Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[N:7]=1)=[O:4].C([Li])CCC.[Br:21]CCBr.O>C1COCC1.CCOC(C)=O>[Br:21][C:11]1[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:15])([CH3:14])[CH3:1])=[N:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=1
Reactant: BrCCBr
Reactant: COc1cccc(NC(=O)C(C)(C)C)n1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(Br)c(NC(=O)C(C)(C)C)n1
Temperature: 0 °C
Reaction time: 7 h
Yield: 60.1 %

Procedure:
A solution of 2,2-dimethyl-N-[6-(methyloxy)-2-pyridinyl]propanamide (55.011 g, 264.467 mmol) in THF (450 ml) in a three necked 1 L flask with an internal thermometer under argon was cooled to −78° C. and treated with n-butyl lithium (232 ml, 581.847 mmol) over 15 minutes and then allowed to warm to 0° C. and stirred at 0° C. for 7 h. The mixture was then recooled to −78° C. and treated with 1,2-dibromoethane (27.3 ml, 317 mmol) over 10 minutes and then the solution was allowed warm to room temperature and stirred at room temperature for 30 minutes by which time all the solid which had formed dissolved again. Gas was evolved at this stage so a gas bubbler was placed on one of the flasks necks. Water (100 ml) was then carefully added over 10 minutes. Further water (500 ml) was then added and the mixture was extracted with Et2O (3×500 ml). The combined organic solvents were then dried (MgSO4), filtered, evaporated to give the crude product. This was then dissolved in warm EtOAc (100 ml) and allowed to stand in the freezer overnight. The resultant solid which crystallised out was filtered off, washed with ice-cooled Et2O (20 ml) and dried in vacuo to give product as a white solid (45.660 g, 159.011 mmol, 60%). The filtrate was evaporated and the residue was chromatographed (0-25% EtOAc/40-60 petroleum ether) to give recovered starting material (7.264 g, 34.9 mmol), and product as a white solid (8.038 g, 27.99 2 mmol, 10%). The product from recrystallisation and chromatography were identical by NMR and LC-MS and so were combined.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[CH:15][N:14]([C:17]4[S:18][C:19]([C:29]([NH2:31])=[O:30])=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=5)[N:21]=4)[C:13]=3[CH:32]=2)[CH2:4][CH2:3]1.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:63][N:64]1[CH2:69][CH2:68][CH:67]([C:70](O)=[O:71])[CH2:66][CH2:65]1>C(OCC)(=O)C.CN(C)C=O>[C:29]([C:19]1[S:18][C:17]([N:14]2[C:13]3[CH:32]=[C:9]([CH2:8][N:5]4[CH2:4][CH2:3][CH:2]([NH:1][C:70]([CH:67]5[CH2:68][CH2:69][N:64]([CH3:63])[CH2:65][CH2:66]5)=[O:71])[CH2:7][CH2:6]4)[CH:10]=[CH:11][C:12]=3[N:16]=[CH:15]2)=[N:21][C:20]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)(=[O:30])[NH2:31]
Reactant: CN1CCC(C(=O)O)CC1
Reactant: NC(=O)c1sc(-n2cnc3ccc(CN4CCC(N)CC4)cc32)nc1-c1cccc(Cl)c1
Agent: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN1CCC(C(=O)NC2CCN(Cc3ccc4ncn(-c5nc(-c6cccc(Cl)c6)c(C(N)=O)s5)c4c3)CC2)CC1
Reaction time: 0.25 h

Procedure:
A mixture of 0.120 g (0.26 mmole) of 2-[6-(4-amino-piperidin-1-ylmethyl)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.13), 5 mL of dimethylformamide, 0.148 g (0.39 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1), 0.105 g (0.39 mmole) of triethylamine was stirred for 15 minutes, then 0.056 g (0.39 mmole) of 1-methyl-piperidine-4-carboxylic acid was added. After 3 hours, the mixture was taken up in 100 mL of ethyl acetate, washed twice with 100 mL of water, and then once with 100 mL of brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-(methanol-ammonium hydroxide, (92.8:0.3)) (gradient 100:0-0:100) to give 1-methyl-piperidine-4-carboxylic acid (1-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazol-2-yl]3H-benzoimidazol-5-ylmethyl}-piperidin-4-yl)-amide (I.14). This material was taken up in 20 mL of dichloromethane, washed with 20 mL of 1M sodium hydroxide solution. The dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.065 g of 1-methyl-piperidine-4-carboxylic acid (1-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazol-2-yl]-3H-benzoimidazol-5-ylmethyl}-piperidin-4-yl)-amide (I.14) as a solid. MH+/Z=592
Reaction SMILES: [OH:1][C:2]1([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH3:17])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:18]1[CH2:20][C@H:19]1[CH2:21][O:22][C:23]1[C:31]2[CH:30]=[CH:29][O:28][C:27]=2[CH:26]=[CH:25][CH:24]=1>CO>[OH2:1].[O:28]1[CH:29]=[CH:30][C:31]2[C:23]([O:22][CH2:21][C@@H:19]([OH:18])[CH2:20][N:5]3[CH2:6][CH2:7][CH:2]([C:8]4[S:12][C:11]5[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=5[C:9]=4[CH3:17])[CH2:3][CH2:4]3)=[CH:24][CH:25]=[CH:26][C:27]1=2.[O:28]1[CH:29]=[CH:30][C:31]2[C:23]([O:22][CH2:21][C@@H:19]([OH:18])[CH2:20][N:5]3[CH2:6][CH2:7][CH:2]([C:8]4[S:12][C:11]5[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=5[C:9]=4[CH3:17])[CH2:3][CH2:4]3)=[CH:24][CH:25]=[CH:26][C:27]1=2
Reactant: c1cc(OC[C@@H]2CO2)c2ccoc2c1
Reactant: Cc1c(C2(O)CCNCC2)sc2ccccc12
Solvent: CO
Product: Cc1c(C2CCN(C[C@H](O)COc3cccc4occc34)CC2)sc2ccccc12
Product: O
Yield: 41.4 %

Procedure:
A solution 4-hydroxy-4-(3-methylbenzo[b]thiophen-2-yl)piperidine (0.074 g, 0.320 mmol) and (S)-(+)-4-(oxiranylmethoxy)-benzo[b]furan (0.061 g, 0.320 mmol) in methanol (3 mL) was heated at reflux for 18 hours and then cooled and evaporated. The residue was purified using silica gel chromatography (dichloromethane/1% methanol in dichloromethane gradient elution) to give the final title compound as a clear colorless oil (0.057 g, 42%). FDMS m/e=422 (M++1). C25H27NO3S.0.5H2O
Reaction SMILES: N#N.[CH2:3]([O:5][C:6](=[O:10])[C:7]([NH2:9])=[S:8])[CH3:4].[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O.CC(=O)OCC>C1(C)C=CC=CC=1>[CH2:3]([O:5][C:6]([C:7]1[S:8][CH:15]=[C:13]([CH2:12][Cl:11])[N:9]=1)=[O:10])[CH3:4]
Reactant: O=C(CCl)CCl
Reactant: CCOC(=O)C(N)=S
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(CCl)cs1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of amino-thioxo-acetic acid ethyl ester (7.29 g. 54.74 mmol) in toluene (58 mL) was treated with 1,3-dichloroacetone (8.41 g, 62.95 mmol). The resulting mixture was stirred at reflux for 2 h. EA (60 mL) was added and the org. layer was washed with sat. aq. NaHCO3, brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (70:30 hept-EA) gave the title compound as an orange oil. TLC:rf (4:1 hept-EA)=0.26. LC-MS-conditions 02: tR=0.89 min; [M+H]+=206.45.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([O:31]CC)=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([OH:31])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2cccc(-c3ccc(OC(F)(F)F)cc3)c12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2cccc(-c3ccc(OC(F)(F)F)cc3)c12
Yield: 83.5 %

Procedure:
{1-Benzyl-4-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-benzyl-4-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetate (0.167 g, 0.357 mmol), and potassium hydroxide. (0.103 g, 1.84 mmol) in THF (5 mL) and water (5 mL), according to the procedure described in Step 4 of Example 5. Drying for 12 hours at 90° C. furnished the title compound as a light yellow solid (0.131 g, 83%), mp: 167-169° C. (dec.). Mass spectrum (+ESI, [M+H]+) m/z 440; 1HNMR (500 MHz, DMSO-d6): δ 13.5-14.0 (br s, 11H), 8.65 (s, 1H), 7.65 (d, 1H, J=8.2 Hz), 7.25-7.4 (m, 10H), 7.15 (d, 2H, J=7.3 Hz), and 5.6 ppm (s, 2H). Elemental Analysis for C24H16F3NO4: Calculated: C, 65.61; H, 3.67; N, 3.19. Found: C, 65.57; 3.50; N, 3.16.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([CH:27]([S:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])=[CH:11][C:12]([NH:15]CC2C=CC(OC)=C(OC)C=2)=[N:13][CH:14]=1.C(=O)(O)[O-].[Na+]>CCCCCC>[Cl:8][C:9]1[C:10]([CH:27]([S:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=1
Reactant: COc1ccc(CNc2cc(C(Sc3ccc(Cl)cc3)c3cc(F)ccc3F)c(Cl)cn2)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Yield: 77.4 %

Procedure:
A trifluoroacetic acid (5 ml) solution of the 5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]-2-(3,4-dimethoxybenzylamino)pyridine (1.89 g, 3.45 mmol) obtained in Example 185 was stirred at 65° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue thus obtained was added a saturated aqueous solution of sodium bicarbonate, followed by extraction with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate (=2:1) eluate was concentrated under reduced pressure to yield a white solid. The resulting white solid was washed with hexane-ether, and collected by filtration to give the title compound (1.06 g, 2.67 mmol, 77%) as a white powder.
Reaction SMILES: [I:1]I.[CH2:3]([O:10][C:11]1[C:16]([CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[CH2:3]([O:10][C:11]1[C:16]([CH2:17][C:18]([F:20])([F:19])[F:21])=[CH:15][C:14]([I:1])=[CH:13][C:12]=1[CH3:22])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: II
Reactant: Cc1cccc(CC(F)(F)F)c1OCc1ccccc1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cc(I)cc(CC(F)(F)F)c1OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of iodine (1.52 g, 6.0 mmol) dissolved in CHCl3 (80 mL) was added dropwise to a stirred mixture of 2-benzyloxy-1-methyl-3-(2,2,2-trifluoro-ethyl)-benzene (2.1 g, 6.0 mmol), silver trifluoroacetate (1.33 g, 6.0 mmol) in CHCl3 (20 mL). After the addition was complete the reaction mixture was stirred for 1 hour. The mixture was filtered through a pad of celite washing with CH2Cl2. The filtrate was washed with satd Na2S2O3, brine, dried over Na2SO4 and concentrated to a pale yellow solid (1.68 g). LCMS: APCI−VE=405
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[OH:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:44]2[CH2:45][CH2:46][CH:41]([OH:40])[CH2:42][CH2:43]2)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCCCN3CCC(O)CC3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 80.1 %

Procedure:
In a similar manner to Step 2 of Example 440, 4-chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (90.2 mg, 0.158 mmol) was dissolved in N,N-dimethylacetoamide (0.9 mL), and the solution was treated with 4-hydroxypiperidine (159 mg, 1.58 mmol). The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-[3-(4-hydroxypiperidin-1-yl)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (80.6 mg, yield 80%).
Reaction SMILES: [Si](OC[CH2:10]/[CH:11]=[CH:12]/[C:13]1[N:17]2[CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH2:22][C:16]2=[C:15]([C:24]([NH:26][C@@H:27]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:28]([NH:30][CH3:31])=[O:29])=[O:25])[N:14]=1)(C(C)(C)C)(C)C.CC[CH2:38][CH2:39][N+:40](CCCC)(CCCC)[CH2:41][CH2:42]CC.[F-].C1C[O:57]CC1>>[CH3:35][C:32]([CH3:34])([CH3:33])[C@H:27]([NH:26][C:24]([C:15]1[N:14]=[C:13](/[CH:12]=[CH:11]/[CH2:10][N:40]2[CH2:41][CH2:42][O:57][CH2:38][CH2:39]2)[N:17]2[CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH2:22][C:16]=12)=[O:25])[C:28]([NH:30][CH3:31])=[O:29]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(/C=C/CCO[Si](C)(C)C(C)(C)C)n2c1CN(C)CCC2)C(C)(C)C
Reactant: C1CCOC1
Agent: [F-]
Product: CNC(=O)[C@@H](NC(=O)c1nc(/C=C/CN2CCOCC2)n2c1CN(C)CCC2)C(C)(C)C
Reaction time: 18 h
Yield: 70 %

Procedure:
Compound 47A (0.126 g, 0.25 mmol) was dissolved in THF and TBAF (1M in THF, 0.50 mL, 0.50 mmol) solution was added. The resulting mixture was stirred for 18 h. The mixture was concentrated, diluted with NaCl saturated solution and extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by Prep LC/MS using 5-95% gradient of acetonitrile/water with 0.1% formic acid. The resulting material was purified by ion exchange chromatography using a Strata SPE SCX column to remove t-butyl dimethylsilane impurity. Compound 514 (0.070 g, 70%) was isolated as a free base.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[C:16]([CH3:17])=[CH:15][C:12]([C:13]#N)=[CH:11][N:10]=1.[OH-:18].[K+].Cl.[OH2:21]>>[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[C:16]([CH3:17])=[CH:15][C:12]([C:13]([OH:21])=[O:18])=[CH:11][N:10]=1
Reactant: COCC1CCCN1c1ncc(C#N)cc1C
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: COCC1CCCN1c1ncc(C(=O)O)cc1C
Yield: 99 %

Procedure:
A mixture of 6-[2-(methoxymethyl)pyrrolidin-1-yl]-5-methylnicotinonitrile (591 mg; 2.56 mmol; 1 eq.) and potassium hydroxide (717 mg; 12.8 mmol; 5 eq.) in water (20 mL) was stirred at reflux for 16 hours. The pH was adjusted to 5-6 with HCl 1M and the aqueous layer extracted with EtOAc. The combined organic phase was dried over MgSO4 and concentrated in vacuo to afford the title compound as a white solid (0.63 g, 99%). LC/MS: 219.1 (M+H)+. HPLC (Method A): Rt 1.44 min (purity 96.6%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)ccc1Oc1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 5-bromo-2-fluoronitrobenzene (1.10 g, 5.0 mmol), phenol (0.52 g, 5.5 mmol) and K2CO3 powder (0.83 g, 5.0 mmol) in DMF (10 mL) was stirred at 80° C. for 3 h. The mixture was concentrated under reduced pressure, and the residue was partitioned between AcOEt and water. The separated organic layer was washed with 1M aqueous HCl and saturated NaCl solution. After the organic layer was dried over Na2SO4, the solvent was removed to give desired product which was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]=[C:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[N:22]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C.O>[Cl:1][C:2]1[C:3]([CH:12]=[C:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[C:4]([S:8]([NH:11][C:30]([NH:29][C:23]2[N:22]=[C:21]([O:20][CH3:19])[CH:26]=[C:25]([O:27][CH3:28])[N:24]=2)=[O:31])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1cccc(Cl)c1C=C1CCOC1=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cccc(Cl)c2C=C2CCOC2=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a stirred suspension of 0.15 g (0.0005 mol) of the product of Example 7 and 0.21 g (0.0008 mol) of (4,6-dimethoxy-2-pyrimidinyl)carbamic acid, phenyl ester in 1 mL dry acetonitrile under nitrogen was added dropwise 0.12 mL (0.12 g, 0.0008 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture was stirred at room temperature for 1 hour and was then diluted with water and acidified with 1N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and washed well with water and ether to yield 0.2 g (83%) of the title compound: m.p. 212°-216° (dec); IR (nujol) 3410, 1765, 1605, 1365, 1340, 1155 cm-1 ; NMR (CDCl3, 200 MHz) δ 2.7-2.8 (2H, m), 3.94 (6H, s), 4.1-4.2 (2H, m), 5.84 (1H, s), 7.2-7.8 (3H, m), 8.25 (1H, m).
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][O:10][C:9]1[CH:12]=[C:2]([CH:3]=[C:4]([O:5][CH3:6])[C:7]=1[O:8][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=1)[CH:1]=[O:13]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C=O)cc(OC)c1OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
A solution of syringaldehyde (10 g, 55 mmol), p-nitrobenzyl bromide (13 g, 60 mmol) and potassium carbonate (9.0 g, 65 mmol) in 40 ml of acetone was heated under reflux for 4 hours. The solvent was distilled off under reduced pressure. The residue was added with water and then with dichloromethane. The organic layer was thereafter dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was added with ether, followed by stirring at room temperature. The insoluble colorless solid was collected by filtration to give 16.7 g of the title compound (yield: 93%).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][C:6](OC)=[N:5][CH2:4]1)[CH3:2].[Cl-:11].[NH4+:12]>CO>[ClH:11].[CH2:1]([CH:3]1[CH2:4][NH:5][C:6](=[NH:12])[CH2:7][CH2:8]1)[CH3:2]
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: CCC1CCC(OC)=NC1
Solvent: CO
Product: CCC1CCC(=N)NC1
Product: Cl

Procedure:
The product of EXAMPLE 148 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: [CH3:1]N(C=O)C.[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[C:18]3[N:19]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:21][C:17]=3[CH:16]=[C:15]([C:37]#[N:38])[N:14]=2)[CH:10]=[N:11][CH:12]=1.CI.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[C:18]3[N:19]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:20]([N:22]([CH3:1])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:21][C:17]=3[CH:16]=[C:15]([C:37]#[N:38])[N:14]=2)[CH:10]=[N:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: C[C@H]1CC[C@H](Cn2c(Nc3ccccc3)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN(c1ccccc1)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 60 °C

Procedure:
DMF (4 mL) was added to a vial containing 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(phenylamino)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (200 mg, 0.438 mmol), followed by methyl iodide (68 mg, 0.481 mmol) and potassium carbonate (121 mg, 0.877 mmol), and the vial was sealed and heated to 60° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 15% ethyl acetate/petroleum ether as eluent to afford 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[methyl(phenyl)amino]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ES/APCl calc'd. for C27H27ClN6 [M+H]+ 471. found 471.
Reaction SMILES: [P:1]([OH:40])([OH:39])([O:3][CH:4]([N:6]1[C:10]2=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH:14]=[C:9]2[C:8]([C:22](=[O:38])[C:23]2[C:28]([F:29])=[CH:27][CH:26]=[C:25]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[C:24]=2[F:37])=[CH:7]1)[CH3:5])=[O:2].[OH-].[Na+:42]>CC(=O)OCC.C1COCC1.O>[P:1]([O-:39])([O-:40])([O:3][CH:4]([N:6]1[C:10]2=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH:14]=[C:9]2[C:8]([C:22](=[O:38])[C:23]2[C:28]([F:29])=[CH:27][CH:26]=[C:25]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[C:24]=2[F:37])=[CH:7]1)[CH3:5])=[O:2].[Na+:42].[Na+:42]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(C)OP(=O)(O)O)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(C)OP(=O)([O-])[O-])c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To the solution of 1-(5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)ethyl dihydrogen phosphate (4 g, 6.5 mmol) in EA/THF (30 mL, 2/1) was added NaOH (0.57 g, 14.3 mmol) in H2O (1 mL) at rt. Then the mixture was stirred at room temperature over night. The mixture was filtered and dried under vacuum at 45° C. for 10 h to give the title compound as a white solid (4.0 g, 93%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: NC(N)=O.[NH2:5][C:6]1[C:7]([OH:17])=[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])[C:9]([Cl:12])=[CH:10][CH:11]=1.[O:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:32]([NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:33])=[C:7]([OH:17])[C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: O=C=Nc1ccccc1Oc1ccccc1
Agent: NC(N)=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Oc2ccccc2)c1O
Yield: 52.5 %

Procedure:
Following the general procedure for urea formation outlined in example 12, 3-amino-6-chloro-2-hydroxybenzenesulfonamide (40 mg, 0.18 mmol) and 2-phenoxyphenylisocyanate (46 mg, 0.22 mmol) were coupled to form the desired urea (41 mg, 52%). 1H NMR (DMSO-d4): δ 10.69 (s, 1H), 9.25 (2, 1H), 9.11 (s, 1H), 8.18 (m, 4H), 7.41 (m, 2H), 7.04 (m, 8H), 6.84 (d, 1H).