Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.Br[CH:18]=[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[CH3:20].N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1/[C:19](/[CH3:20])=[CH:18]\[N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=2[C:13]2[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1=2
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: CC(=CBr)c1ccccc1F
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(C)ccc31)CCN(C)CC2)c1ccccc1F
Temperature: 85 °C

Procedure:
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-2-fluorobenzene (260 mg, 1.2 mmol), L-proline (0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CDCl3, TFA salt) δ (ppm): 7.15 (m, 3H), 7.05 (d, 1H), 6.95 (t, 1H), 6.85 (t, 1H), 6.75 (s, 1H), 6.70 (d, 1H), 3.60 (m, 1H), 3.40 (m, 1H), 3.10 (m, 2H), 2.85 (m, 2H), 2.80 (s, 3H), 2.42 (s, 3H), 2.33 (m, 2H), 2.30 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH2:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O)[CH3:33]>COCCOC>[CH2:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:2]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH3:33]
Reactant: Cc1ccc(OCC(=O)N(NC(=O)c2ccccc2)C(C)C)c(Br)c1
Reactant: CCc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1ccccc1-c1cc(C)ccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 72.4 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-methyl-phenoxy)-acetyl]-N′-isopropyl-hydrazide (100 mg, 0.247 mmol) in DME (3 ml)/2M Na2CO3 (0.435 ml, 0.8645 mmol) was treated with 2-ethylphenylboronic acid (74 mg, 0.493 mmol), Pd[PPh3]4 (29 mg, 0.0247 mmol in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a white solid (77 mg, 72%). MS m/e 431.34 (M+H+)
Reaction SMILES: O1C=C(CO)C(CO)=C1.N1C=CN=C1.C([Si](Cl)(C)C)(C)(C)C.[Si:23]([O:30][CH2:31][C:32]1[C:36]([CH2:37][O:38][Si](C(C)(C)C)(C)C)=[CH:35][O:34][CH:33]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>O1CCCC1>[Si:23]([O:30][CH2:31][C:32]1[C:36]([CH2:37][OH:38])=[CH:35][O:34][CH:33]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCc1cocc1CO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: OCc1cocc1CO
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cocc1CO

Procedure:
According to a similar procedure to that described in Example 21-(2), 3,4-furandimethanol (described in J. Org. Chem., 65, 6153 (2000); 3.4 g, 26.5 mmol) was reacted with imidazole (1.80 g, 26.4 mmol) and tert-butylchlorodimethylsilane (4.00 g, 26.5 mmol) in tetrahydrofuran (50 ml), and the reaction mixture was worked up to afford a mixture of the title compound, 3,4-furandimethanol and 3,4-bis[(tert-butyldimethylsilyl)oxymethyl]furan. The mixture was subjected to chromatography on a silica gel (50 g) column (eluent; ethyl acetate:hexane=3:17˜4:16) to afford the title compound (3.20 g, 50% yield) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>C(Cl)Cl>[C:21]([O:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: CS(=O)(=O)NCc1ccc(O)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1ccc(CNS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 6.04 g (0.03 mol) of N-(4-hydroxybenzyl)methanesulfonamide, 3.04 g (0.03 mol) of triethylamine, and 30 ml of methylene chloride was cooled to approximately 0° C. To this mixture was added a solution of 3.14 g (0.03 mol) of methacryloyl chloride in 15 ml of methylene chloride over approximately 5 minutes. The mixture was stirred for an additional 15 minutes and filtered. The filtrate was washed twice with water, dried over magnesium sulfate and concentrated in a rotary evaporator. The solid residue was recrystallized from 1:1 hexane:1,2-dichloroethane. The yield of N-(4-methacryloyloxybenzyl)methanesulfonamide was 3.0 g (37.13 percent of theory), m.p.=101° to 102.5° C.
Reaction SMILES: [CH:1]([CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)=O.OC1C=CC(C(OC)=O)=CC=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH:26]1([NH:29][CH2:1][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=2)[CH2:28][CH2:27]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(OCC=O)cc1
Agent: COC(=O)c1ccc(O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(OCCNC2CC2)cc1
Reaction time: 8 h
Yield: 49 %

Procedure:
To a stirred solution of 4:1 mixture of methyl 4-formylmethyloxybenzoate and methyl 4-hydroxybenzoate (1.00 g) and cyclopropylamine (425 ml, 6.18 mmol) in MeOH—AcOH (10:1, 11 ml) was added NaBH3CN (681 mg, 10.3 mmol). After stirring overnight, the mixture was quenched by addition of sat. NaHCO3 (50 ml) and extracted with CHCl3 (2×200 ml). The combined extracts were dried over MgSO4 and evaporated. The residue was chromatographed on silica gel with CHCl3-MeOH (20:1) to give methyl 4-(2-cyclopropyl aminoethoxy)benzoate (595 mg, 49%) as a colorless oil. 1H-NMR (CDCl3)δ 0.37–0.49 (m, 4 H), 1.91 (m, 1 H), 2.18–2.23 (m, 1 H), 3.11 (t, J=5.2 Hz, 2 H), 3.88 (s, 3 H), 4.12 (t, J=5.2 Hz, 2 H), 6.92 (d, J=8.8 Hz, 2 H), 7.98 (d, J=8.8 Hz, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:15])[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].F[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N+:30]([O-:32])=[O:31].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:15])[CH2:13][CH3:14]
Reactant: CCC(=O)Nc1ccc(O)cc1C(=O)OC
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)Nc1ccc(Oc2ccccc2[N+](=O)[O-])cc1C(=O)OC
Reaction time: 8 h
Yield: 75.6 %

Procedure:
A mixture of 5-hydroxy-2-propionylamino-benzoic acid methyl ester (1.0 g, 4.5 mmol) and potassium carbonate (0.62 g, 4.5 mmol) was stirred in DMF (5 mL) for 10 minutes. 2-fluoronitrobenzene (0.63 g, 4.5 mmol) was then added and stirring was continued at room temperature overnight. Water (10 mL) was added and the resulting precipitate was collected by filtration, washed with water and dried under vacuum to give pure 2-propionylamino-5-(2-nitro-phenoxy)-benzoic methyl ester (1.16 g, 3.4 mmol).
Reaction SMILES: Cl[C:2]1[CH:19]=[C:18]([F:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][NH:13]2)=[CH:9][CH:8]=1)=[O:5].[NH4+:24].[OH-]>O1CCOCC1>[NH2:24][C:2]1[CH:19]=[C:18]([F:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][NH:13]2)=[CH:9][CH:8]=1)=[O:5]
Reactant: O=C(Nc1ccc2cn[nH]c2c1)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cc(F)c([N+](=O)[O-])cc1C(=O)Nc1ccc2cn[nH]c2c1
Temperature: 60 °C

Procedure:
To a solution of 2-chloro-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide (3 mmol) in dioxane (6 mL) was added concentrated aqueous NH4OH (3 mL). The resulting mixture was heated at 60° C. for 2-3 h. The completed reaction afforded the product, 2-amino-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide. To the crude reaction mixture was added diethylamine (45 mmol). The mixture then heated at 60° C. for 6 h. After the reaction was complete, the volatiles were removed in vacuo, and the residue was suspended in cold water. The solid was collected by filtration, washed with water, and dried in vacuo to provide 4-amino-2-diethylamino-N-(1H-indazol-6-yl)-5-nitrobenzamide.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[O:10][C:9]2([CH3:20])[CH3:19])[CH:6]=[N:5][CH:4]=1.S([O-])([O-])(=O)=O.[Mg+2].[NH3:27]>C1COCC1.[O-2].[O-2].[Mn+4]>[CH3:19][C:9]1([CH3:20])[CH:8]([N:7]2[C:3]([C:2]#[N:27])=[CH:4][N:5]=[CH:6]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[O:10]1
Reactant: N
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1CO
Agent: [Mn+4]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1C#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(5-hydroxymethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one (1.0 g, 3.76 mmol) (Example 6d) in THF (30 mL) is added magnesium sulfate (4.79 g, 0.055 mol) and ammonia (2M isopropanol, 9 mL, 0.018 mol). Manganese dioxide (9 mL, 0.055 mol) is then added and the reaction mixture is stirred at room temperature for 48 h. Filtration through celite and concentration in vacuo affords a residue, which is purified by reverse-phase HPLC to give 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carbonitrile; MS (ESI) m/z 268.0 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.33 (s, 3 H), 1.60 (s, 3 H), 5.87 (s, 1 H), 7.57 (d, J=7.6 Hz, 1 H), 7.67-7.78 (m, 1 H), 7.78-7.98 (m, 3 H), 8.28 (dd, J=7.7, 1.4 Hz, 1 H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH:7](I)([CH3:9])[CH3:8].CN(C)C=O.[OH:16][C@@H:17]1[CH2:31][C@@H:20]2[S:21][C@@H:22]([CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:23][CH2:24][C@@H:19]2[C@H:18]1/[CH:32]=[CH:33]/[C@@H:34]([OH:43])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(OCC)(=O)C>[OH:16][C@@H:17]1[CH2:31][C@@H:20]2[S:21][C@@H:22]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH:7]([CH3:9])[CH3:8])=[O:29])[CH2:23][CH2:24][C@@H:19]2[C@H:18]1[CH2:32][CH2:33][C@@H:34]([OH:43])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(O)CCC[C@H]1CC[C@@H]2[C@@H](/C=C/[C@@H](O)COc3ccccc3)[C@H](O)C[C@@H]2S1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)CCC[C@H]1CC[C@@H]2[C@@H](CC[C@@H](O)COc3ccccc3)[C@H](O)C[C@@H]2S1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Under the argon atmosphere, cesium carbonate (68 mg) and isopropyl iodide (0.016 mL) were added to a dimethylformamide (0.4 mL) solution of the compound 15 (20) (42.8 mg), and the mixture was stirred at 50° C. for 90 minutes. This was cooled to room temperature, ethyl acetate was then added, and the mixture was washed with water two times, and then with a saturated saline once. The mixture was dried with anhydrous magnesium sulfate, and then concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3→1:1) to obtain a titled compound (34 mg) having the following physical property values.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=[N:13][S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[NH4+].[Cl-]>C1COCC1>[CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][S@@:14]([C:16]([CH3:19])([CH3:17])[CH3:18])=[O:15])[CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=N[S@](=O)C(C)(C)C)c1ccc(OC(C)C)nc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc([C@H](C)N[S@](=O)C(C)(C)C)cn1
Temperature: -66 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
A round-bottomed flask was charged with (R)-2-methyl-propane-2-sulfinic acid [1(6-isopropoxy-pyridin-3-yl)-ethylidene]-amide (4.00 g, 14.2 mmol) in THF (50 mL) under N2 and cooled to −66° C. (internal temperature). A 1.00 M solution of L-Selectride in THF (29.0 mL, 29.0 mmol) was added drop wise over 15 minutes. The mixture was stirred at −70° C. for 1 hour. The cold mixture was poured into saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and evaporated to dryness. Flash chromatography (silica, EtOAc) gave (R)-2-methyl-propane-2-sulfinic acid [(S)-1-(6-isopropoxy-pyridin-3-yl)-ethyl]-amide (2.91 g, 72%) as a colorless powder. Diastereomeric excess >95% based on 1H NMR.
Reaction SMILES: CO[CH:3]([O:20]C)[CH2:4][NH:5][C:6](=O)[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[N:16]([CH3:18])[CH3:17].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>CS(O)(=O)=O>[CH3:18][N:16]([CH3:17])[C:8]1[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=1[C:6]1[O:20][CH:3]=[CH:4][N:5]=1
Reactant: COC(CNC(=O)c1cc([N+](=O)[O-])ccc1N(C)C)OC
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: CN(C)c1ccc([N+](=O)[O-])cc1-c1ncco1
Temperature: 25 °C
Yield: 17.4 %

Procedure:
A solution of N-(2,2-dimethoxyethyl)-2-dimethylamino-5-nitro benzamide (1.1 g, 3.7 mmol) in methane sulphonic acid (5 ml) was added to a slurry of phosphorus pentoxide (2.6 g, 18.51 mmol) in methane sulphonic acid (15 ml) and refluxed overnight. The reaction mixture was cooled to room temperature, poured onto ice water, and then basified with dilute sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to a residue. Purification by chromatography over silica gel using 5-30% ethyl acetate/pet ether gave dimethyl-(4-nitro-2-oxazol-2-yl-phenyl)-amine (150 mg, 60%) as solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].Cl[CH2:8][CH:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:21])[CH:15]=2)[C:10]1([CH3:23])[CH3:22].Cl>O1CCCC1>[CH3:22][C:10]1([CH3:23])[C:11]2[C:16](=[CH:15][C:14]([CH3:21])=[CH:13][CH:12]=2)[C:17]([CH3:20])([CH3:19])[CH2:18][CH:9]1[CH3:8]
Reactant: Cc1ccc2c(c1)C(C)(C)CC(CCl)C2(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C(C)(C)CC(C)C2(C)C
Yield: 88.3 %

Procedure:
To a suspension of lithium aluminum hydride (6.5 g; 0.171 mol) in tetrahydrofuran in a nitrogen atmosphere, a solution of 2-chloromethyl-1,1,4,4,6-pentamethyl1,2,3,4-tetrahydronaphthalene (40.9 g; 0.163 mol) in tetrahydrofuran was added dropwise, and the resultant mixture was stirred at 70° C. for 15 hours. The reaction mixture was treated with aqueous tetrahydrofuran, dilute hydrochloric acid was added thereto, and the resultant mixture was extracted with n-hexane. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give 1,1,2,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (31.6 g; 0.144 mol; 88%). B.P., 78° C./1.2 mmHg. M.P., 35°-36° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:12]=3)=[CH:10][C:3]=12.Br[C:32]1[C:33]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:46](=[O:50])[N:47]([CH3:49])[CH3:48])=[CH:41][CH:40]=2)=[N:34][N:35]([CH2:37][CH3:38])[CH:36]=1>>[CH3:48][N:47]([CH3:49])[C:46]([NH:45][C:42]1[CH:43]=[CH:44][C:39]([C:33]2[C:32]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[N:8]([S:22]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)(=[O:23])=[O:24])[C:9]([C:11]5[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:19])=[O:20])=[CH:13][CH:12]=5)=[CH:10][C:3]=34)=[CH:36][N:35]([CH2:37][CH3:38])[N:34]=2)=[CH:40][CH:41]=1)=[O:50]
Reactant: CS(=O)(=O)Nc1ccc(-c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc(NS(C)(=O)=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described for Intermediate 32 with N-{4-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}methanesulfonamide. Using this product crude and following the procedure described in Intermediate 100 with N′-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea provided the title product. ESMS [M+H]+: 684.6
Reaction SMILES: [CH2:1]([N:4]1[C@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:7]2[N:6]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[C:5]1=[O:26])[CH:2]=[CH2:3].Cl>CO>[CH2:1]([N:4]1[C@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:7]2[N:6]([CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[C:5]1=[O:26])[CH:2]=[CH2:3]
Reactant: C=CCN1C(=O)N(C2CCN(C(=O)OC(C)(C)C)CC2)[C@H]2CCCC[C@@H]21
Agent: Cl
Solvent: CO
Product: C=CCN1C(=O)N(C2CCNCC2)[C@H]2CCCC[C@@H]21
Temperature: 25 °C

Procedure:
Tert-butyl 4-[(3aS,7aS)-3-allyl-2-oxooctahydro-1H-benzimidazol-1-yl]piperidine-1-carboxylate was dissolved in methanol (20 mL) and 4 M HCl (7 mL) was then added. The mixture was stirred at room temperature and then concentrated in vacuo. The salt was then converted to freebase by using MP-carbonate. MS (M+1): 264.2.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:4]2[N:5]([C:9]([CH:20]3[CH2:25][CH2:24][N:23](C(OCC4C=CC=CC=4)=O)[CH2:22][CH2:21]3)=[N:10][C:11]=2[C:12]#[C:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:7][N:8]=1>>[ClH:1].[NH:23]1[CH2:22][CH2:21][CH:20]([C:9]2[N:5]3[CH:6]=[CH:7][N:8]=[C:3]([NH2:2])[C:4]3=[C:11]([C:12]#[C:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:10]=2)[CH2:25][CH2:24]1
Reactant: Nc1nccn2c(C3CCN(C(=O)OCc4ccccc4)CC3)nc(C#Cc3cccnc3)c12
Agent: Cl
Product: Nc1nccn2c(C3CCNCC3)nc(C#Cc3cccnc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 122.8 %

Procedure:
Concentrated HCl (10 mL, 10M, 0.3 mol) was added to benzyl 4-(8-amino-1-(pyridin-3-ylethynyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate (650 mg, 0.0014 mol) and the mixture was left to stir at rt overnight prior to dilution with with water (30 mL) and washing with diethyl ether (3×20 mL). The aqueous layer was concentrated in vacuo, to afford 3-piperidin-4-yl-1-(pyridin-3-ylethynyl)imidazo[1,5-a]pyrazin-8-amine hydrochloride (610 mg, 99%).
Reaction SMILES: I[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(O)CCO.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:11]1([N:8]2[C:7]3[C:2]([C:24]4[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=4)=[CH:3][C:4]([C:17]([F:20])([F:19])[F:18])=[CH:5][C:6]=3[N:10]=[CH:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: OCCCO
Product: FC(F)(F)c1cc(-c2ccncc2)c2c(c1)ncn2-c1ccccc1

Procedure:
A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (3.0 g, 7.5 mmol), pyridine 4-boronic acid (1.38 g, 11.2 mmol), 1,3-propanediol (2.7 ml, 37.3 mmol), potassium carbonate (5.2 g, 37.3 mmol) and bis(triphenylphosphin)palladium dichloride (200 mg, 0.28 mmol) in a mixture of dimethoxyethane (30 ml) and water (15 ml) was stirred at reflux for 5 days. The cooled reaction mixture was concentrated under reduced pressure, and the concentrate was partitioned between water and ethyl acetate. The organic phase was dried and concentrated under reduced pressure, and the concentrate was purified by column chromatography on silica gel eluting with a mixture of ligroin and ethyl acetate (1:1 v/v). The product was isolated as a yellowish solid by evaporation of solvent from the eluate (1.55 g, 61%) m/z, 340.1 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:12]3[N:16]4[CH:17]=[CH:18][C:19]([C:21]5[CH:22]=[N:23][CH:24]=[C:25]([CH:28]=5)[C:26]#[N:27])=[CH:20][C:15]4=[N:14][CH:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[OH-:29].[K+]>CC(O)(C)C>[N:1]1([C:6]2[CH:7]=[C:8]([C:12]3[N:16]4[CH:17]=[CH:18][C:19]([C:21]5[CH:22]=[N:23][CH:24]=[C:25]([CH:28]=5)[C:26]([NH2:27])=[O:29])=[CH:20][C:15]4=[N:14][CH:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: N#Cc1cncc(-c2ccn3c(-c4cccc(-n5cccn5)c4)cnc3c2)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)c1cncc(-c2ccn3c(-c4cccc(-n5cccn5)c4)cnc3c2)c1
Temperature: 85 °C

Procedure:
5-[3-(3-pyrazol-1-yl-phenyl)-imidazo-[1,2-a]-pyridin-7-yl]-nicotinonitrile (Ex. 1.8) (1 eq, 0.099 mmol, 40 mg) and potassium hydroxide (10 eq, 0.99 mmol, 64.8 mg) are dissolved in tBuOH (2 ml) and the reaction mixture is heated at 85° C. for 1.5 h. At the completion of this time the solvent is removed in vacuo and the reaction mixture is diluted with NaHCO3. The aqueous phase is extracted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered and evaporated to dryness. The reaction mixture is purified by flash chromatography on silica eluting with DCM/MeOH 9/1 to yield 5-[3-(3-pyrazol-1-yl-phenyl)-imidazo-[1,2-a]pyridin-7-yl]-nicotinamide as a yellow solid; [M+H]+=381