Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][CH:19]=1)=[CH2:17]>CCCCCC>[CH:1]([NH:4][CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([CH:16]=[CH2:17])=[CH:19][CH:20]=1)([CH3:3])[CH3:2]
Reactant: C=Cc1ccc(C=C)cc1
Reactant: CC(C)N
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C=Cc1ccc(CCNC(C)C)cc1
Reaction time: 0.17 h
Yield: 48.7 %

Procedure:
In a 300 ml four necked flask equipped with a thermometer, a reflux condenser, an inlet for nitrogen and a stirrer were charged 1860 ml of dry n-hexane and 148 g of iso-propylamine. While stirring the mixture, 119 ml of a 15% n-butyllithium n-hexane solution were added dropwise thereto. During the addition, the temperature was maintained at 5° C. to 7° C. The color of the solution was changed from colorless to pale yellow. After 10 minutes, 325 g of p-divinylbenzene having a purity of 96% were added to the mixture, whereby the color of the reaction mixture was changed to brown. Then, the inner temperature was elevated to 45° C., at which the reaction was continued for 6 hours. After the reaction, the reaction was terminated with ethanol and the solvent was evaporated. The residue was poured into 2 l of n-hexane and the insoluble are filtered off, followed by evaporation and distillation, whereby there were obtained 230 g of the product having a boiling point of 62° C.-64° C./0.08 mmHg.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([NH:17][C:18](=O)[CH2:19][CH3:20])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[CH2:2][CH3:3].[CH2:22](I)[CH2:23][CH3:24]>>[CH2:1]([O:5][CH2:6][CH:7]([N:17]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:19][CH3:20])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH3:3]
Reactant: CCCI
Reactant: CCC(=O)NC(CCOc1ccccc1)COC(=O)CC
Product: CCCOCC(CCOc1ccccc1)N(CCC)CCC

Procedure:
2-(propionylamino)-4-phenoxy-1-butanol propionate, described in Example 5, with propyliodide, followed by reduction gives 1-propoxy-N,N-dipropyl-4-phenoxy-2-butanamine,
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:9](=[O:10])[O:8][C:6](=[O:7])[CH2:5]1)=[O:2].[CH3:11][O:12][C:13](=[O:23])[C@H:14]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH2:15]>C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:23])[C@H:14]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:15][C:9](=[O:10])[C@H:4]([CH2:5][C:6](=[O:7])[OH:8])[NH:3][CH:1]=[O:2]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=CN[C@H]1CC(=O)OC1=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC=O
Temperature: 25 °C
Yield: 87 %

Procedure:
The resin used carries sulphonic acid groups on a polystyrene matrix and has an exchange capacity of 5 meq. per gram of dry resin. Consequently the ratio of the acid equivalents of the resin acid groups to the moles of N-formyl-L-aspartic anhydride is 0.1. The mass is agitated in the flask to obtain a suspension. The solution of L-phenylalanine methyl ester in ethyl acetate is added to this agitated suspension by means of the dropping funnel over a time of about 8 minutes, while maintaining the temperature of the mass at about 25° C. At the end of this time a solution is obtained from which the cation exchange resin is separated by filtration. The solution is then cooled to 0° C. and a crystalline precipitate is obtained constituted by a mixture of the α and β isomers of N-formyl-L-aspartyl-L-phenylalanine methyl ester (14.1 g, yield 87%). This precipitate is subjected to HPLC analysis in order to check the ratio of the α to the β by comparison with known samples. The HPLC determinations are carried out using a Perkin-Elmer chromatograph, series 3, with a 7 micron RP8 column, 250×4 mm; eluent used: continuous gradient between solvents: (A) 65 parts of monobasic potassium phosphate 0.07 molar at pH 4+35 parts of methanol; and (B) 65 parts of water +35 parts of methanol; flow rate 1 ml per minute.
Reaction SMILES: [C:1]([N:11](C)[C@H:12]([C:16]([N:18]([CH3:37])[C@H:19]([C:32]([NH:34][O:35][CH3:36])=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])(OCC1C=CC=CC=1)=O.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH:11]([CH3:1])[C@H:12]([C:16]([N:18]([CH3:37])[C@H:19]([C:32]([NH:34][O:35][CH3:36])=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:29])([CH3:30])[CH3:31])[CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14]
Reactant: CONC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)NOC)C(C)C
Yield: 99.2 %

Procedure:
To a solution of Z-N-Me-Val-N-Me-Tyr(3-tBu)-NHOMe (1.23 g, 2.33 mmol) in MeOH (20 ml), palladium hydroxide/carbon (350 mg) was added and stirred in a hydrogen atmosphere for 1 hour. Insoluble matters were removed by filtration with Celite and the filtrate was concentrated under reduced pressure to give crude N-Me-Val-N-Me-Tyr(3-tBu)-NHOMe (0.91 g).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([O:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5].C(N(CC)CC)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>O1CCCC1>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:1][N:2]=[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]([O:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCOC(=O)C(=NO)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOC(=O)C(=NOS(=O)(=O)c1ccc(C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
A solution of 8.8 g (0.39 mol) of crude 2-methoxyethyl α-(hydroxyimino)-2-phenylacetate and 5.98 g of triethylamine in 65 ml tetrahydrofuran is cooled in an ice bath, and 8.3 g (0.043 mol) of p-toluenesulfonic acid chloride dissolved in 18 ml of tetrahydrofuran are added dropwise over 30 minutes. The resulting suspension is stirred for 16 hours at room temperature and then poured onto ice/water. The mixture is extracted with ethyl acetate, the organic layer washed with diluted HCI and water and dried over magnesium sulfate. Evaporation of the solvent gives an orange oil which is purified by chromatography on silica gel (eluent hexane/ethyl acetate 3:1). 12.68 g (86%) 2-Methoxyethyl α-(4-methylphenylsulfonyloxyimino)-2-phenylacetate are thus obtained as a colorless liquid. According to 1H-NMR-analysis, the product is a mixture of 72% of the trans isomer and 28% of the cis isomer.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:48]([CH3:51])[CH2:49][CH3:50])[C@H:19]([O:46][CH3:47])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:44][CH3:45])[C@@H:29]([CH3:43])[C:30]([NH:32][C@H:33]([CH3:42])[C@@H:34]([OH:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])[CH:4]([CH3:6])[CH3:5].O=[CH:53][CH2:54][CH2:55][C:56]([OH:58])=[O:57].C([BH3-])#N.[Na+]>>[C:56]([CH2:55][CH2:54][CH2:53][N:2]([CH3:1])[C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:48]([CH3:51])[CH2:49][CH3:50])[C@H:19]([O:46][CH3:47])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:44][CH3:45])[C@@H:29]([CH3:43])[C:30]([NH:32][C@H:33]([CH3:42])[C@@H:34]([OH:41])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:12])[CH3:13])=[O:8])[CH:4]([CH3:6])[CH3:5])([OH:58])=[O:57]
Reactant: O=CCCC(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
100 mg (0.139 mmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 40) were used, in analogy to the preparation of Intermediate 61, by reaction with 4-oxobutanoic acid in the presence of sodium cyanoborohydride, to obtain 94 mg (84% of theory) of the title compound. The title compound was purified by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:24](OC(=O)C)(=[O:26])[CH3:25].C(O)(=O)C>O>[C:24]([NH:1][C:2]1[C:3]([C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:4]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])(=[O:26])[CH3:25]
Reactant: CCCCOc1cc(C(=O)O)cc(N)c1C(=O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCCCOc1cc(C(=O)O)cc(NC(C)=O)c1C(=O)c1ccccc1
Reaction time: 20 h

Procedure:
A mixture of 5-amino-4-benzoyl-3-n-butoxybenzoic acid (0.8 g), acetic anhydride (0.8 ml) and acetic acid (8.0 ml) is heated on a steam-bath for 1 hour. After cooling, the resulting solution is poured into water (about 20 ml) and the mixture is left at room temperature for about 20 hours. The resulting precipitate is collected by filtration and washed with water. After drying and recrystallization twice from aqueous ethanol, 5-acetamido-4-benzoyl-3-n-butoxybenzoic acid is obtained with a melting point of 177°-178° C.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([N:43]=[C:44]=[O:45])[CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40]>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:44]([NH:43][C:35]4[CH:34]=[C:33]([O:32][CH3:31])[C:38]([O:39][CH3:40])=[C:37]([O:41][CH3:42])[CH:36]=4)=[O:45])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(NC(=O)Nc2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 44.7 mg (0.21 mmol) of 3,4,5-trimethoxyphenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 11 mg (17.4% of theory) of the title compound are obtained.
Reaction SMILES: COC(=O)[C@H:4]([NH:12][CH2:13][CH2:14][NH:15][C:16]([O:18]C(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:5]([C@H:4]1[N:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][CH2:14][NH:15][C:16]1=[O:18])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NCCNC(=O)OC(C)(C)C
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NCCN(Cc2ccccc2)[C@@H]1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
(3R)-3-Benzylpiperazin-2-one (4.1 g; 21.6 mmol, prepared as described in Example 1) was dissolved in methanol (40 ml). Benzaldehyde (2.3 g; 21.6 mmol) was added followed by 4 Å molsieves (2 g) and the mixture was stirred under an atmosphere of nitrogen for 1/2 h. Acetic acid (1.2 ml) was added and sodium cyanoborohydride (2.0 g; 32.4 mmol) was added portion wise during 20 minutes. The reaction mixture was stirred overnight and the filtered. From the filtrate the solvent was evaporated and the residue was dissolved into ethyl acetate (15 ml) and purified on silica gel using ethyl acetate as eluent. This afforded 2.6 g of (3R)-3,4-dibenzylpiperazin-2-one.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CN(C)c1ccnc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)c1ccnc(-c2ccc(F)cc2F)c1
Temperature: 90 °C
Yield: 78.3 %

Procedure:
A mixture of 2-iodo-4-dimethylaminopyridine (3 g, 12 mmol), 2,4-difluorophenylboronic acid (2.3 g, 14.5 mmol) and K2CO3 (6 g 43.5 mmol) in toluene (60 ml) and water (10 ml) were degassed with nitrogen for 15 minutes. Pd(PPh3)4 (800 mg, 0.66 mmol) was added and the resulting mixture was heated to 90° C. for 48 hours under nitrogen. After being cooled to room temperature, the aqueous phase was separated and extracted with EtOAc (3×100 ml). The combined organic fractions were washed with brine, dried over MgSO4, filtered and evaporated. To further purify the compound the so-obtained oil was dissolved in Et2O and extracted with 10% HCl solution (3×50 ml). The combined aqueous fractions were washed with Et2O (2×100 ml) and neutralized with concentrated NaOH aqueous solution. The resulting mixture was extracted with EtOAc (4×100 ml), the combined organic fractions were washed with brine (50 ml), dried over MgSO4, filtered and evaporated to dryness. The crude compound was purified by column chromatography (SiO2, CHCl3 then CHCl3/MeOH, 97/3) to afford 2.2 g (78%) of the titled compound as slightly yellow oil which solidified upon standing.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([P:16]([CH3:19])([CH3:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][C:29]2=[O:35])[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:18][P:16]([CH3:19])([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:21][C:22]4[CH:23]=[C:24]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][C:29]5=[O:35])[CH:25]=[CH:26][CH:27]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)=[O:17]
Reactant: CP(C)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CN1CCN(c2cccc(N)c2)C(=O)C1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccc(P(C)(C)=O)cc5)cccn4n3)c2)C(=O)C1

Procedure:
1-(3-{8-[4-(Dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-phenyl)-4-methyl-piperazin-2-one was prepared from 2-chloro-8-[4-(dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3271 mmol) and 1-(3-amino-phenyl)-4-methyl-piperazin-2-one (75.0 mg, 0.365 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (28.0 mg, 0.0512 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow solid (0.076 g, 49%). MP=208-211° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48 (d, J=6.8 Hz, 1H), 8.14 (d, J=7.8 Hz, 2H), 7.92-7.85 (m, 2H), 7.69 (s, 1H), 7.64 (d, J=7.3 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.01 (t, J=7.1 Hz, 1H), 6.97-6.90 (m, 2H), 3.80-3.75 (m, 2H), 3.32 (s, 2H), 2.85-2.80 (m, 2H), 2.43 (s, 3H), 1.80 (s, 3H), 1.77 (s, 3H). MS=475 (MH)+.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CN(C)C(=O)C>[CH3:29][N:15]([CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([CH2:7][O:6][CH2:5]/[CH:4]=[CH:3]/[CH2:2][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH2:9][CH2:10]1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: C1COCCN1
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COC/C=C/CN2CCOCC2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with morpholine in N,N-dimethylacetamide at room temperature to yield trans-N-methyl-N-[4-(4-morpholin-4-yl-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide as light yellow solid, MS: 505 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[S:12][CH:13]([CH2:16][C:17](O)=[O:18])[CH2:14][N:15]=1)=[CH:7]2.[NH4+].O[N:33]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[S:12][CH:13]([CH2:16][C:17]([NH2:33])=[O:18])[CH2:14][N:15]=1)=[CH:7]2
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a solution of [2-(7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg) in N,N-dimethylformamide (12 mL) were added 1-hydroxybenzotriazole ammonium salt (154 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (194 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 2 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0 to 90:10, volume ratio) to give pale-yellow crystals. The obtained crystals were recrystallized from methanol-ethyl acetate to give the title compound (224 mg, yield 75%) as colorless crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([NH:14][CH2:15][CH2:16][CH3:17])[CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:25]([O:29][C:30]([N:32]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][CH2:41][CH:42]=O)[C:34](=[O:44])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:25]([O:29][C:30]([N:32]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][CH2:41][CH2:42][N:14]([CH:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[CH2:11]2)[CH2:15][CH2:16][CH3:17])[C:34](=[O:44])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCCNC1CCc2ccc(OC)cc2C1
Reactant: CC(C)(C)OC(=O)N1CCCN(CCCC=O)C(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCCN(CCCCN1CCCN(C(=O)OC(C)(C)C)CC1=O)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine hydrochloride prepared as described in Example 1 (500 mg, 2 mmol, 1 eq) and triethylamine (0.3 mL, 2.2 mmol, 1.1 eq.) in 1,2-dichlororethane (20 mL) under inert atmosphere was added the 3-oxo-4-(4-oxo-butyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (550 mg, 2 mmol, 1 eq.) in a single portion followed by the sodium triacetoxyborohydride (650 mg, 3 mmol, 1.5 eq.). The reaction was stirred at room temperature for 20 hr, concentrated in-vacuo and then partitioned between 10% KOH (40 mL) and ethyl acetate (75 mL), the organic layer was washed with brine, dried (MgSO4) and concentrated. Purification by chromatography provided 858 mg of 4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-3-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][N:16](C(OCC1C=CC=CC=1)=O)[CH2:15][CH2:14]2)=[O:10].C(O)C.[H][H]>[Pd].C(N(CC)CC)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10]
Reactant: [H][H]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Yield: 90.6 %

Procedure:
A mixture of 5 g benzyl 6-[(tetrahydro-2H-pyran-2-yloxy)carbamoyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate, 250 mg Pd/C (5%), 250 ml ethanol and 5 ml triethylamine is hydrogenated at ambient hydrogen pressure. The reaction mixture is filtered, evaporated and 3.05 g of yellowish foam are obtained.
Reaction SMILES: [OH:1][C:2]1[C:9](C)=CC(C)=C[C:3]=1[CH:4]=O.[OH:12][C:13]1[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:14]=1[CH:15]=O>>[Cl:22][C:18]1[CH:17]=[C:14]2[C:13](=[C:20]([CH3:21])[CH:19]=1)[O:12][CH2:4][C:3]([C:2](=[O:1])[CH3:9])=[CH:15]2
Reactant: Cc1cc(C)c(O)c(C=O)c1
Reactant: Cc1cc(Cl)cc(C=O)c1O
Product: CC(=O)C1=Cc2cc(Cl)cc(C)c2OC1

Procedure:
Using the procedure described in Example 1, stage A, but with 2-hydroxy-3,5-dimethylbenzaldehyde replaced by 2-hydroxy-3-methyl-5-chlorobenzaldehyde, the expected product is obtained, and this is purified by an additional recrystallization in an isopropyl ether/petroleum ether mixture.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.[C:14](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>>[CH3:14][N:4]([CH2:3][C:2]([F:12])([F:13])[F:1])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1
Reactant: Cc1cccc(NCC(F)(F)F)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Product: Cc1cccc(N(C)CC(F)(F)F)c1

Procedure:
The same method as in Example 2 is carried out using 56.7 parts of N-(2,2,2-trifluoroethyl)-m-toluidine, 53 parts of sodium bicarbonate and 75 parts of dimethyl sulphate. 52.8 parts, i.e. a yield equal to 86.7% of the theoretical yield, of N-methyl N-(2,2,2-trifluoroethyl)-m-toluidine are obtained.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH:13]1[CH2:17][O:16][C:15]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[S:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>>[O:1]([CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH:13]1[CH2:17][O:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[S:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)OCC(CSCCCOc2ccccc2)S1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)CCC1(CCC(=O)O)OCC(CSCCCOc2ccccc2)S1

Procedure:
The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 6 (2.44 g, 0.0052 mol) and aqueous lithium hydroxide solution (2M, 9 ml). The product, 1.86 g (82%), was obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[C:5]([OH:10])=[C:4]([CH2:11][OH:12])[CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]([OH:10])=[C:6]([CH:8]=[O:9])[CH:7]=1
Reactant: OCc1cc(Cl)cc(CO)c1O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1cc(Cl)cc(C=O)c1O
Temperature: 25 °C

Procedure:
To a stirred suspension of diol (Step 1) (33.0 g, 0.18 mole) in chloroform (1.5 L) in a 2 L round bottom flask was added manganese dioxide (139 g, 1.60 mole) and the resulting suspension heated to a gentle reflux for 10 hours. The reaction was allowed to cool to room temperature, was filtered through diatomaceous earth, concentrated in vacuo, presorbed on silica gel and purified by flash chromatography (hexane/ethyl acetate) yielding the as a mustard colored powder dialdehyde (22.42 g, 67%): mp 120.7–122.8° C. This solid was of suitable purity to use in the next step without further purification.