Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=2)[CH:3]=1.[C:16]1([NH2:23])[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1>CCCCO>[Br:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:22][C:18]3[CH:17]=[C:16]([NH2:23])[CH:21]=[CH:20][CH:19]=3)[CH:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cccc(N)c1
Reactant: Clc1cc(Nc2cccc(Br)c2)ncn1
Solvent: CCCCO
Product: Nc1cccc(Nc2cc(Nc3cccc(Br)c3)ncn2)c1
Temperature: 150 °C
Yield: 65.1 %

Procedure:
A mixture of (6-chloro-pyrimidin-4-yl)-(3-bromo-phenyl)-amine (300 mg, 1.1 mmol) and benzene-1,3-diamine (300 mg, 2.75 mmol) in 3 mL of n-BuOH was heated in a sealed tube to 150° C. for 16 hr. Solvent was removed by vacuum evaporation and the crude product was purified by flash chromatography on silica gel with EtOAc/DCM solvent system to afford 255 mg (65% yield) of the title compound as a yellow solid. MS (m/z): MH+=356, 358.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][C:12]([CH3:14])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:8][C:7]1[C:11]([C:10]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:14])[N:1]=[C:2]2[S:3][CH:4]=[C:5]([CH3:9])[C:6]=12
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1csc(N)c1C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2scc(C)c2c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
A mixture of 2-amino-4-methyl-3-thiophenecarbonitrile (300 mg, 2.171 mmol), ethyl acetoacetate (0.275 mL, 2.171 mmol) and SnCl4 (0.510 mL, 434 mmol) in toluene (15 mL) was stirred at RT for 30 min and then reflux for 3.5 h. After cooling to RT, the mixture was quenched with 6M NaOH (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organics were washed with brine (30 mL), dried and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in cyclohexane, afforded the title compound (210 mg). LCMS (A) m/z: 251 [M+1]+, Rt 0.77 min (acidic).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][C:7]=1[F:8].[N+:17]([O-])([OH:19])=[O:18]>OS(O)(=O)=O>[Cl:1][C:2]1[C:3]([F:16])=[C:4]([NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14])[C:5]([N+:17]([O-:19])=[O:18])=[CH:6][C:7]=1[F:8]
Reactant: O=[N+]([O-])O
Reactant: O=C(Nc1ccc(F)c(Cl)c1F)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=C(Nc1c([N+](=O)[O-])cc(F)c(Cl)c1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of 15.1 g (58.1 mmol) of 3-chloro-2,4-difluoro(trifluoroacetamido)benzene in 80 mL of H2SO4 kept in an ice-bath was added dropwise 10 mL of HNO3. Solid precipitate was observed during addition of HNO3. The mixture was stirred in an ice-bath for 4 h. It was added into 600 mL of ice-water. The precipitate was filtered and washed by water, and dried to leave almost colorless solid (16.8 g, 95%), mp 124°-125° C. 1H NMR (CDCl3), 7.69 (dd, 1), 8.936 (mb, 1).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[CH2:2][NH:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)CBr
Solvent: ClCCl
Product: COC(=O)CNCc1ccccc1
Yield: 86 %

Procedure:
In scheme 6b), methyl bromoacetate 22 is treated with benzylamine in CH2Cl2 at room temperature for 16 h. The N-benzylglycine methyl ester derivative 23 was obtained in 86% yield. This intermediate can be either acylated with a carboxylic acid derivative and DCC in THF or sulfonated with an appropriate sulfonyl chloride and triethylamine in CH2Cl2 to give derivative 24 or 25 as desired in good to excellent yields.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].CC([N:12]([C@@H:16]([CH2:30][CH3:31])/[CH:17]=[CH:18]/[C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)=[O:20])C(=O)[O-])(C)C>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[N:21]1([C:19](=[O:20])/[CH:18]=[CH:17]/[C@@H:16]([NH2:12])[CH2:30][CH3:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: CC[C@@H](/C=C/C(=O)N1CCc2ccccc21)N(C(=O)[O-])C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](N)/C=C/C(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
TFA (25 mL, 324 mmol) was added to a solution of 1,1-dimethylethyl[(1S,2E)-4-(2,3-dihydro-1H-indol-1-yl)-1-ethyl-4-oxo-2-buten-1-yl]carbamate (7.21 g, 21.82 mmol) in CH2Cl2 (25 mL). The reaction was stirred at RT. After 3.5 h, CH2Cl2 (200 mL) was added, and the reaction was concentrated under reduced pressure and dried under high vacuum. LC-MS m/z 231 (M+H)+, 0.69 (ret time).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@:11]2([C:16]([OH:18])=O)[CH2:15][CH2:14][O:13][CH2:12]2)=[O:9])[CH:5]=[N:6][CH:7]=1.[NH2:19][CH2:20][C:21]1[N:26]=[CH:25][C:24]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[C:36]([F:39])([F:38])[F:37])=[CH:23][C:22]=1[F:40]>>[NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:3]=1)[C:8]([NH:10][C@@:11]1([C:16](=[O:18])[NH:19][CH2:20][C:21]2[C:22]([F:40])=[CH:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[C:36]([F:39])([F:38])[F:37])=[CH:25][N:26]=2)[CH2:15][CH2:14][O:13][CH2:12]1)=[O:9]
Reactant: Nc1cncc(C(=O)N[C@@]2(C(=O)O)CCOC2)c1
Reactant: COc1ccc(Nc2cnc(CN)c(F)c2)c(C(F)(F)F)c1
Product: COc1ccc(Nc2cnc(CNC(=O)[C@]3(NC(=O)c4cncc(N)c4)CCOC3)c(F)c2)c(C(F)(F)F)c1
Yield: 34 %

Procedure:
Analogously to Example 1e), (S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid (from 2b) was reacted with (6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-methoxy-2-trifluoromethyl-phenyl)-amine. The product was obtained in a yield of 34% of theory.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7].O1CCCC1.[H-].[Na+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[CH2:34]([O:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CCOCc1ccccc1
Reaction time: 2 h
Yield: 26.8 %

Procedure:
To a solution of 4-[3-(2-hydroxyethyl)-2-methyloxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (14.4 mg) in a mixture of anhydrous tetrahydrofuran (1 ml) and N,N-dimethylformamide (1 ml) was added sodium hydride (60% oil dispersion, 4.7 mg) in one portion under ice cooling. The mixture was stirred for half an hour at the same temperature and benzylbromide (13.3 mg) was added. After sitrred for 2 hours at ambient temperature, the reaction was quenched with water (2 ml) and extracted with diethyl ether (1 ml) three times. The combined organic layers were washed with water, dried, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (diethyl ether/n-hexane =1/1) to give 4-[3-(2-benzyloxyethyl)-2-methyloxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (4.8 mg).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7]1)=[O:5].Br[CH2:25][CH2:26][O:27][C:28]1[CH:47]=[CH:46][C:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)=[CH:30][CH:29]=1>>[C:37]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:38]=[CH:39][C:34]([CH2:33][O:32][C:31]2[CH:46]=[CH:47][C:28]([O:27][CH2:26][CH2:25][O:1][C:2]3[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][C:3]=3[C:4]([N:6]3[CH2:11][CH2:10][CH:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7]3)=[O:5])=[CH:29][CH:30]=2)=[CH:35][CH:36]=1
Reactant: BrCCOc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reactant: COC(=O)c1ccc(O)c(C(=O)N2CCC(C(=O)OC)CC2)c1
Product: COC(=O)c1ccc(OCCOc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)N2CCC(C(=O)OC)CC2)c1

Procedure:
Preparation takes place in analogy to Example 22 from methyl 1-[2-hydroxy-5-(methoxycarbonyl)benzoyl]piperidine-4-carboxylate and 4-{[4-(2-bromoethoxy)-phenoxy]methyl}biphenyl.
Reaction SMILES: CCCCCC.I[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH:16]1[C:17]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: Ic1cccc2ccccc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Solvent: CCCCCC
Product: c1ccc2ccccc2c1
Yield: 30 %

Procedure:
Following General Procedure I, a mixture of hexane washed KH (160 mg, 4.0 mmol, 2.0 equiv), (Z)-21 (344 mg, 2.0 mmol, 1.0 equiv), 1-iodonaphthalene (292 μL, 2.0 mmol) and Pd(dba)2 (58 mg, 0.1 mmol, 0.05 equiv) was stirred in DME (4 mL) at room temperature for 15 min, and then was filtered through SiO2. Purification by column chromatography (RP C18, MeOH/H2O, 9/1) afforded 219 mg (49%) of (Z)-152a and 77 mg (30%) of naphthalene.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)(=[O:3])[CH3:2].[CH2:15]([O:17][C:18](=[O:28])[CH:19]([N+:25]([O-:27])=[O:26])[CH:20](O)[CH2:21][O:22][CH3:23])[CH3:16]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:15]([O:17][C:18](=[O:28])[CH:19]([N+:25]([O-:27])=[O:26])[CH:20]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[CH2:5][O:4][C:1](=[O:3])[CH3:2])[NH:10][CH:9]=1)[CH2:21][O:22][CH3:23])[CH3:16]
Reactant: CCOC(=O)C(C(O)COC)[N+](=O)[O-]
Reactant: CC(=O)OCc1cccc2[nH]ccc12
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C(COC)c1c[nH]c2cccc(COC(C)=O)c12)[N+](=O)[O-]

Procedure:
4-Acetoxymethylindole (189 g) is dissolved in a mixture of toluene (6 l) and acetic acid (0.7 l). To this solution is added 3-hydroxy-2-nitro-5-oxa-hexanoic acid ethyl ester (570 ml). The flask containing the mixture is evacuated by means of a water jet pump. Then balancing to normal pressure is brought about by argon. Evacuation and pressure balancing are repeated four times. Then the reaction mixture is refluxed for two hours in a water-free argon atmosphere. After concentrating to 2 l the solution is diluted with ethyl acetate and shaken out three times with a liter of 1N hydrochloric acid each. Then it is washed to neutrality with saturated hydrochloric acid solution. The solution, dried over sodium sulfate, is evaporated. The residue is chromatographed on silica gel with dicloromethane. 393 g of the title compound is obtained in oily form.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=2[C:21]#[C:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:13]([O:15]CC)=[O:14])[CH2:3][CH2:2]1.CO>O>[CH3:24][C:23]([CH3:26])([CH3:25])[C:22]#[C:21][C:20]1[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#CC(C)(C)C)c(OCCN2CCOCC2)c1
Solvent: CO
Solvent: O
Product: CC(C)(C)C#Cc1ccc(C(=O)O)cc1OCCN1CCOCC1
Yield: 76.2 %

Procedure:
Ethyl 3-(2-morpholinoethoxy)-4-(3,3-dimethylbut-1-ynyl)benzoate (0.34 g, 0.95 mmol) and LIOH (68 mg, 2.84 mmol) were placed in a 3:1 mixture of methanol:water (30 mL) and heated at 60° C. for 3.5 h. The reaction was cooled and concentrated in vacuo to a volume of 20 mL. The mixture was placed in an ice-water bath and acidified to pH 5 with conc. HCl. A white solid precipitated which was filtered and washed thoroughly with water. The solid was dried in a vacuum oven to give the product (0.24 g, 70%) as a solid. m/z=330.1 (M−1).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:3]1=2.C(Cl)Cl.CN(CCN(C)C)C.[Si]([I:33])(C)(C)C.II>>[I:33][CH:7]1[CH2:8][C:2]([CH3:17])([CH3:1])[C:3]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:4]=2[NH:5][C:6]1=[O:9]
Reactant: CC1(C)CCC(=O)Nc2cc([N+](=O)[O-])ccc21
Reactant: C[Si](C)(C)I
Agent: CN(C)CCN(C)C
Agent: II
Solvent: ClCCl
Product: CC1(C)CC(I)C(=O)Nc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5,5-Dimethyl-8-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (4.00 g, 0.0171 mol) in Methylene chloride (54 mL, 0.84 mol) was cooled to 0° C., treated with TMEDA (7.73 mL, 0.05 mol) then treated dropwise with TMSI (7.29 mL, 0.05 mol). The mixture was stirred at 0° C. for 60 min after which solid Iodine (6.50 g, 0.0256 mol) was added in one portion and the mixture stirred at 0° C. for 60 min. The reaction was quenched with 10% Na2S2O3. Title compound isolated as a beige solid. (5.43 g, 88%) LCMS 361 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[N:9][C:8]([O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([NH:18][CH3:19])[CH2:14][CH2:13]2)=[CH:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH3:4].[ClH:33]>C(OCC)C.C(Cl)Cl>[ClH:33].[ClH:33].[CH2:1]([C:5]1[N:10]=[N:9][C:8]([O:11][CH:12]2[CH2:13][CH2:14][CH:15]([NH:18][CH3:19])[CH2:16][CH2:17]2)=[CH:7][C:6]=1[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(O[C@H]2CC[C@H](NC)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCC(NC)CC2)cc1-c1ccc(OC2CCCCC2)cc1

Procedure:
A solution of trans-N-{4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-cyclohexyl}-formamide in anhydrous THF at 0° C. may be treated with borane-THF complex in THF (1 M, excess). The reaction may be allowed to come to room temperature and may be monitored by LCMS until the reaction is complete. The reaction may be quenched with MeOH and the solvents may be removed under reduced pressure. The crude product may be purified by flash chromatography using with 1-5% (2N NH3 in MeOH) in DCM to give trans-{4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-cyclohexyl}-methyl-amine. The neutral amine may be treated with 2N HCl in diethyl ether and DCM. The volatiles may be removed under reduced pressure and the salt may be triturated with diethyl ether and filtered to provide the title compound. LCMS: m/z 439 [M+1].
Reaction SMILES: C([O-])(O)=O.[Na+].[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]1([CH3:22])[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][CH:14]=1>O>[CH3:12][C:6]1[CH:11]=[CH:10][C:9]([C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:22])=[CH:14][CH:15]=2)=[O:20])=[CH:8][CH:7]=1
Reactant: Cc1ccccc1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Yield: 28 %

Procedure:
The three water extracts from Example 4 (excluding the NaHCO3 extracts) were charged into a 200 mL flask along with toluene (50 mL) and para-toluic acid (1.36 g). The mixture was heated and water was removed azeotropically as in Example 3;once approximately 40 mL of water had been removed a further 50 mL toluene was added. Then, when a total of 75 mL of water had been removed, a final 25 mL toluene was added. The reflux was terminated after 18 hours. After workup (as in Example 3) the reaction gave crude 4,4′-dimethylbenzophenone (0.58 g, 28% yield), which was again practically pure by 1H NMR (M.P. 86.5-87.5° C.). Removal of water from the three water extracts recovered 3.40 g cerium (III) trifluoromethanesulfonate as a damp, off-white solid).
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9](Cl)=[N:10][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:30][OH:31])[CH:20]=[N:21][C:22]=1[N:23]1[CH2:28][CH2:27][NH:26][C@H:25]([CH3:29])[CH2:24]1>O1CCOCC1>[Br:1][C:2]1[C:7]2[NH:8][C:9]([N:26]3[CH2:27][CH2:28][N:23]([C:22]4[N:21]=[CH:20][C:19]([CH2:30][OH:31])=[CH:18][C:17]=4[Cl:16])[CH2:24][C@H:25]3[CH3:29])=[N:10][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1
Reactant: FC(F)(F)c1cc(Br)c2[nH]c(Cl)nc2c1
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1

Procedure:
A mixture of 7-bromo-2-chloro-5-trifluoromethyl-1H-benzoimidazole (96 mg, 0.32 mmol, Example 6b) and {5-chloro-6-[(3R)-3-methyl-piperazin-1-yl]-pyridin-3-yl}-methanol (96 mg, 0.4 mmol, Example 150a) in dioxane (2 mL) reacted under the conditions of Example 3c to give the title compound. MS (ESI, pos. ion) m/z: 506 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11](C)[CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27]>O>[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[O:10])=[CH:6][CH:7]=1)(=[O:28])[CH3:27]
Reactant: CN(Cc1ccncc1)C(=O)Nc1ccc(N)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(NC(=O)NCc2ccncc2)cc1
Reaction time: 0.5 h

Procedure:
To a chilled (circa 0° C.) solution of 5.12 gms. (0.02 mole) of 1-(p-aminophenyl)-3-methyl-3-(4-pyridylmethyl)urea (Example 6., supra.) in 75 ml. of pyridine there is added dropwise 1.48 gms. (0.02 mole) of acetyl chloride with stirring, while maintaining the temperature of the reaction mixture at circa 0° C. Stirring is continued for 30 minutes and then the reaction mixture is allowed to stand at room temperature overnight. Solvent is stripped and the residue suspended in water. Upon removal of the water there is obtained 1-(p-acetamidophenyl)-3-(4-pyridylmethyl)urea.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[C:11](=O)([O-])[OH:12].[Na+]>C=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][OH:12]
Reactant: O=C([O-])O
Reactant: Cn1cnc2ccccc21
Agent: C=O
Agent: [Na+]
Product: Cn1c(CO)nc2ccccc21
Temperature: 25 °C

Procedure:
1-Methylbenzimidazole (5.0 g, 0.038 mol) was stirred at reflux in 37 wt % aqueous formaldehyde (50 ml) for 24 h. The solution was allowed to cool to room temperature then basified with saturated sodium hydrogen carbonate solution and then extracted with. dichloromethane (3×50 ml). The combined organic layers were dried over magnesium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 2.5 to 10% methanol in dichloromethane. The resultant semi-solid was triturated with isohexane to yield a solid, which was then recrystallised from ethyl acetate/isohexane, yielding (1-methyl-1H-benzimidazol-2-yl)methanol as a white solid (0.71 g). Data for the title compound: 1H NMR (400 MHz, CDCl3) δ 3.81 (3H, s), 4.89 (2H, s), 7.26 (3H, m), 7.69 (1H, m); MS (ES+) m/e 163 [MH]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][CH:10]=1.C([Li])CCC.CN(C)[CH:24]=[O:25].Cl>CCCCCC.C(OCC)C>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][C:10]=1[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: COCOCc1coc(-c2ccccc2)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COCOCc1nc(-c2ccccc2)oc1C=O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 52.7 %

Procedure:
To a mixture of 4-methoxymethoxymethyl-2-phenyloxazole (10.86 g) and diethyl ether (300 mL) was dropwise added a solution (1.6 M, 37 mL) of n-butyl lithium in hexane at −78° C., and the mixture was stirred at −78° C. for 1.5 hrs. A solution (10 mL) of N,N-dimethylformamide (6.50 g) in diethyl ether was added to the reaction mixture and the reaction mixture was allowed to warm to room temperature with stirring for 2 hrs. Dilute hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (6.45 g, 53%) of 4-methoxymethoxymethyl-2-phenyl-5-oxazolecarbaldehyde from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 51-52° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:34]=[C:17]3[CH:18]=[CH:19][C:20]([NH:22][C:23]([C:25]4[N:29]([CH3:30])[N:28]=[CH:27][C:26]=4[C:31](O)=[O:32])=[O:24])=[CH:21][N:16]3[N:15]=2)[CH2:10]1>>[CH3:7][O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:34]=[C:17]3[CH:18]=[CH:19][C:20]([NH:22][C:23]([C:25]4[N:29]([CH3:30])[N:28]=[CH:27][C:26]=4[C:31]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:32])=[O:24])=[CH:21][N:16]3[N:15]=2)[CH2:10]1
Reactant: C1COCCN1
Reactant: COC1CCN(c2nc3ccc(NC(=O)c4c(C(=O)O)cnn4C)cn3n2)C1
Product: COC1CCN(c2nc3ccc(NC(=O)c4c(C(=O)N5CCOCC5)cnn4C)cn3n2)C1

Procedure:
Using morpholine and 5-[2-(3-Methoxy-pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Off white solid (42 mg, 51%). MS: m/z=455 (M+H+).
Reaction SMILES: [CH:1]1([N:4]([CH:26]2[CH2:28][CH2:27]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]([NH2:22])=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Cl[CH2:30][C:31](=O)[CH3:32]>CCO>[CH:26]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][CH:30]=[C:31]([CH3:32])[N:22]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:27][CH2:28]1
Reactant: CC(=O)CCl
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Solvent: CCO
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C)cs3)nc21
Temperature: 25 °C
Yield: 20.7 %

Procedure:
N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B, 40 mg, 0.10 mmol) and chloroacetone (62.4 mg, 0.40 mmol) in EtOH (2 ml) were heated at 80° C. for 20 min. The reaction was cooled to room temperature and the solvent removed in vacuo. Saturated NaHCO3 solution was added and the aqueous layer extracted (3×) with dichloromethane. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (dichloromethane/methanol 0-7%) to provide N,N-dicyclopropyl-6-ethyl-1-methyl-4-(4-methylthiazol-2-ylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (9 mg, 12% yield) as a white solid.