Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]=[C:22]([C:24]([O:26]CC)=[O:25])[N:23]=1)=[CH:15]2)(=[O:8])=[O:7].[OH-].[Na+].O1CCCC1>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]=[C:22]([C:24]([OH:26])=[O:25])[N:23]=1)=[CH:15]2)(=[O:8])=[O:7]
Reactant: CCOC(=O)c1csc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1csc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A mixture of ethyl 2-{7-[(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazole-4-carboxylate (0.30 g), 8N aqueous sodium hydroxide solution (0.3 mL), tetrahydrofuran (4 mL) and methanol (4 mL) was stirred at 60° C. for 1 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were dissolved in tetrahydrofuran, treated with activated carbon, and concentrated to give the title compound (0.20 g, yield 71%) as yellow crystals. melting point>273° C. (decomposition).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[CH2:19][C:20]1[C:25]([F:26])=[CH:24][N:23]=[CH:22][C:21]=1[F:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:27][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([F:26])[C:20]=1[CH2:19][O:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Reactant: Fc1cncc(F)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cncc3F)cc(C)cn12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
5.0 g (21.34 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate from Example 87A and 3.83 g (23.48 mmol) of 4-(chloromethyl)-3,5-difluoropyridine from Example 115A were initially charged in 306 ml of abs. DMF, and 20.8 g (64.03 mmol) of caesium carbonate were added. The reaction mixture was stirred at 60° C. overnight. The reaction mixture, cooled to RT, was filtered, washed with ethyl acetate and concentrated. The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate gradient=4:1 to 2:1). This gave 5.40 g (70% of theory) of the target compound.
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])(C)(C)C.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.CN1CCOCC1.[NH2:35][C:36]([C:44]1[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[C:46]([F:52])[CH:45]=1)([C:38]1[N:39]([CH3:43])[CH:40]=[N:41][CH:42]=1)[CH3:37]>CN(C=O)C>[C:48]([C:47]1[CH:50]=[CH:51][C:44]([C:36]([NH:35][C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[OH:5])=[O:13])([C:38]2[N:39]([CH3:43])[CH:40]=[N:41][CH:42]=2)[CH3:37])=[CH:45][C:46]=1[F:52])#[N:49]
Reactant: Cn1cncc1C(C)(N)c1ccc(C#N)c(F)c1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cn1cncc1C(C)(NC(=O)CCNC(=O)O)c1ccc(C#N)c(F)c1
Reaction time: 8 h

Procedure:
To a solution of 3-tert-butoxycarbonylamino-propionic acid (0.77 g, 4.09 mmol) in DMF (8.2 mL) at ambient temperature was added [1,2,3]triazolo[4,5-b]pyridin-3-ol (HOAT) (0.53 g, 3.89 mmol), EDC (0.82 g, 4.30 mmol), and 4-methylmorpholine (0.41 g, 4.09 mmol), followed by (+)-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-fluoro-benzonitrile (Example 1, Step I) (1.00 g, 4.09 mmol). After stirring overnight, the reaction was concentrated in vacuo to remove the DMF. The residue was partitioned between EtOAc and saturated aqueous NaHCO3 solution, the organic layer washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the crude title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)=[O:10].[CH3:17][I:18]>C(#N)C>[I-:18].[CH3:1][O:2][C:3]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([N+:11]1([CH3:17])[CH:15]=[CH:14][NH:13][CH2:12]1)=[O:10])=[O:16]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)n1ccnc1
Reactant: CI
Solvent: CC#N
Product: COC(=O)[C@@H]1CCCN1C(=O)[N+]1(C)C=CNC1
Product: [I-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
1-(1H-Imidazol-1-ylcarbonyl)-L-proline methyl ester obtained in Example (151a) (0.200 g, 0.896 mmol) was dissolved in acetonitrile (2 ml). Methyl iodide (0.508 g, 3.58 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure to obtain 0.327 g of the title compound as a pale yellow foamy substance (100%).
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=2[CH:23]2[C:28]3([C:36]4[C:31](=[CH:32][C:33]([Cl:37])=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:38])[CH:27]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=3)[CH2:26][C:25](=[O:46])[NH:24]2)[CH2:11][CH2:10]1)=[O:7])(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>ClCCl>[Cl:37][C:33]1[CH:32]=[C:31]2[NH:30][C:29](=[O:38])[C:28]3([CH:27]([C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=4)[CH2:26][C:25](=[O:46])[NH:24][CH:23]3[C:17]3[CH:18]=[C:19]([I:22])[CH:20]=[CH:21][C:16]=3[O:15][CH:12]3[CH2:13][CH2:14][N:9]([CH2:8][C:6]([OH:7])=[O:5])[CH2:10][CH2:11]3)[C:36]2=[CH:35][CH:34]=1.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]
Reactant: CC(C)(C)OC(=O)CN1CCC(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1CCC(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of racemic(2′R, 3R, 4′S)-2′-[2-(1-tert-butoxycarbonylmethyl-4-piperidinyloxy)-5-iodo-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.22 g, 0.28 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 18 h, then concentrated. The residue was triturated with dichlormethane and hexanes to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(1-hydroxycarbonylmethyl-4-piperidinyloxy)-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as trifluoroacetic acid salt: yellow solid (Yield 0.18 g)
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:11])[CH2:8][CH2:9][NH2:10].[C:18](OC(=O)C)(=[O:20])C>C(O)=O>[CH:18]([NH:10][CH2:9][CH2:8][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])=[O:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC(CCN)c1ccccc1-c1ccccc1
Solvent: O=CO
Product: CC(CCNC=O)c1ccccc1-c1ccccc1
Reaction time: 8 h

Procedure:
2.25 g of 3-p-biphenylyl-butylamine are dissolved in 30 ml of formic acid, 10 ml of acetic anhydride are added dropwise at 60°, while stirring, and the mixture is allowed to stand overnight and worked up in the customary manner to give 1-formamido-3-p-biphenylyl-butane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19]([CH:21]1[O:23][CH2:22]1)Br>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:19][CH:21]2[CH2:22][O:23]2)=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1
Reactant: CC(=O)Nc1cc(Cl)ccc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Cl)ccc1OCC1CO1
Temperature: 50 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
A solution of N-(5-Chloro-2-hydroxy-phenyl)-acetamide (0.499 g, 2.68 mmol), K2CO3 (0.60 g, 4.35 mmol) and epibromohydrin (0.405 g, 2.95 mmol) in DMF (5 ml) was heated with stirring at 50° C. for 2 hours. The mixture was then partitioned between EtOAc and water 40+40 ml. The organic phase was washed twice with water and once with brine and finally concentrated in vacuo to give a crude product. The crude product was purified on silica (heptane:EtOAc, 1:1), to give 0.43 g (66%) of a white solid.
Reaction SMILES: [I-:1].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[CH3:10][O:11][CH:12]([O:23][CH3:24])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>CO.N1CCCCC1>[I-:1].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([O:14][CH2:13][CH:12]([O:23][CH3:24])[O:11][CH3:10])[CH:16]=1
Reactant: COC(COc1cccc(C=O)c1)OC
Reactant: Cc1cccc[n+]1C
Agent: [I-]
Solvent: C1CCNCC1
Solvent: CO
Product: COC(COc1cccc(C=Cc2cccc[n+]2C)c1)OC
Yield: 85.8 %

Procedure:
In 6 ml of methanol, 1.50 g of 1,2-dimethyl pyridinium iodide and 1.50 g of m-(2,2-dimethoxyethoxy)-benzaldehyde were dissolved. The resultant solution, with two drops of piperidine added thereto, was refluxed for five hours and thereafter cooled off. Consequently, crystals were deposited. When the crystals were collected and washed thoroughly with acetone, there was obtained 2.34 g of 1-methyl-2-[m-(2,2-dimethoxyethoxy)-styryl]pyridinium iodide. In water, this product showed the highest absorption at 336 nm (ε=2.13×104). The infrared absorption spectrum (KBr) showed peaks at 1620, 1600, 1580, 1268, 1137, 1068, 965, 840, 772 and 680 cm-1. The yield was 86%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](SC)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH3:32][CH:33]([NH2:35])[CH3:34].[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH2:40]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:40][CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:35][CH:33]([CH3:34])[CH3:32])=[O:24])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: CC(C)N
Reactant: CN(C)CCN
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(NCCN(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared from 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid by following the procedures in Example 19 using 2-propanamine for the amide formation and N,N-dimethyl-1,2-ethanediamine for the displacement reaction. LC-MS (ES) m/z 521 (M+H)+; 1H-NMR(MeOD) δ 1.26 (d, 6H), 2.12 (s, 6H), 2.30 (m, 2H), 2.36 (m, 5H), 3.27 (m, 2H), 4.23 (m, 1H), 6.38 (d, 1H), 7.25 (m, 2H), 7.44 (d, 1H), 7.49 (d, 1H), 7.59 (m, 1H), 7.79 (s, 1H), 7.93 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])=[C:4]2[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C>[CH2:25]([O:24][C:22](=[O:23])[C:21]1[CH:27]=[CH:28][CH:29]=[C:19]([NH:18][C:6]2[N:5]3[N:9]=[CH:10][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])=[C:4]3[N:3]=[C:2]([Cl:1])[CH:7]=2)[CH:20]=1)[CH3:26]
Reactant: N#CCCCCc1cnn2c(Cl)cc(Cl)nc12
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: CCO
Product: CCOC(=O)c1cccc(Nc2cc(Cl)nc3c(CCCCC#N)cnn23)c1
Temperature: 50 °C
Yield: 54.4 %

Procedure:
To a solution of compound (13a) (1.24 g, 4.62 mmol) in 10 mL of ethanol was added ethyl 3-aminobenzoate (764 mg. 4.62 mmol). The reaction mixture was heated at 50° C. for 2 h and then cooled to room temperature. Solvent was removed and the residue was dissolved in EtOAc (50 mL) and washed with saturated aq NaHCO3, 10% HCl, and brine and dried over anhydrous Na2 SO4. Removal of the solvent provided a residue that was purified by flash column with use of EtOAc/hexane (25% to 50%) to yield 3-[5-chloro-3-(4-cyano-butyl)-pyrazolo[1,5-a]pyrimidin-7-ylamino]-benzoic acid ethyl ester (14a) (1.0 g. 50%).
Reaction SMILES: [H-].[K+].O1[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:8][S:9][CH2:10][S:11](=[O:13])[CH3:12].BrCCCCBr>C(Cl)Cl>[CH3:8][S:9][C:10]1([S:11](=[O:13])[CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CSCS(C)=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [K+]
Solvent: BrCCCCBr
Solvent: ClCCl
Product: CSC1(S(C)=O)CCCC1
Reaction time: 0.67 h

Procedure:
Potassium hydride (940 mg) was suspended in 15 ml. of tetrahydrofuran, and with ice cooling, 1.320g of formaldehyde dimethyl mercaptal S-oxide was added. With ice-cooling, the mixture was stirred for 40 minutes, and then 2.410 g of 1.4-dibromobutane was added. The mixture was stirred for 1 hour with ice cooling, and then for 19 hours at room temperature. Methylene chloride (70ml) was added, and the insoluble matter was separated by filtration. The filtrate was concentrated at reduced pressure, and the residue was separated by column chromatography (silica gel, eluted with CH2Cl2, 25% AcOEt-CH2Cl2, AcOEt, and MeOH) to afford 1.509 g of cyclopentanone dimethyl mercaptal S-oxide as a colorless oily substance. Furthermore, 208 mg of formaldehyde dimethyl mercaptal S-oxide was obtained from the MeOH fraction. The yield was 80%. The physical properties were as follows:
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:17]([CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:16]([CH2:25][O:26][CH2:27][CH3:28])=[N:15][C:9]=3[C:10]([NH2:14])=[N:11][C:12]=2[CH:13]=1.C(N(CC)CC)C.[N:36]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(Cl)(Cl)Cl>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:17]([CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:42]([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[O:43])[CH2:21][CH2:20]4)[C:16]([CH2:25][O:26][CH2:27][CH3:28])=[N:15][C:9]=3[C:10]([NH2:14])=[N:11][C:12]=2[CH:13]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCNCC1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCN(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
A solution of 7-bromo-2-ethoxymethyl-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (4.0 g, 8.1 mmol) and triethylamine (5.67 mL, 40.7 mmol) in chloroform (300 mL) was cooled to 0° C., and 4-morpholinecarbonyl chloride (0.95 mL, 8.1 mmol) was added dropwise. The reaction was allowed to warm to ambient temperature and stirred overnight before it was diluted with chloroform (200 mL); washed sequentially with water (200 mL), 2 M sodium carbonate (2×200 mL), water (200 mL), and brine (200 mL); and concentrated under reduced pressure. The residue was triturated with ethyl acetate and subsequently recrystallized from acetonitrile to provide 3.64 g of 7-bromo-2-ethoxymethyl-1-{[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]methyl }-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 198–199° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([Br:12])[CH:3]=1.[Li]CCCC.[CH3:18][C:19]([CH3:21])=[O:20]>C1COCC1.[NH4+].[Cl-]>[Br:12][C:4]1[CH:3]=[C:2]([C:19]([OH:20])([CH3:21])[CH3:18])[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=1
Reactant: CC(C)=O
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Br)cc(C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1,3-dibromo-5-tert-butylbenzene (404 mg) in dry THF (10 mL) was added n-BuLi (0.84 mL) at −78° C. and after 20 min, acetone was added dropwise to the above solution at −78° C. and the mixture was stirred at this temperature for 30 min and at rt for 1 h, diluted with sat. NH4Cl and extracted with EA (3×30 mL). The organic layer was dried over Na2SO4, evaporated and purified by CC to give compound P23a (380 mg, 70%) as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=1.[OH-].[K+].C(O)C.Cl>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCOc2ccc3ccccc3c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCCCCCOc2ccc3ccccc3c2)cc1

Procedure:
A solution of 4.8 g. of ethyl p-{[6-(2-naphthyloxy)hexyl]amino}benzoate and 4.8 g. of potassium hydroxide in 100 ml. of 95% ethanol is refluxed for 3 hours. The solution is cooled, diluted with water and acidified with concentrated hydrochloric acid. The mixture is filtered and the solid washed with ethanol and water and recrystallized from ether-methylene chloride and acetone to give crystals, m.p. 157°-159° C.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][NH:5][C:6]([C:8]1[C:9]([NH:15][CH2:16][C:17]([N:19]2[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:21][C@H:20]2[CH3:34])=[O:18])=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:7].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:14][C:12]1[CH:13]=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:35])=[O:2])=[O:7])[C:9]([NH:15][CH2:16][C:17]([N:19]2[CH2:24][C@H:23]([CH3:25])[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:21][C@H:20]2[CH3:34])=[O:18])=[N:10][CH:11]=1
Reactant: COC(=O)CNC(=O)c1cc(Cl)cnc1NCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CNc1ncc(Cl)cc1C(=O)NCC(=O)O
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a solution of [(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethylamino}-pyridine-3-carbonyl)-amino]-acetic acid methyl ester (0.043 g, 0.085 mmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (0.25 mL) was added lithium hydroxide monohydrate (0.018 g, 0.43 mmol). The reaction was stirred overnight. The reaction was then concentrated in vacuo, diluted with dichloromethane and passed through a fritted funnel. The filtrate was treated with saturated hydrogen chloride in diethyl ether and the white precipitate formed was collected by filtration to give the title compound (0.022 g, LRMS: 492.2).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(N(CC)CC)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:26][CH2:27]1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: Clc1ccc(Cl)c(N2CCNCC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCN(c3cc(Cl)ccc3Cl)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with (2,5-dichlorophenyl)piperazine dihydrochloride in the presence of triethylamine to give 1-(2,5-dichlorophenyl)-4-(p-nitrobenzyl)piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[NH2:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][CH3:28]>>[CH2:27]([N:23]1[CH2:24][CH2:25][CH2:26][CH:22]1[CH2:21][NH:20][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:28]
Reactant: COc1cc(C(=O)O)cc(OCC=C(C)C)c1OC
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cc(OC)c(OC)c(OCC=C(C)C)c1
Yield: 69 %

Procedure:
In a manner identical to Example 15, 3,4-dimethoxy-5-prenyloxybenzoic acid (0.80 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.39 g), thereby yielding 0.78 g (69%) of the aimed compound.
Reaction SMILES: OS(C(F)(F)F)(=O)=O.CS[CH:11]([N:13]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:14])[CH3:12].[NH2:23][C:24]1[CH:32]=[C:31]2[C:27]([CH2:28][C@@H:29]([OH:48])[C@@H:30]2[NH:33][C:34]([C:36]2[CH:41]=[CH:40][C:39](C3C=CC=CC=3)=[CH:38][CH:37]=2)=[O:35])=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH2:18]([O:17][CH2:16][CH2:15][N:13]([CH3:14])[C:11](=[N:23][C:24]1[CH:32]=[C:31]2[C:27]([CH2:28][C@@H:29]([OH:48])[C@@H:30]2[NH:33][C:34]([C:36]2([C:24]3[CH:32]=[CH:31][CH:27]=[CH:26][CH:25]=3)[CH:37]=[CH:38][CH:39]=[CH:40][CH2:41]2)=[O:35])=[CH:26][CH:25]=1)[CH3:12])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Nc1ccc2c(c1)[C@@H](NC(=O)c1ccc(-c3ccccc3)cc1)[C@H](O)C2
Reactant: CCCCCOCCN(C)C(C)SC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Product: CCCCCOCCN(C)C(C)=Nc1ccc2c(c1)[C@@H](NC(=O)C1(c3ccccc3)C=CC=CC1)[C@H](O)C2
Reaction time: 22 h
Yield: 21.7 %

Procedure:
Dissolve the crude triflic acid salt of (1-methylsulfanylethyl)(2-pentoxyethyl)methylamine (192.1 mg, 0.523 mmol) and biphenyl-4-carboxylic acid (R)-(6-amino-2(R)-hydroxyindan-1-yl)amide (170.8 mg, 0.496 mmol) in 10 mL pyridine and allow it to stir for 22 hours. Remove the solvent in vacuo and partition the residue between methylene chloride and saturated aqueous sodium hydrogen carbonate. Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 112.3 mg of crude product. Purify via Biotage chromatography (10% MeOH/EtOAc 25% MeOH/EtOAc) to afford 27.8 mg of the titled product (11% yield). MS (ES): m/z 514.5 (M+H).
Reaction SMILES: C1C2C(=CC=CC=2)[C@@H](N)[C@H]1O.B.CCN(C1C=CC=CC=1)CC.[Cl:24][C:25]1[C:34]2[C:35](=[O:43])[O:36][C:37]3([CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[C:33]=2[C:32]2[C:31](=[O:44])[CH2:30][C:29]([CH3:46])([CH3:45])[CH2:28][C:27]=2[N:26]=1.CO>O1CCCC1>[Cl:24][C:25]1[C:34]2[C:35](=[O:43])[O:36][C:37]3([CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[C:33]=2[C:32]2[C@@H:31]([OH:44])[CH2:30][C:29]([CH3:46])([CH3:45])[CH2:28][C:27]=2[N:26]=1
Reactant: CC1(C)CC(=O)c2c(nc(Cl)c3c2C2(CCOCC2)OC3=O)C1
Agent: B
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2nc(Cl)c3c(c2[C@@H](O)C1)C1(CCOCC1)OC3=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
213 mg (1R,2S)-(+)-cis-1-Amino-2-indanol are dissolved in 250 ml tetrahydrofurane and to this solution are dropwise added 3.58 ml of a borane-diethylaniline-complex. After completion of gas evolution the solution is cooled to 0° C. and 3.17 g 4-chloro-7,7-dimethyl-2′,3′,5′,6′,7,8-hexahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-3,9(6H)-dione in 250 ml tetrahydrofurane are added dropwise. The temperature is raised during 2 hours to room temperature and the mixture is stirred for 18 hours, 213 mg (1R,2S)-(+)-cis-1-Amino-2-indanol are added and stirring is continued for further 7 hours. 20 ml methanol are added dropwise and the mixture is stirred for additional 10 minutes. The mixture is partitioned between 0.1 M hydrochloric acid and ethylacetate. The aqueous phase is twice extracted with ethylacetate. The combined organic phases are dried with sodium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 0:100).