Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[CH:15](Br)[CH3:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[O:26][C:22]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[CH:15]([NH:19][C:20]2[CH:29]=[CH:28][C:23]3[NH:24][C:25](=[O:27])[O:26][C:22]=3[CH:21]=2)[CH3:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: CC(Br)C(=O)N1CCC(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Nc1ccc2[nH]c(=O)oc2c1)C(=O)N1CCC(Cc2ccccc2)CC1
Yield: 36.4 %

Procedure:
A mixture of 1.03 g (3.33 mmol) of 1-(4-benzyl-piperidine-1-yl)-2-bromo-propan-1-one, 0.5 g (3.33 mmol) of 6-amino-3H-benzoxazol-2-one, 1.0 g (7.2 mmol) of potassium carbonate and 15 ml of dimethylformamide is refluxed for 5 hours. The reaction mixture is filtered and the filtrate is concentrated. The residue is purified by column chromatography using Kieselgel 60 adsorbent (Merck) and hexane:ethyl acetate=4:1 as eluent to yield 0.46 g (36.5%) of the title compound. Melting Point: 91° C. (hexane)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[NH2:20])[CH:8]([O:21][CH3:22])[CH2:7]1)=[O:5])[CH3:2].C([O-])(O)=O.[Na+]>C(O)(=O)C(C)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[N:20]=[C:15]2[CH:16]([CH3:19])[CH3:17])[CH:8]([O:21][CH3:22])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(Nc2ccc(C)cc2N)C(OC)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)C(=O)O
Product: CCOC(=O)N1CCC(n2c(C(C)C)nc3cc(C)ccc32)C(OC)C1
Temperature: 25 °C
Yield: 106 %

Procedure:
A solution of 4-(2-amino-4-methyl-phenylamino)-3-methoxy-piperidine-1-carboxylic acid ethyl ester (750 mg, 2.44 mmol) in isobutyric acid (15 mL) was subjected to microwave irradiation for 1 h with a resulting temperature of 180° C. The reaction mixture was cooled to rt and then diluted with CH2Cl2 (150 mL) and a saturated NaHCO3 solution (200 mL). The aqueous layer was extracted twice with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (15/1 CH2Cl2/CH3OH) to yield 4-(2-isopropyl-5-methyl-benzoimidazol-1-yl)-3-methoxy-piperidine-1-carboxylic acid ethyl ester (465 mg, 56%) as a waxy solid.
Reaction SMILES: Cl[Sn]Cl.O.[Cl:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH3:14])[C:9]([N+:15]([O-])=O)=[CH:8][CH:7]=1.O.[OH-].[Na+]>Cl.CC(O)=O>[NH2:15][C:9]1[C:10]([NH:12][CH2:13][CH3:14])=[N:11][C:6]([Cl:5])=[CH:7][CH:8]=1
Reactant: CCNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCNc1nc(Cl)ccc1N
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 62.4 %

Procedure:
A solution of SnCl2.H2O (616.3 g, 2.73 mol) in aqueous 12 N HCl (500 mL) was rapidly added to a solution of 6-chloro-2-(ethylamino)-3-nitropyridine (169.5 g, 0.84 mol) in AcOH (1.7 L) at room temperature. After 20 min, the mixture was cooled to 0° C. and water (250 mL) was added. Solid NaOH (240 g) was then added in small portions. The resulting suspension was filtered to remove tin salts. The filtrate was diluted with water (3.5 L), the solution rendered basic by addition of aqueous 10 N NaOH and then extracted with EtOAc (3×1.7 L). The combined organic layers were washed with brine (1 L), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:EtOAc, 3:2) to give the title compound (89.9 g, 62% yield) as a brown solid: MS (ESI) m/z 172/174 (MH)+.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][N:15]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[S:28][C:29]6[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=6[N:31]=5)=[CH:22][CH:21]=4)[CH2:16]3)[CH2:12]2)=[CH:6][CH:5]=1.O.[OH-].[K+].Cl>C(O)(C)C.C(Cl)Cl>[S:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:15]2[CH2:14][CH:13]3[CH2:12][N:11]([CH2:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:36])=[O:2])=[CH:9][CH:8]=4)[CH2:18][CH:17]3[CH2:16]2)=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(CN2CC3CN(Cc4ccc(Oc5nc6ccccc6s5)cc4)CC3C2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1ccc(CN2CC3CN(Cc4ccc(Oc5nc6ccccc6s5)cc4)CC3C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.9 %

Procedure:
To a solution of 4-{5-[4-(benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-benzoic acid methyl ester (58.5 mg, 0.12 mmol, 1 equiv) in isopropanol (2.5 mL) was added water (1.1 mL) followed by the addition of aq. KOH (13 mg in 2.5 mL water). The reaction stirred at rt for 16 h. The reaction mixture was acidified to pH 6 with 6 N HCl, and CH2Cl2 was added. The layers were separated and the aqueous layer was extracted with 25% isopropanol/CH2Cl2 (2×10 mL). The combined organics were dried, filtered and concentrated to afford the title compound (32 mg, 56%). MS (ESI): mass calcd. for C28H27N3O3S, 485.61; m/z found, 486.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.01 (d, J=8.2 Hz, 2H), 7.71 (m, 2H), 7.52-7.44 (m, 4H), 7.43-7.34 (m, 4H), 3.95 (m, 4H), 3.13 (s, 3H), 2.81 (m, 5H), 2.03 (s, 1H), 1.27 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([N+:14]([O-])=O)[CH:7]=1.C(O)(=O)C>ClCCl.[Zn]>[CH3:1][O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([NH2:14])[CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(OC)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc(OC)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (E)-3-(4-methoxy-3-nitro-phenyl)-acrylic acid methyl ester (0.5 g) in dichloromethane (5 mL) was added zinc dust (2 g), followed by acetic acid (1 mL) and the resulting mixture was stirred at room temperature for 30 minutes. The solid was filtered off and washed with dichloromethane. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography (DCM/acetone, 95/5) to give (E)-3-(3-amino-4-methoxy-phenyl)-acrylic acid methyl ester.
Reaction SMILES: [O-]CC.[K+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[N:17]=1>C(OCC)C.C(O)C>[CH2:13]([O:12][C:5](=[O:11])[C:6](=[O:8])[CH2:25][C:18]1[N:17]=[C:16]([Cl:15])[CH:21]=[CH:20][C:19]=1[N+:22]([O-:24])=[O:23])[CH3:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of potassium ethoxide (134 mg, 1.59 mmol) in diethyl ether (5 mL) and ethanol (1 mL) was added diethyl oxalate (218 μL, 1.59 mmol) in one portion and the resulting solution was stirred for 30 min at rt. 2-Chloro-6-methyl-5-nitropyridine (Preparation 3, 250 mg, 1.45 mmol) was added as a suspension in diethyl ether (2 mL, anhydrous) and stirring was continued for 17 h at rt. The mixture was filtered on a sinter, washing with cold diethyl ether. The collected precipitate was dissolved in glacial acetic acid then evaporated to dryness in vacuo to give the title compound as a brown powder. δH (CDCl3): 1.40 (3H, t, 7.27 Hz), 4.38 (2H, q, 7.25 Hz), 7.33 (1H, d, 8.59 Hz), 7.37 (1H, s), 8.40 (1H, d, 8.86 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[Cl:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[O:25][CH2:24][CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4cccc(Cl)c4)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4cccc(Cl)c4)cc3)c2cc1OC
Temperature: 0 °C
Yield: 79.9 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-(3-chlorophenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 452 (M++1)
Reaction SMILES: [CH3:1][N:2]([CH3:26])[S:3]([C:6]1[CH:7]=[C:8]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]1[CH:13]=[N:12][C:11]([C:19]3[O:23][N:22]=[C:21]([CH2:24][CH3:25])[N:20]=3)=[CH:10][C:9]2=1)(=[O:5])=[O:4].[H-].[Na+].Br[CH2:30][CH2:31][CH2:32][Cl:33]>CN(C=O)C>[Cl:33][CH2:32][CH2:31][CH2:30][N:15]1[C:14]2[CH:13]=[N:12][C:11]([C:19]3[O:23][N:22]=[C:21]([CH2:24][CH3:25])[N:20]=3)=[CH:10][C:9]=2[C:8]2[C:16]1=[CH:17][CH:18]=[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:26])[CH3:1])[CH:7]=2
Reactant: ClCCCBr
Reactant: CCc1noc(-c2cc3c(cn2)[nH]c2ccc(S(=O)(=O)N(C)C)cc23)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1noc(-c2cc3c4cc(S(=O)(=O)N(C)C)ccc4n(CCCCl)c3cn2)n1
Yield: 7 %

Procedure:
The compound was synthesized by mixing (Compound 12) (3.0 g, 8.8 mM), NaH (0.46 g, 11.0 mmol) and 1-bromo-3-chloropropane (1.5 g, 9.7 mmol) in DMF, in the same manner as illustrated in example 3 to give the title compound (0.25 g, 7%). M.p. 223°-224° C.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:45][N:46]1[CH:50]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH:48]=[N:47]1.CCOC(C)=O>COCCOC.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>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH2:10][C:6]2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]3[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=[C:2]([C:49]3[CH:48]=[N:47][N:46]([CH3:45])[CH:50]=3)[C:7]=2[C:8]1=[O:22]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (200 mg, 0.364 mmol), sodium carbonate (77 mg, 0.729 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (91 mg, 0.437 mmol) and bis(triphenylphosphine)palladium chloride (25.6 mg, 0.036 mmol) in DME (2 mL) and H2O (0.667 mL) was stirred at 85° C. for 2 h. To the resulting mixture was added EtOAc. The aqueous phase was extracted with EtOAc. The organic phases were combined, washed with brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2(Hexane/EtOAc=2/3) to give the title compound as a yellow oil (88 mg, 40.6%). 1H NMR (500 MHz, CDCl3) δ ppm 1.28-2.01 (m, 17 H), 3.80 (d, J=2.93 Hz, 3 H), 3.85 (s, 3 H), 3.91-4.01 (m, 4 H), 4.23 (br s, 2 H), 4.41 (br s, 1 H), 4.68 (d, J=1.95 Hz, 2 H), 5.36 (br s, 1 H), 6.36-6.54 (m, 2 H), 7.15-7.21 (m, 1 H), 8.26 (br s, 1 H), 9.02 (br s, 1 H). [M+H] calc'd for C31H39FN6O5, 595; found, 595.
Reaction SMILES: [C:1]1([C@@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18].O>ClC(Cl)C>[C:1]1([C@@H:7]([NH:9][C:17](=[O:19])[CH3:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(=O)N[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-(−)-1-phenylethylamine (121 g) and triethylamine (168 ml) in dichloroethane (1200 ml) was added dropwise acetyl chloride (78.2 ml) over 1 hr under ice-cooling and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water (1000 ml) and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (143.4 g) as pale-yellow crystals, m.p.=99-101° C.
Reaction SMILES: [Cl:1][C:2]([Cl:19])([F:18])[S:3][C:4]1[CH:5]=[N:6][N:7](CC2C=CC(OC)=CC=2)[CH:8]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>>[Cl:1][C:2]([Cl:19])([F:18])[S:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1
Reactant: COc1ccc(Cn2cc(SC(F)(Cl)Cl)cn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: FC(Cl)(Cl)Sc1cn[nH]c1
Temperature: 65 °C
Reaction time: 3 h
Yield: 29.2 %

Procedure:
1.04 g of 4-{[dichlorofluoromethyl]thio}-1-(4-methoxybenzyl)-1H-pyrazole was dissolved to 6 ml of trifluoroacetic acid, followed by stirring at 65° C. for 3 hours. After the reaction mixture was cooled to room temperature, it was added to saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.19 g of 4-{[dichlorofluoromethyl]thio}-1H-pyrazole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:18][C:19]1[CH:36]=[CH:35][C:22]([CH2:23][CH2:24][NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH2:24][NH:25][C:26]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:8]3[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][C:3]=3[C:1]#[N:2])=[CH:29][CH:28]=2)=[O:34])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 39.7 %

Procedure:
A mixture of tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (1.32 g, 5.59 mmol), N-(4-chlorophenethyl)-4-hydroxybenzamide (1.85 g, 671 mmol), and potassium carbonate (0.93 g, 6.70 mmol) in DMSO (10 ml) was stirred at 90° C. for 1 day. The reaction was cooled, diluted with ethyl acetate, and washed with 10% aqueous Na2CO3. The aqueous layer was back extracted with ethyl acetate. The organic washes were combined, washed with 10% Na2CO3 and brine, dried over sodium sulfate and concentrated. The crude material was purified by silica gel chromatography, eluting with a gradient of 5% ethyl acetate/hexanes to 60% ethyl acetate/hexanes gave tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)acetate (1.09 g, 40%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[N:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][N:29]=1>CN(C=O)C>[CH:35]([O:34][C:31]1[N:32]=[CH:33][C:28]([CH2:27][O:1][C:2]2[CH:10]=[CH:9][C:8]3[NH:7][C:6]4[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=4[C:4]=3[CH:3]=2)=[N:29][CH:30]=1)([CH3:37])[CH3:36]
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: CC(C)Oc1cnc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3cnc(OC(C)C)cn3)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.9 %

Procedure:
Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (0.035 g, 0.135 mmol) and cesium carbonate (0.048 g, 0.148 mmol) were dissolved in DMF (0.5 mL) and stirred at room temperature for 5 min. To this mixture at 0° C. was added a solution of 2-(bromomethyl)-5-isopropoxypyrazine (0.034 g, 0.148 mmol) in DMF (0.20 mL) and was stirred at room temperature for 60 h. The solids were removed by filtration. The filtrate was purified by HPLC to give ethyl 2-(7-((5-isopropoxypyrazin-2-yl)methoxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (11 mg). To the ester dissolved in dioxane (288 μL) was added aqueous LiOH (1 N, 72 μL). The mixture was stirred at room temperature for 16 h; before more aqueous LiOH (1 N, 200 μL) was added. Stirring was continued for 1 h. To the reaction mixture was added water (1.5 mL) and the reaction mixture was acidified to pH 3 with 1 N HCl. The mixture was purified by HPLC to give the title compound as a yellow solid (7 mg). LCMS m/z=382.4 [M+H]+; 1H NMR (500 MHz, CDCl3) δ ppm 1.32 (d, J=6.31 Hz, 6H), 1.95-2.18 (m, 1H), 2.28-2.41 (m, 1H), 2.56-2.79 (m, 4H), 3.36-3.56 (m, 1H), 5.09 (s, 2H), 5.15-5.33 (m, 1H), 6.71 (d, J=8.83 Hz, 1H), 6.94 (s, 1H), 7.20 (d, J=8.83 Hz, 1H), 8.20 (s, 1H), 8.30 (s, 1H), 10.37 (s, 1H).
Reaction SMILES: I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1.[CH:24]([B-](F)(F)F)=[CH2:25].[K+].CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH3:19][N:16]1[CH2:17][CH2:18][CH:13]([O:12][CH:9]2[C:8]3[CH:20]=[CH:21][CH:22]=[CH:23][C:7]=3[CH2:6][CH2:5][N:4]3[C:10]2=[N:11][C:2]([CH:24]=[CH2:25])=[CH:3]3)[CH2:14][CH2:15]1
Reactant: C=C[B-](F)(F)F
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(I)nc32)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cn2c(n1)C(OC1CCN(C)CC1)c1ccccc1CC2
Temperature: 120 °C

Procedure:
To a solution of compound 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 2A) (50 mg, 0.12 mmoles) in 1,4-dioxane (500 μL) in a screw-capped vial under argon are added potassium vinyltrifluoroborate (21 mg, 0.156 mmole), Pd(OAc)2 (1.35 mg, 6 μmole), RuPhos (3 mg, 6 μmole), K2CO3 (50 mg, 0.36 mmole) and water (400 μL). The reaction mixture is heated to 120° C. for overnight. As the reaction is not complete, potassium vinyltrifluoroborate (21 mg, 0.156 mmole), Pd(OAc)2(1.35 mg, 6 μmole), RuPhos (3 mg, 6 μmole) are added and the reaction mixture is heated to 120° C. for 3 hours. Water is added, pH adjusted to 9-10 with saturated Na2CO3 solution. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (99:1:0.1) to (95:5:0.5) and the residue is submitted to a preparative thin-layer chromatography eluting with (CH2Cl2:MeOH:NH4OH) (9:1:1) to afford 4-(1-methylpiperidin-4-yloxy)-2-vinyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[NH:26][C:27](=[O:35])[C:28]2[CH2:34][O:33][CH2:32][CH2:31][C:29]=2[N:30]=1.[H-].[Na+]>C1COCC1.CN(C=O)C.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:24][C:25]4[NH:26][C:27](=[O:35])[C:28]5[CH2:34][O:33][CH2:32][CH2:31][C:29]=5[N:30]=4)[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)C2CCN(C3CCNC3=O)CC2)cc1
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN(C3CCN(Cc4nc5c(c(=O)[nH]4)COCC5)C3=O)CC2)cc1
Temperature: 70 °C
Yield: 107.9 %

Procedure:
To a solution of 3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one (43.7 mmol, 13.2 g) and 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (48 mmol, 9.6 g) in THF (400 mL) and DMF formula (20 mL) was added sodium hydride (60%, 153 mmol, 6.1 g) and heated to 70° C. for 1 hour. The reaction was allowed to cool to ambient temperature, diluted with 1 L of ether, and the resulting solid in suspension was filtered and dried under vacuum provided the title compound as an off-white solid (22 g, 95.3% yield). HRMS calculated for C25H30N4O5 466.5417. found (ESI, [M+H]+) 467.2305. 1H NMR (400 MHz, MeOD) δ ppm 1.67-1.92 (m, 4H) 2.05-2.24 (m, 2H) 2.47-2.64 (m, 3H) 2.72-2.82 (m, 1H) 2.84-2.93 (m, 1H) 3.06-3.15 (m, 1H) 3.26-3.47 (m, 10H) 3.68 (t, J=8.78 Hz, 1H) 3.83-3.99 (m, 5H) 4.16 (d, J=15.56 Hz, 1H) 4.40-4.58 (m, 3H) 7.01 (d, J=9.03 Hz, 2H) 7.97 (d, J=9.03 Hz, 2H), analytical RP-HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.455 min.
Reaction SMILES: Br[C:2](Br)=[CH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5]1.C([Li])CCC.C(=O)([O-])O.[Na+]>O1CCCC1.CCCCCC>[C:3]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5]1)#[CH:2]
Reactant: CCCCC[C@H]1CC[C@H](C=C(Br)Br)CC1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#C[C@H]1CC[C@H](CCCCC)CC1
Temperature: -70 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A solution of 84.5 g of trans-1-(2,2-dibromovinyl)-4-pentylcyclohexane in 800 ml of absolute tetrahydrofuran was cooled to -75° C. under nitrogen gasification and treated dropwise within 30 minutes with 400 ml of an about 1.6M solution of butyl lithium in hexane. The mixture was subsequently stirred at -70° C. for a further 2 hour, then poured into 5.5 l of 2% (wt./vol.) sodium hydrogen carbonate solution and extracted with 1 l of hexane. The aqueous phase was back-extracted with 700 ml of hexane. The combined organic phases were dried over sodium sulphate and freed from solvent on a rotary evaporator. Distillation of the resulting light yellow oil in a high vacuum gave in the main run 40.6 g (91.1%) of trans-1-ethynyl-4-pentylcyclohexane as a colourless liquid which still contained cis-isomer; b.p. 52°-54° C./0.02 Torr. By recrystallization from ethanol at -25° C. and drying up to constant weight at 30° C. in a vacuum drying oven there could be obtained 20.4 g of product free from cis-isomer. From the mother liquor there could be isolated according to the same method a further 6.5 g of product which was almost free from cis-isomer.