Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](N)[C:7]=1[CH3:13])(=[O:3])[CH3:2].[O:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.N(OC(C)(C)C)=O>CCCCCCC>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)[C:7]=1[CH3:13])(=[O:3])[CH3:2]
Reactant: c1ccoc1
Reactant: CC(=O)OCc1cccc(N)c1C
Agent: CC(C)(C)ON=O
Solvent: CCCCCCC
Product: CC(=O)OCc1cccc(-c2ccco2)c1C
Yield: 32.4 %

Procedure:
A stirred solution of 10.0 g (0.056 mol) of 3-amino-2-methylphenylmethyl acetate and 37.4 g (0.055 mol) of furan was heated to reflux, and 8.6 g (0.084 mol) of tert-butyl nitrite was added dropwise during 30 minutes. Upon complete addition, the reaction mixture was heated under reflux an additional 1.5 hours, then cooled, and 300 mL of heptane was added. The solution was filtered through 50 g of silica gel. The silica gel was washed with 400 mL of pentane. The wash and filtrate were combined and concentrated under reduced pressure to give a residual oil which was subjected to column chromatography on silica gel, eluting with toluene. The appropriate fractions were combined and concentrated under reduced pressure to give a residual oil. The oil was subjected to distillation under reduced pressure using a Kugelrohr distilling system to give 4.1 g of 3-(2-furanyl)-2-methylphenylmethyl acetate, b.p. 94±2° C./0.05 mm.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:37]=[CH:36][C:9]2[N:10]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[C:16]4Cl)=[N:12][C:8]=2[CH:7]=1)=[O:5])C.C1(N2C3C=CC(C(O)=O)=CC=3N=C2C2C=C3C(=CC=2)N=C(C2C=CC=CC=2)C=C3N(C)C)CCCCC1.[CH:75]1[C:84]2[C:79](=[CH:80][CH:81]=[C:82]([OH:85])[CH:83]=2)[CH:78]=[CH:77][C:76]=1[OH:86]>>[CH:30]1([N:10]2[C:9]3[CH:36]=[CH:37][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=3[N:12]=[C:11]2[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[C:16]3[O:86][C:76]2[CH:77]=[CH:78][C:79]3[C:84](=[CH:83][C:82]([OH:85])=[CH:81][CH:80]=3)[CH:75]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: Oc1ccc2ccc(O)cc2c1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(Cl)c3c1)n2C1CCCCC1
Agent: CN(C)c1cc(-c2ccccc2)nc2ccc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)cc12
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(Oc4ccc5ccc(O)cc5c4)c3c1)n2C1CCCCC1

Procedure:
In this reaction 51 mg (0.1 mmol) of crude 2-(4-chloro-2-phenyl-quinolin-6-yl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester were used in the same reaction sequence as that used for Compound 481. The nucleophile used was naphthalene-2,7-diol. Yield: 6.2 mg.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=2)=[O:14])[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[O:14])=[N:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Br)cn2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1ccc(Br)cn1)C1CCNC1
Yield: 87.1 %

Procedure:
Stir a solution of 3-(5-bromo-pyridine-2-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.65 g, 1.8 mmol) in 4 M HCl in dioxane (3.7 mL) at 0° C. for 1 h. Concentrate the reaction mixture, dilute the mixture with CH2Cl2, wash with 5 N NaOH (15 mL), and back-extract the aqueous with CH2Cl2. Wash the combined organic layer with brine, dry over Na2SO4, filter and concentrate. Purify the crude material by flash chromatography, eluting with 10% MeOH (2N NH3)/CH2Cl2 to give 0.4 g (85%) of the title compound. LC-MS/ES m/z (81Br) 257.0 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:9]#[CH:10].C([Li])CCC.[Cl-].[Cl-].[Cl-].[Al+3].[OH:25][CH:26]1[CH2:30][C:29](=[O:31])[C:28]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:27]1.Cl>CCCCCC.CCOCC>[OH:25][CH:26]1[CH2:30][C:29](=[O:31])[CH:28]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:27]1[C:10]#[C:9][CH:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C#CC(CCCCC)OC1CCCCO1
Reactant: COC(=O)CCCCCCC1=CC(O)CC1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCC(C#CC1C(O)CC(=O)C1CCCCCCC(=O)OC)OC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.47 parts of 3(RS)-(tetrahydropyran-2-yl)oxy-1-octyne in 7.1 parts of ether is treated at -40° with 2.6 parts by volume of a 2.3 M butyl lithium in hexane solution. The reaction mixture is stirred at room temperature for 1 hour, then cooled to -40°. 0.267 Part of aluminum trichloride is added and the mixture is stirred at room temperature for 2 hours. After that time, 0.240 part of methyl 3(RS)-hydroxy-5-oxocyclopent-1-eneheptanoate, dissolved in ether, is added and the resulting mixture is stirred at room temperature for about 16 hours. The reaction mixture then is poured into a mixture of 35.5 parts of ether and 20 parts by volume of an aqueous 0.5 N hydrochloric acid solution. The ethereal layer is separated, washed with water, dried over anhydrous sodium sulfate and stripped of solvent. The remaining material is chromatographed on silica gel with 20% ethyl acetate in benzene as eluent to yield, as a stereoisomeric mixture, methyl 3(RS)-hydroxy-2-(3(RS)-[tetrahydropyran-2-yl]oxy-1-octynyl)-5-oxocyclopentane-heptanoate.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[S:11][C:12]([CH3:14])=[CH:13][C:3]=12.[NH3:15]>CC(O)C>[NH2:15][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[S:11][C:12]([CH3:14])=[CH:13][C:3]=12
Reactant: N
Reactant: Cc1cc2c(Cl)c([N+](=O)[O-])cnc2s1
Solvent: CC(C)O
Product: Cc1cc2c(N)c([N+](=O)[O-])cnc2s1
Yield: 93 %

Procedure:
To a stirred solution of 1.60 g of 4-chloro-5-nitro-2-methylthieno[2,3-b]pyridine 3 in 50 ml of 2-propanol is introduced excess amount of anhydrous ammonia at 55° C. during 3 hours. The reaction mixture is concentrated in vacuo. The residue is washed with ether and suspended in 7 ml of 1N sodium hydroxide solution with stirring. The resulting crystals are collected by filtration and washed with water and a small amount of ethanol to yield 1.37 g (93%) of Compound 4 as orange crystals melting at 238°-240° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([O:28]C)[C:6]2[S:10][C:9]([CH2:11][N:12]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([OH:26])=[O:25])=[N:13]3)=[N:8][C:7]=2[CH:27]=1>Br>[OH:2][C:3]1[CH:4]=[C:5]([OH:28])[C:6]2[S:10][C:9]([CH2:11][N:12]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([OH:26])=[O:25])=[N:13]3)=[N:8][C:7]=2[CH:27]=1
Reactant: COc1cc(OC)c2sc(Cn3nc(CC(=O)O)c4ccccc4c3=O)nc2c1
Agent: Br
Product: O=C(O)Cc1nn(Cc2nc3cc(O)cc(O)c3s2)c(=O)c2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 3-(5,7-dimethoxy-2-benzothiazolylmethyl)-4-oxo-3H-phthalazin-1-yl acetic acid (0.5 g) and aqueous hydrobromic acid (10 ml, 48%) was refluxed for 4 hours. The hot solution was cooled to room temperature and than poured onto ice-water (50 ml). The resulting pink colored solid was filtered, washed with water (20 ml) and dried. The dried solid was crystallized from methanol to yield the product (0.31 g; m.p. 184° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19][CH3:20])[O:18][C:14]=4[CH:13]=3)[C:7]=2[CH:23]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19]([CH3:20])=[O:32])[O:18][C:14]=4[CH:13]=3)[C:7]=2[CH:23]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2ncn(Cc3ccc4nc(SC)oc4c3)c2c1
Solvent: ClCCl
Product: COc1ccc2ncn(Cc3ccc4nc(S(C)=O)oc4c3)c2c1
Yield: 83 %

Procedure:
A solution of 6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole (799 mg, 2.46 mmol) and m-CPBA (551 mg, 3.20 mmol) in DCM (18 mL) was stirred at 0° C. for 3.5 h. The reaction mixture was washed with aqueous Na2S2O3 and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:1 petroleum ether/ethyl acetate to give 6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole as a light yellow solid (697 mg, 74.9%). 1H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.87-7.92 (m, 2H), 7.47-7.55 (m, 2H), 7.16 (s, 1H), 6.82 (d, J=5.4 Hz, 1H), 5.63 (s, 2H), 3.75 (s, 3H), 3.18 (s, 3H). LCMS (ESI) m/z 342 (M+H)+.
Reaction SMILES: [Cl:1][Si:2]([Cl:5])(Cl)Cl.[CH:6]1([Li])[CH:10]=[CH:9][CH:8]=[CH:7]1.[Cl-].[Li+]>CCCCC.CCOCC>[CH:6]1([Si:2]([CH:9]2[CH:8]=[CH:7][CH:6]=[CH:10]2)([Cl:5])[Cl:1])[CH:10]=[CH:9][CH:8]=[CH:7]1
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: [Li]C1C=CC=C1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCCCC
Product: Cl[Si](Cl)(C1C=CC=C1)C1C=CC=C1
Reaction time: 0.17 h

Procedure:
50 ml of dry n-pentane, 20 ml of dry ether and 8.09 g (47.6 mmol) of tetrachlorosilane were charged in a 200 ml Schlenk tube reactor equipped with a stirring apparatus in a stream of nitrogen, and a liquid having 7.20 g (100 mmol) of the above prepared cyclopentadienyl lithium slurried with 70 ml of n-pentane was dropwise added thereto by means of an injector at room temperature over a period of 10 minutes. After completion of the dropwise addition, stirring was carried out at room temperature for 24 hours. After completion of the reaction, lithium chloride was removed from the reaction liquid slurry by means of a glass filter, and n-pentane was distilled off to obtain dicyclopentadienyldichlorosilane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:18])([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[CH3:7])=[O:5])[CH3:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>CC#N>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([NH:50][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[C:9]([O:8][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])([CH3:7])[CH3:18])[CH:10]=2)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
1.30 g (5.0 mmol) of 3-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzoic acid [U.S. Pat. Appl. Publ. (2005), 89 pp. US 2005096337 A1] and 0.969 g (5.25 mmol) of 2-chloro-4,6-dimethoxy-1,3,5-triazine were dissolved under argon in 5 mL of MeCN and cooled down to 0° C.; then, 1.10 mL (1.064 g=2.0 eq.) of N-methylmorpholine was added and the mixture was stirred at 0° C. for 2 h. To this mixture was added 1.277 g (6.0 mmol) 4-amino-piperidine-carboxylic acid tert-butyl ester in small portions; afterwards the reaction was then warmed up to rt. After stirring for 16 h, it was poured into crashed ice and extracted twice with MeCl2; the organic phases were washed with water, dried over MgSO4, filtered and evaporated i.V. to yield 2.18 g of the crude title compound as off-white solid. MS: 435.2 (MH+).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[C:17]([Cl:23])[CH:16]=1>CN(C)C=O.C1C=CC=CC=1>[Cl:23][C:17]1[CH:16]=[C:15]([Cl:14])[CH:20]=[CH:19][C:18]=1[CH2:21][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COC(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(Cl)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 30 parts of methyl benzeneacetate, 6.8 parts of sodium hydride dispersion 78%, 135 parts of N,N-dimethylformamide and 180 parts of benzene is stirred for 1 hour at room temperature, while nitrogen gas is introduced. Another 90 parts of benzene is added. Then there is added dropwise, during a 30 minutes-period, a solution of 43.4 parts of 1,3-dichloro-4-(chloromethyl)benzene in 45 parts of N,N-dimethylformamide. Upon completion, stirring is continued for 30 minutes at room temperature. The reaction mixture is poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is distilled, yielding 26.5 parts of methyl 2,4-dichloro-α-phenylbenzenepropanoate; bp. 140°-145° C at 0.05 mm. pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[C:11]([OH:18])[CH:10]=2)[CH:7]=1.Cl.[NH2:28][OH:29]>>[F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12](/[C:15](=[N:28]/[OH:29])/[CH3:16])=[C:11]([OH:18])[CH:10]=2)[CH:7]=1
Reactant: NO
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)=O)c(O)c3)c2)CCOCC1
Agent: Cl
Product: COC1(c2cc(F)cc(Sc3ccc(/C(C)=N/O)c(O)c3)c2)CCOCC1
Yield: 77 %

Procedure:
Using an analogous procedure to that described in Example 7, 4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-2'-hydroxyacetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-2'-hydroxyacetophenone oxime in 77% yield, m.p. 140°-142° C.;
Reaction SMILES: C([O:8][NH:9][C:10](=[O:35])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:34])=[C:25]([C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[Pd+2].[OH-]>[CH:16]1([CH2:15][CH2:14][CH2:13][C@@H:12]([C:22]2[O:23][C:24]([CH3:34])=[C:25]([C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[N:26]=2)[CH2:11][C:10]([NH:9][OH:8])=[O:35])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1C(=O)NCC(=O)O
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NO)nc1C(=O)NCC(=O)O
Temperature: 43 °C
Yield: 35.8 %

Procedure:
A solution ({[2-((1R)-1-{2-[(benzyloxy)amino]-2-oxoethyl}-4-cyclohexylbutyl)-5-methyl-1,3-oxazol-4-yl]carbonyl}amino)acetic acid (Preparation 100) (60 mg, 0.12 mmol) in ethanol (3 ml) was treated with ammonium formate (78 mg, 1.23 mmol) and palladium hydroxide (20 mg) and heated at 43° C., under a nitrogen atmosphere for 4 hours. The reaction mixture was filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of 99:1:0.1 (dichloromethane:methanol:acetic acid) gradually changing to 90:10:1 (dichloromethane:methanol:acetic acid) to afford the title compound as a white solid (17 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[OH:13])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23].CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[O:13][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:4][CH:3]=1
Reactant: O[C@@H]1CCC[C@H]1c1ccc(Cl)nc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)O[C@@H]1CCC[C@H]1c1ccc(Cl)nc1
Reaction time: 1 h
Yield: 96.4 %

Procedure:
trans-2-(6-Chloropyridin-3-yl)cyclopentanol (0.225 g, 1.14 mmol) was dissolved in CH2Cl2 (10 mL) in a 50 mL round bottom flask, the solution cooled in an ice bath under nitrogen and treated with Et3N (0.172 g, 1.71 mmol, 0.24 mL) and methanesulfonyl chloride (0.163 g, 1.42 mmol, 0.11 ml) via syringe with stirring. After 1 h, TLC (hexanes:EtOAc/2:1) indicated a complete conversion. The reaction mixture was concentrated in vacuo then partitioned between EtOAc and 1 N HCl, the layers separated, the organics dried (Na2SO4) filtered and concentrated to give trans-methanesulfonic acid 2-(6-chloropyridin-3-yl)cyclopentyl ester (0.303 g, 97%) as an oil: LC/MS (ESI) m/z 275, 1H NMR (300 MHz, CDCl3) δ 8.28 (d, 1H, J=2.7 Hz), 7.56 (dd, 1H, J=8.1, 2.7 Hz), 7.3 (d, 1H, J=8.1 Hz), 4.93 (apparent q, 1H, J=5.7 Hz), 3.28 (apparent q, 1H, J=8.7 Hz), 2.86 (s, 3H), 2.26 (m, 2H), 2.10-1.80 (m, 3H), 1.73 (m, 1H).
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@@H:5]1[NH:16][C:17](=[O:25])[CH2:18][CH2:19][C:20]([F:24])([F:23])[CH2:21]Br)=[N+:2]=[N-:3].[H-].[Na+]>CN(C)C=O>[N:1]([C@H:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@@H:5]1[N:16]1[CH2:21][C:20]([F:24])([F:23])[CH2:19][CH2:18][C:17]1=[O:25])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@H]1CN(Cc2ccccc2)C[C@@H]1NC(=O)CCC(F)(F)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CN(Cc2ccccc2)C[C@@H]1N1CC(F)(F)CCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of the product from Step 6 (22.0 g, 52.8 mmol) in N,N-dimethylformamide (220 mL) was added sodium hydride (60% suspension in mineral oil, 3.38 g, 84.6 mmol) in several portions. The reaction was stirred at room temperature for 16 hours and then ice water (50 mL) was added slowly. The resulting mixture was partitioned between ethyl acetate and H2O and the organic phase washed with 2% aqueous lithium chloride solution and then brine. The organic layer was dried over sodium sulfate and concentrated to an oil that was separated by silica gel chromatography (75M Biotage Si1 (A Dynax Corp.; Charlottesville, Va.) eluting with a pentane/EtOAc gradient (4:1-1:1) to afford 17.7 g (53%) of the product as a solid. MS m/z 336.3 (AP+100).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:30]1[C:31]([N:50]2[CH2:54][CH2:53][C@@H:52]([OH:55])[CH2:51]2)=[N:32][CH:33]=[C:34]([CH:49]=1)[C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=1)=[O:36]>C1(C)C=CC=CC=1.CCOC(C)=O.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>[OH:55][C@@H:52]1[CH2:53][CH2:54][N:50]([C:31]2[C:30]([C:11]3[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=[CH:9][CH:10]=3)=[CH:49][C:34]([C:35]([NH:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:42][CH:43]=3)=[O:36])=[CH:33][N:32]=2)[CH2:51]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccnn2C2CCCCO2)c1
Temperature: 110 °C
Reaction time: 2.5 h

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (59.9 g, 214.4 mmol), K3PO4 (105.7 g, 498.1 mmol) and Pd(PPh3)4 (9.6 g, 8.30 mmol) were added to a suspension of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 2.2, 74 g, 165.8 mmol) in toluene (740 mL) and stirred at 110° C. for 2.5 h under argon. The mixture was then diluted with EtOAc (2 L), washed with water (2×1 L) and dried over Na2SO4. The solvent was evaporated off under reduced pressure and the crude residue was purified by flash chromatography (Silica gel, 2 kg, DCM/MeOH 95:5). The resulting material was dissolved in a mixture of MeOH (500 mL) and THF (800 mL) and was treated with Si-Thiol (Biotage, 15 g, 19.5 mmol) at RT for 17 h. The mixture was filtered and the solvent was evaporated off under reduced pressure to give a residue which was crystallized from MeOH to give the title compound as a white crystalline solid. HPLC (Condition 5) tR=5.99 min, UPLC-MS (Condition 6) m/z=518.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.42 (br. s, 3H) 1.63-1.98 (m, 4H) 2.20-2.37 (m, 1H) 2.71-2.94 (m, 1H) 3.21 (d, J=6.65 Hz, 3H) 3.32-3.51 (m, 1H) 3.69-3.92 (m, 1H) 4.08-4.24 (m, 1H) 4.75-4.88 (m, 1H) 4.89-5.17 (m, 1H) 6.29-6.49 (m, 1H) 7.32 (d, J=8.99 Hz, 2H) 7.59 (s, 1H) 7.78-8.10 (m, 3H) 8.80 (t, J=2.54 Hz, 1H) 10.05-10.28 (m, 1H).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:18][C:17]3[CH:29]=[CH:30][CH:31]=[N:32][C:16]2=3)[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)(=O)C.[ClH:33]>CO>[ClH:33].[ClH:33].[NH2:4][C:5]1[CH:6]=[C:7]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:18][C:17]3[CH:29]=[CH:30][CH:31]=[N:32][C:16]2=3)[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1
Reactant: COC(=O)c1cc(NC(C)=O)cc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(N)cc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1

Procedure:
A mixture of 4-(3-acetylamino-5-methoxycarbonylphenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (847 mg) and hydrochloric acid (35%, 1 ml) in methanol (10 ml) was stirred under reflux for 2 hours. After cooling, the resultant precipitate was collected and washed with methanol to give 4-(3-amino-5-methoxycarbonylphenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazinedihydrochloride (612 mg).
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][C:5]1([CH3:14])[O:7][CH:6]1[CH2:8][CH2:9][C:10]([CH:12]=[CH2:13])=[CH2:11].[NH4+].[Cl-]>O1CCCC1.C(OC(C)C)(C)C>[CH3:4][C:5]([OH:7])([CH:6]([CH3:1])[CH2:8][CH2:9][C:10](=[CH2:11])[CH:12]=[CH2:13])[CH3:14]
Reactant: C=CC(=C)CCC1OC1(C)C
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: C=CC(=C)CCC(C)C(C)(C)O
Temperature: 25 °C
Reaction time: 23 h
Yield: 96.6 %

Procedure:
1230 ml of a solution of CH3MgCl 3M in tetrahydrofurane (Fluka) was added to 26.5 g of CuBr (Fluka) in 11 of diisopropylether with stirring at 0° (bath temperature). After one night, the reaction mixture was cooled to −20° and 467 g of epoxymyrcene [2-(3,4-epoxy-4-methylpentyl)-1,3-butadiene] in 4 l of isopropylether were added dropwise. After the addition, the reaction mixture was warmed to room temperature. After 23 h the reaction was completed. After hydrolysis with a 15% NH4Cl-solution and washing with brine, the product was distilled to obtain 96.6% pure 2,3-dimethyl-6-methylene-7-octen-2-ol with a yield of 453.7 g (88%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[Cl:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[N:21]([S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[C:22]([C:24]3[C:28]4=[N:29][C:30]([O:35][CH3:36])=[C:31]([O:33][CH3:34])[CH:32]=[C:27]4[N:26]([CH2:37][CH2:38]I)[CH:25]=3)=[CH:23][C:16]=12>CC#N>[Cl:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[N:21]([S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[C:22]([C:24]3[C:28]4=[N:29][C:30]([O:35][CH3:36])=[C:31]([O:33][CH3:34])[CH:32]=[C:27]4[N:26]([CH2:37][CH2:38][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:25]=3)=[CH:23][C:16]=12
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCI
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCN1CCN(C)CC1
Temperature: 60 °C
Yield: 167.9 %

Procedure:
Add 1-methylpiperazine (3.5 equiv., 35.2 mg, 39.1 μmol, 0.352 mmol) and K2CO3 (13.8 mg, 0.10 mmol) to bisazaindole 32 (64 mg, 0.10 mmol) in CH3CN (6.0 mL). After heating at 60° C. for 48 h, the reaction medium is concentrated under vacuum and the residue of raw product is submitted to flash chromatography on SiO2 (MeOH at 2-4%/CH2Cl2/heptane) to give 35 (40 mg, 64.3%) as a white solid: 1H NMR (CDCl3) δ 8.23 (d, 1H, J=5.4 Hz), 7.68 (d, 2H, J=8.1 Hz), 7.61 (s, 1H), 7.10 (m, 5H), 4.25 (t, 2H, J=6.6 Hz), 4.01 (s, 3H), 3.97 (s, 3H), 2.83 (t, 2H, J=6.9 Hz), 2.57-2.46 (m broad, 8H), 2.28 (s, 3H), TLC (MeOH at 10%/CH2Cl2, 0.25% of NH3) Rf=0.45, m/z obs.=609.04 (M+1).