Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][C:34]([F:33])=[CH:35][CH:36]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccc(F)cc4)c3)csc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (25.6 mg, 0.078 mmol) (from Example 3 supra) in THF (2 mL) were added diisopropylethyl-amine (22 mg, 0.170 mmol) (Aldrich) and then 4-fluorobenzoyl chloride (13.4 mg, 0.085 mmol) (Aldrich). The reaction was stirred at room temperature for 30 minutes before it was concentrated to remove the solvent. The residue was diluted with EtOAc (40 mL), washed with aqueous 1N NaOH (10 mL), brine (2×10 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (hexanes/EtOAc, 70/30) to give 3-[3-(4-fluoro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 29 mg, 82.5%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][CH:7]([CH3:10])[CH2:8][OH:9].N1C=CC=CC=1>C(OCC)C>[Cl:1][CH2:2][C:3]([O:9][CH2:8][CH:7]([CH3:10])[CH3:6])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC(C)CO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)COC(=O)CCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
A solution of chloroacetyl chloride (3.2 mL, 40 mmol) in anhydrous diethyl ether (20 mL) was added dropwise within 1 h to a solution of 2-methylpropanol (2.96 g, 40 mmol) and pyridine (3.25 mL, 40 mmol) in anhydrous diethyl ether (80 mL) at 0° C. After warming to RT, the white suspension was stirred for 3 h. The precipitate was removed by filtration and washed by diethyl ether (15 mL). The combined organic solution was washed with HCl (2 N, 30 mL), followed by sat. NaHCO3 (30 mL), sat. NaCl (30 mL) solutions and dried with Na2SO4. Removal of the solvent at about 60 mmHg/30° C. afford 2-Methylpropyl Chloroacetate (5.65 g, 94%) which was used without further purification.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]1=[O:18].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[C:3]2=[O:18])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: Nn1nc(-c2ccccc2)c2c(c1=O)CCCC2
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(-c2ccccc2)c2c(c1=O)CCCC2

Procedure:
The product from Example 185A and 2-(3,5-difluorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.68-11.71 (bs, 1H), 7.39-7.51 (m, 5H), 7.04-7.20 (m, 3H), 3.72 (s, 2H), 2.51-2.55 (m, 2H), 2.37-2.41 (m, 2H), 1.69-1.77 (m, 2H), 1.58-1.65 (m, 2H); MS (APCI+) M/Z 396 (M+H)+.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][CH2:6][C:5](=[O:8])[N:4]1[CH2:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([O:19]CCCC)=[O:18])[N:14]=1.[F:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1([C:33](=[O:41])[CH2:34]P(=O)(OC)OC)[CH2:32][CH2:31][CH2:30]1>>[F:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1([C@H:33]([OH:41])/[CH:34]=[CH:2]/[C@H:3]2[CH2:7][CH2:6][C:5](=[O:8])[N:4]2[CH2:9][C:10]2[S:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[N:14]=2)[CH2:30][CH2:31][CH2:32]1
Reactant: COP(=O)(CC(=O)C1(CCCCF)CCC1)OC
Reactant: CCCCOC(=O)CCc1csc(CN2C(=O)CC[C@@H]2CO)n1
Product: O=C(O)CCc1csc(CN2C(=O)CC[C@@H]2/C=C/[C@@H](O)C2(CCCCF)CCC2)n1

Procedure:
By the same procedure as a series of reactions of Example 5→Example 6→Example 7→Example 8 using the compound 75 instead of the compound 4 and using dimethyl {2-[1-(4-fluorobutyl)cyclobutyl]-2-oxoethyl}phosphonate instead of dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate, the title compound having the following physical data was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16](Br)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:22]1[CH2:27][CH:26]=[C:25](B2OCC(C)(C)CO2)[CH2:24][CH2:23]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:25]3[CH2:26][CH2:27][S:22][CH2:23][CH:24]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)COB(C2=CCSCC2)OC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Br)c2)CC1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(C3=CCSCC3)c2)CC1
Temperature: 80 °C
Reaction time: 7 h
Yield: 67 %

Procedure:
To a mixture of 4-(4-amino-3-bromo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (as prepared in Example 13, step (c), 200 mg, 0.563 mmol), 2-(3,6-dihydro-2H-thiopyran-4-yl)-5,5-dimethyl-[1,3,2]dioxaborinane (as prepared in the previous step, 131 mg, 0.619 mmol) and Pd(PPh3)4 (65 mg, 0.056 mmol) in 5 mL of 1,4-dioxane was added 2.0 M aq Na2CO3 solution (2.25 mL, 4.5 mmol). The resulting mixture was stirred at 80° C. for 7 h under Ar, and then cooled to RT. Treated with 50 mL of EtOAc, the mixture was washed with H2O (3×15 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (15-30% EtOAc/hexane) gave 141 mg (67%) of the title compound as a colorless oil. 1H-NMR (CDCl3; 400 MHz): δ 6.91 (dd, 1H, J=8.2, 2.2 Hz), 6.81 (d, 1H, J=2.2 Hz), 6.65 (d, 1H, J=8.2 Hz), 5.91 (m, 1H), 4.22 (br s, 2H), 3.66 (br s, 2H), 3.29-3.31 (m, 2H), 2.87 (dd, 2H, J=5.7, 5.7 Hz), 2.77 (m, 2H), 2.47-2.56 (m, 3H), 1.78 (d, 2H, J=12.6 Hz), 1.50-1.63 (m, 2H), 1.48 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C21H30N2O2S, 375.2 (M+H), found 375.2.
Reaction SMILES: [C:1]1(B(O)O)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[Br:20][C:21]1[CH:22]=[C:23](I)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[C:1]1([C:25]2[CH:26]=[C:21]([Br:20])[CH:22]=[CH:23][CH:24]=2)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Reactant: Brc1cccc(I)c1
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: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2ccc3ccc4cccc5ccc2c3c45)c1
Temperature: 100 °C
Yield: 78.5 %

Procedure:
4.92 g (20 mmol) of pyrene-1-boronic acid, 5.94 g (21 mmol) of 3-bromoiodobenzene, and 0.46 g (0.4 mmol, 2 mol %) of tetrakis(triphenylphosphine)palladium(0) were loaded into a 300-ml three-necked flask, and air in the container was replaced with argon. Further, 10 ml of toluene and 30 ml (3 eq) of a 2M aqueous solution of sodium carbonate were added to the mixture, and the whole was refluxed under heat in an oil bath at 100° C. for 8 hours. After one night, the resultant was extracted with toluene/ion-exchanged water and purified by column chromatography, whereby 5.61 g of 3-pyrenylbromobenzene were obtained (79% yield).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[CH2:29]([NH2:33])[CH:30]([CH3:32])[CH3:31].C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([NH:33][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:17][CH2:18]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)CNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
Sodium triacetoxyborohydride (32.0 g, 151.0 mmol) is added to a stirred solution of tert-butyl 4-oxo-1-piperidine carboxylate (20.0 g, 100.4 mmol), isobutylamine (10.5 ml, 105.7 mmol), acetic acid (6.0 ml, 104.8 mmol) and 1,2-dichloroethane (300 ml). The reaction is stirred for 18 hours at room temperature under nitrogen. The reaction is poured into 2N NaOH (300 ml) and extracted with ethyl acetate (200 ml×3). The ethyl acetate is dried over sodium sulfate and then the sodium sulfate is filtered off. The crude product is concentrated on a rotary evaporator and purified by flash chromatography on silica gel eluting with 0.5% concentrated ammonium hydroxide/5% ethanol/chloroform to yield (24.5 g, 95%) of 4-isobutylamino-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=257.1 (M+1); 1H NMR (CDCl3): δ=4.01 (2H, br s), 2.78-2.75 (2H, m), 2.60-2.53 (1H, m), 2.42 (2H, d), 1.83-1.64 (3H, m), 1.56 (1H, br s), 1.44 (9H, s), 1.28-1.18 (2H, m), 0.90 (6H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(Oc2ccc([N+](=O)[O-])cc2Cl)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
To a solution of 2-chloro-1-fluoro-4-nitrobenzene (3.7 g) and 3-hydroxybenzonitrile (2.5 g) in N,N-dimethylformamide (50 mL) was added potassium carbonate (4.4 g), and the mixture was stirred at 60° C. for 4 hrs. After the completion of the reaction, water (50 mL) was added, and the mixture was stirred for 10 min. The resultant pale-yellow solid was collected by filtration, washed with diisopropyl ether, and dried to give the title compound (5.3 g) as pale-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].C[Si]([N:20]=[C:21]=[S:22])(C)C.CN(C)C=O>CN(C)C(=O)C>[NH2:20][C:21]([NH:1][C:2]1[S:3][C:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])=[S:22]
Reactant: NC(=O)c1cc(-c2ccccc2)sc1N
Reactant: C[Si](C)(C)N=C=S
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccccc2)sc1NC(N)=S
Yield: 35.3 %

Procedure:
A solution of 2-amino-5-phenyl-3-thiophenecarboxamide (1.09 g, 5 mmol) and trimethylsilyl isothiocyanate (0.85 ml, 6 mmol) in N,N-dimethylacetamide was stirred at 75° C. for 7 days. N,N-Dimethylformamide was added until solution. The solvent was removed and the resulting slurry was chromatographed on silica gel eluting with isohexane followed by methylene chloride and diethyl ether to give the product as a yellow solid (0.49 g, 35%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].COC(/C=C/[C:16]1[CH:21]=[C:20](O)[C:19]2[O:23][CH:24](C3C=CC(O)=C(O)C=3)[CH:25](C(OC)=O)[C:18]=2[CH:17]=1)=O>C(Cl)Cl>[Cl:1][CH2:2][C:3]([C:16]1[CH:21]=[CH:20][C:19]2[O:23][CH2:24][CH2:25][C:18]=2[CH:17]=1)=[O:4]
Reactant: COC(=O)/C=C/c1cc(O)c2c(c1)C(C(=O)OC)C(c1ccc(O)c(O)c1)O2
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)c1ccc2c(c1)CCO2
Temperature: 25 °C

Procedure:
Chloroacetyl chloride (10.39 g) was dissolved in methylene chloride (25 ml) and the solution was added to a slurry of aluminium chloride (12.2 g) in methylene chloride (50 ml) at -15° C. A solution of dihydrobenzofuran (10 g) in methylene chloride (25 ml) was added and the solution was allowed to warm to room temperature over 20 hours. The reaction mixture was poured into ice (700 g) and the aqueous layer was back-washed with methylene chloride (2×200 ml). The combined organic extracts were washed with water (800 ml), dried with MgSO4 and concentrated in vacuo. The resulting solid (11 g) was heated in cyclohexane (110 ml) and the supernatant liquid decanted off and allowed to crystallise. Filtration produced the title compound as a white solid, yield 2.1 g, m.p. 85°-87° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1.[N:12]1([CH2:17][C:18](=[CH2:23])[C:19]([O:21]C)=[O:20])[CH:16]=[N:15][CH:14]=[N:13]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[CH2:23][C:18]([C:19]([OH:21])=[O:20])([CH2:17][N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)[O:9][N:8]=2)=[CH:5][CH:4]=1
Reactant: C=C(Cn1cncn1)C(=O)OC
Reactant: COc1ccc(C=NO)cc1
Solvent: ClCCl
Product: COc1ccc(C2=NOC(Cn3cncn3)(C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
4-Methoxybenzaldehyde oxime (1.63, g, 10.8 mmol) and methyl 2-(1,2,4-triazol-1-ylmethyl)acrylate. (1.50 g, 8.97 mol) were added together with 100 mL of CH2Cl2. To the above mixture was added bleach (23 mL of 0.67M aqueous solution) dropwise at room temperature. The reaction mixture was then stirred at RT under N2 for 12 h. The mixture was diluted with CH2Cl2 and washed with water and brine, It was dried over MgSO4, concentrated, and chromatographed with 30-100% EtOAc in CH2Cl2 on silica gel to give 1.81 g of the desired product (66%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:32]=[CH:31][C:15]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[NH:27][CH:26]=[C:25]([C:28]([OH:30])=[O:29])[CH:24]=4)[CH:18]=3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.CN(C)CCCN=C=NCC.[OH:45][CH2:46][C:47]([CH2:52]O)([CH2:50][OH:51])[CH2:48][OH:49]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:32]=[CH:31][C:15]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[NH:27][CH:26]=[C:25]([C:28]([O:30][CH2:52][C:47]([CH2:50][OH:51])([CH2:48][OH:49])[CH2:46][OH:45])=[O:29])[CH:24]=4)[CH:18]=3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Reactant: OCC(CO)(CO)CO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)OCC(CO)(CO)CO)c[nH]4)c3)cc2)c1
Temperature: 60 °C

Procedure:
To a stirred suspension of 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (150 mg, 0.35 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 102 mg, 0.53 mmol) in 10 ml of anhydrous tetrahydrofuran were added pentaerythritol (143 mg, 1.05 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol). The mixture was heated at 60° C. for 16 hours, cooled to room temperature and evaporated to dryness. The residue was purified by C-18 reverse phase chromatography eluting with a gradient of 10˜50% of acetonitrile in water to afford 3-hydroxy-2,2-bis(hydroxymethyl)propyl 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as white solid. Yield: 46 mg, 24%.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]2[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=2)[CH2:15][CH2:14]1)=O.C([BH3-])#N.[Na+].C(Cl)Cl>CO>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=3)[CH2:15][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(CCCN2CCC(C=O)CC2)cc1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CCCN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 1899.1 %

Procedure:
A solution of (1R,2S)-2-phenylcyclopropanamine (1.051 g, 7.89 mmol) and ethyl 4-(3-(4-formylpiperidin-1-yl)propyl)benzoate (1.9 g, 6.26 mmol) in methanol (50 mL) was heated to reflux for 5 minutes. The reaction was cooled to room temperature and sodium cyanoborohydride (0.590 g, 9.39 mmol) was added. The reaction was stirred at room temperature for 16 hours. After concentrating, dichloromethane was added and the solution was washed with water followed by brine and dried over MgSO4, filtered and concentrated. The residue was purified via Biotage (0% to 100% EtOAc:Hex; to get off impurity then 0% to 20% MeOH:DCM to get off product 50 g-HP-silica gel column) to yield 1.18 g 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90-1.18 (m, 2H), 1.20-1.36 (m, 2H), 1.40 (t, J=7.07 Hz, 4H), 1.66-1.80 (m, 2H), 1.81-2.02 (m, 5H), 2.24-2.45 (m, 3H), 2.56-2.79 (m, 4H), 2.95 (d, J=10.86 Hz, 2H), 4.38 (q, J=7.24 Hz, 2H), 6.99-7.10 (m, 2H), 7.10-7.20 (m, 1H), 7.21-7.38 (m, 5H), 7.97 (d, 2H) MS (ES); [M+H]+ 421.3
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.Cl.[OH:34][CH:35]([C:37]1([OH:41])[CH2:40][NH:39][CH2:38]1)[CH3:36].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([C:5]([N:39]2[CH2:40][C:37]([CH:35]([OH:34])[CH3:36])([OH:41])[CH2:38]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: CC(O)C1(O)CNC1
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(O)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reaction time: 0.08 h
Yield: 65.4 %

Procedure:
3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (362 mg, 0.921 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, 4-(dimethylamino)pyridine (337 mg, 2.76 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (212 mg, 1.11 mmol) were dissolved in DMF (3 mL). The mixture was stirred at ambient for 5 minutes and then 3-(1-hydroxyethyl)azetidin-3-ol hydrochloride (0.922 mmol) in DMF (2 mL) was added and the mixture was stirred for 15 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 80% ethyl acetate in hexanes) gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-hydroxyethyl)azetidin-3-ol (296 mg, 0.602 mmol, 65% yield): MS (EI) for C18H16F3IN2O3: 493 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][CH2:12][S:13][CH3:14])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.CO>[Fe].C(O)(=O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([O:11][CH2:12][S:13][CH3:14])=[CH:10][C:4]=1[NH2:1]
Reactant: CSCOc1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CSCOc1ccc(N)c(N)c1

Procedure:
4.5 G. of 2-nitro-4-methylthiomethoxyaniline in 95 ml. of methanol and 5 ml. of acetic acid is treated with 8 g. of iron powder and the mixture is refluxed for 4 hours. The hot solution is filtered and the solvent evaporated. The residue is treated with hot tetrahydrofuran. The mixture is filtered and the solvent evaporated to give 1,2-diamino-4-methylthiomethoxybenzene.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[Cl:11][C:12]1[CH:13]=[CH:14][C:15](F)=[C:16]([CH:19]=1)[C:17]#[N:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:15]2[CH:14]=[CH:13][C:12]([Cl:11])=[CH:19][C:16]=2[C:17]#[N:18])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: c1ccc2c(c1)NCCO2
Reactant: N#Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)ccc1N1CCOc2ccccc21
Temperature: 100 °C
Yield: 48.1 %

Procedure:
To a solution of 3,4-dihydro-2H-benzo[b][1,4]oxazine (500 mg, 3.69 mmol, Tyger Scientific) and 5-chloro-2-fluorobenzonitrile (573 mg, 3.69 mmol) in DMF (10 mL) was added cesium carbonate (3.61 g, 11.0 mmol). The reaction mixture was heated at 100° C. for 24 h. After completion, the reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (2×15 mL). The organic layer was dried over sodium sulfate and concentrated to get crude material which was purified by column chromatography (12 g column: elution: 5% ethyl acetate in hexane) to provide 2-(2h-benzo[b][1,4]oxazin-4(3h)-yl)-5-chlorobenzonitrile (480 mg, 48.4%) as yellow solid. LCMS (ESI) m/z 270.02 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][C@@H:16]([OH:20])[C:17]([OH:19])=O)(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.Cl.Cl.[CH3:24][N:25]1[C:29]([CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:28][S:27]/[C:26]/1=[N:37]\[CH3:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][C@@H:16]([OH:20])[C:17]([N:34]1[CH2:35][CH2:36][N:31]([CH2:30][C:29]3[N:25]([CH3:24])/[C:26](=[N:37]/[CH3:38])/[S:27][CH:28]=3)[CH2:32][CH2:33]1)=[O:19])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C/N=c1\scc(CN2CCNCC2)n1C
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C/N=c1\scc(CN2CCN(C(=O)[C@H](O)CS(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)n1C
Yield: 22.6 %

Procedure:
To a suspension of (2S)-3-((6-chloronaphthalen-2-yl)sulfonyl)-2-hydroxypropanoic acid (0.32 g), N-((2Z)-3-methyl-4-(-1-piperazinylmethyl)-1,3-thiazol-2(3H)-ylidene)methanamine trihydrochloride (0.51 g), HOBt (0.20 g) and triethylamine (0.63 mL) in DMF (5 mL), WSC (0.21 g) was added, and the mixture was mixed at room temperature for 22 hours. The reaction solution was concentrated under reduced pressure. The residue was basified with an aqueous potassium carbonate solution, and then the mixture was extracted with ethyl acetate/THF. The extract was dried over anhydrous magnesium sulfate, the solvent was then distilled off, and the residue was purified with a basic silica gel column to give the title compound (0.12 g, 23%) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CN1CCNCC1
Product: CN1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and N-methylpiperazine according to conditions described in general procedure C. Mp: 182-184° C.;