Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([O:11]CC)=O)[C:6](=[O:14])[C:5]2[CH:15]=[CH:16][S:17][C:4]1=2)[CH3:2].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:9]([C:7]2[C:6](=[O:14])[C:5]3[CH:15]=[CH:16][S:17][C:4]=3[N:3]([CH2:1][CH3:2])[CH:8]=2)=[O:11])=[CH:21][CH:20]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(CC)c2sccc2c1=O
Solvent: Cc1ccccc1
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2ccsc21
Temperature: 190 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A mixture of ethyl 7-ethyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (Eur. J. Med. Chem. 1987, 22, 139) (0.447 g) and 4-chlorobenzylamine (2.42 mL) is stirred at 190° C. for 1 h. The reaction is then allowed to cool to rt and is diluted with toluene. The resulting precipitate is filtered off and washed with toluene followed by hexanes to yield a pale yellow solid. This material is recrystallized from acetic acid/water then ethanol to yield 0.312 g (45%) of the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.ON1C2N=CC=CC=2N=N1.[N+:48]([C:51]1[CH:61]=[CH:60][CH:59]=[CH:58][C:52]=1[O:53][CH2:54][C:55](O)=[O:56])([O-])=O.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[NH2:48][C:51]1[CH:61]=[CH:60][CH:59]=[CH:58][C:52]=1[O:53][CH2:54][C:55]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:8][CH:9]=1)=[O:56]
Reactant: O=C(O)COc1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(-c2ccncc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccccc1OCC(=O)Nc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
To a solution of 4-(4-pyridinyl)aniline (400 mg), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.34 g), 1-hydroxy-7-azabenzotriazole (480 mg) and (2-nitrophenoxy)acetic acid (695 mg) in N,N-dimethylformamide (10 ml) was added N,N-diisopropylethylamine (1.3 ml), which was stirred overnight at ambient temperature. The reaction mixture was poured into water (30 ml) and stirred for 30 minutes. Insoluble material was collected, washed with water, dried and purified by column chromatography on silica gel (gradient, CHCl3, 10% MeOH in CHCl3). The aliquots of obtained product (100 mg) and 10% palladium on carbon (50% wet, 30 mg) in N,N-dimethylformamide (10 ml) was stirred at ambient temperature for 3 hours under an atmospheric pressure of hydrogen. The catalyst was removed and evaporated under reduced pressure. The resultant was purified by column chromatography on silica gel (gradient, CHCl3, 10% MeOH in CHCl3), which was recrystallized from EtOH to give 2-(2-aminophenoxy)-N-[4-(4-pyridinyl)phenyl]acetamide (30 mg) as an off-white powder.
Reaction SMILES: [C:1]([C:5]12[CH2:12][O:11][C:8]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][Si](C)(C)C)=[CH:15][CH:14]=3)([O:9][CH2:10]1)[O:7][CH:6]2[C:25]#[N:26])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([C:5]12[CH2:12][O:11][C:8]([C:13]3[CH:14]=[CH:15][C:16]([C:19]#[CH:20])=[CH:17][CH:18]=3)([O:9][CH2:10]1)[O:7][CH:6]2[C:25]#[N:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C12COC(c3ccc(C#C[Si](C)(C)C)cc3)(OC1)OC2C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C23OCC(C(C)(C)C)(CO2)C(C#N)O3)cc1
Reaction time: 2 h

Procedure:
A mixture of 4-t-butyl-3-cyano-1-[4-(2-trimethylsilylethynyl)-phenyl]-2,6,7-trioxabicyclo[2,2,2]octane (1.3 g.) and anhydrous potassium carbonate in dry methanol (125 ml.) was stirred under dry nitrogen for 2 hours. The resulting solution was evaporated in vacuo. The residue was taken up in diethyl ether and the ethereal solution was washed with water. The ethereal solution was dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by chromatography on alumina eluting with hexane:dichloromethane 4:1, saturated with ammonia. 4-t-butyl-3-cyano-1-(4-ethynylphenyl)-2,6,7-trioxabicyclo[2,2,2]octane was obtained as pale yellow needles (600 mg.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8]2)#[N:2].Cl>CO.[Pd]>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8]2
Reactant: COC(=O)c1ccc2cccc(C#N)c2c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc2cccc(CN)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.5 %

Procedure:
Part B--A mixture of methyl 8-cyano-2-naphthoate (1.0 g, 0.0047 mol) in methanol (35 mL) with concentrated hydrochloric acid (0.69 mL) and palladium on carbon catalyst (0.20 g, 5% Pd/C) was shaken for 6 hours at ambient temperature under an atmosphere of hydrogen (50 psi). The reaction mixture was filtered over Celite@ and washed with methanol. The filtrate was evaporated to dryness under reduced pressure and the residue was triturated with hexane to give methyl 8-aminomethyl-2-naphthoate (0.76 g, 0.0035 mol, 75%) as an oil. 1H NMR (DMSO) d 8.75 (s, 1H), 8.5 (bs, 2H), 8.2-8.05 (m, 3H), 7.75-7.70 (m, 2H), 4.6 (s, 2H), 3.95 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7]
Reactant: BrCCCCBr
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCCCBr)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
3.3 g of 2-(3,3,3-trifluoropropyl)malononitrile and 8.6 g of 1,4-dibromobutane were dissolved in 20 ml of dimethyl sulfoxide, 3.0 g of potassium carbonate was added, and the mixture was stirred at room temperature for 2 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.2 g of 2-(4-bromobutyl)-2-(3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (63)).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:33])[S:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:13])=[CH:11][C:5]=2[S:4]1.[CH:34]([C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1)=O>>[CH3:33][C:3]1([CH3:2])[S:7][C:6]2[CH:8]=[CH:9][C:10](/[C:12](/[CH3:13])=[CH:34]/[C:36]3[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=3)=[CH:11][C:5]=2[S:4]1
Reactant: CC(c1ccc2c(c1)SC(C)(C)S2)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Br-]
Product: COC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)SC(C)(C)S3)cc1

Procedure:
28.9 g of aluminum chloride were added portionwise at 0° C. to 16.8 ml of acetyl chloride in 360 ml of methylene chloride. After an additional 30 minutes at 0° C., a solution of 35.9 g of 2,2-dimethyl-1,3-benzodithiol in 180 ml of methylene chloride was slowly added dropwise and the mixture was stirred at 0° C. for an additional 12 hours and thereafter at 20° C. for 5 hours. Thereafter, the mixture was poured on to ice, extracted with methylene chloride and the extracts were washed neutral with dilute sodium hydroxide solution and water, dried over sodium sulfate and evaporated. After recrystallization from methanol/ water, there were obtained 41.8 g of 2,2-dimethyl-1,3-benzodithiol-5-yl methyl ketone, melting point 75°-76° C. Then, 41.8 g of this ketone were dissolved in 1 l of ethanol, cooled to 0° C. and 7 g of sodium borohydride were added portionwise. Thereafter, the mixture was stirred at 20° C. for 3 hours, evaporated in a vacuum to a large extent, 200 ml of water were added, the mixture was adjusted slowly to pH 4 with 1N sulfuric acid while cooling and extracted three times with ether. The extracts were washed with water, dried and evaporated, and 42.6 g of α,2,2-trimethyl-1,3-benzodithiol-5-methanol were obtained. Thereafter, 39.5 g of this alcohol were reacted with 65.9 g of triphenylphosphine hydrobromide in 500 ml of acetonitrile and worked-up as described in Example 8 and 96.3 g of [1-(2,2-dimethyl-1,3-benzodithiol-5-yl)ethyl]triphenylphosphonium bromide were obtained. Then, 17.0 g of this phosphonium salt were reacted with methyl 4-formyl-benzoate in analogy to Example 8. After working-up and recrystallization from ethyl acetate/hexane, there were obtained 4.9 g of methyl p-[(E)-2-(2,2-dimethyl-1,3-benzo-dithiol-5-yl)propenyl]benzoate in the form of colorless crystals, melting point 86°-87° C.
Reaction SMILES: CCCC[N+](CC[CH2:16][CH3:17])(CCCC)CCCC.[F-].[CH2:19]1[CH2:23][O:22][CH2:21][CH2:20]1.C1[CH2:28][O:27][CH2:26]C1>>[C:16]([C:19]1[CH:20]=[C:21]([CH2:26][O:27][CH3:28])[O:22][CH:23]=1)#[CH:17]
Reactant: C1CCOC1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C#Cc1coc(COC)c1
Reaction time: 0.5 h

Procedure:
A mixture of partially purified 4-bromo-2-(methoxymethyl)furan (1.9 g) as obtained in Example 18-(2), AcOBu (16 mL), CuI (0.33 g), PdCl2(PPh3)2 (0.60 g), triisopropylsilylacetylene (9.6 mL) and TEA (12 mL) was stirred in a nitrogen atmosphere for 7.5 hours at 110° C. After the reaction mixture was allowed to cool, ethyl acetate (0.10 L), OH type silica gel (1.9 g), cellpure (0.95 g) and activated carbon (10 mg) were added. The insolubles were filtered out, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=100/0→80/20) to obtain a yellow oil (1.7 g). THF (4.0 mL) was added to this oil (0.80 g), and a 1 mol/L TBAF-THF solution (4.1 mL) was added dropwise to the mixture under ice cooling. The mixture was stirred for 30 minutes under ice cooling, and then stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by OH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=100/0→90/10) to obtain 4-ethynyl-2-(methoxymethyl)furan (yellow oil) (0.24 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH2:12])=[O:11])=[CH:5][CH:4]=1.C(C1C=C(O)C=C(C(C)(C)C)C=1C)(C)(C)C.Cl[C:30]([S:32]Cl)=[O:31].Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[O:11][C:30](=[O:31])[S:32][N:12]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(N)=O)cc1
Reactant: O=C(Cl)SCl
Agent: Cc1c(C(C)(C)C)cc(O)cc1C(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccc(Cc2nsc(=O)o2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
To a suspension of 4-methoxyphenylacetamide (5.06 g, 30.0 mmol) in toluene (10 mL) was added 2,6-di-t-butyl-4-hydroxytoluene (132 mg, 0.60 mmol) and chlorocarbonylsulfenyl chloride (5.52 mL, 60.0 mmol). The resulting mixture was warmed to 115° C. for 80 min during which time hydrochloric acid gas was evolved resulting in a yellow solution. To this solution additional chlorcarbonyl-sulfenylchloride (1.38 mL, 15.00 mmoles) was added and the mixture heated for 40 min and allowed to stand at room temperature overnight. The reaction mixture was cooled to 0° C. and stirred for 10 min before being filtered to remove a beige solid. The solid was washed with cold toluene (2×10 mL) and the filtrate was concentrated and purified by flash chromatography (silica gel, 20% ethyl acetate/hexanes) which afforded 5-(4-methoxy-benzyl)-[1,3,4]oxathiazol-2-one (1.12 g, 17%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.Cl.CO>O>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])=[CH:16][CH:15]=1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1C(=Cc2ccc(F)cc2)CCc2cc(O)ccc21
Temperature: 25 °C

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 4-fluorobenzaldehyde 0.79 ml were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for 1.5 hours and cooled to room temperature, and water 300 mg was added. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.65 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][SH:17])=[CH:14][CH:13]=1.[Na]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:16]([S:17][CH:16](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=1)[C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=1
Reactant: C#Cc1ccc(Cl)cc1Cl
Reactant: Fc1ccc(CS)cc1
Agent: [Na]
Product: Fc1ccc(C(/C=C\c2ccc(Cl)cc2Cl)SC(/C=C\c2ccc(Cl)cc2Cl)c2ccc(F)cc2)cc1

Procedure:
A solution of 2,4-dichlorophenylacetylene (0.02 mol), 4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,4-dichlorostyryl-4-fluorobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][C:16]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[CH:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[F:30][C:31]([F:36])([F:35])[C:32]([CH3:34])=[O:33]>O1CCCC1>[F:30][C:31]([F:36])([F:35])[C:32]([OH:33])([CH3:34])[C:29]#[C:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([C:16]2[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=2)(=[O:20])=[O:21])=[CH:23][CH:24]=1
Reactant: C#Cc1ccc(S(=O)(=O)c2ccncc2)cc1
Reactant: CC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)(C#Cc1ccc(S(=O)(=O)c2ccncc2)cc1)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.42 h
Yield: 49.4 %

Procedure:
To a solution of diisopropylamine (0.37 mL, 2.66 mmol) in tetrahydrofuran (11 mL) at -20° C. was added n-butyllithium (0.9 mL of 2.5M solution in hexanes, 2.25 mmol) and the resulting solution was stirred for 25 minutes at -20° C. before being cooled to -78° C. To this was added a solution of 4-(4-pyridylsulfonyl)phenylacetylene (0.5 g, 2.05 mmol) in tetrahydrofuran (3 mL) over a five minute period. The mixture was stirred for an additional 15 minutes at -78° C. To this was added 1,1,1-trifluoroacetone (0.20 mL, 2.25 mmol) in one portion. After stirring the mixture at -78° C. for 20 minutes, it was quenched with water, warmed to ambient temperature and the pH adjusted to 7.0 with saturated aqueous NH4Cl . The solution was evaporated and the resulting residue was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed (brine), dried and evaporated. The resulting brown oil was purified by chromatography, with ethyl acetate:dichloromethane as the eluent (1:5), to give the title compound as a white solid (0.36 g, 50%); mp 122°-125° C.; NMR (CDCl3): 1.73 (s,3, CH3), 3.37 (s,1, OH), 7.61 (d,2, J=8.2, At), 7.76 (d,2, J=5.1, Ar), 7.93 (d,2, J=4); MS: m/z=356(M+ 1). Analysis for C16H12F3NO3S: Calculated: C, 54.08; H, 3.40; N, 3.94; Found: C, 53.99; H, 3.41; N, 3.75.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(OC(=O)[N:17]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][N:28]=1)[CH2:18][C:19]1[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)(C)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:33][C:30]3[CH:31]=[CH:32][C:27]([NH:17][CH2:18][C:19]4[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)=[N:28][CH:29]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)cn2)cn1
Reactant: Brc1cnc2[nH]ccc2c1
Product: COc1ccc(CNc2ccc(Cc3c[nH]c4ncc(Br)cc34)cn2)cn1

Procedure:
[5-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine P-2017 was prepared in two steps from 5-bromo-1H-pyrrolo[2,3-b]pyridine 152 and (5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester 153 as shown in Scheme 21.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](O)=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[OH:15][CH2:14][C@@H:13]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](CO)C[C@H]2C[C@H]21
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a solution of (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (9.85 g, 43.3 mmol) in THF (200 mL) at 0° C. was added dropwise borane-methyl sulfide complex (282 mL, 563 mmol) over 30 min. The ice bath was removed, the mixture was stirred for 1 h and then heated at reflux for 2 h. The mixture was cooled to 0° C., slowly quenched with methanol (˜200 mL) and concentrated under vacuum. The residue was dissolved in DCM and washed with water (emulsion), 1N HCl, sat NaHCO3 aq, and brine. The organic layer was dried over Na2SO4, filtered and concentrated to yield (1R,3S,5R)-tert-butyl 3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (8.43 g, 39.5 mmol, 91% yield) as colorless oil. LC-MS retention time 1.398 min; m/z 236.20 [M+Na]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min and an analysis time of 4 min where Solvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 90% methanol/10% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 3.72-3.79 (m, 1H), 3.52-3.64 (m, 3H), 3.15-3.24 (m, 1H), 2.00-2.08 (m, 1H), 1.62-1.72 (m, 1H), 1.54-1.62 (m, 1H), 1.45-1.51 (m, 9H), 0.84 (br s, 1H), 0.36 (td, J=5.0, 2.4 Hz, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:27]=[CH:26][C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:43])[O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>C1COCC1>[C:37]1([O:36][C:35](=[O:43])[NH:3][C:4]2[CH:27]=[CH:26][C:7]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:25])[C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=4)=[CH:13][N:14]=3)=[CH:6][CH:5]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of N-[6-(4-aminophenoxy)pyridin-3-yl]-3,4-dichlorobenzamide dihydrochloride (700 mg, 1.57 mmol) in THF (20 mL) was added triethylamine (1.1 mL, 7.89 mmol). To the resulting solution was then added dropwise phenyl chlorocarbonate (0.39 mL, 3.14 mmol) under ice cooling. The resulting reaction solution was stirred for 1 hour at room temperature. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, whereupon the residue solidified into a powder. The powder was filtered, and washed with diethyl ether, to thereby yield 470 mg of the title compound.
Reaction SMILES: [Br-].[OH:2][C:3]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:4]=1[CH2:5]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:32](Cl)[CH:33]([CH3:35])[CH3:34]>>[CH:33]([C:35]1[O:2][C:3]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:4]=2[CH:5]=1)([CH3:34])[CH3:32]
Reactant: CC(C)CCl
Reactant: O=[N+]([O-])c1ccc(O)c(C[PH](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Product: CC(C)c1cc2cc([N+](=O)[O-])ccc2o1

Procedure:
Reaction of 2-hydroxy-5-nitrobenzyl triphenylphosphine bromide (prepared as described in Example 1(a) (40 g, 0.08 mol) and isobutyl chloride (10,6, 0.1. mol) was carried out with the method described in Example 1(b) to produce 19.7 g of 2-isopropyl-5-nitrobenzofuran.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([N:12]2[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:19])=O)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[CH3:19][C@H:13]1[CH2:14][CH2:15][CH2:16][C@@H:17]([CH3:18])[N:12]1[C:10]1[N:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:8][N:9]=1
Reactant: C[C@@H]1CCC[C@H](C)N1C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(F)cn12
Temperature: 55 °C
Yield: 79.9 %

Procedure:
To an ice cold solution of Intermediate 96a (1.38 g, 5.19 mmol) in THF (50.0 mL) was added sequentially triphenylphosphine (2.72 g, 10.4 mmol), Et3N (2.89 mL, 20.8 mmol) and hexachloroethane (2.46 g, 10.4 mmol). The cooling bath was removed and the reaction was heated to 55° C. overnight. The reaction was cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted with 2M NH3 in MeOH. The residue was concentrated in vacuo then resubmitted to the reaction conditions overnight. After analogous workup the residue was concentrated in vacuo to give the title compound (1.03 g, 80%). 1H NMR (300 MHz, CDCl3): 0.68 (6H, d, J 6.2 Hz), 1.36-1.68 (3H m), 1.74-1.90 (3H, m), 3.35 (2H, m), 7.14 (1H, ddd, J 9.8, 7.5, 2.3 Hz), 7.65 (1H, ddd, J 9.9, 4.7, 0.8 Hz), 8.02 (1H, ddd, J 3.2, 2.3, 0.8 Hz).
Reaction SMILES: [CH2:1]([NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[CH2:2][CH2:3][CH3:4].B.Cl>O1CCCC1>[CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)c1ccccc1Cl
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCCCNCc1ccccc1Cl

Procedure:
A solution of 21.2 g of N-(n-butyl)-2-chlorobenzamide in 100 ml of tetrahydrofuran was added with cooling to 200 ml of 1M borane in tetrahydrofuran and the mixture was stirred under reflux for 18 hours, allowed to cool, and treated with 6N hydrochloric acid. The organic solvent was evaporated, and the residue was partitioned between ether and aqueous sodium hydroxide solution. The ether layer was separated, dried, and evaporated. The residue was distilled to yield N-(n-butyl)-2-chlorobenzylamine as a colorless liquid, b.p. 65°-75° C. at 60μ.