Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3]([O:17]C)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[C:5]=1Br.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH:24]=O.[C:31]([C:38]([O:40][CH2:41][CH3:42])=[O:39])#[C:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:24]2[C:5]3[C:4](=[CH:9][C:8]([O:10][CH3:11])=[C:7]([O:12][CH3:13])[C:6]=3[O:14][CH3:15])[C:3]([OH:17])=[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:31]=2[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1cc(C(OC)OC)c(Br)c(OC)c1OC
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: COc1ccc(C=O)cc1OC
Product: CCOC(=O)c1c(C(=O)OCC)c(-c2ccc(OC)c(OC)c2)c2c(OC)c(OC)c(OC)cc2c1O

Procedure:
2-Bromo-3,4,5-trimethoxybenzaldehyde dimethylacetal, 3,4-dimethoxybenzaldehyde and diethyl acetylenedicarboxylate are treated in the same manner as described in Example 1-(1) & (2), whereby 1-(3,4-dimethoxyphenyl)-2,3-bis(ethoxycarbonyl)-4-hydroxy-6,7,8-trimethoxynaphthalene is obtained as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[N+:18]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1F)([O-:20])=[O:19]>O.C(O)C>[N+:18]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(NCCc2c[nH]c3ccccc23)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
1 mMole of tryptamine was dissolved in 100 ml of water and the pH was adjusted to pH 8.3 with 2.5 moles of sodium bicarbonate (NaHCO3), A 1.5% solution of 2,4-dinitrofluorobenzene in 200 liters ethanol was added and the mixture was stirred during 2 hours at room temperature. The desired product precipitates out, it is washed and dried. The product is obtained in 90% yield, and TLC (chloroform, silica-gel plates, reveals one yellow spot (Rf=0.84) which is well resolved from the starting materials under the same conditions.
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:45]=[CH:44][C:39]([C:40]([O:42]C)=[O:41])=[CH:38][CH:37]=4)[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:45]=[CH:44][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=4)[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(C(=O)OC)cc3)oc2C)c(OC)c1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(C(=O)O)cc3)oc2C)c(OC)c1)OCC
Yield: 93.1 %

Procedure:
To a mixture of methyl 4-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoate (0.34 g), tetrahydrofuran (5 mL) and methanol (5 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was heated under reflux for 1 hr. To the reaction mixture were added 1N hydrochloric acid (2 mL) and water, and tetrahydrofuran and methanol were evaporated under reduced pressure. The precipitated crystals were collected by filtration to give 4-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoic acid as colorless crystals (0.31 g, yield 94%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 194-195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=[O:33])[CH:27]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[C:6]([CH:32]([OH:33])[C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)[CH:7]=1
Reactant: O=Cc1cccnc1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C(O)c1cccnc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
N-(4-Chloro-phenyl)-2,2-dimethyl-propionamide (3.0, 14.2 mmol) was dissolved in 15 mL THF in a dry 100 mL flask fitted with a rubber septa and nitrogen inlet and cooled to 0° C. in ice water bath for 25 minutes. A solution of 2.5M BuLi in hexane (17.0 mL, 42.6 mmol) was added and the mixture stirred for 45 minutes. To the thick yellow precipitate that formed was added a solution of pyridine-3-carboxaldehyde (3.03 g, 28.4 mmol) in 15 mL THF. The ice bath was removed and the mixture was allowed to stir at room temperature for 45 minutes and the reaction was quenched with 25 mL H2O. The mixture was transferred to a separating funnel, and the aqueous phase was discarded. The organics were dried in vacuo to yield product as an orange oil. 1H NMR (CDCl3) δ 8.85 (m, 1H) 8.54 (m, 1H) 8.42 (m, 1H) 8.10 (dd, J=8.8 Hz, 2.8 Hz, 1H) 7.50 (d, J=8.0 Hz, 1H) 7.31 (m, 1H) 7.23 (m, 1H) 7.10 (m, 1H) 5.85 (m, 1H) 1.70 (d, 1H) 1.08 (s, 9H); MS (ES) m/z=319.1 (MH)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C(N(CC)CC)C.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.O>CS(C)=O>[Br:8][C:4]1[N:3]=[C:2]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C1COCCN1
Reactant: Brc1cccc(Br)n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: Brc1cccc(N2CCOCC2)n1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
A stirred solution of 2,6-dibromopyridine (5.0 g, 20.7 mmol), triethylamine (3.0 ml, 21.7 mmol) and morpholine (1.8 g, 20.7 mmol) in dimethylsulfoxide (25 ml) was heated at 85° C. for 4 h. After cooling to ambient temperature the reaction was poured into water. After decanting off the aqueous, the gum was dissolved in dichloromethane, washed with water and saturated brine, then dried over magnesium sulfate, filtered and evaporated in vacuo to give a solid. Purification by chromatography on silica gel eluting with dichloromethane gave 4-(6-bromopyridin-2-yl)morpholine (3.0 g) as a white solid: δH (400 MHz, CDCl3) 3.50 (4H, t, J 5), 3.80 (4H, t, J 5), 6.50 (1H, d, J 8), 6.79 (1H, d, J 8), 7.31 (1H, dd, J 8 and 8); m/z (ES+) 242/244 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[C:3]=1[C:4]#[N:5].O=[C:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[N:1]=[C:19]([CH3:26])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCCC(CCC)Oc1cccc(N)c1C#N
Reactant: CCOC(=O)CC(C)=O
Product: CCCC(CCC)Oc1cccc2nc(C)c(C(=O)OCC)c(N)c12

Procedure:
Prepared as in Example 2a from 2-amino-6-(heptan-4-yloxy)benzonitrile (Example 23b) and ethyl 3-oxobutanoate as a pale yellow solid (65%). 1H NMR (400 MHz, DMSO-d6) δ 0.87 (t, J=7.2 Hz, 6H), 1.31 (t, J=7.2 Hz, 3H), 1.47-1.33 (m, 4H), 1.77-1.59 (m, 4H), 2.54 (s, 3H), 4.30 (q, J=7.2 Hz, 2H), 4.67-4.64 (m, 1H), 6.92 (d, J=7.6 Hz, 1H), 7.19 (dd, J=0.8, 8.4 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 8.13 (brs, 2H). MS 345 (MH+).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][CH:6]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:7]([NH:9][NH2:10])=O.Cl.Cl.[CH3:19][O:20][C:21]1[CH:22]=[C:23](/[CH:33]=[CH:34]/[C:35](=[NH:39])OCC)[CH:24]=[CH:25][C:26]=1[N:27]1[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]1.C(OCC)(=O)C.O>C(O)C>[CH:11]1([CH:6]2[CH2:5][CH2:4][CH2:3][N:9]3[N:10]=[C:35](/[CH:34]=[CH:33]/[C:23]4[CH:24]=[CH:25][C:26]([N:27]5[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]5)=[C:21]([O:20][CH3:19])[CH:22]=4)[N:39]=[C:7]23)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Reactant: NNC(=O)C(CCCCl)C1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCCCC2)ccc1-n1cnc(C)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 13.9 %

Procedure:
A solution of 5-chloro-2-cyclohexyl-valeric acid hydrazide hydrochloride (144 mg) and TEA (0.32 ml) in ethanol (1 ml) was added to a solution of ethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride obtained in Example 1 (167 mg) and TEA (0.32 ml) in ethanol (1.6 ml), and the reaction solution was stirred at 70° C. for two days. The reaction solution was left to cool to room temperature. Then, ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane-ethyl acetate system) and again purified by silica gel column chromatography (elution solvent: ethyl acetate-methanol system) to obtain 27 mg of racemic 8-cyclohexyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine. Then, the racemate was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: 20% ethanol-hexane) to obtain the title optically active compound with a retention time of 16 minutes and positive optical rotation (11.0 mg; 100% ee) and the title optically active compound with a retention time of 39 minutes and negative optical rotation (10.2 mg; 100% ee).
Reaction SMILES: [ClH:1].[NH2:2][NH:3][C:4](=[NH:7])[NH:5][NH2:6].O.[CH3:9][C:10]1([CH3:19])[CH2:15][C:14](=O)[CH2:13][C:12]([CH3:18])([CH3:17])[NH:11]1>C(O)C>[ClH:1].[CH3:9][C:10]1([CH3:19])[CH2:15][C:14](=[N:2][NH:3][C:4]([NH:5][N:6]=[C:14]2[CH2:13][C:12]([CH3:18])([CH3:17])[NH:11][C:10]([CH3:19])([CH3:9])[CH2:15]2)=[NH:7])[CH2:13][C:12]([CH3:18])([CH3:17])[NH:11]1
Reactant: N=C(NN)NN
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1(C)CC(=NNC(=N)NN=C2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of diaminoguanidine hydrochloride (6.28 grams; 0.05 mole) and 2,2,6,6-tetramethyl-4-piperidone monohydrate (17.3 grams; 0.10 mole) in 200 mls. of ethanol 2B was refluxed for a period of 15 hours while stirring. The resulting slurry was cooled to 25° C. and the solid was separated to obtain 10.0 grams of crude 1,3-bis[(2,2,6,6-tetramethyl-4-piperidylidene)amino]guanidine hydrochloride. Recrystallization of the crude hydrochloride from ethanol 2B gave 8.9 grams of white solid, m.p. 210°-220° C. (dec).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Br:13][C:14]1[CH:25]=[CH:24][C:17]([CH:18]=[N+:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:16][CH:15]=1.BrC1C=CC(C=O)=CC=1.N1CCCC1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH:18]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:24][CH:25]=1
Reactant: Brc1ccc(C=[N+]2CCCC2)cc1
Reactant: c1ccc(-n2cccc2)cc1
Agent: O=Cc1ccc(Br)cc1
Agent: [Cl-]
Solvent: C1CCNC1
Product: Brc1ccc(C(c2cccn2-c2ccccc2)N2CCCC2)cc1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-phenyl-1H-pyrrole and 1-(4-bromo-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 4 from 4-bromobenzaldehyde and pyrrolidine.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:43][C@@H:42]([CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][O:40]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][C@H:42]([OH:43])[CH2:41][OH:40])[CH2:50][CH2:49]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2].[ClH:23]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC1(C)OC[C@H](CN2CCNCC2)O1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C[C@H](O)CO)CC1
Product: Cl

Procedure:
In a manner analogous to the method described in examples 8, rac-(4S*,5R*)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 7) was coupled with 1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-piperazine to give the title compound after deprotection with 2N hydrochloric acid. HR-MS (ES, m/z) calculated for C36H46N5O4Cl2 [(M+H)+] 682.2926, observed 682.2922.
Reaction SMILES: Cl.Cl.[I:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[N:10][C:11]=2[NH2:13])[N:6]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:5]=1.C(=O)(O)[O-].[Na+].[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O.O1CCOCC1>[NH2:13][C:11]1[N:10]=[CH:9][N:8]=[C:7]2[N:6]([CH:14]3[CH2:19][CH2:18][N:17]([C:33]([O:32][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:34])[CH2:16][CH2:15]3)[N:5]=[C:4]([I:3])[C:12]=12
Reactant: Nc1ncnc2c1c(I)nn2C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(I)nn2C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.1 %

Procedure:
To a mixture of 3-iodo-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (13.86 g, 0.0333 mol) and sodium bicarbonate (8.4 g, 0.0999 mol) in water (140 mL) was added benzylchloroformate (6.48 g, 0.0383 mol) in dioxane (120 mL) at room temperature. The mixture was stirred at room temperature under an atmosphere of nitrogen for 18 hours. The yellow solid was filtered and washed with ethyl ether to yield benzyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (12 g, 0.025 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 10.5 min. MS: MH+ 479.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.C([Li])CCC.CCCCCC.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:27]=[O:28]>C1COCC1.O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([CH:27]([C:26]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:24]([F:23])[CH:25]=2)[OH:28])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: COc1ccc(C=O)cc1F
Reactant: COc1cc(Br)cc(OC)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(O)c2ccc(OC)c(F)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 105.8 %

Procedure:
To a solution of 1-bromo-3,5-dimethoxy-benzene (5.0 g, 23.1 mmol) in THF (50 mL) was added a solution of n-butyllitium in hexane (8.7 mL, 2.5 N, 22 mmol) at −78° C. and kept for 20 min. To the mixture was added 3-fluoro-4-methoxy-benzaldehyde (3.0 g, 19.4 mmol) at −78° C. After 18 h, water (30 mL) was added to the mixture, and the cold bath was removed. The mixture was stirred at room temperature for 20 min. The mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with HCl (0.5 N, 50 mL), sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent gave (3,5-dimethoxy-phenyl)-(3-fluoro-4-methoxy-phenyl)-methanol (6 g, 100% crude yield). The sample was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[N:15][N:16]([CH3:19])[C:17]=1[CH3:18]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH3:19])[C:17]=2[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(N)cnn1C
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Product: Cc1c(NS(=O)(=O)c2ccc(Br)cc2)cnn1C
Yield: 71 %

Procedure:
Prepared from 4-bromobenzenesulfonyl chloride (0.396 g, 1.55 mmol) and 4-amino-1,5-dimethyl-1H-pyrazole (0.172 g, 1.55 mmol) in pyridine (3 ml) according to the method of intermediate 1, to give the title compound as a yellow solid (0.362 g, 1.10 mmol, 71%). 5H (D-6 DMSO, 300K) 9.43 (1H, s), 7.80 (2H, d J 8.7 Hz), 7.58 (2H, d J 8.7 Hz), 3.63 (3H, s), 1.89 (3H, s). m/z (ES+, 70V) 332.0 (MH+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[N:20][CH:21]=1)#[CH:15].C(N(CC)C(C)C)(C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:23]([NH:22][C:19]1[N:20]=[CH:21][C:16]([C:14]#[C:15][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=2[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:17][CH:18]=1)(=[O:25])[CH3:24]
Reactant: C#Cc1ccc(NC(C)=O)nc1
Reactant: CCOC(=O)c1ccc(C)c(I)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C)c(C#Cc2ccc(NC(C)=O)nc2)c1
Temperature: 25 °C

Procedure:
A mixture of ethyl 3-iodo-4-methylbenzoate (845 mg, 2.9 mmol, 0.8 eq), N-(5-ethynylpyridin-2-yl)acetamide (3.5 mmol, 1.0 eq). Pd(PPh3)4 (51 mg, 0.044 mmol), CuI (20.4 mg, 0.11 mmol), and N,N-diisopropylethylamine (0.8 ml, 4.4 mmol) in 2 ml of DMF is heated at 55° C. (oil bath) for 1 hr under nitrogen. After cooling to r.t., the solvent is evaporated and DCM is added to dissolve the residue. The solution is washed with water and brine, dried and evaporated and the crude material is chromatographed with CombiFlash (DCM/MeOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH2:28]Br>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH2:28][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COc1cccc2nc(-c3c(F)cccc3F)[nH]c12
Reactant: Fc1cccc(F)c1CBr
Product: COc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 90.6 %

Procedure:
2-(2,6-Difluorophenyl)-4-methoxylbenzimidazole (5005) (1.25 g, 4.80 mmol) was reacted with 2,6-difluoro-α-bromo-toluene (1.30 g, 6.28 mmol, 130 M%). The crude product was purified by flash chromatography eluting with 2% MeOH/CH2Cl2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methoxylbenzimidazole (5006) (1.68 g, 4.35 mmol, 91% yield). M.p. 154-155° C. 1H-NMR (200 MHz, CD2Cl2): δ7.52 (m, 1H, H4′), 7.25 (m, 1H, H4″), 7.19 (dd, J=7.8, 1.0 Hz, 1H, H5), 7.13-7.00 (m, 3H, H3′,5′,6), 6.81 (m, 2H, H3″,5″), 6.72 (dd, J=7.8, 1.0 Hz, H7), 5.33 (s, 2H, CH2PhF2), 4.00 (s, 3H, OCH3).
Reaction SMILES: [C:1]([C:3]1[C:4]([F:17])=[C:5]([NH:9]C(=O)OC(C)(C)C)[CH:6]=[CH:7][CH:8]=1)#[CH:2].FC(F)(F)C(O)=O.[Cl:25]CCl>C(O)(C)C.Cl.O1CCOCC1>[ClH:25].[C:1]([C:3]1[C:4]([F:17])=[C:5]([CH:6]=[CH:7][CH:8]=1)[NH2:9])#[CH:2]
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1F
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: C#Cc1cccc(N)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 1,1-dimethylethyl (3-ethynyl-2-fluorophenyl)carbamate (10.5 g, 44.6 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (20 mL). The solution was stirred at room temperature for 1 hr, and was then concentrated in-vacuo. The resultant residue was partition between sodium bicarbonate and ether. The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in-vacuo to afford a brown residue. The residue was diluted with isopropanol (10 mL) and 4N HCl in dioxane (8 mL) was added. The recrystallized product was collected by vacuum filtration to afford 3.7 g, 21 mmol (68%) of 3-ethynyl-2-fluoroaniline hydrochloride as a pale brown solid. 1H NMR (400 MHz, d6-DMSO): 7.08-6.91 (m, 3H), 4.45 (s, 1H); MS (EI) for C8H6FN: 136 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:20]=[C:19]3[C:13]([CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18]3)=[N:12]2)=[CH:7][CH:6]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl.CO>[CH3:1][NH:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:20]=[C:19]3[C:13]([CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[N:12]2)=[CH:7][CH:6]=1
Reactant: CNC(=O)c1ccc(-n2cc3c(n2)CCN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1,1-dimethylethyl 2-{4-[(methylamino)carbonyl]phenyl}-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (184 mg, 0.50 mmol; may be prepared as described in Description 24) in dichloromethane (2 ml) was treated with trifluoroacetic acid (2 ml). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with methanol and passed down a SCX cartridge eluting with methanol and then a 2M solution of ammonia in methanol. The basic fractions were combined and evaporated to afford the title compound (D25); MS (ES+) m/e 271 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C@H:12]1[CH2:15][C@H:14]([OH:16])[CH2:13]1.F[C:18]1[C:23]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:22][CH:21]=[CH:20][N:19]=1.C(OCC)(=O)C>CN(C=O)C>[O:27]1[CH2:28][CH2:29][CH:24]([C:23]2[C:18]([O:16][C@H:14]3[CH2:13][C@H:12]([C:4]4[NH:5][C:6]5[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=5[N:3]=4)[CH2:15]3)=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:25][CH2:26]1
Reactant: Fc1ncccc1C1CCOCC1
Reactant: O[C@H]1C[C@H](c2nc3ccccc3[nH]2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1cnc(O[C@H]2C[C@H](c3nc4ccccc4[nH]3)C2)c(C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Sodium hydride (60% dispersion, 0.049 g, 1.2 mmol) was added to a solution of trans-3-(1H-benzo[d]imidazol-2-yl)cyclobutanol (0.11 g, 0.58 mmol) in DMF (1.5 mL) under argon and the mixture was stirred for 45 min at RT. 2-Fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridine (0.11 g, 0.58 mmol) was added and the mixture was stirred for 16 h at 110° C. Ethyl acetate was added and the mixture was washed with water (2×), saturated aqueous sodium chloride (1×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give 2-(trans-3-(3-(Tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclobutyl)-1H-benzo[d]imidazole (37 mg, 0.11 mmol, 18% yield) as a white solid. [M+1]: 350.3. IC50 (uM) 0.01041.