Azzindani/Open_Reaction_Data huggingface dataset:
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[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.Br>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1
Reactant: COc1ccc(N2CCN(Cc3ccc4ccccc4c3)CC2)cc1
Agent: Br
Product: Oc1ccc(N2CCN(Cc3ccc4ccccc4c3)CC2)cc1

Procedure:
A solution of 2.0 g. of 1-(β-naphthylmethyl)-4-(4-methoxyphenyl)piperazine as prepared in Example 4 in 100 ml. of hot 48% hydrogen bromide is refluxed for 2 hours. The solution is then cooled and filtered. The collected precipitate is then recrystallized from isobutyl alcohol to yield the dihydrobromide salt of 1-(β-naphthylmethyl)-4-(4-hydroxyphenyl)piperazine having a melting point of 225°-227° C.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:7]=1)[C:3](=[O:5])[CH3:4]>[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([N:2]([CH3:1])[C:3](=[O:5])[CH3:4])=[CH:7][C:8]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(=O)N(C)c1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Agent: [Pd]
Product: CC(=O)N(C)c1ccc(N)c(N2CCCCC2)c1

Procedure:
Using a procedure similar to Example 3, step (c), N-methyl-N-(4-nitro-3-piperidin-1-yl-phenyl)-acetamide (67 mg, 0.24 mmol, as prepared in the previous step) was stirred with 5% Pd—C (45 mg) under H2 to afford N-(4-amino-3-piperidin-1-yl-phenyl)-N-methyl-acetamide which was used immediately. Using a procedure similar to Example 3, step (d) this was coupled to 5-cyano-furan-2-carbonyl chloride (52 mg, 0.33 mmol) in the presence of DIEA (107 μL, 0.55 mmol) to afford 7.3 mg (8%) of the title compound as a waxy solid. 1H-NMR (CDCl3; 400 MHz): δ 9.66 (s, 1H), 8.48 (d, 1H, J=9.2 Hz), 7.34 (d, 1H, J=3.7 Hz), 7.26 (d, 1H, J=3.3 Hz), 7.03-7.01 (m, 2H), 3.27 (s, 3H,), 2.88-2.86 (m, 4H), 1.90 (s, 3H), 1.88-1.82 (m, 4H), 1.63 (br s, 2H); Mass spectrum (ESI, m/z): Calcd. for C20H22N4O3, 367.1 (M+1), found 367.2.
Reaction SMILES: [NH:1]1[CH2:85][CH2:84][CH2:83][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:82][CH2:81][CH2:80][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38]([NH:40][C@H:41]([C@H:46]([CH2:48][C:49]([NH:51][C@H:52]([C:57]([NH:59][C@H:60]([C:67]([NH:69][C@H:70]([C:76]([O:78]C)=[O:77])[CH2:71][CH2:72][CH2:73][CH2:74][NH2:75])=[O:68])[CH2:61][C:62]1[N:66]=[CH:65][NH:64][CH:63]=1)=[O:58])[C@H:53]([CH2:55][CH3:56])[CH3:54])=[O:50])[OH:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4].C(O)(C(F)(F)F)=O.N>O>[NH:1]1[CH2:85][CH2:84][CH2:83][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:82][CH2:81][CH2:80][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38]([NH:40][C@H:41]([C@H:46]([CH2:48][C:49]([NH:51][C@H:52]([C:57]([NH:59][C@H:60]([C:67]([NH:69][C@H:70]([C:76]([OH:78])=[O:77])[CH2:71][CH2:72][CH2:73][CH2:74][NH2:75])=[O:68])[CH2:61][C:62]1[N:66]=[CH:65][NH:64][CH:63]=1)=[O:58])[C@H:53]([CH2:55][CH3:56])[CH3:54])=[O:50])[OH:47])[CH2:42][CH:43]([CH3:44])[CH3:45])=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4]
Reactant: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCN)C(=O)OC
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCN)C(=O)O
Reaction time: 0.67 h

Procedure:
370 mg of H-Pro-His-Pro-Phe-His-Sta-Ile-His-Lys-OMe×5 TFA are dissolved in 8 ml of H2O. The pH value is increased to 5.0 with 0.3N NH3, whereupon 40 μl of a 1% aqueous solution of trypsin are added and the pH value is maintained constant by means of a pH stat with the addition of 0.3N NH3. The absorption of base is complete after approximately 40 minutes. 1 ml of glacial acetic acid is added, the whole is heated for 2 minutes in a boiling water bath, concentrated to approximately 3 ml and lyophilised. The residue is dissolved in 3 ml of 0.05N AcOH, converted into the acetate by slowly being filtered through a column (φ=1 cm, length=10 cm) of weakly basic ion exchanger (Merck No. II) in acetate form, and the eluate is again lyophilised, yielding H-Pro-His-Pro-Phe-His-Sta-Ile-His-Lys-OH×AcOH in the form of amorphous white powder; Rf (D)=0.12; Rf (K)=0.14.
Reaction SMILES: ClCC1C=CC(NCC(O)=O)=CC=1.C(OC(Cl)=O)C(C)C.CC1SC(SC[C:30]2[CH2:37][S:36][CH:35]3[N:32]([C:33](=[O:39])[CH:34]3N)[C:31]=2[C:40]([OH:42])=[O:41])=NN=1>C(N(CC)CC)C>[O:39]=[C:33]1[N:32]2[CH:35]([S:36][CH2:37][CH:30]=[C:31]2[C:40]([OH:42])=[O:41])[CH2:34]1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)C3SC2)s1
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CNc1ccc(CCl)cc1
Solvent: CCN(CC)CC
Product: O=C(O)C1=CCSC2CC(=O)N12

Procedure:
p-Chloromethylphenylglycine wherein the amino group is protected with tert-butoxycarbonyl is treated with isobutylchloroformate in the presence of triethylamine. The thus obtained anhydride is reacted with the triethylamine salt of 3-[(2-methyl-1,3,4-thiadiazol-5-ylthio)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid at 0° C. for about 4 hours.The resulting product is isolated, and the amine protecting group is removed by acid hydrolysis to give 3-[(2-methyl-1,3,4-thiadiazol-5-ylthio)methyl]-7-[[2-[4-chloromethyl)phenyl]-2-aminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][OH:26])=[C:17]([F:20])[CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].CCOCC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][O:26][S:37]([CH3:36])(=[O:39])=[O:38])=[C:17]([F:20])[CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Oc1ccc(Cl)cc1)N1CCc2cc(C#CCCCO)c(F)cc21
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCCC#Cc1cc2c(cc1F)N(C(=O)Oc1ccc(Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
A solution of 120 mg (0.321 mmol) 6-Fluoro-5-(5-hydroxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester and 0.164 ml (0.96 mmol) N-ethyldiisopropylamine in 2 ml CH2Cl2 was treated with 0.03 ml (0.385 mmol) of methanesulfonyl chloride and stirred at room temperature for 1 hour. The mixture was poured into Et2O and washed with 0.5 M HCl. Drying of the organic layer with MgSO4, evaporation of the solvent, and chromatography on silica gel with CH2Cl2 gave 91 mg (61%) of 6-Fluoro-5-(5-methanesulfonyloxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester as a colorless oil, MS: 452 (MH+, 1Cl).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([C:30](=[O:32])[CH3:31])=[N:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:33][CH3:34])C1C=CC=CC=1.CS(O)(=O)=O>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([C:30](=[O:32])[CH3:31])=[N:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:33][CH3:34]
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1O
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 100.4 %

Procedure:
1-[3-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone (758 mg) was dissolved in trifluoroacetic acid (6 ml) to prepare a solution, methanesulfonic acid (0.6 ml) was added to the solution, and the mixture was stirred at 70° C. for 1.5 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. An aqueous sodium hydrogencarbonate solution was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (609 mg, yield 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[C:25]2C=CC=C[CH:26]=2)[C:21](=[O:31])[N:20]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C=C2C(C=CN(CC3C=CC(OC)=CC=3)C2=O)=CC=1F)C.C(OC(N1CCC(O)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[CH2:25][CH3:26])[C:21](=[O:31])[N:20]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[CH:19]=[CH:18]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cn2ccc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cc3c2=O)cc1
Agent: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCc1cc2c(=O)n(Cc3ccc(OC)cc3)ccc2cc1F
Product: CCc1cc2c(=O)n(Cc3ccc(OC)cc3)ccc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was synthesized following the method described for 4-[2-(4-methoxy-benzyl)-1-oxo-7-phenyl-1,2-dihydro-isoquinolin-6-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (316), starting from 7-ethyl-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (318) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester. Rt=1.91 min (Method C). Detected mass: 493.6 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([I:14])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[Li+].Cl>CO.CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([I:14])[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(I)cc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)c1cc(I)cc(C(=O)O)c1
Reaction time: 16 h
Yield: 721.6 %

Procedure:
To a mixture of 5-Iodo-isophthalic acid dimethyl ester (9.00 g, 3.12 mmol) in methanol/acetone(3:1, 18 ml) was added 4 N aqueous lithium hydroxide (0.78 ml, 3.12 mmol). This mixture was stirred for 16 hours, neutralized with 1 N hydrochloric acid, extracted with ethyl acetate, dried over magnesium Sulfate and the solvent removed under reduced pressure. The crude was purified by silica gel chromatography to afford 5-iodo-isophthalic acid monomethyl ester (6.89 g, 80% yield) as a white solid. MS: m/z 306.1 (M+H+).
Reaction SMILES: [OH:1][C:2]([C:20]([F:23])([F:22])[F:21])([CH2:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:10]=1[O:18][CH3:19])([CH3:8])[CH3:7])[CH:3]=O.[NH2:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][C:28](=[O:34])[NH:29]2>>[OH:1][C:2]([C:20]([F:21])([F:22])[F:23])([CH2:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:16])[CH3:17])[C:10]=1[O:18][CH3:19])([CH3:8])[CH3:7])[CH:3]=[N:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][C:28](=[O:34])[NH:29]2
Reactant: Nc1cccc2c1CC(=O)N2
Reactant: COc1c(C(C)C)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Product: COc1c(C(C)C)cccc1C(C)(C)CC(O)(C=Nc1cccc2c1CC(=O)N2)C(F)(F)F
Yield: 92.2 %

Procedure:
250 mg (0.903 mmol) of the 2-hydroxy-4-(3-isopropyl-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal that is described in Example 162 is reacted with 4-amino-1,3-dihydro-indol-2-one as described in the example above and worked up. After chromatography, 334.9 mg (92.2%) of the desired imine is isolated.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[C:8]([CH3:17])=[N:7]1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[S:42][CH2:43][C:44](=[O:46])[N:45]=2)[CH2:37][C@@H:36]1[CH2:47][OH:48])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[S:42][C:43](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:23])[F:24])=[CH:21][C:3]=3[C:2]([F:26])([F:1])[F:27])[N:7]=[C:8]4[CH3:17])[C:44](=[O:46])[N:45]=2)[CH2:37][C@@H:36]1[CH2:47][OH:48])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)CS2)C[C@@H]1CO
Reactant: Cc1nn(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2ccc(C=O)cc12
Product: Cc1nn(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2ccc(C=C3SC(N4CCN(C(=O)OC(C)(C)C)[C@@H](CO)C4)=NC3=O)cc12

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazole-5-carbaldehyde and 2-(R)—Hydroxymethyl-4-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester following general procedure D.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:6]=1)=[O:4].[H-].[Na+].[CH2:26](I)[CH2:27][CH3:28]>C1COCC1.C(OCC)(=O)C>[CH2:26]([O:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)[N:6]=1)=[O:4])[CH2:27][CH3:28]
Reactant: CCCI
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NO)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCONC(=O)c1cc(OC)cc(Oc2cccc(C(F)(F)F)c2)n1

Procedure:
0.6 g (0.0018 mol) of N-hydroxy-4-methoxy-6-{3-(trifluoromethyl)phenoxy)-2-pyridine carboxamide was dissolved in THF, and the obtained solution was mixed with 0.08 g (ca. 60% in mineral oil; 0.0018×1.1 mol) of NaH and then with 0.62 g (0.0018×2.0 mol) of n-propyl iodide, followed by treating the solution under reflux for about 2 hours. The reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water and then washed with saturated brine. The organic phase of the solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [CH2:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][CH:2]1[OH:15])[N:11]=[CH:10][CH:9]=[CH:8]3.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:15][CH:2]2[CH2:3][O:4][C:5]3[C:6](=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]=[CH:10][CH:9]=[CH:8]4)[CH2:1]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: OC1COc2ccc3ncccc3c2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2COc3ccc4ncccc4c3C2)cc1
Yield: 94.2 %

Procedure:
A solution of 2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-ol (intermediate 10) (0.47 g, 2.3 mmol) and p-toluene sulfonyl chloride (0.89 g, 4.6 mmol) in anhydrous pyridine (20 mL) was stirred at room temperature for 2.5 days. It was then poured into ice-H2O and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Chromatography ((15:4:1) EtOAc-Hexane-MeOH) afforded 0.77 g (93%) of 2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-yl 4-methylbenzenesulfonate as an off-white solid: mp 167.5–169.5° C. MS ESI m/z 356 [M+H]+. Elemental Analysis for C19H17NO4S: Calculated: C, 64.21; H, 4.82; N, 3.94. Found: C, 63.98; H, 4.79; N, 3.84.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42]Cl>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[C:39]([Cl:38])[CH:40]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1cccc(Cl)c1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3cccc(Cl)c3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 3-chlorobenzyl chloride (0.38 mL) as starting materials, 5-benzyloxy-N-({1-[(3-chlorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.77 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2>C1COCC1.CO.[Ni]>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1c([N+](=O)[O-])ccc2ncccc12
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2ncccc2c1N

Procedure:
A solution of 5-amino-6-nitroquinoline (25 g, 0.13 mol) in THF (500 mL) and methanol (500 mL) was treated with Raney nickel (7 g) under a hydrogen atmosphere (50.4 psi) on a Parr apparatus for 3.4 hours. Standard work-up gave the 5,6-diaminoquinoline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][C:5]#[N:6].[OH:8][NH2:9].Cl>C1COCC1>[CH3:1][O:2][C:3](=[O:7])[CH2:4][C:5](=[NH:6])[NH:9][OH:8]
Reactant: COC(=O)CC#N
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)CC(=N)NO
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2-Cyano-acetic acid methyl ester (990 mg, 10 mmol) was dissolved in THF (30 mL). Hydroxy amine (690 mg, HCl salt, 10 mmol) was added thereto, and the mixture was stirred for 2 h at 80° C. After completion of the reaction, 1N HCl was added. The reaction mixture was extracted with EtOAc, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was used in the next reaction without further purification.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[CH:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[C:14]1=[O:23])[CH2:20]2.Cl>C1COCC1>[CH2:6]([C:7]1[CH:8]=[C:9]([C:14]2([OH:23])[CH:15]3[CH2:21][CH:19]4[CH2:18][CH:17]([CH2:22][CH:13]2[CH2:20]4)[CH2:16]3)[CH:10]=[CH:11][CH:12]=1)[CH3:5]
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCc1cccc(C2(O)C3CC4CC(C3)CC2C4)c1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A stirring mixture of magnesium turnings (0.89 g, 36.6 mmol) and iodine (catalytic) in dry THF (60 mL) was treated with 3-bromoethylbenzene (5 ML, 36.6 mmol), refluxed for 3 h, cooled to room temperature, treated with a solution of 2-adamantanone (5.0 g, 33.3 mmol) in dry THF (20 mL) and refluxed for 2 h. The mixture was cooled to room temperature, treated with 3-M HCl (20 mL), extracted with EtOAc (2×20 mL), the combined extracts were washed with water (10 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; heptane-EtOAc (9:1)] to give the product (7.84 g, 92%) as a white solid: mp 63-65° C.; IR νmax (Nujol)/cm−1 3442, 3281, 2921, 2855, 1604, 1451, 1101, 1043, 1009, 803 and 708; NMR δH (400 MHz, CDCl3) 1.23 (3H, t, J 7.5 Hz), 1.61-1.70 (9H, m), 1.89 (1H, s), 2.38-2.41 (2H, m), 2.56 (2H,s), 2.65 (2H, q, J7.5 Hz), 3.46 (1H, s), 7.11 (1H, d, J7.5 Hz) and 7.24-7.36 (3H, m); Anal. Calcd for C18H24O: C, 84.32; H, 9.43. Found: C, 84.24; H, 9.28.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.[CH:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31]([CH:28]5[CH2:30][CH2:29]5)=[O:32])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1
Reactant: O=C(O)C1CC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1)C1CC1

Procedure:
The title compound, white crystals (118 mg, 87%), MS (ISP) m/z=397.2 [(M+H)+], was prepared in analogy to example 4 starting from trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate A) (150 mg, 0.34 mmol) and cyclopropanecarboxylic acid (41 mg, 0.47 mmol).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1([CH2:14][OH:15])[CH:10]([OH:11])[CH:9]([OH:12])[CH:8]([OH:13])[CH2:7][NH:6]1.CO.[C:18]1(=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([BH3-])#N.[Na+]>O.C(O)(=O)C>[CH:18]1([NH:3][CH2:4][C:5]2([CH2:14][OH:15])[CH:10]([OH:11])[CH:9]([OH:12])[CH:8]([OH:13])[CH2:7][NH:6]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NCC1(CO)NCC(O)C(O)C1O
Reactant: O=C1CCCCCCCCCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: OCC1(CNC2CCCCCCCCCCC2)NCC(O)C(O)C1O
Reaction time: 18 h
Yield: 67 %

Procedure:
2.65 g of 2-aminomethyl-2-hydroxymethyl-3,4,5-trihydroxypiperidine dihydrochloride (Preparation example 11) are dissolved in 21 ml of water, and 60 ml of methanol 1.5 ml of acetic acid and 6 g of cyclododecanone are then added. When a solution is obtained, 1.35 g of sodium cyanoborohydride are added. The mixture is stirred for 18 hours and the product which has precipitated is filtered off and washed with water. 2.4 g of a colourless complex are obtained, and the complex is discharged onto an Amberlite IR 120 H+ exchange column to liberate the base. The column is washed with about 3 l of water and the desired compound is liberated with 2% strength aqueous ammonia. The product fractions, determined by thin layer chromatography, are collected and concentrated. The evaporation residue crystallises on trituration with isopropanol. 1.8 g of a colourless product of melting point 171°-172° C. are obtained.
Reaction SMILES: B([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Br[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:40]1([C:45]2[C:50]([C:4]3[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=3)=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:41]=[CH:42][CH:43]=[CH:44][CH:39]=1
Reactant: Brc1ccccc1-c1ccccc1
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cccc(-c2ccccc2-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
3-Boronobenzoic acid (300 mg, 1.81 mmol), palladium acetate (40.4 mg, 0.18 mmol), triphenylphosphine (94.6 mg, 0.36 mmol) and potassium carbonate (374.6 mg, 2.71 mmol) were added to a solution of 2-bromo-1,1′-biphenyl (0.3 ml, 1.81 mmol) in acetonitrile (10 mL)-water (2.5 ml), and the mixture was heated with stirring at 100° C. overnight. The reaction mixture was cooled and then filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give [1,1′;2′,1″]terphenyl-3″-carboxylic acid (191 mg, 39%).