Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]C/C=C\CCCCCCCC.[OH:25]O.O=O.[C:29]([OH:33])([CH3:32])(C)C>O[W](O)(=O)=O>[C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:32][C:29]([OH:33])=[O:25]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Reactant: OO
Reactant: CC(C)(C)O
Agent: O=[W](=O)(O)O
Agent: O=O
Product: O=C(O)CCCCCCCCCCCC(=O)O

Procedure:
To a 1000-ml three-necked flask equipped with refluxing condenser and mechanic stirrer, erucic acid (101.4 g, 0.300 mol; recrystallized with 95% ethanol) , tert-butanol (600 ml; freshly distilled), H2O2 (20.4 ml 50% aqueous solution, 0.3 mol) and tungstic acid (7.47 g, 0.03 mol). The mixture was refluxed for 70 hours while a stream of oxygen gas was bubbled through the solution. The reaction was monitored with TLC (ethyl acetate/hexane). After the reaction was completed, the yellow catalyst was filtered off and washed with hot methanol (2×20 ml) at once. The catalyst was recovered (about 100%). Most of the solvent in the mother liquor was removed under reduced pressure. The residue was then held at about -5° C. for several hours. Once a white solid appeared, hexane (100 ml) was added. The product brassylic acid was obtained by filtration (63.2 g, 76%). The brassylic acid was purified by recrystallization in methanol. (mp: 110°-114° C.) The stoichiometry of the reaction dictates that the oxidative cleavage of a 1,2-disubstituted olefinic double bond results in the formation of equal amounts of pelargonic acid and brassylic acid. Of the two acids formed, the generation of brassylic acid was monitored simply due to the relative ease of the analysis.
Reaction SMILES: [OH-:1].[Na+].[NH2:3][CH2:4][C:5]12[CH2:12][N:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH:9]1[CH2:8][CH2:7][O:6]2>O.C(O)(C)(C)C>[CH2:13]([N:11]1[CH2:12][C:5]2([CH2:4][NH:3][C:7]([O:6][C:5]([CH3:12])([CH3:9])[CH3:4])=[O:1])[CH:9]([CH2:8][CH2:7][O:6]2)[CH2:10]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [OH-]
Reactant: NCC12CN(Cc3ccccc3)CC1CCO2
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NCC12CN(Cc3ccccc3)CC1CCO2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2 g of NaOH in 45 ml of water are added to 10.4 g (44.7 mmol) of 1-aminomethyl-7-benzyl-2-oxa-7-azabicyclo[3.3.0]octane in 56 ml of tert-butanol, and 10.2 g (47 mmol) of di-tert-butyl pyrodicarbonate are then added dropwise. The mixture is stirred at room temperature for 15 hours, and then extraction with chloroform, drying over potassium carbonate, concentration and distillation are carried out. Yield: 12.2 g (82% of theory) Boiling point: 170° C./0.15 mbar The product is 94% pure by gas chromatography.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=1)[C:3](=O)[CH3:4].[NH2:16][C:17]([NH2:19])=[S:18]>>[BrH:1].[CH3:15][S:12]([C:8]1[CH:7]=[C:6]([C:2]2[S:18][C:17]([NH2:19])=[N:16][C:3]=2[CH3:4])[CH:11]=[CH:10][CH:9]=1)(=[O:14])=[O:13]
Reactant: NC(N)=S
Reactant: CC(=O)C(Br)c1cccc(S(C)(=O)=O)c1
Product: Br
Product: Cc1nc(N)sc1-c1cccc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A stirred solution of 1-bromo-1-(3-methanesulphonyl-phenyl)-propanone (176c) (0.32 g, 1.01 mmol) is treated with thiourea (0.067 g, 0.88 mmol) added in one portion. The reaction mixture is allowed to stir at room temperature over two days. The product precipitates out and is filtered to yield the tittle compound as while solid.
Reaction SMILES: C1([C@H](NC(C(C2C=CC=C(F)C=2C(O)=O)C(=O)C)=O)C2C=CC=C(F)C=2)CCC1.C(OC(C)(C)C)(=O)NN.C(OC(=O)[NH:45][N:46]1[C:55]([CH3:56])=[C:54]([C:57](=[O:71])[NH:58][C@@H:59]([CH:67]2[CH2:70][CH2:69][CH2:68]2)[C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([F:66])[CH:61]=2)[C:53]2[C:48](=[C:49]([F:72])[CH:50]=[CH:51][CH:52]=2)[C:47]1=[O:73])(C)(C)C.C(O)(C(F)(F)F)=O>C1C=CC=CC=1.ClCCCl>[CH:67]1([C@H:59]([NH:58][C:57]([C:54]2[C:53]3[C:48](=[C:49]([F:72])[CH:50]=[CH:51][CH:52]=3)[C:47](=[O:73])[N:46]([NH2:45])[C:55]=2[CH3:56])=[O:71])[C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([F:66])[CH:61]=2)[CH2:70][CH2:69][CH2:68]1
Reactant: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c(=O)n1NC(=O)OC(C)(C)C
Agent: CC(=O)C(C(=O)N[C@H](c1cccc(F)c1)C1CCC1)c1cccc(F)c1C(=O)O
Agent: CC(C)(C)OC(=O)NN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: c1ccccc1
Product: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c(=O)n1N

Procedure:
A solution of 2-(1-{[(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-2-oxo-propyl)-6-fluoro-benzoic acid (2.148 g, 5.351 mmol) and tert-butyl carbazate (1.628 g, 12.32 mmol) in benzene (100 mL) was stirred under reflux for 20 hours. LC-MS indicated the formation of (4-{[(S)-Cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-yl)-carbamic acid tert-butyl ester (tR=1.54, UV 39%, ELSD 80%, m/z 398.4 (major), 442.5, 498.7 (MH+)). The reaction mixture was rotovaped. The residue was dissolved in 1,2-dichloroethane (15 ml) and TFA (15 ml) was added. After 60 min it was evaporated, partitioned between sat. aq. NaHCO3 and ethyl acetate, evaporated to give a crude residue of the title compound (1.7 g) that was used in the next step without purification. LC-MS (m/z) 398.0 (MH+), tR=1.24.
Reaction SMILES: CO[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][N:12]=2)[CH2:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH3:3])[CH2:6][CH2:7]3)=[N:12][NH:13]2)=[CH:18][CH:17]=1
Reactant: COC(=O)N1CCC(c2n[nH]c3cc(Cl)ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(c2n[nH]c3cc(Cl)ccc23)CC1
Yield: 68.8 %

Procedure:
To a stirred solution, under nitrogen, of 13.0 g of 4-(6-chloro-1H-indazol-3-yl)piperidine-1-carboxylic acid methyl ester in 150 ml of tetrahydrofuran was added, dropwise, 48 ml of a 1M solution of lithium aluminum hydride (0.048 mole) in tetrahydrofuran. The solution was stirred under reflux for 1 hr. The reaction mixture was cooled in an ice-salt bath and water was added slowly. The reaction mixture was filtered, the filter cake washed with tetrahydrofuran and methanol, and the filtrate was concentrated. Recrystallization of the residue from ethanol-water yielded 7.6 g (69%) of product, mp 211-213° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12](I)=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(N(C(C)C)C(C)C)C.O>O1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(Cl)cc1)CCCC3
Temperature: 100 °C
Yield: 62 %

Procedure:
To a solution of Methyl (2S)-tert-butoxy(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)acetate (Preparation 16, 100 mg, 212 μmol) in dioxane (2 mL) was added 4-chlorobenzene boronic acid (66 mg, 422 μmol), ethyl-di-isopropyl-amine (120 μL, 636 μmol), water (500 μL) and palladium tetrakis(triphenylphosphine) (25 mg, 20 μmol). The reaction mixture was degassed and stirred at 100° C. in a sealed tube. The reaction was cooled to room temperature and diluted with ethyl acetate (10 mL). The mixture was passed through a pad of Celite. The organic filtrate was washed with water (10 mL) and brine (10 mL), dried over MgSO4 and concentrated in vacuo to yield the crude product. The residue was purified by flash chromatography eluting with ethyl acetate in heptane (0-6%) to give the title compound as a white semi-solid, 60 mg, in a 62% yield. 1H NMR (400 MHz, CDCl3) δ ppm 0.97 (s, 9H), 1.45-1.48 (m, 1H), 1.62-1.73 (m, 3H), 1.78-1.82 (m, 2H), 2.71 (s, 3H), 2.78-2.81 (m, 2H), 3.66 (s, 3H), 4.99 (s, 1H), 7.18-7.21 (m, 1H), 7.39-7.42 (m, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]=2[Cl:34])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42].O>ClCCl>[C:41]([NH:1][CH2:2][C:3]1[N:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][O:16][Si:17]([C:30]([CH3:31])([CH3:33])[CH3:32])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:9]=2[Cl:34])[CH:5]=[CH:6][CH:7]=1)(=[O:43])[CH3:42]
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2CN)c1Cl)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1cccn1-c1ccc(Cl)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a mixture of 2-aminomethyl-1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)pyrrole (87 mg) and pyridine (20.3 mg) in dichloromethane (1 ml) was added acetic anhydride (20.9 mg) under ice-cooling, and the mixture was stirred for 3 hours at ambient temperature. The mixture was poured into water and extracted with dichloromethane. The organic layer was washed with 1N hydrochloric acid, water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo to give 2-acetamidomethyl-1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)pyrrole (94 mg) as amorphous powder.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)C(C(O)=O)=[CH:20][CH:19]=[CH:18]3)[CH:9]=1.CN(C=O)C>C(Cl)Cl>[Cl:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:1]([C:2]([Cl:4])=[O:3])=[CH:20][CH:19]=[CH:18]3)[CH:9]=1
Reactant: O=C(O)c1cccc2cc(Oc3cc(Cl)ncn3)ccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc2cc(Oc3cc(Cl)ncn3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 571 μl (6.66 mMol) oxalyl chloride in 15 ml CH2Cl2 is added to an ice-cooled solution of 1 g (3.33 mMol) 6-(6-chloro-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (preparation see WO 2006/59234; Step 25.1) and 10 μl DMF in 30 ml CH2Cl2. The reaction mixture is stirred at room temperature for 1 h. The solvent is then evaporated off under reduced pressure to afford the title compound as a brown solid, which is used directly without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C@H:8]([O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][C:23]2[CH:35]=[CH:34][C:26]3[C:27](=[O:33])[N:28]([CH3:32])[CH2:29][CH2:30][O:31][C:25]=3[CH:24]=2)[CH:21]=1)[C:16]([OH:18])=O)[CH2:9][O:10][CH3:11].[NH2:36][C:37]1[CH:42]=[N:41][C:40]([CH3:43])=[CH:39][N:38]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH3:7][C@H:8]([O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][C:23]2[CH:35]=[CH:34][C:26]3[C:27](=[O:33])[N:28]([CH3:32])[CH2:29][CH2:30][O:31][C:25]=3[CH:24]=2)[CH:21]=1)[C:16]([NH:36][C:37]1[CH:42]=[N:41][C:40]([CH3:43])=[CH:39][N:38]=1)=[O:18])[CH2:9][O:10][CH3:11]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)O)c1
Reactant: Cc1cnc(N)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.8 %

Procedure:
Oxalyl chloride (0.17 mL, 1.94 mmol) and DMF (1 drop) were added to a solution of 3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]benzoic acid (625 mg, 1.56 mmol) in DCM (15 mL) and the mixture stirred at RT for 4 hours. The solvent was evaporated in vacuo to a residue which was added to a solution of 2-amino-5-methylpyrazine (255 mg, 2.34 mmol) and pyridine (0.64 mL, 7.8 mmol) in DCM (5 mL). The resultant mixture was heated at 60° C. in a microwave reactor for 5 minutes. The mixture was cooled to RT and pressure, the DCM was evaporated in vacuo to a residue which was partitioned between ethyl acetate (50 mL) and 1N citric acid (25 mL). The organic layer was washed with 1N citric acid (25 mL), brine, dried (MgSO4) and evaporated in vacuo to a residue which was chromatographed on silica, eluting with ethyl acetate, to give the desired compound (352 mg).
Reaction SMILES: [Cl-].[NH4+].C[NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20].C(OCC)(=O)C.ClCCl>CO.[Fe]>[N+:19]([C:6]1[CH:7]=[C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:5]=1[NH2:4])([O-:21])=[O:20].[N:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:8]2[CH:7]=[C:6]([NH2:19])[C:5]([NH2:4])=[CH:10][CH:9]=2)=[CH:14][CH:15]=1
Reactant: CNc1ccc(OCc2ccncc2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(OCc2ccncc2)cc1N
Product: Nc1ccc(OCc2ccncc2)cc1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
A single necked 50 ml flask fitted with a Teflon stirrer, Claisen head fitted with a rubber septa and reflux condenser was charged with iron powder (Aldrich, 6.2 mmoles, 3 equivalents, 0.358 g) and an aqueous solution of ammonium chloride (10.70 mmoles, 5 equivalents, 0.573 g). The slurry was rapidly stirred and a solution of 2-nitro-4-(pyridin-4-ylmethoxy)aniline (2.14 mmoles, 0.525 g) in methanol (10 ml, 5 ml./mmole of nitro compound) was prepared with gentle heating to ensure complete dissolution. The methanolic solution of methyl 2-nitro-4-(pyridin-4-ylmethoxy)aniline was added over a period of 10 minutes using a syringe and needle. Upon completion of addition the reaction mixture was brought to a gentle reflux and the progress of the reaction was monitored by TLC (silica, 100% ethyl acetate or dichloromethane, visualizing by UV). After 1.5 hours, additional iron powder (Aldrich, 6.2 mmoles, 3 equivalents, 0.358 g), ammonium chloride (10.70 mmoles, 5 equivalents, 0.573 g) and methanol (10 ml) was added. The reaction was found to be complete after 2.5 hours. A sintered filtered funnel (60 ml, medium grade sintered) was packed with Celite (20 mm thick) and connected to a Buchner flask. The hot reaction mixture was filtered through the pad of Celite, the flask rinsed with hot methanol (2×25 ml), filtered and the filtered pad washed with more hot methanol (2×40 ml). The combined filtrate was evaporated to dryness. The recovered material was dissolved in 50 ml cold water and 100 ml dichloromethane and allowed to separate. The dichloromethane layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give 0.497 of 4-(pyridin-4-ylmethoxy)benzene-1,2-diamine which was used in the next step without any further purification. 1H-NMR (400 MHz, DMSO-d6) 10.50 (br s, 4H), 7.68 (d, 2H), 7.42 (m, 2H), 6.60 (d, 1H), 6.41 (s, 1H), 6.22 (d, 1H), 5.12 (s, 2H). (MS (EI): 216 (MH+).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CCO>[ClH:19].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][S:18][C:9]2[NH:8][C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:10]=2)=[CH:22][CH:21]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CCO
Product: Cl
Product: Clc1ccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 4-chlorobenzyl chloride (0.253 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 151 mg of the product 200. 1H NMR (DMSO-d6) δ 11.30 (s, 2 H), 7.75-7.60 (d, 2 H), 7.60-7.55 (d, 2 H), 7.20-6.90 (m, 6 H), 6.85-6.65 (m, 4 H), 5.78 (s, 2 H), 4.90 (s, 2 H); MS: m/z 379 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:51][N:52]([CH3:67])[S:53]([C:56]1[C:64]2[C:59](=[CH:60][CH:61]=[C:62]([F:65])[CH:63]=2)[N:58]([NH2:66])[CH:57]=1)(=[O:55])=[O:54]>CN(C=O)C>[CH3:51][N:52]([CH3:67])[S:53]([C:56]1[C:64]2[C:59](=[CH:60][CH:61]=[C:62]([F:65])[CH:63]=2)[N:58]([NH:66][C:15]([C:11]2[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:17])[CH:57]=1)(=[O:54])=[O:55]
Reactant: CN(C)S(=O)(=O)c1cn(N)c2ccc(F)cc12
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(S(=O)(=O)N(C)C)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 36.1 %

Procedure:
A solution of 2-(3-fluorophenyl)-4-methylpyrimidine-5-carboxylic acid (116 mg) and HATU (190 mg) in dry DMF is treated with DIPEA (0.09 mL) and stirred at rt for 40 min. 1-Amino-5-fluoro-1H-indole-3-sulfonic acid dimethylamide (192 mg) is added and the mixture is stirred at rt for 24 h. The mixture is concentrated in vacuo. The residue is dissolved in EtOAc, washed with 2 N aqueous NaOH, water and brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 30% EtOAc/heptane to afford 2-(3-fluorophenyl)-4-methylpyrimidine-5-carboxylic acid-(3-dimethylsulfamoyl-5-fluoroindol-1-yl)amide (85 mg, 40%) as a solid. MS: 472 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.68 (s, 6H), 2.79 (s, 3H), 7.25-7.35 (m, 1H), 7.45-7.55 (m, 1H), 7.57-7.80 (m, 3H), 8.20 (d, 1H), 8.35 (s, 1H), 8.47 (s, 2H), 9.28 (s, 1H), 12.40 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[NH2:1][C:2]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(O)ccc(C#N)c1N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(C#N)c(N)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.5 %

Procedure:
A mixture of compound 76 (12 g, 0.08 mol), K2CO3 (11 g, 0.08 mol) in dry DMF (200 mL) was stirred for 15 min at RT. To this was added MeI (13.6 g, 0.096 mol) and the mixture was stirred for 4 h at RT. The reaction mixture was diluted with water (800 mL), extracted with 30% ethyl acetate in pet. ether (3×300 mL). The combined organic layers were washed with water and brine, dried and concentrated to give a crude product. The crude product was washed with pet. ether to give pure title compound (12 g, 93%).
Reaction SMILES: F[C:2]1[C:7]([CH:8]=O)=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])[C:5]([N+:19]([O-:21])=[O:20])=[C:4]([O:22][CH3:23])[CH:3]=1.O.[NH2:25][NH2:26]>COCCOC>[F:18][C:12]1[CH:13]=[C:14]([I:17])[CH:15]=[CH:16][C:11]=1[NH:10][C:6]1[C:5]([N+:19]([O-:21])=[O:20])=[C:4]([O:22][CH3:23])[CH:3]=[C:2]2[C:7]=1[CH:8]=[N:25][NH:26]2
Reactant: COc1cc(F)c(C=O)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Reactant: NN
Solvent: COCCOC
Solvent: O
Product: COc1cc2[nH]ncc2c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
A biphasic mixture of 6-fluoro-2-(2-fluoro-4-iodo-phenylamino)-4-methoxy-3-nitro-benzaldehyde (1.5 g, 3.46 mmol) in hydrazine hydrate (10 mL) and DME (10 mL) was stirred at room temperature for 4 hours, then heated at 50° C. for 3 hours. The reaction mixture was concentrated in vacuo, the residue treated with water and the resultant solid precipitate collected by filtration to give a red/orange solid. The solid was recrystallised from IMS to give the title compound as a yellow solid (956 mg, 64%). LCMS (Method B) RT=3.62 min, [M+H]+=429 [M−H]−=427.
Reaction SMILES: C(OCC1C2C(=CN=C(C([NH:21][OH:22])=O)C=2)N(CC2C=CC(F)=CC=2F)C=1)C1C=CC=CC=1.[F:32][C:33]1[CH:56]=[CH:55][C:36]([O:37][CH2:38][C:39]2[C:43]3[CH:44]=[N:45][C:46]([C:48]([O:50]CC)=O)=[CH:47][C:42]=3[N:41]([CH2:53][CH3:54])[CH:40]=2)=[CH:35][CH:34]=1.FC1C=CC(O)=C(C=1)CC1C2C=NC(C(OCC)=O)=CC=2N(CC)C=1>>[F:32][C:33]1[CH:56]=[CH:55][C:36]([O:37][CH2:38][C:39]2[C:43]3[CH:44]=[N:45][C:46]([C:48]([NH:21][OH:22])=[O:50])=[CH:47][C:42]=3[N:41]([CH2:53][CH3:54])[CH:40]=2)=[CH:35][CH:34]=1
Reactant: CCOC(=O)c1cc2c(cn1)c(COc1ccc(F)cc1)cn2CC
Reactant: O=C(NO)c1cc2c(COCc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Agent: CCOC(=O)c1cc2c(cn1)c(Cc1cc(F)ccc1O)cn2CC
Product: CCn1cc(COc2ccc(F)cc2)c2cnc(C(=O)NO)cc21

Procedure:
Ethyl 3-(4-fluoro-phenoxymethyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate. The title compound can be prepared from ethyl 3-hydroxymethyl-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and 4-fluorophenol using a methods similar to step (e) of Example 54. (b) 3-(4-Fluoro-phenoxymethyl)-1-ethyl-N-hydroxy-1H-pyrrolo[3,2-c]pyridine-6-carboxamide. The title compound can be prepared from the mixture of ethyl 3-(4-fluoro-phenoxymethyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and ethyl 3-(5-fluoro-2-hydroxy-benzyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate in a manner similar to step (e) of Example 11. Purification by HPLC can provide the pure title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[CH3:11])(C)(C)C.[CH3:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][C:36]=1[CH:41]=O>C(Cl)CCl>[NH2:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]([C:19]2[CH:20]=[CH:21][C:22]([O:25][Si:26]([C:29]([CH3:30])([CH3:32])[CH3:31])([CH3:27])[CH3:28])=[CH:23][CH:24]=2)[CH2:41][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][C:35]=2[CH3:34])[CH2:16][CH2:17]1)[CH3:11]
Reactant: Cc1ccncc1C=O
Reactant: C[C@H](CCNC(=O)OC(C)(C)C)N1CCC(Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2)CC1
Solvent: ClCCCl
Product: Cc1ccncc1CN(c1ccc(O[Si](C)(C)C(C)(C)C)cc1)C1CCN([C@H](C)CCN)CC1
Yield: 12.8 %

Procedure:
Using general procedure A with ((R)-3-{4-[4-(tert-butyl-dimethyl-silanyloxy)-phenylamino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (see EXAMPLE 233) (796 mg, 2.10 mmol) and 4-methyl-3-pyridinecarboxaldehyde (see EXAMPLE 356) (367 mg, 3.00 mmol) in ClCH2CH2Cl (6 mL) followed by general procedure C afforded [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-(4-methyl-pyridin-3-ylmethyl)-amine (130 mg, 17% over 2 steps) as a white foam.