Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:22][C:23]#[N:24])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.CC(O)C.Cl.C(OC(C)C)(C)C>CO>[ClH:21].[NH2:8][CH:9]([CH2:22][C:23]#[N:24])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NC(CC#N)COc1noc2ccc(Cl)cc12
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Solvent: CC(C)OC(C)C
Product: N#CCC(N)COc1noc2ccc(Cl)cc12

Procedure:
To a suspension of 1.0 g of 3-(2-tert-butoxycarbonylamino-3-cyanopropoxy)-5-chloro-1,2-benzoisoxazole in 15 ml of methanol is added 7.8 ml of a 2-propanol solution (6.5M) of hydrogen chloride at room temperature, and they are subjected to reaction at the same temperature for seven hours. Thereafter, the solvent is removed by distillation under reduced pressure. To the residue obtained is added diisopropyl ether, and the crystals precipitated are collected by filtration, to obtain 0.78 g of colorless, crystalline 3-(2-amino-3-cyanopropoxy)-5-chloro-1,2-benzoisoxazole hydrochloride having a melting point of 188.8°-190.9° C. (decomp.).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl.[Cl-].[Na+].O>[S:30]([O:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)([C:27]1[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=1)(=[O:32])=[O:31]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (1 g) in dichloromethane (50 mL) was added triethylamine (1.604 mL) and 4-methylbenzene-1-sulfonyl chloride (1.097 g). The mixture was stirred at ambient temperature under nitrogen for 72 hours. The reaction was diluted with methylene chloride (50 mL) and brine (100 mL). The brine layer was extracted with methylene chloride (75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The crude material was purified on a silica gel column eluting with a 15-65% ethyl acetate in hexane gradient to provide the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].Cl.[OH2:10].[CH3:11]O>C[O-].[Na+]>[OH:10][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([O:6][CH3:11])=[O:5]
Reactant: CO
Reactant: CC(C)(CCl)C(=O)O
Reactant: O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COC(=O)C(C)(C)CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 30.0 grams (0.22 mole) of 3-chloro-2,2-dimethylpropionic acid in 100 ml of absolute methanol was added dropwise 35.6 grams (0.66 mole) of a methanolic solution 25% in sodium methoxide. The exothermic reaction caused the reaction mixture temperature to rise to 40°. Upon completion of addition the reaction mixture was heated at reflux for 4 hours, then cooled to ambient temperature where it was stirred for one hour. The reaction mixture was acidified with concentrated hydrochloric acid and 150 ml of water was added. The mixture was extracted with four portions of 100 ml each of methylene chloride. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 20.8 grams of methyl 3-hydroxy-2,2-dimethylpropionate as an oil.
Reaction SMILES: Cl[C:2]1[N:6](C)[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=2)[C:3]=1[CH:19]=[O:20].O1CCCC1.[CH3:26][S-:27].[Na+]>O>[CH:19]([C:3]1[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=2)=[N:5][NH:6][C:2]=1[S:27][CH3:26])=[O:20]
Reactant: C[S-]
Reactant: Cc1cc(-c2nn(C)c(Cl)c2C=O)ccc1OC(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1[nH]nc(-c2ccc(OC(C)C)c(C)c2)c1C=O
Reaction time: 8 h
Yield: 104.9 %

Procedure:
At room temperature, to a mixture of 5-chloro-4-formyl-3-(4-isopropoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole (described in Reference Preparation example 96) 10 g and tetrahydrofuran 100 ml was added sodium thiomethoxide 2.9 g and the resulting mixture was stirred for eight hours. To the reaction mixture was added water 50 mL and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 4-formyl-3-(4-isopropoxy-3-methyl-phenyl)-5-methylthio-1H-pyrazole 10.4 g.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1([CH3:25])[CH2:23][NH:22][C:21](=[O:24])[CH2:20][CH2:19]1>>[CH3:17][C:18]1([CH3:25])[CH2:23][N:22]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][N:13]=2)[C:21](=[O:24])[CH2:20][CH2:19]1
Reactant: OCc1ccc(C#Cc2ccccc2)cn1
Reactant: CC1(C)CCC(=O)NC1
Product: CC1(C)CCC(=O)N(Cc2ccc(C#Cc3ccccc3)cn2)C1

Procedure:
The title compound, yellow oil, MS: m/e=319.2 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and 5,5-dimethyl-piperidin-2-one.
Reaction SMILES: [OH-].[K+].Br[C@@H:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]1[OH:13].C(=O)([O-])[O-:15].[K+].[K+].[CH:20]([C:22]1[N:26]2[CH:27]=[CH:28][CH:29]=[C:30](O)[C:25]2=[N:24][C:23]=1[CH3:32])=[O:21]>C(O)(C)C.CO.O>[CH:20]([C:22]1[N:26]2[CH:27]=[CH:28][CH:29]=[C:30]([O:13][C@@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:12][C@H:4]3[OH:15])[C:25]2=[N:24][C:23]=1[CH3:32])=[O:21]
Reactant: O[C@@H]1c2ccccc2C[C@H]1Br
Reactant: Cc1nc2c(O)cccn2c1C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3O)cccn2c1C=O

Procedure:
39.7 ml of 10 N potassium hydroxide solution is added to 85.2 g (400 mmol) (trans)-2-bromo-1-indanol in 600 ml isopropyl alcohol dropwise at room temperature while stirring, and the mixture is stirred for a further 15 minutes at room temperature. The isopropyl alcohol is distilled off at 40° C./5-8 mbar, 350 ml methanol/water (4:1), 30.4 g potassium carbonate and 35.2 g (200 mmol) 3-formyl-8-hydroxy-2-methyl-imidazo[1,2-a]pyridine are added and the mixture is stirred for a further 10 hours at 40° C. and 8 hours at room temperature. The mixture is worked up analogously to Example 21 and the yield of the title compound m.p. 200°-202° C. is 47.2 g (76.5%).
Reaction SMILES: CS(C)=O.[C:5]([O:8][C:9]1[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]2[O:16][C:15]([CH2:18]Br)([CH3:17])[CH2:14][C:13]=2[C:20]=1[CH3:21])(=[O:7])[CH3:6].[C-:24]#[N:25].[Na+]>O>[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:20]=1)(=[O:7])[CH3:6].[C:5]([O:8][C:9]1[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]2[O:16][C:15]([CH2:18][C:24]#[N:25])([CH3:17])[CH2:14][C:13]=2[C:20]=1[CH3:21])(=[O:7])[CH3:6]
Reactant: [C-]#N
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(C)(CBr)O2
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(C)(CC#N)O2
Product: CC(=O)Oc1ccc2c(c1)CCO2
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a dimethyl sulfoxide (5 ml) solution of 5-acetoxy-2-bromomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran [1.5 g(4.58 mmol)] was added sodium cyanide [270 mg (5.5 mmol)], and the mixture was stirred at 80° C. for 6 hours under argon atmosphere. The reaction mixture was, after cooling, diluted with water, and subjected to extraction with ethyl acetate. The extract was washed with water and dried, followed by distilling off the solvent. The residue was purified by means of a silica gel column chromatography [hexane - isopropyl ether (2:1)] to obtain 5-acetoxy-2,3-dihydrobenzofuran (Compound 6) (350 mg) and 5-acetoxy-2-cyanomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (Compound 5)(158 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:19]([OH:21])=O)[CH3:18])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([NH2:24])[CH3:23].[NH:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27](O)=[O:28]>CN(C)C=O>[CH2:22]([NH:24][C:27](=[O:28])[C@@H:26]1[CH2:30][CH2:31][CH2:32][N:25]1[C:19](=[O:21])[C@H:17]([CH3:18])[NH:16][C:14](=[O:15])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:23]
Reactant: CCN
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: -5 °C

Procedure:
11 grams of N,N-dicyclohexylcarbodiimide was added to a solution of 14.7 grams of benzyloxycarbonylalanyl alanine in 100 ml of dimethylformamide and 7.6 g of proline ethylamine (prepared from the corresponding benzyloxycarbonyl derivative) cooled to -5 degrees C. and the reaction mixture treated by conventional techniques. 10.6 g of product having a melting point of 139 to 140 degrees C. was obtained. [α]D20 -46.5 degrees (c 0.3; dimethylformamide).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N:10]=[C:11]=[S:12].[N:13]1[C:22]2[CH2:21][CH2:20][CH2:19][CH:18]([NH2:23])[C:17]=2[CH:16]=[CH:15][CH:14]=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]([NH:23][CH:18]1[CH2:19][CH2:20][CH2:21][C:22]2[N:13]=[CH:14][CH:15]=[CH:16][C:17]1=2)=[S:12]
Reactant: Fc1ccc(N=C=S)c(Cl)c1Cl
Reactant: NC1CCCc2ncccc21
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CC#N
Product: Fc1ccc(NC(=S)NC2CCCc3ncccc32)c(Cl)c1Cl

Procedure:
The title compound was prepared from 2,3-dichloro-4-fluorophenylisothiocyanate and 5,6,7,8-tetrahydroquinolin-5-ylamine using General Procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 1.77-1.93 (m, 2H), 1.93-2.12 (m, 2H), 2.81-2.97 (m, 2H), 5.70-5.83 (m, 1H), 7.28 (dd, 1H, J=4.7 Hz, J=7.8 Hz), 7.51 (t, 1H, J=8.9 Hz), 7.62-7.78 (m, 2H), 8.37 (d, 1H, J=8.5 Hz), 8.43 (dd, 1H, J=1.4 Hz, J=4.5 Hz), 9.39 (s, 1H); RP-HPLC (Hypersil®-100 C18, 5 μm, 100 Å, 10 cm; 5%-100% acetonitrile −0.1M ammonium acetate over 5 min, 2 mL/min), then 100% acetonitrile isocratic 1 minutes, Rt min. (98.9%); MS: M+H+ 370.
Reaction SMILES: [Br:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:3]=1[C:4]([O:6]C)=[O:5].CS(C)=O.[OH-].[Na+]>O>[Br:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(-c2ccc(Cl)cc2)ccnc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1c(-c2ccc(Cl)cc2)ccnc1Br
Temperature: 80 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
50.0 g (0.15 mol) of methyl 2-bromo-4-(4-chlorophenyl)nicotinate was weighed, and 300 ml of dimethylsulfoxide and 60 ml of 30% sodium hydroxide aqueous solution were added thereto and the mixture was stirred at 80° C. for 3 hours. The mixture was then poured into water and was washed with 300 ml of ethyl acetate. Thereafter, the aqueous layer was acidified with 10% HCl aqueous solution to precipitate a crystal, which was then filtrated out. The crystal thus precipitated was washed with water and isopropyl ether, and was dried to obtain 41.0 g of a white crystal of the aimed product.
Reaction SMILES: [F:1][C:2]([F:24])([C:20]([F:23])([F:22])[F:21])[C:3]([F:19])([F:18])[C:4]([F:17])([F:16])[C:5]([F:15])([F:14])[C:6]([F:13])([F:12])[C:7]([CH2:10][OH:11])([F:9])[F:8].C(N(CC)CC)C.[F:32][C:33]([F:39])([F:38])[S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[F:1][C:2]([F:24])([C:20]([F:21])([F:22])[F:23])[C:3]([F:18])([F:19])[C:4]([F:16])([F:17])[C:5]([F:15])([F:14])[C:6]([F:13])([F:12])[C:7]([CH2:10][O:11][S:34]([C:33]([F:39])([F:38])[F:32])(=[O:36])=[O:35])([F:9])[F:8]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 40 g of (pentadecafluoroheptyl)methanol, 11 g. of triethylamine, and 200 ml. of methylene chloride is stirred at -20° C. while a solution of 18 g. of trifluoromethanesulfonyl chloride in 50 ml. of methylene chloride is added. The solution is stirred for one hour at room temperature and then washed with ice-cold 10% hydrochloric acid, saturated aqueous sodium bicarbonate solution, and water; dried over anhydrous magnesium sulfate; and evaporated. The residual brown liquid is distilled to yield the product as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[C:11](OS(C(F)(F)F)(=O)=O)=[CH:10][CH:9]=[C:8]([F:20])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CO.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[C:11]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[CH:27]=2)=[CH:10][CH:9]=[C:8]([F:20])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1c(F)ccc(OS(=O)(=O)C(F)(F)F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1c(F)ccc(-c2cccc(F)c2)c1F
Temperature: 80 °C
Yield: 67.9 %

Procedure:
A mixture of methyl 2,6-difluoro-3-(trifluoromethylsulfonyloxy)benzoate (3.0 g, 9.4 mmol, 1.0 eq), 3-fluorophenylboronic acid (1.57 g, 11.2 mmol, 1.2 eq), K2CO3 (5.2 g, 37.6 mmol, 4.0 eq) and Pd(PPh3)4 (543 mg, 0.47 mmol, 0.05 eq) in a mixture of MeOH (10 mL) and dioxane (30 mL) was heated to 80° C. under N2 overnight. After cooling, the resulting mixture was concentrated in vacuo and purified by flash column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (1.7 g, 68%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CS(O[CH:15]1[CH2:18][N:17]([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16]1)(=O)=O>C1(C)C=CC=CC=1>[C:20]1([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:17]2[CH2:18][CH:15]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:16]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Phenol (6.68 g, 75 mmol) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 2.82 g, 75 mmol) in toluene (50 mL) and the mixture was heated at 60° C. for 2 hours. The temperature was then increased to 80° C. and a solution of 1-(diphenylmethyl)-3-azetidinyl methanesulfonate (15 g, 47 mol) in toluene (150 mL) was added dropwise. The reaction mixture was stirred for 2 hours at 80° C., cooled then washed with water and dilute sodium hydroxide solution. The organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was re-crystallised from water/isopropanol to afford the title compound as a solid in 84% yield, 12.4 g. LRMS APCI m/z 316 [M+H]+
Reaction SMILES: C([Si](C(C)C)(C(C)C)[O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([NH:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@@H:8]1[OH:32])(C)C.C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C.CCCCCCC>[OH:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([NH:12][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9][C@@H:8]1[OH:32]
Reactant: CC(C)[Si](OC[C@@H]1C[C@@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1O)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC[C@@H]1C[C@@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1O
Reaction time: 3 h
Yield: 344 %

Procedure:
A reactor was charged with (1S,2S,4R)-2-{[(triisopropylsilyl)oxy]methyl}-4-(tritylamino)cyclopentanol (2.94 kg total, ˜1.6 kg assumed pure material, 3.02 mol). The reactor was charged with THF (6 L) and agitation started. While maintaining the temperature less than 25° C., tetrabutylammonium fluoride (1M solution in THF, 3.02 L, 3.0 mol) was added. The reaction mixture was allowed to stir at 20° C. to 22° C., for 3 hours. TLC (50% ethyl acetate/heptane, UV visualization) confirmed a complete conversion of the starting material to the product. The reaction mixture was concentrated under reduced pressure to ˜2 L volume and transferred to a second reactor. The concentrate was diluted with methylene chloride (16 L), washed with saturated aqueous ammonium chloride (8 L), and DI water (8 L). The organic phase was dried over anhydrous magnesium sulfate, filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give an amber oil (3.88 kg) which was purified by silica gel chromatography. Two columns were performed as follows. A 20 cm diameter glass column was loaded with a slurry of silica gel (5 kg) in 10% ethyl acetate/heptane. About 1.9 kg of the oil was adsorbed onto silica gel (1.5 kg) and loaded on the column and the polarity was gradually increased from 10% to 50% ethyl acetate/heptane. Pure fractions were combined and concentrated under reduced pressure to afford the title compound (800 g) as a white solid. 1H NMR (300 MHz, CDCl3, δ): 7.57-7.53 (m, 5H), 7.32-7.18 (m, 10H), 4.26-4.23 (m, 1H), 3.65-3.46 (m, 2H), 3.36-3.29 (m, 1H), 2.17-2.07 (m, 2H), 1.65-1.62 (d, 1H), 1.51-1.39 (m, 2H), 1.37-1.26 (m, 1H) and 1.2-1.17-1.11 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4([C:21]#N)[CH2:20][CH2:19]4)[CH:14]=3)[C:9]2=[O:23])=[CH:5][CH:4]=1.CC(C[AlH]CC(C)C)C.C1C[O:38]CC1>ClCCl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4([CH:21]=[O:38])[CH2:20][CH2:19]4)[CH:14]=3)[C:9]2=[O:23])=[CH:5][CH:4]=1
Reactant: C1CCOC1
Reactant: COc1ccc(CN2CCc3cc(C4(C#N)CC4)ccc3C2=O)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(CN2CCc3cc(C4(C=O)CC4)ccc3C2=O)cc1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a solution of 722 mg of 1-[2-(4-Methoxy-benzyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-cyclopropanecarbonitrile in 3 ml of dichloromethane and 9 ml toluene, cooled at −50° C. was added dropwise 4.8 mL of 1.0 M DIBAL in THF. After stirring 1 hour at −50° C., the reaction was quenched with 5 ml of 1N HCl, left to warm to room temperature and stirred 0.5 hour. Next the mixture was extracted with ethyl acetate and the organic layer was washed with 0.5 N HCl, sodium carbonate 5% solution, and brine. After drying over sodium sulfate and removal of solvent in vacuo, the residue was purified by silica gel column chromatography using 30%-60% ethylacetate in hexane to provide 0.075 g of 1-[2-(4-Methoxy-benzyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-cyclopropanecarbaldehyde.
Reaction SMILES: C([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][C:18]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([OH:21])[CH2:17][CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=O)CCC.[OH-].[Na+]>CO.ClCCl>[CH2:22]([C:18]1([OH:21])[CH2:19][CH2:20][N:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([C@H:7]([OH:6])[CH3:8])[N:14]=2)[CH2:16][CH2:17]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCC(=O)O[C@H](C)c1nccc(N2CCC(O)(Cc3ccccc3)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: C[C@@H](O)c1nccc(N2CCC(O)(Cc3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-1-[4-(4-benzyl-4-hydroxy-piperidin-1 yl)-pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Example 174, Step A, 0.20 g, 0.52 mmol) in methanol (5 mL) was added 1 N aqueous sodium hydroxide (1 mL) and stirred for 4 h at ambient temperature. The mixture was diluted with dichloromethane and washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to give the title compound as a foam, 0.12 g (68%). 1H HNMR (CDCl3, 300 MHz) δ 1.49 (d, 3H), 1.74 (br s, 2H), 1.82 (m, 2H), 2.08 (m, 2H), 3.42 (m, 2H), 4.42 (br s, 1H), 4.71 (q, H), 6.43 (d, 1H), 7.33-7.48 (m, 5H), 8.21 (d, 1H); MS (CI) 314 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:10]NC(=O)CCC(N)=O.S(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: NC(=O)CCC(=O)NCl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1c[nH]c2ccccc12
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 110.2 %

Procedure:
To a 3 L round bottom flask equipped with a mechanical stirrer, thermometer and a Gooch tube was added sieve-dried dimethylformamide (1.2 L) and indole (200 g). The solution was stirred under an atmosphere of nitrogen and cooled to about 10° C. N-Chlorosuccinamide (216.6 g) was added via the Gooch tube at a rate such as to maintain a reaction temperature of 10-18° C. After the addition was complete, a second charge of N-chlorosuccinamide (34.2 g) was added. When the reaction was found to be >97% complete by high performance liquid chromatography, the reaction mixture was poured into a well-stirred, cold solution of aqueous sodium bisulfite (5.2 L of 0.1% sodium bisulfite in water and 640 g of ice). After about 15 min, the precipitate was collected and washed with water (2×1 L). The filtrate was partitioned between dichloromethane (1.3 L) and 0.1% aqueous sodium bisulfite solution (1 L). The phases were separated and the aqueous solution was extracted with dichloromethane (300 ml). The organic fractions were combined, washed with water (800 mL), dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated (at about 25° C. and about 50 mm Hg). The residue was dried in a vacuum oven at 25° C. and about 125 mm Hg for 2 to 4 hrs to yield 240.3 g (92.9%) of product, 3-chloroindole (91.6% pure).