Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.CCCCCC.[C:22]([C:24]1[N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:26]=[CH:27][CH:28]=1)#[N:23].[B:36](OC)([O:39]C)[O:37]C.[NH4+].[Cl-]>C1COCC1>[C:32]([O:31][C:29]([N:25]1[C:24]([C:22]#[N:23])=[CH:28][CH:27]=[C:26]1[B:36]([OH:39])[OH:37])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: COB(OC)OC
Reactant: CC(C)(C)OC(=O)n1cccc1C#N
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1B(O)O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (0.461 mL, 2.73 mmol) in THF (10 mL) at −78° C. under an argon atmosphere was added a solution of 1.6 M n-BuLi in n-hexane (1.951 mL, 3.12 mmol). The mixture was stirred at −78° C. for 15 min and then allowed to warm to RT. The mixture was cooled to −78° C. prior and a solution of tert-butyl 2-cyano-1H-pyrrole-1-carboxylate (500 mg, 2.60 mmol) in THF (2 mL) was added. The RM was stirred at −78° C. for 30 min and then trimethyl borate (1.450 mL, 13.01 mmol) was added. The RM was allowed to reach RT and stirred overnight. Sat. aq. NH4Cl solution (10 mL) was added to the mixture and the mixture was extracted with Et2O. The combined extracts were washed with 1 M HCl (2×10 mL), brine (10 mL) then the solvent was evaporated off under reduced pressure to give a residue which was crystallized from Et2O/cyclohexane (1:3) to yield the title compound as an off-white solid (which was stored at −20° C.). UPLC-MS (Condition 3) tR=0.72 min, m/z=237.1 [M+H]+, m/z=281.1 [M+formic acid-H]−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.F[B-](F)(F)F.[N:20]1(OC(N(C)C)=[N+](C)C)[C:24]2C=[CH:26][CH:27]=[CH:28][C:23]=2N=N1.C(N(C(C)C)C(C)C)C.N1CCCCC1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:20]1[CH2:26][CH2:27][CH2:28][CH2:23][CH2:24]1)=[O:14])[CH:6]=[CH:5]2
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C(c1ccc2cc(O)ccc2c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.5 g (0.003 mol) 6-hydroxy-2-naphtoic acid, 1.2 g (0.003 mol) 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate, 2.3 ml (0.013 mol) N-ethyldiisopropylamine and 0.29 ml (0.030 mol) piperidine in 10 ml DMF was stirred for 16 h at room temperature. The mixture was concentrated to dryness and 50 ml ethyl acetate, 30 ml water and 20 ml NaHCO3 aq. (10%) was added. The aqueous phase was extracted with 50 ml ethyl acetate and the combined organic layers were purified with column chromatography on silica. The product fractions were concentrated to dryness and titurated twice with 20 ml diethyl ether/heptane 1/1. The residue was dried under vacuum at 50° C. to yield 0.58 g (0.0227 mmol; 85%) of the title compound as light brown solid. MS (m/e): 254.3 (MH−, 100%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][C:15]([NH2:17])=S)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[OH-].[K+].O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][C:15]#[N:17])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccc(NC(N)=S)c(-c2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(NC#N)c(-c2ccccc2)c1

Procedure:
A suspension of N-(5-methyl-2-biphenylyl)thiourea (6.5 g) in water (50 ml) was reacted with a solution of potassium hydroxide (15 g) in water (50 ml). Lead acetate trihydrate (10.2 g) in water (50 ml) was added and the mixture heated at 90°-95° C. for 1 hour to give 5-methyl-2-biphenylylcyanamide as a colourless solid (m.p. 80° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9](O)=[O:10])[CH:7]=1.CSC.B>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[CH2:9][OH:10])[CH:7]=1
Reactant: CC(C(=O)O)n1cc(Br)ccc1=O
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CC(CO)n1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
To a solution of 2-(5-bromo-2-oxopyridin-1(2H)-yl)propanoic acid (3.36 g, 13.7 mmol) in 50 mL of THF was added borane-dimethyl sulfide (3.89 ml, 41.0 mmol) via a syringe. The reaction was stirred at rt for 16 hours and was quenched with 10 mL of 1N HCl. The mixture was extracted with 70 mL of EtOAc twice. The combined organic phases were washed with brine and dried over Na2SO4. The solution was concentrated in vacuo to give a light yellow oil (2.50 g, 78.9% yield) which was used in the next step without further purification. MS (ESI pos. ion) m/z (MH+): 231.9. Calc'd Exact Mass for C8H10BrNO2: 230.99.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH:20]([CH2:24][CH2:25][CH2:26][CH3:27])[C:21]([OH:23])=O)[CH2:16][CH2:15]2)=[O:11])=[CH:4][C:3]=1[Cl:28].C(P(=O)(OCC)OCC)#N.Cl.[CH3:40][NH:41][CH3:42].C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:1][C:2]1[C:3]([Cl:28])=[CH:4][C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([CH:20]([C:21]([N:41]([CH3:42])[CH3:40])=[O:23])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:19]2)=[O:11])=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: CNC
Reactant: CCCCC(C(=O)O)N1CCC(CNC(=O)c2cc(Cl)c(N)nc2OC)CC1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCC(C(=O)N(C)C)N1CCC(CNC(=O)c2cc(Cl)c(N)nc2OC)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 10.4 %

Procedure:
To a solution of 2-[4-({[(6-amino-5-chloro-2-methoxypyridin-3-yl)carbonyl]amino}methyl)piperidine-1-yl]hexanoic acid (500 mg, 1.2 mmol) in dimethylformamide (30 ml) was added diethyl cyanophosphonate (300 mg, 1.8 mmol), N,N-dimethylamine hydrochloride (148 mg, 1.8 mmol) and N,N-diisopropylethylamine (0.63 ml, 3.6 mmol). The mixture was stirred for 72 h at room temperature. The mixture was concentrated in vacuo. The resultant amorphous solid was chromatographed on a column of silica gel eluting with dichloromethane/methanol (20:1) to give 55 mg (10%) of the title compound as a colorless amorphous solid.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=2)[CH:12]=1)=[O:10])C1C=CC=CC=1.[OH-].[K+]>O.C(O)C>[CH2:22]([O:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:9]([OH:10])=[O:8])[CH:20]=[CH:19]2)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(OCc1ccccc1)c1ccc2cc(OCc3ccccc3)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 25 °C

Procedure:
A solution of 6-benzyloxy -naphthalene-2-carboxylic acid benzyl ester (52) (1 equi.) and potassium hydroxide (3.5 equi.) in water-ethanol (1:1) (25 mL/mmole) was stirred at 80 C temperature for 2 h., cooled to room temperature and quenched with hydrochloric acid (5%), filtered resulted white solid, washed with water, and dried under vacuum to 6-benzyloxy-naphthalene-2-carboxylic acid (53) as a white solid (81%).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][C:7]1[N:8]([CH3:24])[CH:9]=[C:10]2[C:16]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:14][CH2:13][C:12](=[O:23])[NH:11]2.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:4][C:9]1[N:8]([CH3:24])[C:7]([CH3:6])=[C:16]2[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:14][CH2:13][C:12](=[O:23])[NH:11][C:10]=12
Reactant: Cc1c2c(cn1C)NC(=O)CN=C2c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c2c(c(Cl)n1C)NC(=O)CN=C2c1ccccc1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A solution of freshly distilled sulphuryl chloride (4.0 ml) in methylene chloride (40 ml) is added dropwise over a period of 20 minutes to a solution of 3,7-dihydro-6,7-dimethyl-5-phenylpyrrolo[3,4-e][1,4]diazepin-2(1H)-one (5.0 g) in methylene chloride (80 ml) cooled to -60° C. and maintained under inert atmosphere. The reaction is allowed to proceed at -55° C.±5° C. for one hour, then the reaction mixture is poured into a 5% aqueous solution of NaHCO3 (210 ml) and vigorously stirred for 20 minutes. The organic phase is separated, washed with water, dried and evaporated to dryness under vacuum. The obtained residue is crystallized from ethanol yielding 3.7 g of the compound of the title. M.p. 195° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]([S:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=2)[N:12]=1)([CH3:6])[CH3:5].[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[CH:25].O>CN(C)C=O.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:23])[C:4]([CH3:6])([S:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:25]#[C:24][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:18][CH:17]=2)[N:12]=1)[CH3:5]
Reactant: C#Cc1ccccc1
Reactant: COC(=O)C(C)(C)Sc1nc(CCOc2ccc(I)cc2)cs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Sc1nc(CCOc2ccc(C#Cc3ccccc3)cc2)cs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
Under nitrogen atmosphere, 2-({4-[2-(4-iodophenoxy)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid methyl ester (600 mg) synthesized in Example 144-2 and ethynylbenzene (145 mg) were dissolved in N,N-dimethylformamide (2 mL) and triethylamine (6 mL), dichlorobis(triphenylphosphine)palladium (10 mg) and copper(I) iodide (5 mg) were added, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (400 mg) as a yellow oil.
Reaction SMILES: [C:1]1([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.C(O)(=O)[CH2:18][C:19]([OH:21])=[O:20].N1C=CC=CC=1.N1CCCCC1>O>[CH:9]([C:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:18][C:19]([OH:21])=[O:20])=[CH:3][CH:2]=1)=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(C=Cc2ccccc2)cc1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(C=Cc2ccccc2)cc1
Yield: 97.4 %

Procedure:
A mixture of 9.4 g of stilbene-4-aldehyde thus-obtained, 10.6 g of malonic acid, 30 ml of pyridine and 3 ml of piperidine was reacted on a steam bath at 100° C. for 4 hours. After the completion of the reaction, the mixture was poured into an exess amount of water and the precipitate thus-obtained was collected and recrystallized from acetic acid to obtain 11.0 g of p-styryl cinnamic acid.
Reaction SMILES: [CH:1]1([N:6]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]([OH:34])[CH2:24][N:25]3[CH2:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26]3)[CH:16]=2)C(=O)OC(C)(C)C)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[CH:1]1([NH:6][CH2:14][C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[O:21][CH2:22][CH:23]([OH:34])[CH2:24][N:25]2[CH2:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:33]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(OCC(O)CN2Cc3ccccc3C2)c1)C1CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC(COc1cccc(CNC2CCCC2)c1)CN1Cc2ccccc2C1
Reaction time: 4 h
Yield: 57 %

Procedure:
To a solution of tert-butyl cyclopentyl(3-(2-hydroxy-3-(isoindolin-2-yl) propoxy) benzyl)carbamate (200 mg, 0.43 mmol) in ethyl acetate (10 mL) was added HCl/ethyl acetate (5 mL) at 0° C. After 4 h, the reaction mixture was concentrated and purified by preparative HPLC purification. (90 mg, yield 57%) MS (ESI+) e/z: 367.3 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.42-7.37 (m, 5H), 7.15-7.05 (m, 3H), 4.72-4.59 (m, 4H), 4.48-4.42 (m, 1H), 4.18 (s, 2H), 4.11-4.08 (m, 2H), 3.74-3.30 (m, 3H), 2.19-2.12 (m, 2H), 1.84-1.65 (m, 6H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.Cl.[CH3:26][C@@H:27]1[CH2:31][CH2:30][C@@H:29]([CH3:32])[NH:28]1>>[CH3:26][C@@H:27]1[CH2:31][CH2:30][C@@H:29]([CH3:32])[N:28]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: CCN(CC)C(=O)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Reactant: C[C@@H]1CC[C@@H](C)N1
Agent: Cl
Product: CCN(CC)C(=O)c1ccc(-c2ccc(OCCCN3[C@H](C)CC[C@H]3C)cc2)cc1

Procedure:
The product from Example 2A and (2R,5R)-2,5-dimethylpyrrolidine hydrochloride were processed as described in Example 10F to provide the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:11]=2[O:19][CH3:20])[O:7][C:6]=1[CH3:21])=[O:4].[OH-].[Na+]>CO>[CH3:20][O:19][C:11]1[C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[O:7][C:6]([CH3:21])=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=1
Reactant: COC(=O)c1cc(-c2cccc([N+](=O)[O-])c2OC)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(-c2cc(C(=O)O)c(C)o2)cccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
5-(2-Methoxy-3-nitro-phenyl)-2-methyl-furan-3-carboxylic acid methyl ester 53b (650 mg, 2.23 mmol) was dissolved in methanol, followed by addition of sodium hydroxide (268 mg, 6.7 mmol). Upon completion of the addition, the reaction mixture was stirred at 50° C. for 3 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and adjusted to pH 3˜4 with 1 N hydrochloric acid to form a copious amount of precipitates. The mixture was filtered and the filter cake was recrystallized from a solvent mixture of hexane/ethyl acetate (V:V=5:1) to obtain the title compound 5-(2-methoxy-3-nitro-phenyl)-2-methyl-furan-3-carboxylic acid 53c (450 mg, yield 84%) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:8][CH:7]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(OCC)(=O)C.C(#N)C>[CH2:22]([NH:29][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Fc1ccc2c(-c3ccc(OCCCBr)cc3)noc2c1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Fc1ccc2c(-c3ccc(OCCCNCc4ccccc4)cc3)noc2c1
Yield: 55.1 %

Procedure:
Mix 3-[4-(3-bromo-propoxy)-phenyl]-6-fluoro-benzo[d]isoxazole (150 mg, 0.43 mmol), benzylamine (92.2 mg, 0.861 mmol), potassium carbonate(130.6 mg, 0.95 mmol, 2.2 equivalents), potassium iodide (7.2 mg, 0.043 mmol) and 4%-5% aqueous acetonitrile (4-6 mL). Under a nitrogen atmosphere, heat (70°-75° C.) overnight. Dilute reaction mixture with ethyl acetate, filter to remove the solids and concentrate (in vacuo). Purify the crude reaction mixture by column (silica) chromatography using a Waters Sep-Pak 10 g cartridge eluted with ethyl acetate to give the title compound as a solid (89.23 mg, 55.1% Yield). Purity by LC/MS=95%, [M+H]+=377.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:23][CH2:22][C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.CO.O>C(Cl)Cl>[OH:2][CH2:3][C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:23][CH2:22][C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:13]=3[CH2:12]2)=[N:9][CH:10]=1
Reactant: COC(=O)c1cnc(N2CCc3c(n(C(=O)OC(C)(C)C)c4ccccc34)C2)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)n1c2c(c3ccccc31)CCN(c1ncc(CO)cn1)C2
Yield: 75.6 %

Procedure:
To a stirred solution of tert-butyl 2-[5-(methoxycarbonyl)pyrimidin-2-yl]-1,2,3,4-tetrahydro-9H-b-carboline-9-carboxylate (3.0 g, 0.0073 moles) in dry DCM (30 mL) was added diisobutyl aluminum hydride (14.7 mL, 0.022 moles, 1.5N in DCM) at −78° C. The temperature was slowly allowed to rise to −25° C. and continued the stirring for further 6.0 hours. After completion of the reaction, MeOH (20 mL) and water (20 mL) was added to the reaction and allowed to come to room temperature. The reaction mixture was then extracted using DCM. The combined organic layer was washed with water (20 mL), brine (20 ml), dried (Na2SO4) and concentrated. The compound was purified by recrystallization using mixture of diethyl ether and hexane to give pure tert-butyl 2-[5-(hydroxymethyl)pyrimidin-2-yl]-1,2,3,4-tetrahydro-9H-b-carboline-9-carboxylate (2.1 g, 75% yield). Rf=0.3. 1H NMR (DMSO-d6, 400 MHz) ppm: 8.38 (s, 2H, 2Ar—H), 8.05 (d, 1H, J=8 Hz, 1—H), 7.49 (d, 1H, J=8 Hz, 1Ar—H), 7.31-7.22 (m, 2H, 2Ar—H), 5.15 (s, 2H, CH2), 5.10 (t, 1H, J=8 Hz, OH), 4.34 (d, 2H, J=8 Hz, CH2), 4.11 (t, 2H, CH2), 2.75 (brs, 2H, CH2), 1.68 (s, 9H, 3CH3). M/e=381 (M+1) (M, 380.440 Calcd. for C21H24N4O3).
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[CH2:4][C:5]#[C:6][CH2:7][NH:8][C:9](=[O:30])[C:10]([NH:23]C(=O)C(F)(F)F)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]>CC(C)=O.Cl>[CH2:31]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]#[C:6][CH2:7][NH:8][C:9](=[O:30])[C:10]([NH2:23])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:32]
Reactant: CCN(CC)CC#CCNC(=O)C(NC(=O)C(F)(F)F)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(C)=O
Product: CCN(CC)CC#CCNC(=O)C(N)(c1ccccc1)c1ccccc1
Yield: 57.9 %

Procedure:
A mixture of N-(4-diethylamino-2-butynyl)-2-(2,2,2-trifluoroacetylamino)-2,2-diphenylacetamide (0.11 g) in acetone (2 ml) and 6N hydrochloric acid (1.0 ml) was refluxed for 24 hours. After being cooled, the solvent was evaporated in vacuo. The resulting solution was adjusted to pH 12 with aqueous solution of sodium hydroxide and the separated oil was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol as an eluent to give N-(4-diethylamino-2-butynyl)-2-amino-2,2-diphenylacetamide (0.05 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH:12]=[O:13])[CH:9]=[C:8]([OH:14])[C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl.CCO>CO>[F:1][C:2]1[CH:11]=[C:10]([CH:12]=[O:13])[CH:9]=[C:8]([OH:14])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(O)cc(C=O)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: O=Cc1cc(O)c(C(=O)O)c(F)c1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
A mixture of methyl 2-fluoro-4-formyl-6-hydroxybenzoate (Intermediate 7) (300 mg, 1.50 mmol) and aqueous NaOH (2 M, 10 mL) in MeOH (10 mL) was stirred at 20° C. for 5 hours. The mixture was acidified with aqueous HCl until pH=2 followed by a standard aqueous/EtOH workup. The residue was used for next step without further purification.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([Si](C)(C)C)([F:22])[F:21].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[CH:1]([N:14]1[CH2:17][C:16]([C:20]([F:22])([F:21])[F:19])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1(C(F)(F)F)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 46.32 %

Procedure:
1-Benzhydrylazetidin-3-one (5.0 g, 1.0 eq.) was dissolved in THF (50 mL). Trifluoromethyl trimethylsilane was added at 5-10° C. The reaction mixture was stirred at 10° C. for 10 min. Tetrabutyl ammonium fluoride was then added. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by chromatography (6% ethyl acetate-hexane) to give 3 g of 1-benzhydryl-3-(trifluoromethyl)azetidin-3-ol (Yield: 46.32%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:16][S:17](O)(=[O:19])=[O:18]>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)N1CCC(c2ccccc2)CC1
Product: CC(=O)N1CCC(c2ccc(S(=O)(=O)Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Acetyl-4-phenylpiperidine, [Chem. Abs., 75, 5728b (1971] (16.30 g) was added portionwise over 1 hour to stirred chlorosulphonic acid (53.3 ml) at 0°. The solution was stirred at 0° for 1 hour, then at room temperature for 2 hours, and then finally poured cautiously onto an excess of ice. When the ice had melted the mixture was extracted several times with dichloromethane. The combined organic extracts were washed with water, dried (Na2SO4) and evaporated to give the title compound, (23.0 g), m.p. 133°-134°, used directly in the next step.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][CH:14]1[C:21](=[O:22])[N:20]2[CH:23]([C:27](O)=[O:28])[CH2:24][CH2:25][CH2:26][CH:19]2[CH2:18][CH:17]=[CH:16][CH2:15]1)=[O:12].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.[CH2:59]([O:66][C:67](=[O:80])[CH2:68][CH:69]([NH2:79])[CH2:70][O:71][Si:72]([C:75]([CH3:78])([CH3:77])[CH3:76])([CH3:74])[CH3:73])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>C1COCC1.O>[CH2:59]([O:66][C:67](=[O:80])[CH2:68][CH:69]([NH:79][C:27]([CH:23]1[N:20]2[C:21](=[O:22])[CH:14]([NH:13][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[O:12])[CH2:15][CH:16]=[CH:17][CH2:18][CH:19]2[CH2:26][CH2:25][CH2:24]1)=[O:28])[CH2:70][O:71][Si:72]([C:75]([CH3:76])([CH3:77])[CH3:78])([CH3:74])[CH3:73])[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(N)CC(=O)OCc1ccccc1
Reactant: O=C(NC1CC=CCC2CCCC(C(=O)O)N2C1=O)c1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)[Si](C)(C)OCC(CC(=O)OCc1ccccc1)NC(=O)C1CCCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Reaction time: 0.33 h

Procedure:
7-[(Naphthalene-2-carbonyl)-amino]-6-oxo-1,3,4,6,7,8,11,11a-octahydro-2H-pyrido[1,2-a]azocine-4-carboxylic acid (0.44 gm) is dissolved in 15 mL THF to which 0.24 gm of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC), 0.15 mL of N-methylmorpholine, and 0.17 gm of 1-hydroxybenzotriazole (HOBt) is added. The reaction mixture is stirred for 20 min then added to a solution of 3-amino-4-(tert-butyl-dimethyl-silanyloxy)-butyric acid benzyl ester (0.52 gm, prepared by methods described in Chem. Pharm. Bull. 1999, 47, 11–21) in 5 mL THF. The resulting mixture is striired at RT for ˜18 h, then poured into water, and extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, then dried over sodium sulfate powder. Filtration and evaporation produces a crude product which is then purified over silica (1:1 ethylacetate:hexanes) to afford the desired product.