Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][CH2:15][C:14]2[NH:13][N:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][C:27]=1[CH3:34]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]2[C:10]3[CH2:9][NH:8][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([F:25])=[C:27]([CH3:34])[CH:28]=3)[N:12]=2)=[CH:23][CH:22]=1
Reactant: Cc1cc(CBr)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCCc2[nH]nc(-c3ccc(Cl)cc3)c2C1
Product: Cc1cc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCCNC3)ccc1F
Yield: 0.9 %

Procedure:
The title compound (0.001 g) was prepared from 3-(4-chloro-phenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 4-fluoro-3-methylbenzyl bromide (0.09 g) in place of benzyl chloride in Example 59, Step D. MS (ESI): exact mass calculated for C21H21ClFN3, 369.14. found, m/z 370.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.48-7.43 (m, 4H), 7.08-7.06 (m, 1H), 6.99-6.97 (m, 2H), 5.32 (s, 2H), 3.88 (s, 2H), 3.16-3.14 (m, 2H), 2.89-2.86 (m, 2H), 2.22 (d, J=1.6 Hz, 3H), 1.80 (m, 2H).
Reaction SMILES: C(NC(C)C)(C)C.CON(C)[C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.[CH3:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([S:31][CH3:32])[N:26]=1.C([Li])CCC>O1CCCC1>[CH3:32][S:31][C:27]1[N:26]=[C:25]([CH2:24][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)=[O:22])[CH:30]=[CH:29][N:28]=1
Reactant: CSc1nccc(C)n1
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSc1nccc(CC(=O)c2cccc(C(F)(F)F)c2)n1
Reaction time: 0.17 h

Procedure:
Diisopropylamine (106 mL, 761 mmol) and tetrahydrofuran (THF) 750 mL) were combined in a 3-neck 2L round bottom flask under argon. Two addition funnels, one containing a solution of Compound 1 in THF (100 mL), the other containing Compound 2 in THF (100 mL) were attached to the reaction flask. The contents of the reaction flask were cooled in an IPA/dry ice bath. A solution of n-butyl lithium (2.5M in hexanes, 304 mL, 761 mmol) was added dropwise via syringe. The THF solution of Compound 1 was added dropwise over 0.5 h. This was followed by the addition of the THF solution of Compound 2. A dark solution resulted. After 10 min, ice was added and the THF was removed in vacuo. Water was added followed by sat. sodium bicarbonate and the aqueous mixture was extracted several times with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give an oil. Purification by flash column chromatography (hexane:ethyl acetate 95:5 to 75:25) gave a solid which was triturated with hexane:ether 80:20 then isolated by vacuum filtration to afford Compound 3 as a solid: 60g (220 mmol, 43%)
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[C:14]([C:17]([F:25])([F:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:27])([CH3:26])[CH2:9]1)=O)(C)(C)C.[ClH:28]>CO>[ClH:28].[F:25][C:17]([F:24])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:14]1[N:13]=[CH:12][C:11]2[C:10]([CH3:27])([CH3:26])[CH2:9][NH:8][C:16]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(C(F)(F)c3ccccc3)cc21
Agent: Cl
Solvent: CO
Product: CC1(C)CNc2cc(C(F)(F)c3ccccc3)ncc21
Temperature: 35 °C
Reaction time: 4 h

Procedure:
A mixture of 6-(difluoro-phenyl-methyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (6.22 g, 16.6 mmol), methanol (30 mL) and hydrochloric acid (5M, 30 mL) was stirred at 20° C. for 3 h, at 35° C. for 4 h, then left at 20° C. for 14 h. Mixture was evaporated in vacuo and the residue azeotroped with toluene (×3), isopropanol and methanol (×3). Residue was dried in vacuo at 50° C. for 4 h to give the title compound. MS: [M+H]+=275.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].BrC(C)(C)C([O-])=O>CN(C)C=O.O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:3][CH:4]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)(Br)C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(C=O)cc1
Yield: 42 %

Procedure:
24.42 g (200 mmol) of 4-hydroxybenzaldehyde are dissolved in 250 ml of N,N-dimethylformamide and treated with 27.64 g (200 mmol) of potassium carbonate. At 100° C., 53.55 g (240 mmol) of tert-butyl α-bromoisobutyrate are added dropwise. The mixture is stirred for another hour, a further 200 mmol of potassium carbonate and 240 mmol of tert-butyl (α-bromoisobutyrate are added and, after 4 hours at 100° C., 1 l of water is added. Following extraction with diethyl ether, washing with 1 N aqeuous sodium hydroxide solution and saturated sodium chloride solution and drying over magnesium sulphate, the solvent is distilled off and the residue is purified by flash chromatography on silica gel (cyclohexane→cyclohexane/ethyl acetate 20:1→10:1→5:1) and dried under reduced pressure. The target compound is obtained in the form of colourless crystals in a yield of 42%.
Reaction SMILES: [C:1]1([C:7]23[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:11][NH:10][CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]=O.Cl.[OH-].[Na+]>O.C(O)=O>[C:1]1([C:7]23[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:11][N:10]([CH3:16])[CH2:9][CH2:8]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=O
Reactant: c1ccc(C23CCCC2CNCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: CN1CCC2(c3ccccc3)CCCC2C1
Temperature: 95 °C

Procedure:
A solution of 3.0 g. of 4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine in 10 ml. of 88% formic acid was stirred at 20° C. while 10 ml. of 38% formaldehyde was added dropwise over fifteen minutes. The reaction mixture was then heated at 95° C. for eight hours. After cooling the reaction mixture to 25° C. 100 ml. of 4 N hydrochloric acid was added dropwise over thirty minutes. The aqueous acidic reaction mixture was concentrated under reduced pressure to provide an oily residue. The oil was then dissolved in 100 ml. of water, and the aqueous solution was made basic by the addition of 50 percent aqueous sodium hydroxide solution. The product precipitated out of the aqueous alkaline solution, and was extracted into diethyl ether. The ethereal extracts were combined, washed with water, dried, and the solvent was evaporated under reduced pressure to provide 4a-phenyl-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine as an oil. The oil so formed was dissolved in 150 ml. of diethyl ether. The ethereal solution was stirred at 25° C. while a solution of 10 ml. of 48 percent hydrobromic acid in 10 ml. of ethanol was added dropwise over ten minutes. The product precipitated out of solution and was recovered by filtration. The solid precipitate was recrystallized from diisopropyl ether and isopropanol to afford 2.7 g. of 4a-phenyl-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindinium bromide. M.P. 209°-210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](/[CH:9]=[CH:10]\[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH:6]=[C:5]([O:23][CH3:24])[C:4]=1[OH:25].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]2[NH:54][C:53](=[O:55])[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[NH:46]2)=[CH:41][C:40]=1[O:56][CH3:57]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH3:24][O:23][C:5]1[CH:6]=[C:7](/[CH:9]=[CH:10]\[C:11]2[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=2)[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[O:25][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]2[NH:54][C:53](=[O:55])[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[NH:46]2)=[CH:41][C:40]=1[O:56][CH3:57]
Reactant: COc1cc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc(OC)c1O
Reactant: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCOc1c(OC)cc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OC
Temperature: 30 °C
Reaction time: 30 h
Yield: 79.7 %

Procedure:
(Z)-2,6-dimethoxy-4-(3,4,5-trimethoxystyryl)phenol (38b) (346.37.36 mg 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.29 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (43d) (546 mg, 80% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Li]CCCC.[CH3:16][S:17]SC.CI>C1COCC1>[Cl:1][C:2]1[C:3]2[S:10][C:9]([S:17][CH3:16])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CSSC
Reactant: Clc1ncnc2ccsc12
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CSc1cc2ncnc(Cl)c2s1
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of 20 (shown in the scheme 4) (200 mg, 1.18 mmol) in THF (11 mL) was added n-BuLi (566 μL, 1.42 mmol, 2.5M in THF) very slowly at −78° C. and the mixture was stirred for 15 min at the same conditions. A solutions of dimethyl disulfide (160 uL, 1.77 mmol) and MeI (110 μL, 1.77 mmol) in THF (1 mL) was added drop wise. The reaction mixture was stirred for 2 h at −78° C., quenched with saturated aqueous NH4Cl solution, and extracted with DCM. The extract was dried over anhydrous Na2SO4 and concentrated to afford the title compound 280 (210 mg, 82% yield) as a yellowish solid. MS (m/z): 217.0 (M+H) (found).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](\[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[CH:25].ClCCl>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](\[C:13]1[CH:18]=[CH:17][C:16]([C:25]#[C:24][CH2:23][N:22]([CH3:26])[CH3:21])=[CH:15][CH:14]=1)/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: C#CCN(C)C
Reactant: CCOC(=O)/C=C(/c1ccccc1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)/C=C(/c1ccccc1)c1ccc(C#CCN(C)C)cc1

Procedure:
A solution of (Z)-3-(4-bromo-phenyl)-3-phenyl-acrylic acid ethyl ester (1.200 g, 3.6 mmol), dimethyl-prop-2-ynyl-amine (0.9 ml, 10.88 mmol), bis(triphenylphosphine) palladium(II) chloride (0.102 g, 0.144 mmol), copper(I) iodide (2.06 mg, 0.0108 mmol) in dry triethylamine (10 ml) were heated to 100° C. by microwave irradiation for 20 min. The cooled reaction mixture was added dichloromethane (20 ml) and silica gel Fluka 60 (10 g) and evaporated in vacuo. The resulting residue was purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) giving (Z)-3-[4-(3-Dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-acrylic acid ethyl ester as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[S:9][C:10](Cl)=[N:11][N:12]=1>C(O)C>[NH2:7][C:8]1[S:9][C:10]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:11][N:12]=1
Reactant: Nc1nnc(Cl)s1
Reactant: C1COCCN1
Solvent: CCO
Product: Nc1nnc(N2CCOCC2)s1
Temperature: 40 °C

Procedure:
Morpholine (200 μl) was added to a solution of 2-amino-5-chloro-1,3,4-thiadiazole (60 mg) in ethanol (2 ml) and the mixture heated in a sealed vial at 40° C. for 6 hours. The ethanol was evaporated from the cooled reaction under vacuum, the residue diluted with water and filtered. The filtrate was extracted with ethyl acetate (x2), the extracts dried (MgSO4) and the solvent removed under vacuum to give 2-amino-5-morpholinyl-1,3,4-thiadiazole.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]([O-:12])(=[O:11])[CH:8]([CH3:10])[OH:9].C[N+](C)(C)C>CN(C)C=O>[C:7]([O:12][CH2:2][C:3]([O:5][CH3:6])=[O:4])(=[O:11])[CH:8]([CH3:10])[OH:9]
Reactant: CC(O)C(=O)[O-]
Reactant: COC(=O)CBr
Agent: C[N+](C)(C)C
Solvent: CN(C)C=O
Product: COC(=O)COC(=O)C(C)O

Procedure:
Methyl bromoacetate (4.73 mL, 50 mmol) was added to a stirring solution of tetramethylammonium lactate dehydrate (11.0 g, 55 mmol) in 20 mL dimethylformamide at room temperature. Tetramethylammonium bromide separated from the reaction mixture as a white solid and the title compound was formed quantitatively within 60 min as determined by CG (Method A). The reaction mixture was filtered, the solids were washed with ethyl ether, and the combinated filtrate and ether solution was washed with 5% NaCl/5% NaHCO3. Sufficient ethyl ether was added to effect rapid separation of the phases, the aqueous phase was extracted with CH2Cl2, and the organic phases were combined and dried with MgSO4. The solvent was removed and the resulting residue was distilled under reduced pressure to give the title compound: b.p. 79° C./0.15 mm Hg.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([N+:14]([O-])=O)[C:8]=1[OH:17])(=[O:6])=[O:5])[CH3:2].[H][H]>[Pd]>[CH2:1]([NH:3][S:4]([C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([NH2:14])[C:8]=1[OH:17])(=[O:5])=[O:6])[CH3:2]
Reactant: CCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Product: CCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Yield: 66.8 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, crude N-ethyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (1.34 g) was reduced with hydrogen and 10% Pd/C (400 mg) to form the desired product (800 mg, 82% for two steps). 1H NMR (MeOD-d4): δ 6.85 (d, 1H), 6.78 (d, 1H), 2.85 (q, 2H), 0.95 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[N:29]=[C:28]3[C:23]([C:24](=[O:33])[C:25]([CH3:32])([CH3:31])[C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[N:29]=[C:28]3[C:23]([CH:24]([OH:33])[C:25]([CH3:31])([CH3:32])[C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: CC1(C)C(=O)Nc2nc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)C(=O)Nc2nc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ccc2C1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a solution of 7-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,3-dimethyl-1H-[1,8]naphthyridine-2,4-dione (0.132 g, 0.268 mmol) in THF (2 mL), cooled to 0° C. was added NaBH4 (0.013 g, 0.335 mmol). The reaction was warmed to room temperature and stirred for 3 hours. The reaction was quenched with saturated NaHCO3 and partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give the title compound as a white solid (0.095 g, 0.192 mmol, 57%). MS: APCI: M+1: 493.1 (Exact Mass: 492.17).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH2:16])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH:16][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc(C(=O)Nc2cccc(Cl)c2)c(N)s1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Cc1nc(C(=O)Nc2cccc(Cl)c2)c(NC(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.7 %

Procedure:
A solution of 5-amino-2-methyl-thiazole-4-carboxylic acid (3-chloro-phenyl)-amide (0.04 g, 0.17 mmol) in dry dioxane (0.50 ml) and pyridine (0.02 ml) was cooled to 0° C. and treated with benzoyl chloride (0.02 g, 0.17 mmol). The mixture was then left to warm to room temperature and stirred overnight. After evaporation of the solvent, the residue was triturated in acetonitrile to yield the title compound (0.003 g, 4%) as a white solid, MS (ISP): m/e=372.3 (M+H+)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][C:22]3[C:23](=[C:25]([C:29](O)=[O:30])[CH:26]=[CH:27][CH:28]=3)[N:24]=2)=[CH:16][CH:15]=1)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=[N:38]C=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[Cl-].[NH4+].Cl>CN(C)C=O.O>[C:29]([C:25]1[C:23]2[N:24]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([CH2:13][N:11]([CH3:12])[C:9](=[O:10])[O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:15][CH:16]=3)[O:21][C:22]=2[CH:28]=[CH:27][CH:26]=1)(=[O:30])[NH2:38]
Reactant: CN(Cc1ccc(-c2nc3c(C(=O)O)cccc3o2)cc1)C(=O)OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccc(-c2nc3c(C(N)=O)cccc3o2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.4 %

Procedure:
2-(4-(((Benzyloxycarbonyl)(methyl)amino)methyl)phenyl)benzo[d]oxazole-4-carboxylic acid, (0.060 g, 0.14 mmol) in dimethyl formamide (10 mL) was added HOBT (0.025 g, 0.165 mmol), EDCI (0.035 g, 0.18 mmol), DIPEA (0.058 g, 0.45 mmol) and ammonium chloride (0.008 g, 0.15 mmol). The reaction mixture was stirred at room temperature for 20 hr, cooled and poured into water (10 mL). The pH was adjusted to 3 with 1N aqueous hydrochloric acid. The solution was extracted with dichloromethane (70 mL×3). The solution was washed with brine, dried, condensed in vacuum and separated by silica gel chromatography (ethyl acetate:methanol=1:0 to 10:1) to afford benzyl 4-(4-carbamoylbenzo[d]oxazol-2-yl)benzyl(methyl)carbamate 0.045 g solid (yield: 75.2%); LC-MS (ESI) m/z 416 [M+1]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:16][CH:17]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>>[N:24]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:16][CH:17]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: c1c[nH]cn1
Reactant: ClCCCCOc1ccccc1-c1csc(-c2ccccc2)n1
Product: c1ccc(-c2nc(-c3ccccc3OCCCCn3ccnc3)cs2)cc1

Procedure:
The title compound was prepared as described in Example 13, starting with 4-(4-chlorobutoxyphenyl)-2-phenylthiazole (7.8 g, 18 mmol) and using imidazole (3.8 g, 55 mmol) in place of dibutylamine to produce 3.6 g (53% yield) of the free base of the title compound which was converted to the HCl salt, mp 178°-180° C. IR(KBr): 3500, 2720, 1615 cm-1, MS: 376(MH+). 1H NMR (CD3OD): δ9.00 (s, 1H), 8.03-6.96 (m, 12H), 4.38 (t, J=6.0 Hz, 2H), 4.09 (t, J=6.0 Hz, 2H), 2.22-1.79 (m, 4H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[NH2:13]
Reactant: COCCCOc1cccc([N+](=O)[O-])c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCCCOc1cccc(N)c1
Temperature: 60 °C
Yield: 93.2 %

Procedure:
1-(3-methoxypropoxy)-3-nitrobenzene (10A) (2.0 g, 11.84 mmol) and tin chloride dihydrate (13.36 g, 59.18 mmol) in 25 mL of ethyl acetate was combined. The mixture was heated at 60° C. for about two hours. The reaction was then chilled at 0° C. Triethylamine (25-30 mL) was added slowly until a white precipitate formed. The white precipitate was filtered over a Celite plug, washed with brine, and then dried over MgSO4. The dried filtrate was then concentrated in vacuo and dried under vacuum to provide 10B (2.0 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.90 (q, J=6.32 Hz, 2H) 3.24 (s, 3 H) 3.44 (t, J=6.32 Hz, 2H) 3.89 (t, J=6.44 Hz, 2H) 5.02 (br. s., 2H) 6.05 (dd, J=8.08, 1.26 Hz, 1H) 6.11-6.14 (m, 2H) 6.87 (t, J=8.21 Hz, 1H). ESI-MS: m/z 182.3 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:16]=[C:15]([C:17]([F:25])([F:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[OH-].[Li+]>C1COCC1>[F:24][C:17]([F:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:15]1[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=[C:4]([CH:16]=1)[C:3]([OH:26])=[O:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(F)(F)c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(F)(F)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
Chill a solution of 5-(difluorophenyl-methyl)-N-methyl-N-propyl-isophthalamic acid methyl ester (0.043 g, 0.119 mmol) in THF (1 mL) in an ice bath. Add 1 N lithium hydroxide (0.18 mL, 0.18 mmol) and stir at room temperature for 3 h. Acidify the solution to about pH=2 and concentrate to one half of the solvent. Partition the residue between ethyl acetate and H2O. Extract the aqueous layer with ethyl acetate (2×10 mL). Wash the combined organic extract with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound (95%).
Reaction SMILES: [NH2:1][C@@H:2]([CH:44]([CH3:46])[CH3:45])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[NH:31][C:30]([C@@H:32]5[CH2:36][CH2:35][CH2:34][N:33]5[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[N:29][CH:28]=4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:4].Br[C:48]1[N:53]=[CH:52][CH:51]=[CH:50][N:49]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.CS(C)=O>[CH3:45][CH:44]([CH3:46])[C@H:2]([NH:1][C:48]1[N:53]=[CH:52][CH:51]=[CH:50][N:49]=1)[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[NH:31][C:30]([C@@H:32]5[CH2:36][CH2:35][CH2:34][N:33]5[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[N:29][CH:28]=4)=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:4]
Reactant: Brc1ncccn1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](Nc1ncccn1)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Temperature: 90 °C
Yield: 110.8 %

Procedure:
A mixture of (S)-tert-butyl 2-(5-(4′-(2-((S)-1-((s)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (cj-2) (0.45 g, 0.72 mmol), 2-bromopyrimidine (0.37 g, 2.34 mmol) and iPr2NEt (0.20 mL, 1.18 mmol) in toluene-DMSO (4:1, 5 mL) was heated at 90° C. overnight. The volatiles were removed in vacuo and the residue was purified by preparative HPLC (YMC Pack C-1 8, 30×100 mm/MeCN—H2O-TFA). The title compound (0.56 g, 74%), as its TFA salt, was obtained as a yellow-orange glass.
Reaction SMILES: [OH:1][CH:2]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][C@H:5]([CH3:17])[CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1.[ClH:26].[C:27](O)(=[O:29])[CH3:28]>>[ClH:26].[C:27]([O:1][CH:2]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:3][NH:4][C@H:5]([CH3:17])[CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)O
Reactant: C[C@H](CCc1ccc(C(N)=O)cc1)NCC(O)COc1ccccc1
Agent: Cl
Product: CC(=O)OC(CN[C@H](C)CCc1ccc(C(N)=O)cc1)COc1ccccc1

Procedure:
0.5 g of p-[(R)-3-[[(RS)-2-hydroxy-3-phenoxypropyl]amino]butyl]benzamide was warmed to 40° for 24 hours in 25 ml of acetic acid saturated with hydrochloric acid gas. Thereupon, the solvent was removed in vacuo and the crystalline residue was recrystallized from acetonitrile, and there was obtained p-[(R)-3-[[(RS)-2-acetoxy-3-phenoxypropyl]amino]butyl]-benzamide hydrochloride of m.p. 83°-85°, [α]D20 =+10° (c=0.6 in methanol), ε222 =15020, ε234 =13590.