Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1.C(N(CC)CC)C.[C:50](OC(=O)C)(=[O:52])[CH3:51]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:23][C:24]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:12][N:13]([C:50](=[O:52])[CH3:51])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1
Reactant: COc1ccccc1CNCC(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1CN(CC(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)=O
Reaction time: 4 h
Yield: 87 %

Procedure:
To a stirring solution of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-(N-triphenylmethylamino)propane (0.404 mole) in anhydrous tetrahydrofuran (1.2 liters) under a nitrogen atmosphere at 0° C. was added triethylamine (66.5 ml, 0.477 mole) and acetic anhydride (45.0 ml, 0.477 mole). After 4 hours, the mixture was concentrated on a rotary evaporator, redissolved in methylene chloride and ethyl acetate, washed with water (2×) and brine (2×), dried over anhydrous sodium sulfate, filtered, and concentrated to a solid on a rotary evaporator. The resulting solid was dissolved in chloroform and loaded onto silica gel 60 (230-400 mesh) and eluted with a 1:1 mixture of ethyl acetate and hexanes. The product was then crystallized from an ethyl acetate/hexanes mixture. The resulting product of 3-(1H-indol-3-yl)-1-(N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane was crystallized and isolated over three crops giving 208.97 grams (87% yield) of analytically pure material.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].BrCCC1C=CC2[O:42][CH2:41][CH2:40]C=2C=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[O:42]1[C:21]2[CH:20]=[C:19]([CH2:18][CH2:17][N:16]([C@H:25]3[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]3)[C:14](=[O:15])[NH:13][C:11]3[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=3)[CH:24]=[CH:23][C:22]=2[CH2:40][CH2:41]1
Reactant: BrCCc1ccc2c(c1)CCO2
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCc2ccc3c(c2)OCC3)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 5-(2-bromo-ethyl)-2,3-dihydro-benzofuran and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][O:11][C:4]=2[CH2:3]1.[CH3:12][C:13]([C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1F)=[O:14]>>[ClH:21].[C:13]([C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[O:8][CH:6]1[CH2:7][N:2]([CH3:1])[CH2:3][C:4]2[O:11][CH:10]=[CH:9][C:5]1=2)(=[O:14])[CH3:12]
Reactant: CN1Cc2occc2C(O)C1
Reactant: CC(=O)c1c(F)cccc1Cl
Product: CC(=O)c1c(Cl)cccc1OC1CN(C)Cc2occc21
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-chloro-6-fluoroacetophenone instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:15]=[C:16]([CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH:35]=[CH:36][CH:37]=3)[CH2:28][CH2:27]2)[CH:17]=[CH:18][CH:19]=1>>[F:13][C:14]1[CH:15]=[C:16]([CH:20]([O:12][C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][CH:29]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:41])[CH3:42])[CH:35]=[CH:36][CH:37]=3)[CH2:30][CH2:31]2)[CH:17]=[CH:18][CH:19]=1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3cccc(F)c3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3cc(C(F)(F)F)ccc3F)c3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[6-(3-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 603.3 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH:7]=O.[C:9](#[N:13])[CH2:10][C:11]#[N:12].[NH2:14]/[C:15](/[CH3:19])=[CH:16]\[C:17]#[N:18].C[O-].[Na+]>C(O)C>[NH2:12][C:11]1[C:10]([C:9]#[N:13])=[C:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[N:14]=1
Reactant: N#CCC#N
Reactant: C/C(N)=C/C#N
Reactant: O=CC1CCCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(N)c(C#N)c(C2CCCCO2)c1C#N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
870 mg (7.62 mmol) of tetrahydro-2H-pyran-2-carbaldehyde, 504 mg (7.62 mmol) of malononitrile and 626 mg (7.62 mmol) of 3-aminocrotononitrile are dissolved in 8.4 ml of dry ethanol. The solution is cooled to 0° C., and 412 mg (7.62 mmol) of sodium methoxide are added a little at a time. The reaction mixture is then warmed to RT and stirred for 10 min. The mixture is then heated at reflux for 10 h. After cooling, the brown precipitate formed is filtered off with suction, washed three times with a total of 100 ml of ethanol and then dried at 50° C. under reduced pressure. The product is used without further purification for the next reaction. Purification may be carried out by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: C([O:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)C=C.[C:18]1(OC2C=CC=CC=2)[CH:23]=CC=C[CH:19]=1>>[CH2:23]([C:17]1[CH:16]=[C:8]([CH:7]=[CH:6][C:5]=1[OH:4])[O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:18]=[CH2:19]
Reactant: C=CCOc1ccc(OCC(=O)OCC)cc1
Reactant: c1ccc(Oc2ccccc2)cc1
Product: C=CCc1cc(OCC(=O)OCC)ccc1O
Temperature: 25 °C

Procedure:
A solution of ethyl 4-allyloxyphenoxyacetate (2.0 g) in diphenylether (15 ml) was heated at reflux for 12 minutes. The reaction mixture was allowed to cool to ambient temperature and the reaction mixture was poured onto a silica gel pad (Merck Art. No. 9385). Elution with hexane followed by a 4:1 (v/v) mixture of hexane and ethyl acetate gave ethyl 3-allyl-4-hydroxyphenoxyacetate (1.62 g) as a solid, mp 52.8° C.; microanalysis, found: C, 66.3; H, 7.20%; C13H16O4 requires: C, 66:1; H, 6.83%; NMR (CDCl3): 1.28 (3H, t), 3.35 (2H, d), 4.25 (2H, q), 4.55 (2H, s), 4.73 (1H, s), 5.07-5.20 (2H, m), 5.88-6.10 (1H, m) and 6.62-6.78 (3H, m); m/z 237 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=2)[N:3]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+].COC=COC>C(O)C.O>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:32]3[C:27]([F:26])=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:12]=2)[N:3]=1
Reactant: OB(O)c1cccnc1F
Reactant: N#Cc1ccc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)cc1
Agent: COC=COC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)c3ccccc32)cc1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
4-[3-Amino-1-(3-bromophenyl)-1H-isoindol-1-yl]benzonitrile (0.086 g, 0.22 mmol) (Example 50), (2-fluoropyridin-3-yl)boronic acid (0.047 g, 0.33 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (0.018 g, 0.022 mmol), potassium carbonate (0.091 g, 0.66 mmol) and solvent (3 mL of a mixture of dimethoxyethene, water and ethanol in a ratio of 6:3:1) was irradiated under argon atmosphere in a microwave at 125° C. for 6 min. When cooled to ambient temperature the mixture was partitioned between ethyl acetate and water; the organic phase was dried over magnesium sulfate and evaporated. Purification by preparative HPLC to give 0.062 g (70% yield) of the title compound. 1H NMR (DMSO-d6) δ 8.22 (dd, J=3.28, 1.52 Hz, 1 H), 8.05-7.94 (m, 1 H), 7.84-7.75 (m, 2 H), 7.75-7.69 (m, 2 H), 7.56-7.34 (m, 9 H), 6.90 (br s, 2 H); MS (AP) m/z 405 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH:16]([OH:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].S(OC)(O[CH3:28])(=O)=O>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH:16]([O:21][CH3:28])[CH2:15]2)(=[O:12])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)N2CCC(O)C(O)C2)ccc1Cl
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC1CN(S(=O)(=O)c2ccc(Cl)c(C(=O)O)c2)CCC1O
Temperature: 25 °C

Procedure:
2-Chloro-5-(3,4-dihydroxypiperidinosulfonyl)benzoic acid (4.0 g.) is heated for 16 hours at 90° C. with water (15 ml.), NaOH (1.0 g. and dimethyl sulfate (0.5 ml.). Dimethyl sulfate and NaOH are added during the course of the reaction to maintain basicity. After cooling to room temperature, the reaction mixture is washed with ether and the aqueous phase is acidified with concentrated hydrochloric acid and decanted from the precipitated gum. The gum is dissolved in ethyl acetate and chromatographed on a silica gel column. The product fractions in the column effluent are identified by paper chromatography, with development in a solvent system of ethyl acetate-acetic acid. Concentration of the column fraction yields the product, m.p. 170°-174° C.
Reaction SMILES: Cl.Cl.[O:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[CH:16][C:17]4[N:21]=[C:20]([NH:22][C:23](=[O:26])[O:24][CH3:25])[NH:19][C:18]=4[CH:27]=3)=[CH:13][C:8]=2[CH2:7][NH:6][CH2:5][CH2:4]1.CN(C=O)C.CCN(C(C)C)C(C)C.[F:42][CH2:43][CH:44]1[CH2:49][CH2:48][N:47]([C:50](Cl)=[O:51])[CH2:46][CH2:45]1>ClCCl>[F:42][CH2:43][CH:44]1[CH2:49][CH2:48][N:47]([C:50]([N:6]2[CH2:7][C:8]3[CH:13]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]5[N:21]=[C:20]([NH:22][C:23](=[O:26])[O:24][CH3:25])[NH:19][C:18]=5[CH:27]=4)[CH:11]=[CH:10][C:9]=3[O:3][CH2:4][CH2:5]2)=[O:51])[CH2:46][CH2:45]1
Reactant: O=C(Cl)N1CCC(CF)CC1
Reactant: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CNCCO4)cc2[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CN(C(=O)N3CCC(CF)CC3)CCO4)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
Methyl [6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-yl]carbamate dihydrochloride salt (51.7 mg, 0.13 mmol) was taken into DMF (1 mL) and dichloromethane (1 mL) followed by addition of DIPEA (88 uL, 0.52 mmol) and the mixture was cooled to 0° C. 4-(Fluoromethyl)piperidine-1-carbonyl chloride (reagent preparation 37) (33 mg, 0.13 mmol) was added to the mixture in a minimum of dichloromethane then stirred for 30 minutes. The mixture was partitioned with ethyl acetate and water and the organic phase washed twice with water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (4:1 ethyl acetate:hexanes) to give methyl [6-(4-{[4-(fluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-yl]carbamate (40.3 mg, 66% yield) as a white solid. 1H NMR (400 MHz, d6-DMSO): 7.58 (s, 1H), 7.47 (s, 1H), 7.45-7.42 (m, 2H), 7.31 (dd, 1H), 7.02 (d, 1H), 4.42 (s, 2H), 4.37 (d, 1H), 4.26 (d, 1H), 4.17 (br s, 1H), 3.77 (s, 3H), 3.60 (br m, 4H), 2.75 (tr, 2H), 1.85 (br, 1H), 1.63 (d, 2H), 1.25 (q, 2H). MS (EI) for C25H18FN5O4: 483 (MH+).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([C:10]([O:12]C)=[O:11])=[CH:9][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[Na+:22].[Na+].O>CO>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([C:10]([O-:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1.[Na+:22]
Reactant: COC(=O)c1cc2cc(C(F)(F)F)ccc2s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C([O-])c1cc2cc(C(F)(F)F)ccc2s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A mixture of 5.00 g of methyl 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 4.00 g of sodium carbonate, 20 ml of water and 60 ml of methanol was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was recrystallized from water to obtain 5.10 g of sodium 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (hereinafter referred to as “the present compound 5”).
Reaction SMILES: N[CH:2]1[CH:7]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:6][CH2:5][N:4]([CH2:18][CH:19]([OH:21])[CH3:20])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]1[C:31]([CH2:36]Br)=[CH:32][CH:33]=[CH:34][CH:35]=1.[ClH:38].C(#[N:41])C>C(O)C>[ClH:38].[ClH:38].[F:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([CH:7]3[CH2:6][CH2:5][N:4]([CH:18]([CH:36]4[C:31]5[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:29][NH:41]4)[CH:19]([OH:21])[CH3:20])[CH2:3][CH2:2]3)=[N:9][O:10][C:11]=2[CH:16]=1
Reactant: CC(O)CN1CCC(c2noc3cc(F)ccc23)C(N)C1
Reactant: BrCc1ccccc1CBr
Reactant: CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(O)C(C1NCc2ccccc21)N1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
To a stirred mixture of 1-(3-amino-2-hydroxypropyl-4-(6-fluoro-1,2-benzisoxazol3-yl)piperidine (2.24 g, 7.6 mmol), K2CO3 (1.61 g, 11.7 mmol) in acetonitrile (100 ml) was added α,α'-dibromo-o-xylene (1.54 g, 6.1 mmol). The mixture was heated at reflux for 4 hours then cooled. The insolubles were filtered. The dark red solution was concentrated down. The residue was purified by flash chromatography over s silica gel column (SiO2, 30 g; eluted with 1% CH3OH in dichloromethane). The product so obtained weighed 940 mg as an oil. This oil was dissolved in ethanol and was treated with a solution of HCl in ethanol (188 mg of AcCl in ethanol). The dark solids were collected and recrystallized again in ethanol to yield off-white crystals (1.01 g), m.p. 240°-243° C.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:15][C:16]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:17]=1[NH2:18]>>[CH3:15][C:16]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:17]=1[NH:18][C:12](=[O:13])[CH2:11][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Cc1cc(C)c(N)cc1C
Product: Cc1cc(C)c(NC(=O)CC23CC4CC(CC(C4)C2)C3)cc1C
Yield: 14.3 %

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (0.2 g) and 2,4,5-trimethylaniline (0.13 g) to give the title compound as a white solid (0.042 g).
Reaction SMILES: [CH2:1]([CH:3]1[CH:7]([CH3:8])[CH2:6][C:5](OC)=[N:4]1)[CH3:2].[Cl-:11].[NH4+:12]>CO>[ClH:11].[CH2:1]([CH:3]1[NH:4][C:5](=[NH:12])[CH2:6][CH:7]1[CH3:8])[CH3:2]
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: CCC1N=C(OC)CC1C
Solvent: CO
Product: CCC1NC(=N)CC1C
Product: Cl

Procedure:
The product of EXAMPLE 216 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]([OH:34])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[C:10](=[O:19])[C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N+:35](=[CH2:37])=[N-:36].CN(N=O)S(C1C=CC(C)=CC=1)(=O)=O.[OH-].[K+]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][C:25]([OH:34])([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)[C:10]([C:11]2[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:36][NH:35][CH:37]=2)=[O:19])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(C#Cc1ccccc1)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reactant: C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(c1c[nH]nc1-c1ccccc1)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-(3,4-dichlorophenyl)-6-(4-hydroxy-4-phenylpiperidino)-1-phenyl-hex-1-yne-3-one (0.30 g) in diethyl ether (25 mL) was cooled to 0° C. and was treated with diazomethane (generated by the reaction of and ethereal solution of N-methyl-N-nitroso-p-toluenesulfonamide with ethanolic potassium hydroxide (Anal. Chem., 45, 2302, 1973)). The resulting mixture was allowed to warm to room temperature and stirred for 3 days. The solvent was evaporated. Radial chromatography, eluting with dichloromethane:methanol (gradient 97.5:2.5, 95:5), afforded the title compound (50 mg) as a white powder; mp 112°-114° C.; NMR: 8.13 (s,1), 7.56-7.26 (m, 12), 7.08 (d,1), 4.33 (broad s,1), 2.68 (m,2), 2.37 (m,3), 2.05 (broad s,1), 1.86 (broad s,1), 1.73-1.43 (m, 5); MS: m/z=534(M+l). Analysis for C30H29Cl2N3O2 ·0.75 H2O: Calculated: C, 65.75; H, 5.61; N, 7.67; Found: C, 65.71; H, 5.60; N, 7.83.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:20](O)(=[O:23])[CH2:21][CH3:22].CCN=C=NCCCN(C)C.OP([O-])(O)=O.[K+]>C(Cl)Cl>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]3[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][C:20](=[O:23])[CH2:21][CH3:22])[C:11]=3[CH:10]=[N:9][CH:8]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: N#Cc1ccc(-c2cncc3c2CCCC3N)cc1
Reactant: CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Product: CCC(=O)NC1CCCc2c(-c3ccc(C#N)cc3)cncc21
Temperature: 25 °C
Yield: 94.7 %

Procedure:
To a stirred solution of (rac)-4-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (example 1) (480 mg, 1.93 mmol) and propionic acid (158 μL, 2.12 mmol) in CH2Cl2 (10 mL) at 0° C. under Argon was added EDCI (406 mg, 2.12 mmol). Stirring was continued over night and the reaction mixture was allowed to warm up to room temperature. The reaction mixture was poured into aq. 10% KH2PO4 solution followed by extraction with AcOEt (3×). The organic phases were washed once with aq. 10% KH2PO4, aq. sat. NaHCO3 and with aq. sat. NaCl solution. The combined organic phases were dried over Na2SO4, filtered and evaporated to afford the title compound (558 mg, 95%) as light brown solid. MS: 306.2 (M+H+).
Reaction SMILES: Cl[C:2]1[C:31]([O:32][CH2:33][CH3:34])=[CH:30][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])[CH:16]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:35][CH2:36][CH3:37].C(OC1C=C(C=O)C=C(OCC)C=1[C:52]1[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=1)C.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:36]([O:35][C:3]1[CH:4]=[C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])[CH:16]=3)[CH2:9][CH2:8]2)[CH:30]=[C:31]([O:32][CH2:33][CH3:34])[C:2]=1[C:52]1[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=1)[CH3:37]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCC(O)CO)c3)CC2)cc(OCC)c1Cl
Reactant: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCC(O)CO)c3)CC2)cc(OCC)c1-c1ccc(F)cc1

Procedure:
In analogy to the procedure described in example 50k), rac-3-(2,3-dihydroxy-propoxy)-5-methoxy-N-piperidin-4-yl-benzamide hydrochloride (example 248) was reacted with 2,6-diethoxy-4′-fluoro-biphenyl-4-carbaldehyde (example 102), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 597.3 (MH+).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH3:24])[N:19]=3)[O:12]2)=[C:4]([NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[N:3]=1.[NH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34][CH2:33]1.CS(C)=[O:41]>>[CH:18]([OH:22])=[O:41].[NH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([NH:38][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@H:11]3[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]4[O:22][N:21]=[C:20]([CH2:23][CH3:24])[N:19]=4)[O:12]3)=[C:4]([NH:25][CH:26]([CH2:27][CH3:28])[CH2:29][CH3:30])[N:3]=2)[CH2:34][CH2:33]1
Reactant: CS(C)=O
Reactant: CCc1noc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Reactant: N[C@H]1CC[C@H](N)CC1
Product: CCc1noc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(N[C@H]5CC[C@H](N)CC5)nc43)[C@H](O)[C@@H]2O)n1
Product: O=CO
Temperature: 85 °C

Procedure:
Intermediate 9 (0.070 g, 0.161 mmol) and trans-1,4-diaminocyclohexane (0.092 g, 0.807 mmol) were dissolved in DMSO (0.03 ml) and heated at 80-90° C. in a sealed vial (eg Reacti vial™), for 66 h, a further portion of trans-1,4-diaminocyclohexane (0.092 mg, 0.807 mmol) was added after the first 20 h. The product was purified by Autoprep. HPLC to give the title compound after freeze drying as a brown solid (0.082 g). LC/MS system B Rt=2.21 min, m/z=516 MH+.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:20][C@H:21]([C:27]([O:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31])=[O:28])[CH2:22][CH2:23][CH:24](C)C.Br.[C:39]1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1>>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([NH:20][C@H:21]([C:27]([O:29][C:30]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:31])=[O:28])[CH2:22][CH:23]([CH3:24])[CH3:39])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)CC[C@H](N)C(=O)OC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: Br
Product: CC(C)C[C@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OC(=O)c1ccccc1
Yield: 54 %

Procedure:
Condensation of BocDPheOH (2.65 g.) and HLeuOBz hydrobromide salt (3.02 g.) by the mixed anhydride method using diphenylphosphinyl chloride gave BocDPhe-LeuOBz in 54% yield. Debenzylation of BocDPhe-LeuOBz (2.25 g.) by hydrogenation with palladium catalyst gave BocDPhe-LeuOH in 87% yield. Condensation of BocDPhe-LeuOH (1.50 g.) and HNleNH2 hydrochloride salt (0.667 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocDPhe-Leu-NleNH2 in 60% yield. De-t-butoxycarbonylation of BocDPhe-Leu-NleNH2 (1.00 g.) using hydrogen chloride in acetic acid gave HDPhe-Leu-NleNH2 hydrochloride salt in 79% yield.