:
A mixture of 6.5 parts of intermediate 21, namely 5-benzoyl-N-methyl-2-nitrobenzamide, 2 parts of a solution of thiophene in methanol 4% and 97 parts of 2-methoxyethanol was hydrogenated at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was recrystallized from 2-propanol, yielding 4.64 parts (79.3%) of 2-amino-5-benzoyl-N-methylbenzamide; mp. 140.5° C. (interm. 22).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH2:3][CH3:4].[CH3:7][N:8]([CH3:31])[C:9]1(C#N)[CH2:14][CH2:13][CH:12]([CH:15]([O:23][CH:24]([O:26][CH2:27][CH3:28])[CH3:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10]1.O.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C:9]1([N:8]([CH3:31])[CH3:7])[CH2:14][CH2:13][CH:12]([CH:15]([O:23][CH:24]([O:26][CH2:27][CH3:28])[CH3:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(C)OC(Cc1ccccc1)C1CCC(C#N)(N(C)C)CC1
Reactant: CCCC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC1(N(C)C)CCC(C(Cc2ccccc2)OC(C)OCC)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 2 M solution of n-butylmagnesium chloride in tetrahydrofuran (4.62 ml, 9.25 mmol) was added dropwise to a solution of 1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexanecarbonitrile (1.06 g, 3.1 mmol) in tetrahydrofuran (15 ml), while cooling with ice and under an argon atmosphere. The mixture was stirred at room temperature for 48 h and thereafter water and saturated ammonium chloride solution (10 ml of each) were added. The phases were separated and the aqueous phase was extracted with diethyl ether (3×10 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: [N:1]1[C:2]2[N:3]([C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:4]=[CH:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[N:11][CH:12]=1.CC1C=CC(S(O[CH2:32][CH2:33][CH2:34][F:35])(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.CCOC(C)=O>[F:35][CH2:34][CH2:33][CH2:32][O:13][C:10]1[N:11]=[CH:12][C:7]([C:6]2[CH:5]=[CH:4][N:3]3[C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=4[N:16]=[C:2]3[N:1]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCF)cc1
Reactant: Oc1ccc(-c2ccn3c(n2)nc2ccccc23)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: FCCCOc1ccc(-c2ccn3c(n2)nc2ccccc23)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
To 5-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)pyridin-2-ol (8 mg, 0.03 mmol), and 3-fluoropropyl 4-methylbenzenesulfonate (21 mg, 0.09 mmol) in 0.3 mL of NMP was added Cs2CO3 (15 mg, 0.045 mmol). The reaction was stirred at rt for 4 h and diluted with EtOAc (10 mL). The mixture was washed with water (3×10 mL) and dried over MgSO4 and concentrated under reduced pressure. The residue was purified by reversed phase HPLC (water/MeCN with TFA buffer) to afford 2-(6-(3-fluoropropoxy)pyridin-3-yl)benzo[4,5]imidazo[1,2-a]pyrimidine as a off-white solid (3 mg, 31%). 1H NMR (400 MHz, methanol-d4): δ 9.79 (d, J=7.2 Hz, 1H), 8.66 (d, J=2.8 Hz, 1H), 8.69 (dd, J=8.8, 2.8 Hz, 1H), 8.40 (d, J=8.8 Hz, 1H), 8.29 (d, J=7.2 Hz, 1H), 7.90-7.82 (m, 2H), 7.72 (m, 1H), 7.04 (d, J=8.8 Hz, 1H), 4.68 (t, J=5.6 Hz, 1H), 4.57 (t, J=6.4 Hz, 2H), 4.56 (t, J=5.6 Hz, 1H), 2.30-2.16 (m, 2H); MS (ESI) m/z [M+H]+323.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[N:11]([N:19]=[C:20]([NH2:22])[N:21]=3)[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Mg].II>CO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH:13]([C:15]([F:17])([F:16])[F:18])[CH2:12][N:11]3[N:19]=[C:20]([NH2:22])[N:21]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1nc2c(-c3ccc(F)c(F)c3)cc(C(F)(F)F)cn2n1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc2n(n1)CC(C(F)(F)F)CC2c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 8-(3,4-difluorophenyl)-6-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (500 mg, 1.59 mmol) and magnesium (309 mg, 12.7 mmol) in methanol (80 mL) and THF (40 mL) was added iodine (2 mg, 7.88 μmol), stirred for 10 minutes at room temperature, then sonicated for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was dissolved in THF and dried over Na2SO4, then filtered off, washed thoroughly with THF and the solvents were evaporated. The crude material was purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). The title compound was obtained as mixture of racemic diastereomers as white solid (324 mg, 64%).
Reaction SMILES: C1(C2C=CC3C(=C(N)C=CC=3)N=2)C=CC=CC=1.C(OC(N1CCC(C(O)=O)CC1)=O)(C)(C)C.[C:34]1([C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[C:43]([NH:50][C:51]([CH:53]4[CH2:58][CH2:57][N:56](C(OC(C)(C)C)=O)[CH2:55][CH2:54]4)=[O:52])[CH:44]=[CH:45][CH:46]=3)[N:41]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:34]1([C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[C:43]([NH:50][C:51]([CH:53]4[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]4)=[O:52])[CH:44]=[CH:45][CH:46]=3)[N:41]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc3ccc(-c4ccccc4)nc23)CC1
Agent: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Nc1cccc2ccc(-c3ccccc3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc2ccc(-c3ccccc3)nc12)C1CCNCC1

Procedure:
2-Phenylquinolin-8-amine (60 mg, 0.27 mmol) was subjected to the same general amide coupling procedure outlined above using 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid. The resulting intermediate, namely tert-butyl 4-(2-phenylquinolin-8-ylcarbamoyl)piperidine-1-carboxylate, was further treated with 2 mL of 25% TFA in CH2Cl2 for 6 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (using aqueous CH3CN that has been buffered with 0.1% TFA) to afford 25 mg of the product. MS (ESI) calcd for C21H21N3O (m/z): 331.17. found: 332 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[CH:8][C:9]=1[CH3:10])=[O:4].[NH2:14][CH:15]([C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)[CH3:16].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:13])[NH:14][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[CH3:16])=[CH:8][C:9]=1[CH3:10])=[O:4]
Reactant: CC(N)c1cccc(O)c1
Reactant: COC(=O)c1sc(C(=O)O)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C(=O)NC(C)c2cccc(O)c2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of 3-methyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (0.1 g, 0.5 mmol) and 3-(1-amino-ethyl)-phenol (82 mg, 0.6 mmol) in DMF (4 ml) was added at rt triethylamine (0.1 ml, 0.75 mmol), HOBT (81 mg, 0.6 mmol) and HBTU (228 mg, 0.6 mmol). The mixture was stirred at rt for 30 min, then quenched with 1NHCl and extracted with EtOAc. The layers were separated. The organic layer was washed with brine, then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 30-70% EtOAc in hexane to afford the desired product (121 mg, 75% yield).
Reaction SMILES: C(C1C=CC(CC[OH:9])=CC=1)#N.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.[C:30]1([P:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:43]1([P:36](=[O:9])([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: N#Cc1ccc(CCO)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
Ethyl 2-ethoxy-3-(4-hydroxyphenyl) propanoate, described in example 3(b)(6.62 g; 27.78 mmole) and p-cyanophenethyl alcohol (2.73 g; 18.52 mmole) were mixed in dichloromethane (85 ml). ADDP (7.01 g; 27.78 mmole) was added followed by addition of triphenylphosphine (5.83 g; 22.23 mmole). The reaction was interrupted after 2 hours. Triphenylphosphine oxide formed in the reaction was filtered off and the filtrate was evaporated. The residue was purified bychromatography on silica gel using first dichloromethane and then petroleum ether:diethyl ether as eluants giving a mixture of product and starting material which was dissolved in ethyl acetate and washed with sodium hydroxide (1 N). The organic phase was washed with water, dried (sodium sulfate), filtered and the solvent was evaporated to give 4.23 g (yield 62%) of the desired product.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[CH:5][C:6]([N:18]2[C:22]([CH2:23][N:24]3C(=O)C4=CC=CC=C4C3=O)=[N:21][N:20]=[C:19]2[CH2:35][N:36]2C(=O)C3=CC=CC=C3C2=O)=[C:7]([CH:17]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])=O.O.NN>C(O)C>[F:1][C:2]([F:47])([F:48])[C:3]1[CH:4]=[CH:5][C:6]2[N:18]3[C:19]([CH2:35][NH2:36])=[N:20][N:21]=[C:22]3[CH2:23][N:24]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[C:7]=2[CH:17]=1
Reactant: O=C(c1ccccc1Cl)c1cc(C(F)(F)F)ccc1-n1c(CN2C(=O)c3ccccc3C2=O)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 22, 5-trifluoromethyl-2'-chloro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol4-yl]benzophenone in ethanol is heated with hydrazine hydrate to give 8-trifluoromethyl-1-(aminomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[CH:14][NH:13][C:12]1=[S:16].[C:17]([O-])(=[O:19])C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.C1C=CC=CC=1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[C:14]([CH:17]=[O:19])[NH:13][C:12]1=[S:16]
Reactant: CC(=O)[O-]
Reactant: S=c1[nH]ccn1C1CCc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Pb+4]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: O=Cc1cn(C2CCc3ccccc3C2)c(=S)[nH]1
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
A suspension of 4-(1R,2R,3S,4)-tetrahydroxybut-1-yl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (0.252 g, 0.72 mmol) and lead tetraacetate (0.851 g, 1.92 mmol) in 15 mL of 33% acetic acid/benzene was stirred until the mixture was homogenous and 30 minutes. The reaction mixture was poured into 125 mL of saturated sodium carbonate solution and the mixture was filtered. The organic layer was separated, dried over magnesium sulfate and concentrated. The residue was dissolved in 40 mL of THF and 2 mL of sulfurous acid (6% SO2). Evaporation of the solvent gave 3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-5-carbaldehyde (0.15 g, 0.59 mmol), m.p. 206°-210° C.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[CH2:8]([NH:10][C:11]1[C:16]([C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=O)=[CH:15][CH:14]=[CH:13][N:12]=1)[CH3:9].O>O1CCCC1>[CH2:8]([N:10]1[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:16]=2[C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[N:5][C:6]1=[O:7])[CH3:9]
Reactant: CCNc1ncccc1C(=O)c1cccs1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(=O)nc(-c2cccs2)c2cccnc21
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
Chlorosulfonyl isocyanate (0.5 ml, 5.6 mmol) was added to a solution of 2-ethylamino-3-(2-thiophenecarbonyl)pyridine (1.01 g, 4.35 mmol) in tetrahydrofuran (50 ml) under ice-cooling, followed by stirring for 30 minutes. The reaction solution was mixed with water and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the resulting filtrate was concentrated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform-ethyl acetate) and recrystallized from ethyl acetate to give 1-ethyl-4-(2-thienyl)pyrido[2,3-d]pyrimidin-2(1H)-one (613 mg, 2.38 mmol, 55%).
Reaction SMILES: C([CH:3]([C:26]([OH:28])=[O:27])[N:4]([C:16](OCC1C=CC=CC=1)=O)[CH2:5][P:6]([CH2:12][CH:13]([CH3:15])[CH3:14])([CH2:8][CH:9]([CH3:11])[CH3:10])=[S:7])C.Br.[CH3:30]COCC>C(O)(=O)C>[CH2:16]([N:4]([CH2:5][P:6]([CH2:12][CH:13]([CH3:15])[CH3:14])([CH2:8][CH:9]([CH3:11])[CH3:10])=[S:7])[CH2:3][C:26]([OH:28])=[O:27])[CH3:30]
Reactant: CCC(C(=O)O)N(CP(=S)(CC(C)C)CC(C)C)C(=O)OCc1ccccc1
Reactant: CCOCC
Agent: Br
Solvent: CC(=O)O
Product: CCN(CC(=O)O)CP(=S)(CC(C)C)CC(C)C
Reaction time: 1 h

Procedure:
Ethyl N-carbobenzoxy-N-(diisobutylthiophosphinylmethyl)glycine (4 g., 0.009 mole) was dissolved in 10 ml. of 35% hydrogen bromide in glacial acetic acid at 0° C. The mixture was stirred for one hour. Ether was added and the oily precipitate isolated by decanting the ether layer. The oil was washed twice with diethyl ether and then suspended in benzene and treated with propylene oxide. The solution was concentrated in vacuo to yield ethyl N-(diisobutylthiophosphinylmethyl)glycine (0.3 g., 0.001 mole) as an oil, ND25 =1.5121.