Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([O:13][C:14]2[CH:15]=[CH:16][C:17]([F:24])=[C:18]([CH:23]=2)[C:19]([O:21][CH3:22])=[O:20])=[N:4][N:3]=1.C(O)(=[O:27])C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[C:5]([O:13][C:14]1[CH:15]=[CH:16][C:17]([F:24])=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20])=[N:4][NH:3][C:2]2=[O:27]
Reactant: COC(=O)c1cc(Oc2nnc(Cl)c3cccc(Cl)c23)ccc1F
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Oc2n[nH]c(=O)c3cccc(Cl)c23)ccc1F

Procedure:
Methyl 5-((4,8-dichlorophthalazin-1-yl)loxy)-2-fluorobenzoate (5d) (700 mg, 1.9 mmol), acetic acid (20 mL) and sodium acetate (420 mg, 3 mmol) were added into a reaction flask successively, the mixture was refluxed for one hour, and diluted with 50 mL ethyl acetate. The reaction solution was washed with 50 mL saturated sodium bicarbonate solution and saturated sodium chloride solution successively for three times, the organic layers were combined, concentrated and dried to give methyl 5-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)-2-fluorobenzoate (5e), 650 mg white solid (yield 95%). 1H NMR (600 MHZ, DMSO-d6): δ 12.12 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.95-8.00 (m, 1H), 7.83-7.87 (m, 1H), 7.74-7.77 (m, 1H), 7.61-7.64 (m, 1H), 7.42-7.47 (m, 1H), 3.86 (s, 3H); ESI-MS m/z; calculated for 348.0. found 371.6 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[O:20][CH3:21].[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[N:33]=1)[C:28](O)=[O:29]>>[CH3:1][O:2][C:3](=[O:22])[CH2:4][N:5]([C:28]([C:27]1[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[N:33]=[C:25]([C:24]([F:39])([F:23])[F:38])[CH:26]=1)=[O:29])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[O:20][CH3:21]
Reactant: COC(=O)CNc1cnccc1-c1cc(F)c(F)cc1OC
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1)c1cnccc1-c1cc(F)c(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester (example 172, intermediate a) and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:80). Colorless solid (48%). MS (ESI): m/z=550.102 [M+H]+.
Reaction SMILES: [OH-].[NH4+:2].Cl[C:4]([CH:6]([CH3:28])[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=2[N:11]=[C:10]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:5]>CO>[C:4]([CH:6]([CH3:28])[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=2[N:11]=[C:10]1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)(=[O:5])[NH2:2]
Reactant: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(N)=O
Temperature: 25 °C
Reaction time: 64 h
Yield: 73 %

Procedure:
In an ammonium hydroxide solution (28%, 10 ml) was placed 1-[3-(chlorocarbonyl)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (400 mg, 1.0 mmol). To this mixture 10 ml of methanol were added, to enhance solubility and the mixture was stirred for about 64 hours at room temperature. The reaction mixture was then concentrated under reduced pressure to produce a tan foam. The crude material was further purified by flash silica gel chromatography, eluting with a gradient solvent of 19:1 ethyl acetate:methanol to 9:1 ethyl acetate:methanol. The fractions containing the desired material were combined and concentrated in vacuo to yield 300 mg (73%) of the desired title compound as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]2=[C:15]3[N:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]3=[CH:5][C:4]=1[CH:16]=[CH:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1.[C:25]([C:27]1[C:28](=[C:35]([C:38]#[N:39])[C:36]#[N:37])[O:29][C:30]([CH3:34])([CH3:33])[C:31]=1[CH3:32])#[N:26].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[C:25]([C:27]1[C:28](=[C:35]([C:36]#[N:37])[C:38]#[N:39])[O:29][C:30]([CH3:33])([CH3:34])[C:31]=1[CH:32]=[CH:23][C:21]1[S:22][C:18]([CH:17]=[CH:16][C:4]2[CH:5]=[C:6]3[C:15]4[N:10]([CH2:9][CH2:8][CH2:7]3)[CH2:11][CH2:12][CH2:13][C:14]=4[C:3]=2[O:2][CH3:1])=[CH:19][CH:20]=1)#[N:26]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: COc1c(C=Cc2ccc(C=O)s2)cc2c3c1CCCN3CCC2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1c(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)s2)cc2c3c1CCCN3CCC2
Temperature: 25 °C
Reaction time: 42 h
Yield: 61.3 %

Procedure:
In 5 ml of ethanol and 1.5 ml of tetrahydrofuran were dissolved 158 mg (0.47 mmol) of 5-[2-(8-methoxy-2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine-9-yl)vinyl]thiophene-2-carboaldehyde and 102 mg (0.51 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. To this mixture was added 36 mg of ammonium acetate, and the mixture was stirred at room temperature for 42 hours. The crystal was filtrated and washed with ethanol. The residue was purified by silica gel column chromatography and washed with ethanol to give 150 mg of a black powdered crystal (yield: 62.0%; mp: 201-204° C.).
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:30]O>>[CH3:30][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:2]=1[F:1]
Reactant: CO
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Yield: 81 %

Procedure:
To 2-fluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoic acid (31, 4.0 g, 11 mmol) in 40 mL of methanol, sulfuric acid (8.8 mL, 0.16 mol) was added and the reaction mixture was refluxed overnight. The resulting reaction mixture was concentrated under vacuum, and the residue was combined with 5% aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (32, 3.35 g, 81%). MS(ESI) [M−H+]−=376.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([NH2:22])(=[O:21])=[O:20]>N1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([NH2:22])(=[O:20])=[O:21])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1cccc(Br)c1
Reaction time: 4 h
Yield: 47.6 %

Procedure:
3-Bromo-benzenesulfonyl chloride (8.34 mL, 57.9 mmol) was added to a solution of 2-amino-benzenesulfonamide (9.965 g, 57.9 mmol) dissolved in pyridine (90 mL). The reaction was stirred for 4 h followed by solvent removal under vacuo. The reaction mixture was added to water and the product was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated to furnish a dark yellow oil. The oil was dissolved in EtOAc and precipitated by addition of heptane. The solid was finally recrystallized from EtOH to give the title compound (10.784 g, 48%) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1([C:13]#[N:14])[CH2:10][CH:9]2[CH2:11][CH2:12][CH:6]1[CH2:7][CH2:8]2)(=[O:3])[CH3:2].[C:15](O)(=[O:17])[CH3:16]>C(OC(=O)C)(=O)C.[Pt]=O>[C:1]([NH:4][C:5]1([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[CH2:10][CH:9]2[CH2:11][CH2:12][CH:6]1[CH2:7][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)NC1(C#N)CC2CCC1CC2
Agent: O=[Pt]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NCC1(NC(C)=O)CC2CCC1CC2

Procedure:
The procedure is as in Example 1, but starting from 2-acetylamino-2-cyano-bicyclo[2.2.2]octane (5.8 g) in acetic acid (100 cc) and acetic anhydride (5.6 cc) in the presence of Adams platinum oxide (0.6 g); chromatographing the residue from the evaporation on a column 5.5 cm in diameter containing silica gel (200 g), eluting with a mixture of ethyl acetate and ethanol (75/25 by volume) and collecting fractions of 50 cc. The fractions between 800 and 1750 cc are concentrated to dryness; 2-acetylamino-2-acetylaminomethyl-bicyclo[2.2.2]octane (5.45 g) is thus obtained in the form of a pale yellow viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:8][CH:9]=1)([O-])=O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C.Cl.O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccn2)nc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(OCc2ccccn2)nc1
Temperature: 50 °C
Yield: 77.7 %

Procedure:
5-Nitro-2-(pyridin-2-ylmethyloxy)pyridine (D1, 2.0 g, 0.0087 mole) in ethanol (70 ml) was treated with tin (II) chloride (8.3 g, 0.044 mole) in conc. HCl (15 ml). The mixture was heated to 50° C. for 0.5 hour. After cooling to room temperature, the mixture was diluted with water, basified with 10% aqueous sodium hydroxide solution, extracted into ethyl acetate, dried (Na2SO4) and evaporated in vacuo to afford the title compound (1.36 g, 78%) as a brown oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[O:16]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1F
Reactant: Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Oc1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 2-fluorobenzaldehyde (0.5 ml) in dimethylformamide (5 ml), 676 mg of phenol and 993 mg of potassium carbonate were added, and the reaction solution was stirred overnight at 100° C. The reaction solution was cooled, then 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-50/50)) to afford the title compound as a pale yellow oil.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[C:17]3[S:25][C:24]([CH2:26][O:27][N:28]=[C:29]([CH3:31])[CH3:30])=[N:23][C:18]=3[CH:19]=[N:20][C:21]=2[CH:22]=1>C(Cl)(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[C:17]3[S:25][C:24]([CH2:26][O:27][N:28]=[C:29]([CH3:31])[CH3:30])=[N:23][C:18]=3[CH:19]=[N+:20]([O-:9])[C:21]=2[CH:22]=1
Reactant: CC(C)=NOCc1nc2cnc3cc(Br)ccc3c2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)=NOCc1nc2c[n+]([O-])c3cc(Br)ccc3c2s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
mCPBA (5.50 g of 77% purity, 24.6 mmol) was added to a solution of acetone O-(7-bromo[1,3]thiazolo[4,5-c]quinolin-2-ylmethyl)oxime (3.44 g, 9.82 mmol) in chloroform (100 mL), and the reaction was stirred for 1.5 hours at room temperature and subsequently washed with aqueous sodium carbonate (100 mL of 10% w/w). The organic layer was dried over magnesium sulfate and filtered to provide a solution of acetone O-(7-bromo-5-oxido[1,3]thiazolo[4,5-c]quinolin-2-ylmethyl)oxime in chloroform.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:35][C@H:36]1[CH2:41][C:40]2[C:42]([N:46]3[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]3)=[CH:43][CH:44]=[CH:45][C:39]=2[O:38][CH2:37]1>CN(C)C=O>[CH3:52][N:49]1[CH2:50][CH2:51][N:46]([C:42]2[C:40]3[CH2:41][C@H:36]([NH:35][C:18](=[O:19])[C:17]4[CH:21]=[CH:22][C:14]([N:11]5[CH2:10][CH2:9][N:8]([CH2:1][C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=6)[CH2:13][CH2:12]5)=[CH:15][CH:16]=4)[CH2:37][O:38][C:39]=3[CH:45]=[CH:44][CH:43]=2)[CH2:47][CH2:48]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: O=C(O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCN(Cc5ccccc5)CC4)cc2)CO3)CC1
Temperature: 75 °C
Reaction time: 20 h

Procedure:
A suspension of 4-(4-benzylpiperazin-1-yl)benzoic acid (1.3 g, 4.2 mmol) and 1,1′-carbonyldiimidazole (740 mg, 4.2 mmol) in N,N-dimethylformamide (30 mL) was heated to 75° C. for 1.5 h. The reaction mixture was cooled to 50° C. and a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4 dihydro-2H-1-benzopyran (1.0 g, 4.0 mmol) was added. The solution was stirred at 50° C. for 20 h and the solvent was evaporated in vacuo giving 3.5 g of a crude product. Purification by chromatography on a silica gel column using chloroform/methanol/concentrated ammonia 95:5:0.5 as the eluent gave 1.7 g (80% yield) 25 of the title compound as a pale yellow solid: mp sinters >85° C.; TSPMS m/z (relative intensity) 526 (100, M+1); [α]22D −130° (c 1.0, chloroform).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=O)[CH3:2].[OH:8][C:9]1[CH:14]=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:12]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])=[CH:11][C:10]=1C(C)=O.C([O-])(=O)C.[Na+].C(OCC)(=O)C>O>[CH3:19][S:16]([NH:15][C:13]1[C:12]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])=[CH:11][C:10]2[C:9](=[O:8])[CH:14]=[C:5]([CH3:6])[O:4][C:1]=2[CH:2]=1)(=[O:17])=[O:18]
Reactant: CC(=O)c1cc(Oc2ccc(F)cc2F)c(NS(C)(=O)=O)cc1O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(=O)c2cc(Oc3ccc(F)cc3F)c(NS(C)(=O)=O)cc2o1
Yield: 14.4 %

Procedure:
1.06 ml of acetic anhydride was added to 2.0 g of methyl 2-hydroxy-4-methylsulfonylamino-5-(2,4-difluorophenoxy)phenyl ketone and 550 mg of sodium acetate. The mixture was refluxed for 1 hour. The reaction mixture was introduced into a mixture of 50 ml of ethyl acetate and 50 ml of water. The organic layer was separated and washed with water. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 20 ml of ethanol. 12 ml of a 1N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed for 10 minutes. The reaction mixture was introduced into a mixture of 50 ml of ethyl acetate and 50 ml of water. The resulting mixture was adjusted to pH 2.0 with 4N hydrochloric acid. The organic layer was separated, washed with water, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 10 : 1 mixture of toluene and ethyl acetate) to obtain 300 mg (yield: 14.4%) of 7-methylsulfonylamino-2-methyl-6-(2,4-difluorophenoxy)-4H-1-benzopyran-4-one.
Reaction SMILES: C(OC1C=CC=CC=1CN(CC1C=CC=CN=1)CCCCCCC1CCC(C2C=CC=CC=2OC)CC1)(C)(C)C.Br[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][N:48]([CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[O:63][C:64]([CH3:67])([CH3:66])[CH3:65])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1.[CH3:68][O:69][C:70]1[CH:71]=[C:72]2[C:77](=[CH:78][C:79]=1[O:80][CH3:81])[CH2:76][NH:75][CH2:74][CH2:73]2>>[C:64]([O:63][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=1[CH2:56][N:48]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][N:75]1[CH2:74][CH2:73][C:72]2[C:77](=[CH:78][C:79]([O:80][CH3:81])=[C:70]([O:69][CH3:68])[CH:71]=2)[CH2:76]1)([CH3:67])([CH3:66])[CH3:65]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: CC(C)(C)Oc1ccccc1CN(CCCCCCBr)Cc1ccccn1
Agent: COc1ccccc1C1CCC(CCCCCCN(Cc2ccccn2)Cc2ccccc2OC(C)(C)C)CC1
Product: COc1cc2c(cc1OC)CN(CCCCCCN(Cc1ccccn1)Cc1ccccc1OC(C)(C)C)CC2
Yield: 99 %

Procedure:
The same procedure as described for compound 11 was applied to starting material 10 (0.4 g, 0.92 mmol) and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (0.267 g, 1.38 mmol). Purification was carried out on a silica gel TLC plate that was developed in with a 4.5% methanolic NH3 (7 M NH3 in methanol/94.5% CH2Cl2. The product was isolated as pale yellow oil (99%). 1H NMR (CDCl3) δ 8.463 (dt, 1H, Ar), 7.574 (m, 3H, Ar), 7.082 (m, 2H, Ar), 6.996 (m, 2H, Ar), 6.552 (s, 1H, Ar), 6.486 (s, 1H, Ar), 3.797 (s, 3H, —OCH3), 3.792 (s, 3H, —OCH3), 3.723 (s, 2H, —CH2—), 3.646, (s, 2H, —CH2—), 3.504 (s, 2H, —CH2—), 2.784 (t, 2H, —CH2—), 2.655 (t, 2H, —CH2—), 2.430 (m, 4H, —CH2—CH2—), 1.521 (m, 4H, —CH2—CH2—), 1.333 (s, 9H, —C(CH3)3—), 1.264 (m, 4H, —CH2—CH2—). Mass Spec=546.37 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]([OH:11])=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.S(Cl)([Cl:14])=O>CN(C)C=O>[CH3:1][O:2][C:3]1([C:9]([Cl:14])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC1(C(=O)O)CCCCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC1(C(=O)Cl)CCCCC1

Procedure:
76 g (480 mmoles) of 4 methoxycyclohexane carboxylic acid (cis/trans mixture) were boiled for 7 hours with refluxing in 350 ml of thionyl chloride to which several drops of dimethyl formamide had been added. The obtained 4 methoxycyclohexane carboxylic acid chloride was composed almost completely of the trans compound. After distilling off of the thionyl chloride the residue was incorporated into 75 ml of dry tetrahydrofuran. At a temperature of from 0° to 5° C. this solution was slowly added dropwise to a solution of 158.4 g (1440 mmoles) of hydroquinone in 650 ml of tetrahydrofuran and 375 ml of pyridine. When, after this addition, the mixture had attained room temperature, it was poured onto ice and concentrated sulphuric acid. Extraction with dichloromethane, evaporation of the dichloromethane, and, in succession, conversion of the evaporation residue to the crystallised form from an ethanol-water mixture and from toluene gave a yield of 24.45 g (20%) of pure trans 4 hydroxyphenyl 4'methoxycyclohexyl carboxylate. 24.3 g (97 mmoles) of the above compound were boiled, with refluxing, for 24 hours with 17.6 g of allyl bromide (145 mmoles) and 13.4 g (97 mmoles) of potassium carbonate in 350 ml of methylethyl ketone. After cooling the reaction mixture was poured into 1 .right brkt-top.of ice water, which was extracted with the aid of diethyl ether. After drying and evaporation of the diethyl ether 28.9 g (97%) of 4 allyloxyphenyl 4'methoxycyclohexyl carboxylate were obtained. To 28.7 g (99 mmoles) of said compound in 250 ml of dichloromethane there were added 32.9 g of chloroperbenzoic acid, and the mixture was stirred for 24 hours under an atmosphere of nitrogen. After being diluted with dichloromethane the reaction mixture was washed with sodium carbonate solution and water. After drying the dichloromethane was distilled off, and the residue was purified on a column filled with silica gel and eluted with a hexane-ethyl acetate mixture (75/25). The yield was 20.8 g (66%) of 4(2,3 epoxypropyl oxy)phenyl 4'methoxycyclohexyl carboxylate.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[C:14]([C:27]#[N:28])=[N:15][CH:16]=[C:17]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]4[NH2:26])[N:18]=3)[CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1.[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[N:1]1[N:2]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[C:14]([C:27]([NH2:28])=[O:35])=[N:15][CH:16]=[C:17]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]4[NH2:26])[N:18]=3)[CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-n2nccn2)c1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-n2nccn2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The compound 3-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-((1R,2S)-2-aminocyclohexylamino)pyrazine-2-carbonitrile (28 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (26 mg). MS 394.4 (M+H); UV 201.7, 262.8, 304.6, 359.2 nm; t 0.520 min.
Reaction SMILES: COC([C:5]1[C:6]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[N:13]=2)[CH:8]=[CH:9][N:10]=1)=O.CO.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:12]1[N:13]=[C:6]2[CH:5]=[N:10][CH:9]=[CH:8][N:7]2[CH:11]=1
Reactant: COC(=O)c1nccn2cc(-c3ccc(F)cc3F)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Fc1ccc(-c2cn3ccncc3n2)c(F)c1
Temperature: 105 °C
Yield: 70.2 %

Procedure:
2-(2,4-Difluorophenyl)-imidazo[1,2-a]pyrazine-8-carboxylic acid methyl ester (prepared from general procedure B using 3-aminopyrazine-2-carboxylic acid methyl ester and 2-bromo-1-(2,4-difluorophenyl)-ethanone; 5.0 g, 17 mmol) was dissolved in DCM (30 mL) and MeOH (30 mL) and was treated with 1.0 M aqueous HCl (160 mL). The mixture was heated at about 105° C. for about 13 h, allowed to cool to ambient temperature, and neutralized with NaHCO3. The solid was filtered and dried overnight to yield the title compound (2.76 g, 70%): LC/MS (Table 1, Method b) Rt=1.9 min; MS m/z: 232.0 (M+H)+.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([O:51][CH2:52][C:53]([F:56])([F:55])[F:54])=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[O:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:67][C:68]1[O:69][C:70]2[CH:76]=[CH:75][CH:74]=[CH:73][C:71]=2[N:72]=1>>[O:69]1[C:70]2[CH:76]=[CH:75][CH:74]=[CH:73][C:71]=2[N:72]=[C:68]1[S:67][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([O:51][CH2:52][C:53]([F:56])([F:54])[F:55])=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[O:44][CH2:45][C:46]([F:47])([F:48])[F:49])=[O:36])[CH2:30][CH2:29]1
Reactant: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCO)CC2)c(OCC(F)(F)F)n1
Reactant: Sc1nc2ccccc2o1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCSc3nc4ccccc4o3)CC2)c(OCC(F)(F)F)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercaptobenzoxazole, to thereby yield the title compound as a colorless crystalline powder.
Reaction SMILES: [OH:1][C:2]12[C:14](=[O:15])[C:10](=[CH:11][CH2:12][CH2:13]1)[CH:9]([OH:16])[C:8]#[C:7][CH:6]=[CH:5][C:4]#[C:3]2.CN(C1C=CC=CN=1)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:16][CH:9]1[C:10]2[C:14](=[O:15])[C:2]([OH:1])([CH2:13][CH2:12][CH:11]=2)[C:3]#[C:4][CH:5]=[CH:6][C:7]#[C:8]1)(=[O:28])[CH3:27]
Reactant: O=C1C2=CCCC1(O)C#CC=CC#CC2O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CC(=O)OC1C#CC=CC#CC2(O)CCC=C1C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of 1,8-dihydroxy-bicyclo[7.3.1]trideca-4,9-diene-2,6-diyn-13-one (product of Example 4, 32 mg, 0.149 mmol) in 1 ml of pyridine Was added dimethylaminopyridine and 1 eq of acetic anhydride (14 ul, 0.149 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and then pyridine was stripped off on rotovap and on high vacuum. This residue was purified on a silica gel column using 10% and 20% ethyl acetate/hexane mixture as the solvent system. The title compound was obtained as light yellow foam in 85% yield (32.4 mg).