Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[C:4]([O:10][CH3:11])[CH:3]=1.[CH:12]([O:17][CH3:18])([O:15][CH3:16])OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:12]([O:15][CH3:16])[O:17][CH3:18])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COC(OC)OC
Reactant: COc1cc(Br)ccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1cc(Br)ccc1C(OC)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4-bromo-2-methoxybenzaldehyde (1 g, 4.67 mmol) was dissolved in MeOH (20 ml) and trimethyl orthoformate (562 μl, 5.139 mmol) and p-toluene sulphonic acid monohydrate (89 mg, 0.467 mmol) were added to the resulting solution. The mixture was stirred overnight at room temperature and then the solvent was removed under vacuo. The residue was taken up with Et2O and washed with 5% Na2CO3 and with water. The organic phase was dried over Na2SO4 and evaporated to give 1.22 g of 4-bromo-1-dimethoxymethyl-2-methoxy-benzene as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.C(OO)(=[O:18])C.C(O)(C)C>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C:7]1[CH:8]=[N+:9]([O-:18])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(Oc2cccnc2)c1
Reactant: CC(=O)OO
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COc1cccc(Oc2ccc[n+]([O-])c2)c1
Temperature: 35 °C
Reaction time: 16 h

Procedure:
A solution of 68 g of 3-(3-methoxyphenoxy)pyridine in 100 ml of glacial acetic acid is treated with 75 g of 40% peracetic acid in acetic acid. The mixture is stirred 16 hours at 35° C. and then is refluxed 1 hour. The mixture is cooled, 100 ml isopropanol added, and the mixture is concentrated at reduced pressure. The oily residue is dissolved in 500 ml of dichloromethane and is washed with excess cold 25% sodium hydroxide solution. The organic layer is concentrated to yield 3-(3-methoxyphenoxy)pyridine 1-oxide, m.p. 75°-77° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.Br>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CCC(C(=O)O)c1ccc(OC)cc1
Agent: Br
Product: CCC(C(=O)O)c1ccc(O)cc1

Procedure:
The m- or p-hydroxyphenyl alkanol can also be prepared using conventional techniques. For example, a m- or p-methoxyphenylbutyric acid can be reacted at reflux temperature with hydrogen bromide to form a m- or p-hydroxyphenylbutyric acid. This acid can then be reacted with borane in tetrahydrofuran to form m- or p-hydroxyphenylbutanol. This latter compound is reported in JACS, 84, 788 (1962).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=2)[N:7]=1.[Cl:19]N1C(=O)CCC1=O.O>C(OCC)(=O)C>[Cl:19][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[C:11]([CH3:17])([CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(C)(C)c1nc2ccc(Cl)nn2c1Cl
Yield: 97.5 %

Procedure:
4.07 g of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate was suspended in 60 ml of ethyl acetate; 2.13 g of N-chlorosuccinimide was added, followed by thermal refluxing for 4 hours. After cooling, water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (5:1). The desired fraction was collected and concentrated under reduced pressure to yield 4.48 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[N:27]1([CH2:36][C:37](O)=[O:38])[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]1=[O:29]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:37](=[O:38])[CH2:36][N:27]1[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]1=[O:29])[CH3:2]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2Cl)s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2Cl)s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(2,4-dichlorophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with (thymin-1-yl)-acetic acid as per the procedure of example 13. 1H NMR (400 MHz; DMSO-d6) δ 11.28 (s, 0.6H), 11.27 (s, 0.4H), 9.11 (brs, 1H), 8.28 (d, 0.6H), 8.27 (d, 0.4H), 8.00 (d, 0.6H), 7.98 (d, 0.4H), 7.72–7.68 (m, 1H), 7.33 (s, 0.6H), 7.25 (s, 0.4H), 4.66 (s, 1.2H), 4.48 (s, 0.8H), 4.33 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (q, 1.2H), 4.06 (s, 1.2H), 3.57 (t, 1.2H), 3.45–3.39 (m, 2H), 3.26 (t, 0.8H), 1.75 (s, 3H), 1.25 (t, 1.2H), 1.17 (t, 1.8H).
Reaction SMILES: CN(C)C=O.[O:6]=[C:7]1[N:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15](=[O:23])[C:14]2[C:9](=[CH:10][C:11]([C:25]3[NH:26][CH:27]=[CH:28][N:29]=3)=[C:12]([F:24])[CH:13]=2)[NH:8]1.C(=O)([O-])[O-].[K+].[K+].[Cl:36][C:37]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:38]=1[CH2:39]Cl>O>[Cl:36][C:37]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:38]=1[CH2:39][N:8]1[C:9]2[C:14](=[CH:13][C:12]([F:24])=[C:11]([C:25]3[NH:29][CH:28]=[CH:27][N:26]=3)[CH:10]=2)[C:15](=[O:23])[N:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]1=[O:6]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)Cn1c(=O)[nH]c2cc(-c3ncc[nH]3)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)c2cc(F)c(-c3ncc[nH]3)cc2n(Cc2ccc(Cl)cc2Cl)c1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 65.3 %

Procedure:
Into 50 ml of dimethylformamide were dissolved 2.33 g of ethyl 1,4-dihydro-2,4-dioxo-6-fluoro-7-imidazolyl-3(2H)-quinazolineacetate, and, after added 0.97 g of potassium carbonate and 1.51 g of 2,4-dichlorobenzyl chloride, the mixture was stirred for 5 hours at 100° C. After cooling by allowing to stand, the reaction mixture was poured into 500 ml of water and the deposits were collected by filtration. They were recrystallized from ethanol to obtain 2.25 g of title compound. m.p. 192°-193° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:9]2)[O:7][NH:31]1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2cccc(C(F)(F)F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1cccc(C(F)(F)F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 88.6 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate (157 mg, 0.39 mmol) (from example 30, step 1) was dissolved in MeOH (2 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.115 mL, 0.39 mmol) dissolved in water (0.200 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.024 mL, 0.39 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 15 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (2.014 mL, 12.09 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield crude trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate (128 mg, 88%) as a white solid. MS m/z 371 (M+H)+
Reaction SMILES: B.C1COCC1.[Br:7][C:8]1[C:9]([CH3:33])=[N:10][O:11][C:12]=1[NH:13][S:14]([C:17]1[CH:21]=[CH:20][S:19][C:18]=1[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)=O)(=[O:16])=[O:15]>C1COCC1>[Br:7][C:8]1[C:9]([CH3:33])=[N:10][O:11][C:12]=1[NH:13][S:14]([C:17]1[CH:21]=[CH:20][S:19][C:18]=1[CH2:22][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)(=[O:16])=[O:15]
Reactant: COc1cccc(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Br)c1
Agent: B
Solvent: C1CCOC1
Product: COc1cccc(NCc2sccc2S(=O)(=O)Nc2onc(C)c2Br)c1
Yield: 11.6 %

Procedure:
BH3.THF (15 ml, 1 M in THF) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide (Example 22) (1.0 g, 2.12 mmol) in dry THF (15 ml). The mixture was refluxed for 8 hours and cooled. THF was evaporated on a rotavap and MeOH was added to the residue. The resulting solution was concentrated. The final residue was purified by HPLC to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3-methoxyphenyl)aminomethyl]thiophene-3-sulfonamide (113 mg., 12% yield) as a grey powder, m.p. 70-73° C.
Reaction SMILES: [N:1]([CH:4]([CH3:28])[CH2:5][O:6][CH:7]1[CH2:27][CH2:26][C:10]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]4[CH2:24][CH2:23]4)=[C:16]([F:25])[CH:15]=3)[O:13][C:9]=2[CH2:8]1)=[N+]=[N-].C1C[O:32][CH2:31][CH2:30]1>[C].[Pd]>[CH:22]1([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]3[O:13][C:9]4[CH2:8][CH:7]([O:6][CH2:5][CH:4]([NH:1][C:31](=[O:32])[CH3:30])[CH3:28])[CH2:27][CH2:26][C:10]=4[N:11]=3)=[CH:15][C:16]=2[F:25])[CH2:24][CH2:23]1
Reactant: CC(COC1CCc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2C1)N=[N+]=[N-]
Reactant: C1CCOC1
Agent: [Pd]
Product: CC(=O)NC(C)COC1CCc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 6-(2-azidopropoxy)-2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-4,5,6,7-tetrahydro-1,3-benzoxazole (870 mg), 10% palladium-carbon (containing water (50%), 800 mg) and THF (10 mL) was stirred at room temperature for 10 min. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. To the obtained residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) to give the title compound (725 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(N(CC)CC)C>O1CCOCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Nc1ccc(N2CCC(=O)CC2)cc1
Yield: 103.4 %

Procedure:
5.6 g of 1-(4-nitrophenyl)-4-piperidone were suspended in 60 ml of dioxan under argon, treated with 2.6 ml of triethylamine and 0.6 g of palladium-on-charcoal (5%) and hydrogenated at room temperature and normal pressure. Filtration and concentration yielded 5.0 g of 1-(4-aminophenyl)-4-piperidinone.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][CH2:19][C:9]=2[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)(=O)=O.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][OH:36])=[CH:30][CH:29]=1>>[OH:36][CH2:35][CH2:34][C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:7]2[C:8]3[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][CH2:19][C:9]=3[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)=[CH:29][CH:30]=1
Reactant: O=S1(=O)CCCc2nc(-c3ccccc3)nc(OS(=O)(=O)C(F)(F)F)c21
Reactant: Nc1ccc(CCO)cc1
Product: O=S1(=O)CCCc2nc(-c3ccccc3)nc(Nc3ccc(CCO)cc3)c21
Yield: 68.3 %

Procedure:
Following general procedure G, 5,5-dioxido-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.123 g, 0.30 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.045 g, 0.33 mmol) to afford the desired product (0.081 g, 68%) as a light yellow solid. MW=395.47. 1H NMR (DMSO-d6, 500 MHz) δ 8.72 (s, 1H), 8.29-8.25 (m, 2H), 7.61-7.49 (m, 5H), 7.30 (d, J=8.5 Hz, 2H), 4.65 (t, J=5.5 Hz, 1H), 3.76-3.71 (m, 2H), 3.67-3.61 (m, 2H), 3.07 (t, J=6.5 Hz, 2H), 2.75 (t, J=7.0 Hz, 2H), 2.43-2.35 (m, 2H); APCI MS m/z 396 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=4)[N:14]=[CH:13][C:12]=3[C:24]#[N:25])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.NN>[Pd].C(O)C>[NH2:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:24]#[N:25])=[C:11]2[NH:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc2[nH]ccc2c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1ccc2[nH]ccc2c1
Yield: 104 %

Procedure:
Covered 200 mg of 10% Palladium on carbon with 75 ml ethanol. Added 2.00 g (6.07 mmol) 4-(1H-indol-5-ylamino)-6-nitro-quinoline-3-carbonitrile and 477 μl (15.2 mmol) hydrazine. Heated to reflux under N2 for 2 hours. Filtered hot through celite and washed through with hot methanol. Removed solvent and dried in vacuo (50° C.), giving 1.89 g brown solid: mass spectrum (m/e electrospray): M+H=300.2.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]([F:37])([F:36])[O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>>[CH2:1]([O:8][CH2:9][N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:12]([CH2:32][C:31]2[CH:34]=[CH:35][C:28]([O:27][C:26]([F:25])([F:36])[F:37])=[CH:29][CH:30]=2)[C:11]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCCN(COCc2ccccc2)C(=O)C1
Product: CC(C)(C)OC(=O)N1CCCN(COCc2ccccc2)C(=O)C1Cc1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared from tert-butyl 4-[(benzyloxy)methyl]hexahydro-3-oxo-1H-1,4-diazepine-1-carboxylate and 4-(trifluoromethoxy)benzylbromide essentially following the procedure described in Example 3, Step 1.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[O:6]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=4)=[CH:22][C:17]=3[CH:16]=[C:15]([C:36]([OH:38])=O)[CH2:14][CH2:13]2)=[CH:7]1.S(Cl)(Cl)=O>O1CCCC1>[O:6]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=4)=[CH:22][C:17]=3[CH:16]=[C:15]([C:36]([NH:12][C:18]3[CH:19]=[CH:20][C:21]([CH2:4][N:2]([CH3:1])[CH:3]4[CH2:9][CH2:10][O:6][CH2:7][CH2:8]4)=[CH:22][CH:17]=3)=[O:38])[CH2:14][CH2:13]2)=[CH:7]1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccoc2)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccoc2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 1-(3-furylmethyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (159 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (25 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (118 mg) and triethylamine (546 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 4.5 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1 8), which was recrystallized from hexane-ethyl acetate to give 1-(3-furylmethyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 61) (153 mg) as yellow crystals.
Reaction SMILES: NN.O=C1C2C(=CC=CC=2)C(=O)[N:5]1[CH2:14][C:15]([CH3:21])([CH3:20])[C:16]([O:18][CH3:19])=[O:17]>CO.C(OCC)C>[NH2:5][CH2:14][C:15]([CH3:21])([CH3:20])[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(C)(C)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(C)(C)CN
Temperature: 65 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
Hydrazine (1.1 eq., 0.27 mL, 8.42 mmol) was added to the solution of methyl 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2,2-dimethylpropanoate (0.2 g, 7.66 mmol) in methanol (60 mL) maintained under magnetic stirring at 65° C. After 5 hours the reaction mixture was allowed to cool to room temperature, diluted with diethyl ether and filtered. The filtrate was washed thoroughly with diethyl ether. The title compound was obtained after evaporation of the solvents and it was used in the next step without any further purification. (0.8 g, 75% yield).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1)=[O:2].[BH4-].[Na+]>C(Cl)(Cl)Cl.CO>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1
Reactant: N#Cc1ccccc1-c1cccc(-c2cnc3cc(C=O)ccn23)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N#Cc1ccccc1-c1cccc(-c2cnc3cc(CO)ccn23)c1
Yield: 75.8 %

Procedure:
3′-(7-Formylimidazo[1,2-α]pyridin-3-yl)biphenyl-2-carbonitrile (140 mg, 0.43 mmol) was suspended in chloroform (4 ml) and methanol (7 ml), sodium borohydride (82 mg, 2.17 mmol) added portionwise over 5 min then the reaction was heated under reflux for 1.5 h. The mixture was evaporated to dryness, the residue diluted with water (40 ml) and extracted with chloroform (2×50 ml). The combined organics were washed with brine (40 ml), dried over anhydrous sodium sulfate and evaporated to dryness. Purification was effected by silica gel chromatography eluting with dichloromethane and 1% conc. ammonia on a gradient of methanol (1-5%). The solid obtained was triturated with diethyl ether which gave the title compound (106 mg, 75%) as a white powder. 1H NMR (400 MHz, MeOD) δH 4.70 (2H, d, J 1), 6.97 (1H, dd, J 7 and 2), 7.55-7.60 (2H, m), 7.61-7.65 (1H, m), 7.67-7.80 (5H, m), 7.84-7.88 (2H, m), 8.65 (1H, dd, J 7 and 1); m/z (ES+) 326 (M++H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:21](O)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].O=S(Cl)[Cl:27]>>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:21]([Cl:27])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)Cl)C1c1cccc([N+](=O)[O-])c1

Procedure:
Compounds of formula 1 may also be prepared by the following variation of Scheme IV, especially where optically active compounds are desired. A suitable dihydropyridine derivative acid is prepared and the optical isomers separated (where desired) following the procedure set forth by T. Shibanuma, et al., Chem. Pharm. Bull., 28, 2809-2812 (1980). For example, 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine is N-protected, and subsequently resolved with an optically active amine, e.g., cinchonine, to prepare (+)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine (12+) and (-)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine (after deprotection). The resolved dihydropyridine acid derivative is then treated with SOCl2 in a suitable solvent, e.g., dichloromethane, to produce a dihydropyridine acyl chloride for condensation with an intermediate of the formula X--A--OH, where X is halo. For example, (-)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine is reacted with SOCl2 to yield 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-chlorocarbonyl-1,4-dihydropyridine, which is then reacted 3-bromopropanol to give the 3-bromopropoxy carbonyl derivative, which is then reacted with 4-(2-tetrahydropyran- 2-yloxyethyl)phenol (10) in CH2Cl2 with triethylamine to generate (S,RS)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(3-[4-(2-tetrahydropyran-2-yloxyethyl)phenoxy]propoxycarbonyl)-1,4-dihydropyridine (1+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][CH2:10][CH:9]2[C:14]([O:16]C)=[O:15])[CH:5]=[CH:6][CH:7]=1.O[Li].O.CO>O>[OH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][CH2:10][CH:9]2[C:14]([OH:16])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCC(=O)N1c1cccc(O)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)C1CCC(=O)N1c1cccc(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A mixture of methyl 1-(3-hydroxyphenyl)-5-oxo-2-pyrrolidinecarboxylate (10.00 g, 42 mmol), LiOH.H2O (5.36 g, 128 mmol), MeOH (200 mL) and H2O (50 mL) was stirred at room temperature for about 1 hour. The MeOH was removed in vacuo and the residue diluted with H2O and 2N HCl solution to pH=1. The solid was filtered off, dried in air and suspended in hot CH3CN (200 mL). Filtration gave 1-(3-hydroxyphenyl)-5-oxo-2-pyrrolidinecarboxylic acid (8.06 g, 85%), mp 183-185° C. IR (KBr) 3600-2300 (OH), 1710 (CO2H), 1695 (CONH) cm-1. 1H NMR (DMSO-d6/CDCl3) δ2.05 to 2.15 (1H, m, pyrrolidine ring H), 2.30-2.50 (3H, m, pyrrolidine ring H), 4.58 (1H, dd, J=9 Hz, J'= 2 Hz, CHCO2H), 6.52 (1H, dd, J=8 Hz, J'=2 Hz, aromatic H), 6.81 (1H, dd, J=8 Hz, J'=2Hz, aromatic H), 7.02 to 7.08 (2H, m, aromatic H), 9.16 (1H, bs, OH); MS m/z 222 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[N:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CS(O[CH2:41][CH2:42][CH2:43][N:44]1[CH2:50][CH:49]([OH:51])[C:46]2([CH2:48][CH2:47]2)[CH2:45]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:51][CH:49]1[C:46]2([CH2:48][CH2:47]2)[CH2:45][N:44]([CH2:43][CH2:42][CH2:41][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]5[C:23](=[O:35])[N:24]([C:29]6[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=6)[N:25]([CH3:28])[C:26]=5[CH3:27])=[O:21])=[N:17][CH:18]=4)=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH2:50]1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCN5CC(O)C6(CC6)C5)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
To a solution of N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (300 mg, 0.642 mmol) in DMA (3 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (240 mg, 0.963 mmol) and Cs2CO3 (417 mg, 1.284 mmol). The reaction was stirred at rt for 24 hrs. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (15 mL) and CHCl3 (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1(v/v/v) EtOAc/CH3OH/Et3N) to afford the title compound as a white solid (259 mg, 65%).