Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+].[CH:29]1([C:32]([C:34]2[CH:61]=[CH:60][C:37]([O:38][CH:39]([C:41]3[N:45]=[C:44]([C:46]4[CH:58]=[CH:57][C:49]([C:50]([O:52]C(C)(C)C)=[O:51])=[C:48]([F:59])[CH:47]=4)[O:43][N:42]=3)[CH3:40])=[CH:36][CH:35]=2)=[O:33])[CH2:31][CH2:30]1.FC(F)(F)C(O)=O>C(Cl)Cl.O.CN(C)C=O>[CH:29]1([C:32]([C:34]2[CH:61]=[CH:60][C:37]([O:38][CH:39]([C:41]3[N:45]=[C:44]([C:46]4[CH:58]=[CH:57][C:49]([C:50]([OH:52])=[O:51])=[C:48]([F:59])[CH:47]=4)[O:43][N:42]=3)[CH3:40])=[CH:36][CH:35]=2)=[O:33])[CH2:31][CH2:30]1
Reactant: CC(Oc1ccc(C(=O)C2CC2)cc1)c1noc(-c2ccc(C(=O)OC(C)(C)C)c(F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(Oc1ccc(C(=O)C2CC2)cc1)c1noc(-c2ccc(C(=O)O)c(F)c2)n1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
1-Hydroxybenzotriazole monohydrate (574 mg, 3.75 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.44 g, 7.49 mmol) were added to an N,N-dimethylformamide (20 mL) solution of the compound obtained in Reference Example 80 (900 mg, 3.75 mmol) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The compound obtained in Reference Example 83 (930 mg, 3.75 mmol) was added to the mixture at room temperature, and the resulting mixture was stirred at room temperature for 20 minutes, and then heated at 90° C. for 6 hours. After the reaction mixture was cooled to room temperature, water and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction mixture. The resulting mixture was extracted three times with ethyl acetate. The organic layer thus obtained was washed with a 10% aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-41:1, v/v) to give a mixture containing tert-butyl 4-(3-{1-[4-(cyclopropylcarbonyl)phenoxy]ethyl}-1,2,4-oxadiazol-5-yl)-2-fluorobenzoate. Subsequently, a methylene chloride (2 mL) solution of trifluoroacetic acid (2 mL) was added to a methylene chloride (4 mL) solution of the mixture thus obtained at room temperature, and the resulting mixture was stirred at the same temperature for 30 minutes. Trifluoroacetic acid (2 mL) was added to the mixture at room temperature, and the resulting mixture was stirred at the same temperature for 20 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:4, v/v) to give the title compound (655 mg, yield: 44%).
Reaction SMILES: [C:1]([NH:4][C@@:5]1([C:13]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][CH2:7][C@@H:6]1[CH2:10][CH:11]=[CH2:12])(=[O:3])[CH3:2].[CH3:20][C:21]1([CH3:28])[C:25]([CH3:27])([CH3:26])[O:24][BH:23][O:22]1.O>C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([NH:4][C@@:5]1([C:13]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][CH2:7][C@@H:6]1[CH2:10][CH2:11][CH2:12][B:23]1[O:24][C:25]([CH3:27])([CH3:26])[C:21]([CH3:28])([CH3:20])[O:22]1)(=[O:3])[CH3:2]
Reactant: CC1(C)OBOC1(C)C
Reactant: C=CC[C@H]1CCC[C@@]1(NC(C)=O)C(=O)NC(C)(C)C
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CCC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
A stirred solution of (1S,2R)-1-acetamido-2-allyl-N-tert-butylcyclopentanecarboxamide (0.599 g, 2.25 mmol) in anhydrous methylene chloride (9 mL) under nitrogen was treated with Ir2Cl2(COD)2 (45 mg, 0.07 mmol) and DiPhos (54 mg, 0.136 mmol) and stirred at room temperature for 30 min. 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.65 mL, 4.48 mmol) was added dropwise and the solution stirred at room temperature for 20 h. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (40 mL, then 2×15 mL), and the combined organic solution was washed with saturate aqueous sodium chloride (30 mL), dried over MgSO4, and concentrated. The residue was dissolved in minimal dichloromethane and purified by flash column chromatography (silica gel, 40-50% ethyl acetate in heptane) to afford (1S,2S)-1-acetamido-N-tert-butyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)cyclopentanecarboxamide (0.695 g, 78%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 6.72 (br s, NH, 1 H), 5.68 (br s, NH, 1 H), 2.46-2.29 (m, 2 H), 2.10-2.19 (m, 1 H), 2.02 (s, 3 H), 2.00-1.88 (m, 1 H), 1.75-1.60 (m, 3 H), 1.52-1.38 (4 H), 1.32 (s, 9 H), 1.31 (s, 12 H), 0.81-0.70 (m, 2 H); MS (+CI): m/z for C21H39BN2O4: expected 394.3; found 395.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([CH2:8][NH:9][CH:10]([CH3:12])[CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1>CC(C)=O.ClCCl>[Cl:20][C:21]1[N:26]=[C:25]([N:9]([CH:10]([CH3:12])[CH3:11])[CH2:8][C:2]([F:13])([F:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1
Reactant: CCOC(=O)C(F)(F)CNC(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
Ethyl 2,2-difluoro-3-(isopropylamino)propanoate (1.50 g, 7.68 mmol) was dissolved in acetone and K2CO3 (2.12 g, 15.3 mmol) was added. The solution was purged with nitrogen gas and cooled to 0° C. A solution of 2,4-dichloro-5-nitropyrimidine (1.64 g, 8.45 mmol) in acetone (10 mL) was added dropwise at 0° C. over 1 h. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. It was diluted with dichloromethane (50 mL) and filtered thru a celite plug. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography on silica gel (120 g SiO2, hexanes:ethyl acetate 10:1-3:1) to afford the title compound as a yellow oil (1.96 g, 72%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (d, J=6.82 Hz, 6 H) 1.34 (t, J=7.20 Hz, 3 H) 3.63-3.75 (m, 1 H) 4.24 (t, J=13.14 Hz, 2 H) 4.34 (q, J=7.07 Hz, 2 H) 8.74 (s, 1 H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(O)C>[N+:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:20][C:7]=2[C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1oc2ccc(CN3CCOCC3)cc2c1-c1ccccc1

Procedure:
Using the method of Example 1, 5-bromomethyl-2-nitro-3-phenylbenzofuran is reacted with morpholine in ethanol to provide yellow crystals of N-(2-nitro-3-phenyl-5-benzofuranylmethyl)-morpholine, m.p. 151°-154° C., having the structure ##STR13##
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[Br:5][C:6]1[CH:11]=[C:10]([C:12]2[C:21]3[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[S:24][C:20]=3[C:19]([Br:29])=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[CH:17]3)[CH:9]=[C:8]([Br:30])[C:7]=1[OH:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:5][C:6]1[CH:11]=[C:10]([C:12]2[C:21]3[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[S:24][C:20]=3[C:19]([Br:29])=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[CH:17]3)[CH:9]=[C:8]([Br:30])[C:7]=1[O:31][CH2:2][C:3]#[N:4]
Reactant: N#CCBr
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reaction time: 2.5 h
Yield: 96.1 %

Procedure:
Bromoacetonitrile (0.25 mL, 3.56 mmol) was added to a room temperature, stirred suspension of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenol (1.0 g, 1.78 mmol) and potassium carbonate (0.615 g, 4.45 mmol) in DMF (5 mL). After 2.5 h, the reaction mixture was added to water, filtered, washed with water and triturated with petroleum ether. The solid was dried in vacuo at 80° C. to provide the title compound as a white solid (1.03 g, 96%): NMR (DMSO-d6); δ8.29 (d, J=8 Hz, 1 H), 8.08 (d, J=8 Hz, 1 H), 7.92 (s, 2 H), 7.80 (ddd, J=8, 7, 1 Hz, 1 H), 7.65-7.51 (m, 3 H), 7.27 (ddd, J=8, 7, 1 Hz, 1 H), 6.68 (d, J=8 Hz, 1 H), 5.36 (s, 2 H); MS (+FAB): [M+], 3 bromine isotope pattern, 599, 601, 603, 605; Anal. Calc. for C24H12Br3NOS: C, 47.87, H, 2.01, N, 2.33. Found: C, 47.83, H, 1.92, N, 2.32.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]([NH:13][CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[O:12])[CH:8]=2)[CH:3]=[CH:2]1.[CH2:28]([O:30][C:31](=[O:34])[CH2:32]Br)[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[CH2:28]([O:30][C:31](=[O:34])[CH2:32][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11](=[O:12])[NH:13][CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][CH:18]=3)[CH:8]=2)[CH:3]=[CH:2]1)[CH3:29]
Reactant: O=C(Cc1ccc2cc[nH]c2c1)NCC#Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)Cn1ccc2ccc(CC(=O)NCC#Cc3ccc(OC(F)(F)F)cc3)cc21

Procedure:
In analogy to the procedure described for example 1 b], 2-(1H-indol-6-yl)-N-[3-(4-trifluoromethoxy-phenyl)-prop-2-ynyl]-acetamide was reacted with bromo-acetic acid ethyl ester in the presence of cesium carbonate and potassium iodide in acetonitrile under reflux conditions to give the title compound as off-white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:11]([CH3:12])=[CH:10][NH:9][CH:8]=1)=[O:6].Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.O>CN(C)C=O>[C:14]1([N:9]2[CH:10]=[C:11]([CH3:12])[C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:8]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: COC(=O)c1c[nH]cc1C
Reactant: Clc1nccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2nccc3ccccc23)cc1C
Temperature: 40 °C
Reaction time: 0.3 h

Procedure:
0.208 g (6.5 mmol) of sodium hydride, at 75% by weight in liquid petroleum jelly, is added at a temperature in the region of 20° C. under an argon atmosphere to a solution of 0.903 g (6.5 mmol) of 3-methoxycarbonyl-4-methyl-1H-pyrrole in 20 mL of dimethylformamide. After stirring at a temperature in the region of 40° C. for 0.3 hour, 1.07 g (6.5 mmol) of 1-chloroisoquinoline and 10 mL of dimethylformamide are added. After stirring at a temperature in the region of 120° C. for 4 hours, the reaction mixture is poured into 200 mL of salt water and then extracted with 100 mL of ethyl acetate. The organic phase is partially concentrated under reduced pressure. 100 mL of salt water are added to the residue, which is then extracted with 50 mL of ethyl acetate. The organic phase is dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) to give a solid which is purified by silica gel chromatography [eluent: cyclohexane/dichloromethane/ethyl acetate (60/36/4 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa), 1.5 g of 1-(isoquinol-1-yl)-3-methoxycarbonyl-4-methyl-1H-pyrrole are obtained. Mass spectrum (EI): m/e 266 (M+.), m/e 235.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].[CH2:32](Br)C#C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][C:29]#[CH:32])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: C#CCBr
Product: C#CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting propargylbromide and making non-critical variations provided the title compound as a white solid. IR (diffuse reflectance) 3451, 3293, 2964, 2932, 1563, 1493, 1469, 1390, 1204, 1184, 1087, 1076, 820, 742, 646 cm−1; OAMS supporting ions at: ESI+ 465.8; MS (EI) m/z 465 (M+); HRMS (FAB) calcd for C26H25CL2N3O+H1 466.1453, found 466.1455. [α]25D=−56 (c 0.83, methylene chloride). Anal. Calcd for C26H25Cl2N3O: C, 66.96; H, 5.40; N, 9.01. Found: C, 66.96; H, 5.49; N, 8.93.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH:32]([CH3:34])[CH3:33])[C:20]([O:22]CC1C=CC(OC)=CC=1)=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH:32]([CH3:34])[CH3:33])[C:20]([OH:22])=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COC(=O)[C@@H](OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)C(C)C)cc1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O[C@H](C(=O)O)C(C)C

Procedure:
4-methoxybenzyl 2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyrate was de-esterified by the method described in Example A-I-1, step c. The title compound (3.41 g) was obtained after silica gel column chromatography (2, 10, 20% ethanol in dichloromethane). Rf (2% MeOH/CHCl3) 0.45. The compound may be activated and esterified directly to a drug or further modified as described below:
Reaction SMILES: [N+:1]([C:4]1[C:13]([Br:14])=[C:12]([Br:15])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:17])[C:8](=[O:16])[NH:9]2)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[C:13]([Br:14])=[C:12]([Br:15])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:17])[C:8](=[O:16])[NH:9]2
Reactant: O=c1[nH]c2cc(Br)c(Br)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1c(Br)c(Br)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 90 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
To a stirred mixture of 5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (327 mg, 0.89 mMol) in ethanol (10 mL) was added SnCl2.2H2O (1.0 g, 4.45 mMol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) with stirring for 4 h. The mixture was then cooled to room temperature and the yellow precipitate was collected by filtration, followed by washing with cold ethanol (2×1 mL), to get 227 mg (76%) of crude title product (contains minor impurities by NMR). Crystallization from DMSO/H2O gave 193 mg of pure title product as bright yellow needles; mp: 324°-6° C. (dec.), changed color from 270° C. IR (KBr, cm-1): 3456; 3281; 1700; 1643. NMR (1H, DMSO-d6): d 5.844 (s, 2H); 6.732 (s, 1H); 11.257 (s, 1H); 11.810 (s, 1H). Purity: >96.96% by HPLC. HRMS: calcd for C8H8N3O2Br2 (M+) m/z 332.8747; found: 332.8754. Potency relative to DCK: 341%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:9]=O)=[CH:4][CH:3]=1.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([BH3-])#N.[Na+].O>CO>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][N:28]([CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1
Reaction time: 18 h
Yield: 11.1 %

Procedure:
To a solution of bis-(4-chloro-phenyl)-acetaldehyde (3.74 mmol) in methanol under a nitrogen atmosphere, N—BOC-piperazine (1.05 g, 5.61 mmol) was added, the reaction mixture was stirred for 1 hour before addition of sodium cyanoborohydride (0.28 g, 4.49 mmol). The reaction mixture was stirred for 18 hours, water added (3 ml) and the solvent removed under reduced pressure. The residue was partitioned between dichloromethane and water, the organic layer was separated, dried (MgSO4), filtered and concentrated. Purified over flash silica chromatography eluting with ethyl acetate/petroleum ether (3:7) to yield the title compound (0.18 g, 11% yield for steps 30A and 30B combined). LC/MS: (PS-A2) Rt 2.66 [M-BOC+H]+ 335.02.
Reaction SMILES: CC([O-])(C)C.[K+].CC1C=CC(S([CH2:17][N+:18]#[C-])(=O)=O)=CC=1.[CH2:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][C:29]=1[Cl:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO>C1COCC1.O>[CH2:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][C:17]#[N:18])=[CH:30][C:29]=1[Cl:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#CCc1ccc(OCc2ccccc2)c(Cl)c1
Reaction time: 0.25 h
Yield: 34.9 %

Procedure:
To a suspension of t-BuOK (11.7 g, 96 mmol) in THF (200 mL) was added a solution of TosMIC (9.4 g, 48 mmol) in THF (100 mL) at −78° C. The mixture was stirred for 15 minutes, treated with a solution of 4-benzyloxy-3-chloro-benzaldehyde (7.5 g, 30 mmol) in THF (50 mL) dropwise, and continued to stir for 1.5 hours at −78° C. To the cooled reaction mixture was added methanol (30 mL). The mixture was heated at reflux for 30 minutes. Solvent of the reaction mixture was removed to give a crude product, which was dissolved in water (300 mL). The aqueous phase was extracted with EtOAc (3×100 mL). The combined organic layers were dried and evaporated under reduced pressure to give crude product, which was purified by column chromatography (petroleum ether/EtOAc 10:1) to afford 2-(4-(benzyloxy)-3-chlorophenyl)acetonitrile (2.7 g, 34%). 1H NMR (400 MHz, CDCl3) δ 7.52-7.32 (m, 6 H), 7.15 (dd, J=2.4, 8.4 Hz, 1 H), 6.95(d, J=8.4 Hz, 1 H), 5.26 (s, 2 H), 3.73 (s, 2 H) 13C NMR (100 MHz, CDCl3) δ 154.0, 136.1, 129.9, 128.7, 128.7, 128.1, 127.2, 127.1, 127.1, 124.0, 123.0, 117.5, 114.4, 70.9, 22.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:17][CH2:16][C:15]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=3)([CH2:18][CH2:19][N:20]3[C@H:25]4[CH2:26][CH2:27][C@@H:21]3[CH2:22][CH:23]([N:28]3[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[C:29]3[CH3:37])[CH2:24]4)[CH2:14][CH2:13]2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.FC1C=C(C2(CCN3[C@H]4CC[C@@H]3CC(N3C5C=CC=CC=5N=C3C)C4)CC[NH:55][CH2:54]C2)C=CC=1.FC1C=CC(B(O)O)=CC=1.CN.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:17][CH2:16][C:15]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=3)([CH2:18][CH2:19][N:20]3[C@H:21]4[CH2:27][CH2:26][C@@H:25]3[CH2:24][CH:23]([N:28]3[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[C:29]3[CH3:37])[CH2:22]4)[CH2:14][CH2:13]2)[C:9]([NH:55][CH3:54])=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCNCC1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(C(=O)O)c2ccc(F)cc2)CC1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)C(c1ccc(F)cc1)N1CCC(CCN2[C@@H]3CC[C@H]2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1

Procedure:
(4-Fluorophenyl)(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)acetic acid (prepared from 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole and 4-fluorophenylboronic acid following the procedure outlined in example 412. (19 mg, 0.032 mmol) was coupled with methylamine (16 μL, 2M in THF) under promotion of HATU (12 mg, 0.032 mmol) The title compound was obtained as solid (12 mg, 60%) after purification by flash chromatography, eluting with a gradient of 0-10% methanol in ethyl acetate. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=7.1 Hz, 1H), 7.32-7.24 (m, 4H), 7.19-7.12 (m, 2H), 7.03-6.89 (m, 6H), 4.59 (br, 1H), 3.75 (s, 1H), 3.22 (br, 2H), 2.84 (d, J=4.9 Hz, 3H), 2.55 (s, 3H), 2.52-2.47 (m, 1H), 2.40-2.09 (m, 6H), 1.93-1.87 (m, 7H), 1.78-1.61 (m, 6H). HRMS m/z (M+H)+ calcd 612.3514, obsd 612.3530.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.FC(F)(F)C(O)=O.[Br:59][C:60]1[CH:72]=[CH:71][CH:70]=[CH:69][C:61]=1[O:62][CH:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1>CN(C=O)C.O>[Br:59][C:60]1[CH:72]=[CH:71][CH:70]=[CH:69][C:61]=1[O:62][CH:63]1[CH2:68][CH2:67][N:66]([C:16](=[O:18])[CH2:15][NH:14][C:12](=[O:13])[C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:20][CH:19]=2)[CH2:65][CH2:64]1
Reactant: Brc1ccccc1OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Br)CC1)c1ccc(Nc2ccccc2)cc1
Reaction time: 8 h
Yield: 32.8 %

Procedure:
To a stirred solution of (4-phenylamino-benzoylamino)-acetic acid (0.087 g, 0.00032 mol) in DMF (5 mL) was added DIPEA (0.104 g, 0.00081 mol), HOBt (0.043 g, 0.00032 mol) and EDCI.HCl (0.061 g, 0.00032 mol) at ambient temperature. After 2 minutes 4-(2-bromo-phenoxy)-piperidine trifluoroacetate (0.1 g, 0.00027 mol) and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layer was washed with brine solution and dried over sodium sulfate. The organic layer was collected and concentrated under reduced pressure to afford 0.045 g (32%) of N-{2-[4-(2-bromo-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-4-phenylamino-benzamide. LCMS: 508.12 (M+1)+, 96.85%, 1H NMR (DMSO-d6): δ 8.6 (s, 1H), 8.3 (t, 1H), 7.8 (d, 2H), 7.6 (dd, 1H), 7.3 (m, 4H), 7.2 (d, 2H), 7.1 (d, 2H), 6.9 (q, 2H), 4.8 (m, 1H), 4.2 (t, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 2.0 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13].[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH:18]=O.CC(OC)(C)C.C([BH3-])#N.[Na+].[OH-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH:4]=1
Reactant: CN(C)CCOc1cc(N)ccc1Cl
Reactant: COC(C=O)OC
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: COC(CNc1ccc(Cl)c(OCCN(C)C)c1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a suspension of 4-chloro-3-(2-dimethylaminoethoxy)aniline (D6, 1.22 g, 0.006 mol) in McOH (30 ml) containing dimethoxyethanal in MTBE (1.76 g, 0.17 mol) and glacial acetic acid (1.71 g) was added sodium cyanoborohydride (1.78 g, 0.03 mol) portionwise at 0 C. After addition, the reaction was left to stir at room temperature for 1 hour, and then 10% aqueous NaOH was added and the mixture was extraced with CH2Cl2 and the combined organic layers were dried (Na2SO4), and concentrated in vacuo to give a brown oil. Purification by FCC, eluting with CH2Cl2 gave the title compound (1.49 mg, 87% )