Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=1.C(Cl)(=O)C(Cl)=O.[NH2:22][N:23]1[CH2:28][C:27]([CH3:29])=[N:26][NH:25][C:24]1=[O:30].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:29][C:27]1[CH2:28][N:23]([NH:22][C:13]([C:10]2[CH:11]=[N:12][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][CH:9]=2)=[O:15])[C:24](=[O:30])[NH:25][N:26]=1
Reactant: CC1=NNC(=O)N(N)C1
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1=NNC(=O)N(NC(=O)c2cnc(-c3ccccn3)nc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
To a solution of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (0.152 g, 0.75 mmol), in dry DCM (3 mL) and DMF (0.9 μL) in a dry flask under N2 is added oxalyl chloride (74 μL, 0.86 mmol). The reaction mixture is stirred at rt for 1 h. The solvent is evaporated and toluene is added and evaporated three times. The residue is dissolved in dry DCM (3 mL), and a solution of 4-amino-6-methyl-4,5-dihydro-2H-1,2,4-triazin-3-one (0.77 g, 0.6 mmol) in DCM (5 mL) is added followed by the addition of DIPEA (0.14 mL, 0.79 mmol). The mixture is stirred at rt overnight, and then concentrated in vacuo. The residue is diluted with water and adjusted to pH ˜8.5 with saturated aqueous NaHCO3 solution. The resulting precipitate is filtered to afford 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (6-methyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)amide (0.043 g, 23%). MS: 312 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.95 (s, 1H), 9.31 (s, 2H), 8.78 (d, 1H), 8.45 (d, 1H), 8.01 (tr, 1H), 7.58 (dd, 1H), 4.22 (2, 2H), 1.91 (s, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18]>>[CH2:17]([O:19][P:20]([CH2:13][C:12]1[CH:15]=[CH:16][C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)(=[O:24])[O:21][CH2:22][CH3:23])[CH3:18]
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(C(=O)c2ccccc2)cc1)OCC
Temperature: 125 °C

Procedure:
A mixture of 4.8 g of 4-benzoylbenzyl bromide and triethylphosphite was heated at 125° C. for 0.5 hours and cooled to room temperature. The resulting oil was purified by flash chromatography (70% ethyl acetate/hexanes) to afford 3.2 g of diethyl 4-benzoylbenzylphosphonic acid, as an oil. A mixture of 3.2 g (9.6 mmol) of diethyl 4-benzoylbenzylphosphonic acid and 40 ml of concentrated hydrochloric acid was refluxed for 7 hours and cooled to room temperature. The two phase mixture was partitioned between 125 ml of water and 400 ml of EtOAc, the EtOAc layer was dried over Na2SO4, filtered and evaporated to give 0.7 g of product; m.p. 172°-175° C.
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[OH:36][C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1.O1C2C=CC(C3(C(NC4C=CC(C(N(C)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH:6]([N:39]5[CH2:40][CH2:41][C@@H:37]([OH:36])[CH2:38]5)[C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])=[CH:16][N:17]=4)=[O:23])[CH2:26][CH2:25]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: O[C@@H]1CCNC1
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Product: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N1CC[C@@H](O)C1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-(((R)-3-hydroxypyrrolidin-1-yl)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and (R)-3-hydroxypyrrolidine in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11]O)=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)C=C(CO)C=1.O=S(Cl)[Cl:27]>C(Cl)Cl>[ClH:27].[Cl:27][CH2:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccnc2ccccc12
Agent: OCc1cnc2ccccc2c1
Solvent: ClCCl
Product: Cl
Product: ClCc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of quinolin-4-ylmethanol MDE 32014 (0.28 g, 1.76 mmol) in dry CH2Cl2 (18 mL) at 0° C. under N2 in a 50 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (2.6 mL, 36.0 mmol) and the mixture was stirred for 1 h at RT. The volatiles were then removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give 4-(chloromethyl)quinoline hydrochloride MDE 32016 as an off-white solid (246 mg, 65% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5])C.[OH-].[Li+]>CO.O>[C:4]([C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ncccc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To a solution of 2-ethoxycarbonyl-3-nitropyridine (0.5 g, 2.5 mmoL, 1 eq.) in 20 mL of methanol and 5 mL of water was added lithium hydroxide (0.2 g, 4.5 mmoL, 1.8 eq.) and the mixture stirred for 16 hours at ambient temperature. The reaction was concentrated and 50 mL of 1N KOH was were added. The solution was washed with 25 mL of ethyl actetate, acidified with 1 N HCl, and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate extractions were dried over sodium sulfate and concentrated to give 2-carboxy-3-nitropyridine as a yellow solid (0.4 g, 95% yield).
Reaction SMILES: C(NC1CCC([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])CC1)(C)C.[N:20]1([CH:29]=[O:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2N=N1.[CH2:31]1[CH2:35]OC[CH2:32]1>>[CH:31]([C:29]([NH:20][CH:24]1[CH2:25][CH2:26][CH:27]([N:12]([CH3:11])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:28][CH2:23]1)=[O:30])([CH3:35])[CH3:32]
Reactant: CC(C)NC1CCC(CNC(=O)OC(C)(C)C)CC1
Reactant: O=Cn1nnc2ccccc21
Reactant: C1CCOC1
Product: CC(C)C(=O)NC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of a tert-butyl N-[4-(isopropylamino)-cyclohexyl]methylcarbamate (7.89 mmol, 1 equivalent) in 5 ml of THF was added dropwise to a solution of 1H-benzotriazole-1-carboxaldehyde (8.68 mmol, 1.2 equivalents) in 10 ml of THF at room temperature. The reaction mixture was stirred overnight and heated at reflux temperature for two hours. 1H-benzotriazole-1-carboxaldehyde (additional 1 equivalent) was added to the reaction mixture and stirred overnight. The solvent was removed and dichloromethane was added to the residue. The organic phase was washed with 2N NaOH solution, saturated with NaCl solution, dried over Na2SO4, the solvent removed, and the residue chromatographed to give tert-butyl N-[4-(isopropylformylamino)cyclohexyl]-methyl-carbamate: 100% yield, 299 (ESMS, MH+); 1H NMR (CD3OD) δ 8.22 & 8.18 (two s, 1H), 4.63 (broad, 1H), 4.30 & 3.60 (two m, 1H), 3.76 (m, 1H), 2.99 (m, 2H), 1.44 (s, 9H), 1.27 (d, 3H, J=6.5 Hz), 1.21 (d, 3H, J=6.5 Hz), 1.91-0.82 (m, 9H).
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:4][N:5]2[C:10]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][C:6]=12.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].CCOCC>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]1([NH:11][C:10]2[N:5]3[N:4]=[C:3]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[C:2]([C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)=[C:6]3[CH:7]=[CH:8][CH:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Fc1ccc(-c2nn3c(NC4CCCC4)cccc3c2Br)cc1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Fc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccncc2)cc1
Temperature: 25 °C
Yield: 46 %

Procedure:
To a solution of 3-bromo-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-amine (106 mg, 0.28 mmol) in N,N-dimethylformamide (5 mL) was added 4-pyridinylboronic acid (70 mg, 0.56 mmol), sodium carbonate (0.28 mL, 2 M aqueous, 0.56 mmol) and dichlorobis(triphenylphosphine)palladium(II) (10 mg, 0.01 mmol). The resultant solution was heated to 100° C. for 18 hours. The reaction mixture was cooled to room temperature and ether was added. The organic layer was washed with water and brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (2:1 hexanes:ether) provided N-cyclopentyl-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridin-7-amine (48 mg, 46%) as a yellow solid. 1H NMR (CDCl3): δ 8.50 (d, 2H), 7.53 (m, 2H), 7.22–7.18 (m, 3H), 7.06–6.97 (m, 3H), 6.00 (d, 1H), 5.95 (d, 1H), 3.99 (m, 1H), 2.16–2.08 (m, 2H), 1.83–1.66 (m, 6H); 13C NMR (CDCl3) δ 162.99 (d, JCF=246.6 Hz), 150.07, 149.98, 142.77, 141.98, 140.13, 131.02 (d, JCF=8.0 Hz), 129.04, 127.64, 123.98, 115.56 (d, JCF=21.2 Hz), 106.51, 102.22, 89.25, 53.88, 33.36, 24.05; 19F NMR (CDCl3) δ −113.49; MS m/z 373 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=O.[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.O=[C:20]([CH2:27][CH2:28][CH3:29])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([CH2:27][CH2:28][CH3:29])[NH:13][C:14]2=[N:15][NH:16][CH:17]=[C:18]12
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: Nc1cc[nH]n1
Product: CCCC1=C(C(=O)OCC)C(c2cc(OC)ccc2OC)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2,5-dimethoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O.C(OCC)(=O)C>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Brc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
4-Bromophenol (2 g, 0.0116 mol) in acetone (40 mL) was treated with potassium carbonate anhydrous (1.91 g, 1.2 equivalents) and benzyl bromide (1.44 mL, 1.05 equivalents). The reaction was refluxed under a nitrogen atmosphere. After 5-6 hours reflux, the reaction was cooled to room temperature and diluted with an equal volume of ethyl acetate. This solution was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. A white fluffy solid was obtained. Yield=2.36 g (73%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8](Cl)[N:9]=2)[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C(N(CC)CC)C>CN(C=O)C.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]>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:18]3[CH:19]=[CH:20][S:16][CH:17]=3)[N:9]=2)[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1sc2ncc(Cl)nc2c1N
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc2ncc(-c3ccsc3)nc2c1N
Temperature: 95 °C
Yield: 88 %

Procedure:
A solution of the methyl 7-amino-2-chlorothieno[2,3-bjpyrazine-6carboxylate prepared as described in Example 10C (0.190 g), thiophene-3-boronic acid (0.100 g), Pd(dppf)Cl2 (0.032 g) and triethylamine (0.22 mL) in degassed DMF was heated to 95° C. for 4 h, cooled, quenched in water and extracted with 1:1Et2O/EtOAc (3×). The organics were washed 3× with water, brine, dried (Na2SO4), filtered and solvent evaporated to give 0.200 g (88%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.95 (3H, s), 6.23 (2H, br s), 7.50 (1H, dd), 7.79 (1H, dd), 8.05 (1H, dd), 9.00 (1H, s).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.[C:32]([O:35]CC)(=[O:34])C.Cl.[C:39](=[O:42])([OH:41])[O-].[Na+]>C(O)C>[C:32]([OH:35])(=[O:34])[C:39]([OH:41])=[O:42].[O:2]=[C:3]1[C:8]([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:14][CH2:15]2)=[CH:7][CH:6]=[CH:5][NH:4]1
Reactant: O=C([O-])O
Reactant: COc1ncccc1CN1CCC(CCc2ccccc2OCC2CCCCC2)CC1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(=O)O
Product: O=c1[nH]cccc1CN1CCC(CCc2ccccc2OCC2CCCCC2)CC1

Procedure:
In ethanol (4 ml) was dissolved 226 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-[2-(cyclohexylmethyloxy)phenyl]ethyl]piperidine. To the mixture was added 1 ml of a 4N-hydrogen chloride-ethyl acetate solution, followed by heating under reflux for 1.5 hours. An aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting oil was dissolved in ethanol, 49 mg of oxalic acid and ethyl acetate were added thereto, and then the resulting precipitates were collected by filtration, to give 229 mg of the title compound as a white powder.
Reaction SMILES: [H-].[Na+].FC(F)(F)[C:5]([N:7]([CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)C)=O.O.Cl>CO.C1COCC1>[CH3:5][NH:7][CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(CCN(C)C(=O)C(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CNCCc1ccc(C(=O)OC)cc1
Temperature: 22 °C
Reaction time: 36 h

Procedure:
A solution of 0.80 g (5.5 mmol) of sodium hydride (60% mineral oil dispersion) dissolved in 20 mL of methanol was prepared and added to a separate solution of 1.05 g (3.64 mmol) of methyl 4-(2-(2,2,2-trifluoro-N-methylacetamido)ethyl)benzoate dissolved in 12 mL of THF at 0° C. The solution was warmed to 22° C. and stirred for about 36 h. Water was added (100 mL) and the solution was acidified to pH 1 with 1 N HCl. The mixture was washed with DCM (2×100 mL) and then basified with 1 N NaOH to pH 8-9. The aqueous solution was extracted with DCM (3×100 mL) and the organic extracts dried (Na2SO4) and evaporated to give 2b as a white solid which was used without further purification in the subsequent transformation.
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:25])[CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[N:11][C:10]=2[CH3:26])[N:8]=1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([CH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:25])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[N:11][C:10]=2[CH3:26])[N:8]=1)#[N:2]
Reactant: Cc1nc(NC(=O)CCC(=O)OC(C)(C)C)sc1-c1csc(CC#N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(NC(=O)CCC(=O)O)sc1-c1csc(CC#N)n1
Temperature: 25 °C

Procedure:
Tert-butyl 4-{[2-(cyanomethyl)-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl]amino}-4-oxobutanoate, Compound (58), (63 mg; 0.16 mmol; 1 eq.), is dissolved in DCM (3 ml). Trifluoroacetic acid (0.16 ml; 2.09 mmol; 13 eq) is added dropwise and the reaction mixture is stirred at RT. The solvents are evaporated and the crude product is purified by preparative HPLC, affording Compound (63) as a white-off solid (54 mg; 29%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[C:8](OC(C)C)[C:7]=2[CH:18]=1.N[C:20]1[NH:24][N:23]=[N:22][N:21]=1.C([N:27](CC)CC)C.C(O)(=O)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH2:27])=[O:13])=[C:8]([C:20]3[NH:24][N:23]=[N:22][N:21]=3)[C:7]=2[CH:18]=1
Reactant: CCN(CC)CC
Reactant: Nc1nnn[nH]1
Reactant: COc1ccc2oc(C(=O)O)c(OC(C)C)c2c1
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccc2oc(C(N)=O)c(-c3nnn[nH]3)c2c1
Temperature: 0 °C
Yield: 82 %

Procedure:
A mixture of 5.7 g (0.023 mole) of 5-methoxy-3-(1-methylethoxy)-2-benzofurancarboxylic acid and 4.2 g (0.026 mole ) of 1,1-carbonylbis(1H-imidazole) in 140 ml of acetonitrile is stirred at reflux for one hour. The mixture is cooled, treated with 2.3 g (0.027 mole) of anhydrous 5-aminotetrazole plus 7.7 ml (5.6 g; 0.055 mole) of triethylamine, and heated at reflux for an additional five hours. The cooled reaction mixture is added to 1.5 kg of ice/water and acidified with glacial acetic acid to precipitate the tetrazole product. The precipitate is filtered, washed with water, and recrystallized from aqueous acetonitrile to yield 6.0 g (82% yield) of the analytically pure 5-methoxy3-tetrazol-5-yl-2-benzofurancarboxamide, mp 241°-245° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OC(O)C)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][CH:6]=1)[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: CCOC(C)O
Product: CCOC(=O)c1ccc(Nc2ccccc2)nc1
Yield: 87.9 %

Procedure:
A mixture of 6-chloronicotinic acid ethyl ester (0.2 g, 0.00108 mole) and aniline (0.119 g, 0.00129 mole) in ethoxyethanol (10 mL) was heated to reflux for overnight. The mixture was then concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (5% ethyl acetate in hexane) to afford 0.23 g (88%) of 6-phenylamino-nicotinic acid ethyl ester. To a stirred solution 6-phenylamino-nicotinic acid ethyl ester (0.23 g, 0.00095 mol) in a mixture of THF (4 mL), methanol (4 mL) and H2O (2 mL) was added LiOH.H2O (0.159 g, 0.0038 mol) at ambient temperature and the resulting mixture was stirred overnight. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous citric acid solution. The resulting precipitate was isolated by filtration and dried to afford 0.174 g (85%) of 6-Phenylamino-nicotinic acid.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][S:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH3:11][C:12]1[CH:13]=C(O)[CH:15]=[C:16]([CH:18]=1)[OH:17]>>[OH:17][C:16]1[C:15]2[C:2]3[CH2:6][CH2:5][S:4][C:3]=3[C:7](=[O:8])[O:9][C:10]=2[CH:11]=[C:12]([CH3:13])[CH:18]=1
Reactant: COC(=O)C1SCCC1=O
Reactant: Cc1cc(O)cc(O)c1
Product: Cc1cc(O)c2c3c(c(=O)oc2c1)SCC3

Procedure:
Following a procedure similar to that described in Example 1B hereinabove, methyl 3-oxo-2,3,4,5-tetrahydrothiophene-2-carboxylate is reacted with 5-methylresorcinol to give 1,2-dihydro-9-hydroxy-7-methyl-4-oxo-4H-thieno[2,3-c] [1]benzopyran.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:15].[Cl:16][C:17]1[N:18]=[C:19]([C:24](O)=[O:25])[NH:20][C:21]=1[CH2:22][CH3:23].O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>>[Cl:16][C:17]1[N:18]=[C:19]([C:24]([NH:1][C@@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][C@H:3]2[OH:15])=[O:25])[NH:20][C:21]=1[CH2:22][CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)nc1Cl
Yield: 92 %

Procedure:
The same operation as in Example (196b) was performed using tert-butyl trans(±)-4-amino-3-hydroxypiperidine-1-carboxylate synthesized in Example (201a) (600 mg, 2.77 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (2405d) (484 mg, 2.77 mmol), 1-hydroxybenzotriazole hydrate (562 mg, 4.16 mmol), WSC hydrochloride (798 mg, 4.16 mmol) and triethylamine (580 μL, 4.16 mmol), to obtain 950 mg of the title compound (92%) as a colorless solid.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[S:8][C:9]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[C:10]([OH:13])[C:11]=1[CH3:12])=[O:6])([CH3:3])[CH3:2].[CH2:20]([O:24][C:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]=[C:33]=[O:34])=[O:26])[CH2:21][CH2:22][CH3:23]>C(#N)C.C1N2CCN(CC2)C1>[CH:1]([O:4][C:5]([C:7]1[S:8][C:9]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[C:10]([O:13][C:33]([NH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:25]([O:24][CH2:20][CH2:21][CH2:22][CH3:23])=[O:26])=[O:34])[C:11]=1[CH3:12])=[O:6])([CH3:2])[CH3:3]
Reactant: CCCCOC(=O)CCCCCN=C=O
Reactant: Cc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1O
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CCCCOC(=O)CCCCCNC(=O)Oc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1C
Yield: 93.4 %

Procedure:
10.0 g of 2,5-bis-(isopropoxycarbonyl)-3-methyl-4-hydroxythiophene, 20 ml of anhydrous acetonitrile, 15 g of butoxycarbonylpentyl isocyanate (b.p. 149°-151°/13 millibar) and 100 mg of triethylene diamine are maintained at 100° C. for 18 hours. The mixture is diluted with 20 ml of acetonitrile. To remove the excess butoxycarbonylpentyl isocyanate, the reaction mixture is shaken three times with 50 ml of ligroin in each case. The acetonitrile phase is evaporated in vacuo. The evaporation residue is dried at 100° C./0.1 mbar. 16.3 g of 2,5-bis-(isopropoxycarbonyl)-3-methyl-4-[5-(butyloxycarbonyl)pentylaminocarbonyloxy]-thiophene are obtained as a viscous material.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:14])([N+:11]([O-])=O)[CH3:10])=[CH:4][CH:3]=1.[H][H].[CH2:17]([OH:19])C>[Ni]>[CH3:10][C:9]([NH2:11])([CH3:14])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:19][CH3:17])=[CH:3][CH:4]=1
Reactant: CCO
Reactant: [H][H]
Reactant: Cc1ccc(CC(C)(C)[N+](=O)[O-])cc1
Agent: [Ni]
Product: COc1ccc(CC(C)(C)N)cc1

Procedure:
The 1-(4-methylphenyl)-2-methyl-2-nitropropane (1.3 g) was hydrogenated for 5 hours at 65 p.s.i. hydrogen in ethanol (30 mL) using 1.4 g of Raney nickel as catalyst. Removal of the catalyst by filtration and evaporation of the solvent yielded 1.15 g of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine as a clear oil.