Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][CH:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=3[Cl:23])=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:25][O:26][CH2:27][CH2:28][CH2:29]O.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1(C)C=CC=CC=1.C1COCC1.O>[Cl:23][C:17]1[CH:18]=[C:19]([O:22][CH2:29][CH2:28][CH2:27][O:26][CH3:25])[CH:20]=[CH:21][C:16]=1[CH2:15][O:14][C:12]1[CH:11]=[CH:10][C:9]2[CH:5]([CH2:4][C:3]([OH:2])=[O:24])[CH2:6][O:7][C:8]=2[CH:13]=1
Reactant: COC(=O)CC1COc2cc(OCc3ccc(O)cc3Cl)ccc21
Reactant: COCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COCCCOc1ccc(COc2ccc3c(c2)OCC3CC(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To the solution of methyl(6-((2-chloro-4-hydroxybenzyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)acetate (34.9 mg) in toluene (0.25 mL) and THF (0.25 mL) were added a solution of 3-methoxy-1-propanol (13.5 mg) in toluene (0.5 mL) and a solution of tributylphosphine (40.5 mg) in toluene (0.5 mL). To the mixture was added ADDP (50.5 mg) and the mixture was stirred at room temperature overnight. To the mixture was added water (1.0 mL), and the mixture was extracted with EtOAc (2.0 mL). The organic layer was separated and concentrated. The residue was purified by preparative HPLC (C18, eluent: water/CH3CN (including 0.1% TFA)). After solvent evaporated, the residue was added 1.0 N NaOH (0.5 mL) and the mixture was stirred at 50° C. overnight. The mixture was added EtOAc (3.0 mL), and the organic layer was separated. The aqueous layer was acidified with 10% aqueous citric acid solution (0.5 mL), and extracted with EtOAc (3.0 mL). The organic layer was separated and concentrated. The residue was purified by preparative HPLC (C18, eluent: water/CH3CN (including 0.1% TFA)). The solvent was evaporated to give the title compound (13.1 mg).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.FC(F)(F)C(O)=O.[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([C:33]3([C:36]([N:38]4[CH2:42][CH2:41][C@@:40]5([C:46]6[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=6[C:44](=[O:51])[O:43]5)[CH2:39]4)=[O:37])[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.[N:52]1[CH:57]=[CH:56][C:55](O)=[CH:54][CH:53]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>>[N:52]1[CH:57]=[CH:56][C:55]([O:20][CH:21]2[CH2:22][CH2:23][N:24]([C:27]3[N:32]=[CH:31][C:30]([C:33]4([C:36]([N:38]5[CH2:42][CH2:41][C@@:40]6([C:46]7[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=7[C:44](=[O:51])[O:43]6)[CH2:39]5)=[O:37])[CH2:34][CH2:35]4)=[CH:29][CH:28]=3)[CH2:25][CH2:26]2)=[CH:54][CH:53]=1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCC(O)CC5)nc4)CC3)C2)c2ccccc21
Reactant: Oc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCC(Oc6ccncc6)CC5)nc4)CC3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl azodicarboxylate (3.0×10−1 μL, 0.00019 mol) was added to a mixture of (1R)-1′-({1-[6-(4-hydroxypiperidin-1-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one trifluoroacetate (salt) (42 mg, 0.000077 mol, example 172), 4-pyridinol (18 mg, 0.00019 mol) and triphenylphosphine (5.0×10−1 mg, 0.00019 mol) in tetrahydrofuran (1.0 mL, 0.012 mol). The reaction mixture was stirred at room temperature overnight. The crude product was purified by prep-LCMS. LC/MS: 511.2 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:20]([CH3:21])[C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[N:17]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(O)(=O)C>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[CH3:21][N:20]1[C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[N:17]=[C:16]1[NH:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: Cn1c(Nc2ccc(OCc3ccccc3)cc2)nc2ccccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: Cn1c(Nc2ccc(O)cc2)nc2ccccc21
Reaction time: 3 h

Procedure:
To a solution of compound (4-benzyloxy-phenyl)-(1-methyl-1H-benzoimidazol-2-yl)-amine (1.8 g, 5.4 mmol) in 18 mL of THF and 18 mL of MeOH was added Pd(OH)2 (0.36 g, 20%) and 9 mL of acetic acid. The resulting mixture was kept and kept at 50 psi H2 atmosphere for 3 h. The reaction mixture was then filtered over a cake of Celite™. The filtrate was concentrated and purified by silica gel column chromatography (EtOAc/hexane) to get desired product 4-(1-methyl-1H-benzoimidazol-2-ylamino)-phenol. [M+1]=240
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:14][CH:13]=[CH2:12])[CH:7]=1
Reactant: C=CCBr
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C)ccc1[N+](=O)[O-]
Yield: 94.4 %

Procedure:
A solution of 5-methyl-2-nitrophenol (2.00 g, 13.1 mmol), allyl bromide (1.30 mL, 15.0 mmol), and cesium carbonate (5.5 g, 17 mmol) in DMF (100 mL) was stirred at ambient temperature. After 20 hrs the reaction was filtered, frit washed with methanol, and the filtrate evaporated in vacuo at 50° C. The residue was purified by flash column chromatography (4:1 then 2:1 hexane:ethyl acetate eluant) giving the title compound as a yellow oil (2.39 g, 95%) that crystallized after sitting 3 days at ambient temperature. 1H NMR (300 Mz, DCl3) δ 7.79 (d, 1H, J=8.2 Hz), 6.86 (s, 1H), 6.82 (m, 1H), 6.05 (ddt, 1H, J=17.3 Hz, 10.6 Hz, 5.0 Hz), 5.50 (ddd, 1H, J=17.3 Hz, 3.3 Hz, 1.7 Hz), 5.33 (ddd, 1H, J=10.6 Hz, 2.9 Hz, 1.5 Hz), 4.67 (dt, 2H, J=4,9 Hz, 1.6 Hz), 2.40 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[C:13](=[O:14])[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.C(N(CC)CC)C.C(O)=O.C(=O)([O-])[O-].[K+].[K+].CCCCCC.CC(O)C.C(NCC)C>ClCCl.C(O)=O.C(N(CC)CC)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[CH:13]([OH:14])[CH:12]3[CH2:11][CH2:10][N:9]2[CH2:16][CH2:15]3)[CH:2]=1
Reactant: O=C1C2CCN(CC2)C1Cc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCNCC
Solvent: CCN(CC)CC
Solvent: O=CO
Product: OC1C2CCN(CC2)C1Cc1cccnc1
Temperature: 40 °C
Reaction time: 19 h
Yield: 49 %

Procedure:
0.518 g (2.39 mmol) of racemic 2-(3-pyridinylmethyl)-3-quinuclidinone, 0.65 ml (4.66 mmol) of triethylamine, 0.44 ml (11.7 mmol) of formic acid (formic acid/triethylamine=5/2 to the substrate molar ratio), 5.5 mg (8.6×10−3 mmol, S/C=200) of RuCl [(S,S)— TsDPEN] (p-cymene) were introduced into a 20 mL Schlenk flask under an argon atmosphere and stirred for 19 hours at 40° C. The reaction liquid was diluted in dichloromethane, neutralized by potassium carbonate, and after removing the solids by filtration, the target substance was obtained with a yield of 49% by concentrating and drying to solids. By NMR spectroscopy it was confirmed that 2-(3-pyridinylmethyl)-3-quinuclidinol of only one of the diastereomers was obtained. The optical purity, determined by HPLC analysis (Daicel Chiralcel OD-H two columns connected in series, Hexane/2-propanol/diethylamine=80/20/0.1, 0.3 mL/min., 25° C., the retention times of the two types of optical isomers in the diastereomer obtained were 64.0 min. and 83.2 min.) was 85% ee.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][O:29]C(=O)C5C=CC=CC=5)[CH2:26][O:25][C:24]4=[O:38])=[C:19]([F:39])[CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH-].[Na+].Cl.[Cl-].[Na+]>C(COC)OC.C(OCC)(=O)C>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][OH:29])[CH2:26][O:25][C:24]4=[O:38])=[C:19]([F:39])[CH:18]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4COC(=O)c4ccccc4)c(F)c3)CC2)c(C)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)c(F)c3)CC2)c(C)c1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
benzoic acid (R)-3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-2-fluorophenyl}-2-oxooxazolidin-4-ylmethyl ester (309 mg) described in Example 125 was dissolved in dimethoxyethane, 4N aqueous sodium hydroxide solution was added and the mixture was stirred at room temperature. Under ice-cooling, the mixture was neutralized with 1N hydrochloric acid, ethyl acetate and sodium chloride were added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed once with saturated aqueous sodium chloride solution, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (181 mg).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.C(N(CC)CC)C.[CH3:14][N:15]([CH3:19])[C:16](Cl)=[O:17].O>C(#N)C>[CH3:14][N:15]([CH3:19])[C:16](=[O:17])[NH:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: Nc1nnn[nH]1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CN(C)C(=O)Nc1nnn[nH]1

Procedure:
Anhydrous 5-aminotetrazole (8.5 g, 0.1 mole) was slurried in 150 ml of acetonitrile. On the addition of triethylamine (10 g, 0.1 mole), the solids dissolved. Dimethylcarbamoyl chloride (13 g, 0.12 mole) was added at once with no exotherm. The mixture was refluxed two hours with the formation of white solids. After cooling, the material was added to cold water to remove by-product triethylamine hydrochloride. The water insoluble material was collected.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2.[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OC(C)C)(C)C.CCCCCC>O1CCOCC1>[C:13]1([NH:19][C:20]([NH:1][C:2]2[C:11]3[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cccc2c1CC(O)CC2
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Solvent: CCCCCC
Product: O=C(Nc1ccccc1)Nc1cccc2c1CC(O)CC2
Reaction time: 16 h
Yield: 51 %

Procedure:
To a solution of 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol (20.0 mg, 0.123 mmol) in 1,4-dioxane (1.0 mL) was added phenyl isocyanate. (14.6 mg, 0.123 mmol) at room temperature. The mixture was stirred for 16 hours, and then added diisopropyl ether and hexane. The precipitate was filtered and dried to give N-phenyl-N′-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea (17.8 mg, 51% yield).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16][C@H:17]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:18]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:22](=[O:30])[C:21]2=[CH:31][CH:32]=[CH:33][N:20]2[N:19]=1.[I-].[K+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[O:30]=[C:22]1[C:21]2=[CH:31][CH:32]=[CH:33][N:20]2[N:19]=[C:18]([C@@H:17]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:38])[CH3:39])[CH2:16][CH2:15][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:23]1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCBr)c1nn2cccc2c(=O)n1-c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCOc1ccccc1)c1nn2cccc2c(=O)n1-c1ccccc1
Temperature: 70 °C
Yield: 57.9 %

Procedure:
Phenol (6 mg, 0.06 mmol) was dissolved in 450 μl of N,N-dimethylformamide. Potassium carbonate (6 mg, 0.05 mmol) was added and the reaction was stirred at room temperature for 30 min. (S)-tert-Butyl (3-bromo-1-(4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)propyl)carbamate (45 mg, 0.03 mmol) and potassium iodide (1 mg, 0.001 mmol) were added and the reaction was heated at 70° C. for 3 h. The mixture was poured into a 4% aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic phases were washed with water, brine, dried over sodium sulphate and evaporated under reduced pressure. The crude was purified by SP1® Purification System (0% to 50%, hexane-ethyl acetate) to give 8 mg (57% yield) of the title compound. Purity 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18][CH:19]2[CH2:23][CH2:22][N:21](C(OCC3C=CC=CC=3)=O)[CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:42])[N:13]2[C:34]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=1[Cl:41].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18][CH:19]2[CH2:23][CH2:22][NH:21][CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:42])[N:13]2[C:34]1[C:35]([Cl:41])=[CH:36][CH:37]=[CH:38][C:39]=1[Cl:40]
Reactant: O=C(OCc1ccccc1)N1CCC(Oc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)CC3)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCc2c(-c3ccccc3Cl)cc(OC3CCNC3)cc2N1c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl 3-([5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl]oxy}pyrrolidine-1-carboxylate (0.051 g) in 6 mL of CH2Cl2 was added 1 mL of TFA and the mixture was stirred for 1 h at rt. The reaction mixture was purified by preparative thin layer chromatography eluting with 10% ethanol/dichloromethane to give the product. Mass spectrum m/z (ESI) 487.15 (M+1).
Reaction SMILES: COC1C=CC(C2CCCC3C=C(OC)C=CC=3C2)=C(N)C=1.Cl.[N:24]1([CH2:31][CH2:32][O:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=O)=[CH:36][CH:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.N1(CCOC2C=C[C:56]([CH2:57][NH:58][C:59]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=3[CH:67]3[CH2:73][CH2:72][CH2:71][C:70]4[CH:74]=[C:75]([O:78][CH3:79])[CH:76]=[CH:77][C:69]=4[CH2:68]3)=CC=2)CCCCCC1>>[N:24]1([CH2:31][CH2:32][O:33][C:34]2[CH:42]=[CH:41][C:37]([CH2:38][N:58]([CH2:57][CH3:56])[C:59]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=3[CH:67]3[CH2:73][CH2:72][CH2:71][C:70]4[CH:74]=[C:75]([O:78][CH3:79])[CH:76]=[CH:77][C:69]=4[CH2:68]3)=[CH:36][CH:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Reactant: COc1ccc2c(c1)CCCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCCC3)cc1)C2
Agent: COc1ccc(C2CCCc3cc(OC)ccc3C2)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1cc(OC)ccc1C1CCCc2cc(OC)ccc2C1

Procedure:
Synthesized from 5-methoxy-2-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][5-methoxy-2-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)phenyl]amine (485 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[5-methoxy-2-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)phenyl]amine (459 mg). This compound (457 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (394 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH:10][C:11]1[S:12][CH:13]([CH3:17])[C:14](=[O:16])[N:15]=1)[CH3:9].Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH:10][C:11]1[S:12][C:13]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)([CH3:17])[C:14](=[O:16])[N:15]=1)[CH3:9]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CC1SC(N[C@@H](C)c2ccccc2F)=NC1=O
Agent: [Pd]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1F
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-((S)-1-(2-fluorophenyl)ethylamino)-5-methylthiazol-4(5H)-one (0.0500 g, 0.198 mmol), 4-bromobenzonitrile (Aldrich, 0.0721 g, 0.396 mmol), Pd2(dba)3 (Aldrich, 0.0127 g, 0.0139 mmol), 2-(diphenylphosphino)-1-(2-(diphenylphosphino)naphthalen-1-yl)naphthalene (Strem, 0.0123 g, 0.0198 mmol), and NaN(TMS)2 (Aldrich, 0.0727 g, 0.396 mmol) was added toluene (2 mL) in a dry box. The mixture was gradually heated to 95° C. and stirred overnight. The reaction was cooled to ambient temp. and quenched with NH4Cl (5 mL). The reaction mixture was extract with EtOAc. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography. MS: 354 (M+1)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][N:3]=1.[N:24]1[CH:25]=[CH:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][C:28]=12.C(N(CC)CC)C.C(Cl)(Cl)Cl>C(OCC)(=O)C>[N:24]1[CH:25]=[CH:26][N:27]2[CH2:32][CH2:31][N:30]([C:2]3[N:7]=[C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=4)[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][N:3]=3)[CH2:29][C:28]=12
Reactant: CCOC(=O)c1cnc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Reactant: c1cn2c(n1)CNCC2
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(N2CCn3ccnc3C2)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (prepared in Example 95) 285 mg, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 197 mg, triethylamine 0.22 ml and chloroform 3 ml is stirred at room temperature for 2,5 hours, followed by stirring at 60° C. for 2,5 hours. The mixture is diluted with ethyl acetate, and washed with water. The water layer is extracted with ethyl acetate, and the organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified with silica gel chromatography (silica gel 10 g, solvent; chloroform:methanol=50:1) and concentrated in vacuo and triturated with isopropyl ether to give 2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine as a colorless crystalline powder, 290 mg. mp 179–182° C.,
Reaction SMILES: [CH3:1][C:2]1[C:3](B2OC(C)(C)C(C)(C)O2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Na+].[Na+].O>CC1OCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][C:2]1[C:3]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Clc1ncccn1
Reactant: COC(=O)c1cccc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC1CCCO1
Product: COC(=O)c1cccc(C)c1-c1ncccn1
Temperature: 150 °C
Yield: 22.7 %

Procedure:
In a microwave vial was dissolved methyl 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (619 mg, 2.24 mmol) and 2-chloropyrimidine (314 mg, 2.69 mmol) in 2-MeTHF (10 mL). Na2CO3 (713 mg, 6.73 mmol) was then added followed by water (3.4 mL) and the reaction mixture was degassed with N2 for 45 minutes. Pd(dppf)Cl2 (66 mg, 0.09 mmol) and the reaction mixture was heated at 75° C. for 28 h. More Pd(dppf)Cl2 (33 mg, 0.045 mmol) was added and the reaction mixture was heated at 150° C. for 3.5 h. The mixture was filtered through a pad of celite and rinsed with EtOAc and water. The layers were separated and the aqueous was extracted once with EtOAc. The combined organic layers were dried over MgSO4, filtered and evaporated. The crude was purified via silica gel chromatography (0-50% EtOAc in hexanes) to afford the title compound (116 mg, 23%). MS (ESI) mass calcd. for C13H12N2O2, 228.1; m/z found 229.1 [M+H]+. 1H NMR (500 MHz, CDCl3) 8.95-8.76 (m, 2H), 7.99-7.75 (m, 1H), 7.50-7.44 (m, 1H), 7.43-7.37 (m, 1H), 7.32-7.24 (m, 1H), 3.64 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:18][CH2:17][C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1)=O.ClS([N:25]=[C:26]=[O:27])(=O)=O.CO.C[O-].[Na+]>ClCCl>[CH2:17]1[C:9]2=[C:10]([C:26]([NH2:25])=[O:27])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][NH:5][CH2:18]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C(N1CCc2cc3ccccc3n2CC1)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1c2n(c3ccccc13)CCNCC2
Reaction time: 1 h
Yield: 37.3 %

Procedure:
A solution of 2,2,2-trifluoro-1-(1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indol-3-yl)-1-ethanone (448 mg, 1.6 mmol) in dichloromethane (20 mL) is treated with chlorosulfonyl isocyanate (0.19 mL, 2.1 mmol). The resulting golden homogenous solution is stirred for 1 hour and treated with methanol (10 mL) and a solution of 25% sodium methoxide in methanol (2 mL, 8.8 mmol). The reaction mixture quickly turns to a white suspension and after 30 min is filtered to give a crude white solid. This material is triturated with hot methanol, filtered through a pad of celite, and concentrated to 184 mg of a white solid that is further purified by LC (230-400 silica gel) eluting with 9:1:89 methanol/NH4OH/dichloromethane to afford 137 mg of 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole-11-carboxamide as a white solid. IR (drift) 3353, 3341, 3173, 1641, 1602, 1549, 1463, 1432, 1418, 1322, 1314, 778, 740, 729, 654 cm−1.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[S:19][C:18]([CH2:20][CH3:21])=[N:17][C:16]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)[CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.C(OC(NC1C=C(CC(C2C=CC=C(C)C=2)=O)C=CN=1)=O)(C)(C)C.Cl>C(=O)([O-])O.[Na+]>[CH2:20]([C:18]1[S:19][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:8])[CH:14]=2)=[C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)[N:17]=1)[CH3:21]
Reactant: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(NC(=O)OC(C)(C)C)c2)s1
Agent: Cc1cccc(C(=O)Cc2ccnc(NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Agent: O=C([O-])O
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(N)c2)s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To 5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-2-ethyl-4-(3-methylphenyl)-1,3-thiazole (synthesized from 2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3-methylphenyl)ethanone (35 g, 170 mmol) according to the method described in Example 3) was added 2N-hydrochloric acid (200 mL), and the mixture was stirred for 1 hour at 100° C. The reaction mixture was cooled to room temperature, then, made alkaline with a 2N aqueous sodium hydrogen carbonate solution (200 mL) and aqueous sodium hydrogen carbonate solution. The resulted mixture was extracted by ethyl acetate, and the extracts were washed with water. This extracts were dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=1:1) to obtain a crystal. This crystal was washed with isopropyl ether, to obtain a title compound (17 g, yield 55%).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([CH2:11][CH3:12])[NH:5][N:4]=1)[CH3:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([C:6]1[C:7]([CH2:8][CH2:9][O:10][S:14]([CH3:13])(=[O:16])=[O:15])=[C:3]([CH2:1][CH3:2])[N:4]([S:14]([CH3:13])(=[O:16])=[O:15])[N:5]=1)[CH3:12]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1n[nH]c(CC)c1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nn(S(C)(=O)=O)c(CC)c1CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.4 %

Procedure:
To a solution of 2-(3,5-diethyl-1H-pyrazol-4-yl)-ethanol (0.8 g, 4.8 mmol) in methylene chloride (20 mL) was added methanesulfonyl chloride (0.92 mL, 12 mmol) and triethylamine (2.0 mL, 14 mmol). The mixture was stirred at room temperature for 16 h and was loaded directly on to a silica gel column and eluted (methylene chloride/heptane followed by ethyl acetate/methylene chloride) to provide methanesulfonic acid 2-(3,5-diethyl-1-methanesulfonyl-1H-pyrazol-4-yl)-ethyl ester (940 mg, 41% yield).