Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1I)[C:8](=[O:11])[O:9][CH3:10].CCO.[CH:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39](B(O)O)=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:36]=[N:37][CH:38]=1)[C:8](=[O:11])[O:9][CH3:10]
Reactant: OB(O)c1cncc2ccccc12
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cncc2ccccc12
Temperature: 97.5 °C

Procedure:
To a solution of methyl [3,5-bis(trifluoromethyl)benzyl](2-iodo-5-trifluoromethyl-benzyl)carbamate (41 mg, 0.070 mmol) (Example 5) in 3:2 EtOH:toluene, 4-isoquinolineboronic acid (18.2 mg, 0.105 mmol) and 2.5 M sodium carbonate (0.175 mmol) were added. The solution was degassed, followed by the addition of a catalytic amount of tetrakis(triphenylphosphine)palladium. The solution was stirred at 95-100° C. until completion of the reaction. Upon cooling, the solvent was removed in vacuo. The desired product was obtained by preparative thin layer chromatography using 25% acetone/hexane. 1H NMR (CDCl3, 500 MHz) δ 9.36 (s, 1H), 8.38 (s, 1H), 8.10-8.13 (m, 1H), 7.68-7.80 (m, 4H), 7.26-7.64 (m, 5H), 4.22-4.48 (m, 4H), 3.64-3.78 (m, 3H). LC-MS (M+1) 587.2 (3.48 min).
Reaction SMILES: C(NC(C)C)(C)C.I[C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>[Cu]I.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.O1CCCC1>[CH3:14][Si:15]([C:18]#[C:19][C:9]1[S:10][CH:11]=[CH:12][N:13]=1)([CH3:17])[CH3:16]
Reactant: Ic1nccs1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1nccs1
Temperature: 50 °C

Procedure:
Copper(I)iodide (38 mg, 0.20 mmol), dichlorobis(triphenylphosphine)palladium(II) (250 mg, 0.40 mmol) and N,N-diisopropylamine (1.40 g, 14 mmol) were added to a solution of 2-iodothiazole (1.50 g, 7.0 mmol; prepared as described in J. Org. Chem. 1988, 53, 2489) and dry tetrahydrofuran (50 mL). The reaction mixture was degassed and trimethylsilylacetylene (1.40 g, 14 mmol) was added in two portions under nitrogen atmosphere. The reaction was heated to 50° C. for 12 h. The formed precipitate and separated palladium were removed by filtration through a short path of silica gel. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel Fluka 60: hexane/ethyl acetate 98:2-90:10) yielding 2-(trimethylsilylethynyl)thiazole as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([I:10])[CH:9]=1)=[O:4].C(N(CC)CC)C.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[CH:7]=[C:8]([I:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(I)c[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(I)cn1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.5 %

Procedure:
4-Iodo-1H-pyrrole-2-carboxylic acid methyl ester (24.6 g, 98 mmol, 1.0 equivalent) was dissolved in dichloromethane (150 mL) and triethylamine (30 mL, 215.6 mmol, 2.2 equivalents). 4-(Dimethylamino)pyridine (1.2 g, 9.8 mmol, 0.1 equivalent) and p-toluenesulfonylchloride (20.6 g, 107.8 mmol, 1.1 equivalents) were added and the reaction mixture was stirred for 16 hours at room temperature. The reaction was quenched with 1 M HCl and the organic layer was washed with aqueous sodium bicarbonate and brine. After drying over magnesium sulfate, the solvent was removed under reduced pressure and the residue was crystallized from tert-butylmethyl ether, yielding the title compound as a pale yellow solid (30 g, 75%). Rt(min) 8.259 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=[O:5].[C:13]([N:16]1[CH:21]([CH3:22])[CH2:20][N:19]([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH2:18][CH:17]1[CH3:31])(=[O:15])[CH3:14].S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[C:13]([N:16]1[CH:21]([CH3:22])[CH2:20][N:19]([C:23]2[CH:24]=[CH:25][C:26]([C:27]3[NH:6][C:4](=[O:5])[C:3]4[C:2](=[CH:10][C:9]([F:11])=[CH:8][C:7]=4[F:12])[N:1]=3)=[CH:29][CH:30]=2)[CH2:18][CH:17]1[CH3:31])(=[O:15])[CH3:14]
Reactant: NC(=O)c1c(N)cc(F)cc1F
Reactant: CC(=O)N1C(C)CN(c2ccc(C=O)cc2)CC1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)N1C(C)CN(c2ccc(-c3nc4cc(F)cc(F)c4c(=O)[nH]3)cc2)CC1C
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-amino-4,6-difluoro-benzamide (0.66 g, 3.84 mmol) and 4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-benzaldehyde (1.00 g, 3.84 mmol) in N,N-dimethyl acetamide (20 mL), was added sodium hydrogen sulfite (58.5 wt %, 1.04 g, 5.76 mmol) and p-toluenesulfonic acid monohydrate (0.88 g, 4.61 mmol) and the reaction mixture was stirred at 115° C. for 16 hours. The solvent was evaporated in vacuo, water was added, and the precipitated solid was filtered off, to give 2-[4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-phenyl]-5,7-difluoro-3H-quinazolin-4-one as a yellow solid, which was used in the next step without further purification.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].ClC(O[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])=O.C(=O)=O>O>[CH3:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:9]=1[Cl:1]
Reactant: Cc1cccc(C)c1OC(=O)Cl
Reactant: [Cl-]
Agent: O=C=O
Agent: [Al+3]
Solvent: O
Product: Cc1cccc(C)c1Cl
Temperature: 200 °C
Reaction time: 3.5 h
Yield: 64 %

Procedure:
0.8 g of anhydrous aluminium chloride was added to 50 g of 2,6-dimethylphenyl chloroformate and the mixture was heated to 200° C. at normal pressure. The evolution of carbon dioxide started above 180° C. and finished after 3.5 hours. The reaction mixture was then cooled, water was added, the organic phase was separated off, the aqueous phase was extracted with methylene chloride, the organic phase which had been separated off was combined with the methylene chloride phase and the combined phases were dried over sodium sulphate and distilled under vacuum. 2,6-Dimethylchlorobenzene was obtained in a yield of 64%.
Reaction SMILES: [C-]#N.[Na+].[N:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[C:12](#[N:15])[CH:13]=[CH2:14]>C(#N)C>[O:11]=[C:10]([C:7]1[CH:8]=[CH:9][N:4]=[CH:5][CH:6]=1)[CH2:14][CH2:13][C:12]#[N:15]
Reactant: C=CC#N
Reactant: O=Cc1ccncc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CC#N
Product: N#CCCC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
C-1. 4-Oxo-4-(4-pyridinyl)butanenitrile--To a stirred mixture containing 29.4 g. of sodium cyanide and 500 ml. of acetonitrile, after stirring said mixture for ten minutes, was added dropwise over a period of three hours a solution containing 64.2 g. of 4-pyridinecarboxaldehyde in 500 ml. of acetonitrile and the resulting mixture was stirred at room temperature for one hour. To the stirred mixture was added slowly over a period of one hour a solution of 24.5 g. of acrylonitrile in 200 ml. of acetonitrile and the resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was stripped in vacuo of solvent at a temperature not exceeding 54° C. The semi-solid residue was cooled, mixed well with 400 ml. of chloroform, and the mixture filtered. The chloroform was distilled off in vacuo at a temperature not exceeding 50° C. and the residual oily residue was extracted with three 200 ml. portions of toluene. The toluene solution was filtered through diatomaceous earth and the filtrate was distilled in vacuo below 50° C. to remove the toluene. The residue on chilling crystallized. A tiny sample was saved and the remainder was dissolved in 50 ml. of warm isopropyl alcohol. The solution was cooled and then diluted slowly with 125 ml. of ether, chilled and seeded with a crystal obtained from said tiny sample. The crystalline product that separated was collected, washed with 25 ml. of 1:3 (v:v) mixture of isopropyl alcohol:ether, and air-dried to yield 52.1 g of 4-oxo-4-(4-pyridinyl)butanenitrile, m.p. 53.5°-55° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]CN.[C:12](CP(=O)(OCC)OCC)#[N:13].[H-].[Na+].CC1C=CC=CC=1C=O>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH2:9])[C:12]#[N:13]
Reactant: Cc1ccccc1CCCN
Reactant: CCOP(=O)(CC#N)OCC
Agent: Cc1ccccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C#N)c1ccccc1C
Reaction time: 0.5 h

Procedure:
Procedure for the preparation of 3-(2-Methylphenyl)propylamine ##STR142## 3-(2-Methylphenyl)propylamine: Diethyl cyanomethylphosphonate (5.0 ml, 30.9 mmol) was added to a stirring suspension of sodium hydride (60% oily suspension, 1.24 g, 31 mmol) in tetrahydrofuran (50 ml) under argon. After 30 min, 2-methylbenzaldehyde (3.6 ml, 31.1 mmol) was added and stirring continued for 1 h. The reaction was quenched by the addition of water and extracted with dichloromethane followed by drying and evaporation of the organic solution. Column chromatography (hexane; hexane:ethylacetate=3:1) provided 2-(2-methylphenyl)acrylonitrile as an oil. This material (3.8 g), 10% palladium on carbon (3.8 g) and 12 N hydrochloric acid (11.8 ml, 142 mmol) in methanol (125 ml) were hydrogenated with hydrogen at atmospheric pressure for 2 d. The catalyst was removed by filtration and the solvent was evaporated. The resultant material was partitioned between dichloromethane and water. The aqueous layer was made basic with 10 N sodium hydroxide and extracted with dichloromethane, followed by drying and evaporation. The resultant material was purified on a silica gel column (chloroform:methaol:triethylamine=85:10:5) to provide the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].CC(C)([O-])C.[K+].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br>CN(C)C=O.C(#N)C>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[C:24]([F:23])([F:33])[F:34])[N:8]=1)=[O:5]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(Nc1ccn(Cc2ccccc2C(F)(F)F)n1)c1c(F)cccc1F
Reaction time: 0.17 h

Procedure:
A solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide ((for a preparation see Intermediate 9)(31.9 mg, 0.1 mmol) in dimethylformamide (0.4 ml) was treated with potassium t-butoxide (11.3 mg, 0.1 mmol) and allowed to stand at room temperature for 10 min. A solution of 2-(trifluoromethyl)benzyl bromide (22.3 mg, 0.1 mmol, Aldrich) in acetonitrile (0.2 ml) was finally added and the solution left to stand for 16 h at room temperature. The solvent was removed using a Genevac and the crude mixture dissolved in a 1:1 mixture of dimethylsulphoxide:methanol (0.6 ml) and the solution purified by MDAP on SUNFIRE C18 (Method D). The appropriate fraction was concentrated in vacuo using a Genevac to give the title compound (2.3 mg);
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[F:30][C:31]([F:46])([F:45])[C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[C:35](Cl)=[O:36]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:35](=[O:36])[C:34]3[CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=[C:32]([C:31]([F:30])([F:45])[F:46])[CH:33]=3)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 91, Step 3, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and 3,5-bis(trifluoromethyl)benzoyl chloride.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][C@H:15]3[C@H:17]([NH2:20])[CH2:18][CH2:19][C@H:14]3[CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(=O)C(C)(C)C>>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:20][C@@H:17]2[C@@H:15]3[C@@H:14]([CH2:13][N:12]([S:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=4)(=[O:10])=[O:11])[CH2:16]3)[CH2:19][CH2:18]2)=[CH:26][CH:25]=1
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: O=Cc1ccc(F)cc1
Agent: CC(C)(C)C=O
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](NCc3ccc(F)cc3)[C@H]2C1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Step D of Example 252 for (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine and 4-fluorobenzaldehyde for pivalaldehyde in the procedure described in Example 281: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.39-8.40 (bs, 1H), 8.22-8.24 (m, 1H), 7.93-7.95 (m, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.41 (dd, J=8.3, 5.5 Hz, 2H), 7.13 (t, J=8.7 Hz, 2H), 3.71 (d, J=13.3 Hz, 1H), 3.67 (d, J=13.2 Hz, 1H), 3.39 (dd, J=9.8, 3.1 Hz, 1H), 3.16 (dd, J=9.6, 3.0 Hz, 1H), 3.06 (dd, J=9.8, 8.0 Hz, 1H), 2.96 (dd, J=9.6, 7.6 Hz, 1H), 2.85 (q, J=6.1 Hz, 1H), 2.47-2.56 (m, 1H), 2.30-2.35 (m, 1H), 1.93-2.07 (m, 1H), 1.87-1.94 (m, 1H), 1.79-1.87 (m, 1H), 1.29-1.38 (m, 1H), 1.20-1.29 (m, 1H); MS (ESI+) m/z 443 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[CH3:11][CH:12]1[C:18]2=[N:19][C:20]3[C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C:21]=3[N:17]2[CH:16]=[CH:15][CH:14]=[CH:13]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([N:19]1[C:20]2[C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C:21]=2[N:17]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]([CH3:11])[CH:18]12)=[O:10]
Reactant: O=C=Nc1ccccc1F
Reactant: CC1C=CC=Cn2c1nc1c2CCCC1=O
Solvent: ClCCl
Product: CC1C=CC=CN2C3=C(C(=O)CCC3)N(C(=O)Nc3ccccc3F)C12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Fluorophenylisocyanate (0.28 g, 2.06 mmol) was added to a solution of 6-methyl-1,2,3,4-tetrahydro-4-oxo-6H-azepino(1,2-a)benzimidazole (0.4 g, 1.87 mmol; Ohta, S. et al. Chem. Pharm. Bull. 1990, 38(2), 301) in methylene chloride (5 mL) and the reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated in vacuo and purified by medium pressure chromatography, using EtOAc/MeOH as an eluent and recrystallization from EtOAc/methylene chloride to give the title compound as a solid: mp 139-141° C.; MS: 352 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[NH:7][CH:6]=1)=O.[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[Br:14][C:11]1[CH:12]=[C:13]2[C:5]([C:3]3[S:17][C:16]([NH2:18])=[N:15][CH:2]=3)=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: O=C(CBr)c1c[nH]c2ncc(Br)cc12
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1ncc(-c2c[nH]c3ncc(Br)cc23)s1
Temperature: 100 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
A mixture of 2-bromo-1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone (0.5 g, 1.6 mmol), thiourea (180 mg, 2.4 mmol) in ethanol (15 ml) were stirred at 100° C. under nitrogen overnight. Solvent was removed and the crude was titurated with DCM, filtered, and washed with more DCM afforded 5-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-ylamine (114 mg, 24% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.21 (s, 1H), 8.15 (s, 1H), 8.42 (s, 1H), 8.58 (s, 1H), 8.98 (s, 2H), 12.42 (s, 1H). MS: m/z 295.0 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:33]2[CH2:35][CH2:34]2)[C:15]([C:17]2[CH:18]=[N:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)=[N:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:33]1([N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15]([C:17]2[CH:22]=[N:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)=[N:19][CH:18]=2)=[O:16])[CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(-c3ccc(S(C)(=O)=O)cc3)nc2)C2CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ncc(C(=O)N(C3CCNCC3)C3CC3)cn2)cc1

Procedure:
The title compound is prepared from 4-{cyclopropyl-[2-(4-methanesulfonyl-phenyl)-pyrimidine-5-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester by treatment with trifluoroacetic acid in dichloromethane. LC (method 10): tR=1.20 min; Mass spectrum (ESI+): m/z=401 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([OH:18])[CH:17]=1>>[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([O:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1cncc(Cl)c1
Product: O=[N+]([O-])c1ccc(Oc2cncc(Cl)c2)cc1
Yield: 87.6 %

Procedure:
4-Fluoro-nitrobenzene (5.0 g) and 3-chloro-5-hydroxypyridine (4.59 g) were combined at 60° C. using a method similar to that of Example 21.2 to provide 7.78 g of 4-(3-chloro-5-pyridyloxy)nitrobenzene. mp 80-82° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:19][CH2:20]O>>[CH2:19]([O:12][C:11]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:10][CH2:9]1)=[O:13])[CH3:20]
Reactant: CCO
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(c2ccc(Br)cc2)CC1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
1-(4-Bromo-phenyl)-cyclopropanecarboxylic acid (5 g, 20.7 mmol) in EtOH (50 mL) was treated with sulfuric acid (2 mL), and the reaction was stirred at 75° C. for 1 hour. The mixture was worked up to give the title compound.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)#[N:28]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([C:27]#[N:28])=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: N#Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)cc1

Procedure:
The title compound, yellow solid (54 mg, 47%), MS (ISP) m/z=456.5 [(M+H)+], mp 195° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-cyano-benzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].[CH3:36][N:37]([CH3:41])[C:38](Cl)=[O:39]>>[CH3:35][O:34][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:2]=1[O:1][C:38](=[O:39])[N:37]([CH3:41])[CH3:36])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:21][C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: CN(C)C(=O)Cl
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC(=O)N(C)C)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with N,N-dimethyl-carbamoyl chloride
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][O:16]C(=O)C)=[CH:14][C:9]=2[O:8][CH:7]=1)C.[NH3:21]>>[OH:16][CH2:15][C:13]1[CH:12]=[CH:11][C:10]2[C:6]([CH2:5][C:4]([NH2:21])=[O:3])=[CH:7][O:8][C:9]=2[CH:14]=1
Reactant: CCOC(=O)Cc1coc2cc(COC(C)=O)ccc12
Reactant: N
Product: NC(=O)Cc1coc2cc(CO)ccc12
Temperature: 60 °C

Procedure:
(6-Acetoxymethyl-benzofuran-3-yl)-acetic acid ethyl ester (0.80 g, 2.90 mmol) was added to liquid ammonia at −78° C., the reaction flask was sealed and heated at 60° C. for 6 days. The reaction mixture was cooled, the excess of ammonia was allowed to evaporate and the residue was washed with in hexane and precipitated to give the 2-(6-hydroxymethyl-benzofuran-3-yl)-acetamide as an off white solid (0.54 g, 90%). 1H NMR (DMSO-d6, 400 MHz) 3.46 (s, 2H), 4.60 (d, J=5.6 Hz, 1H), 5.25 (t, J=5.6 Hz, 1H), 6.98 (brs, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.47 (s, 1H), 7.53 (brs, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 13C NMR (DMSO-d6, 400 MHz) 30.8, 63.4, 109.4, 115.4, 120.0, 121.6, 127.0, 139.9, 143.4, 155.2, 171.7.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:40]CC1.C(O)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: C=CCC(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=CCC(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 48 %

Procedure:
Treat a mixture of (R)-4-benzyl-3-[2-(4-benzyloxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one (0.96 g, 1.8 mmol), THF (21 mL) and water (7 mL) with 2.5% osmium tetroxide in t-butanol (46 mg, 0.18 mmol). Add sodium periodate (1.17 g, 5.5 mmol) and stir the reaction 4 hr at room temperature. Quench the reaction with water and extract with ethyl acetate. Wash the organic phase with aqueous 1N sodium thiosulfate then brine. Dry the organic layer over magnesium sulfate, filter, and concentrate under vacuum. Purify the crude material by silica gel chromatography using hexanes:ethyl acetate to elute the pure product. Concentrate the fractions containing product under vacuum to afford 0.46 g (48%) of desired product. MS (m/z): 526 (M+).