Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.[CH3:8][O:9][C:10]([NH:12][C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([S:21][C:22]3[CH:27]=[CH:26][C:25](OC(=O)C)=[CH:24][CH:23]=3)=[CH:17][N:16]2[CH:32]=1)=[O:11].CS(C)([O-])=O>O>[C:1]([C:25]1[CH:24]=[CH:23][C:22]([S:21][C:18]2[CH:19]=[CH:20][C:15]3[N:16]([CH:32]=[C:13]([NH:12][C:10]([O:9][CH3:8])=[O:11])[N:14]=3)[CH:17]=2)=[CH:27][CH:26]=1)#[N:2]
Reactant: COC(=O)Nc1cn2cc(Sc3ccc(OC(C)=O)cc3)ccc2n1
Reactant: [C-]#N
Agent: C[SH](C)(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Nc1cn2cc(Sc3ccc(C#N)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.7 g. of cuprous cyanide and 2.6 g. of finely powdered sodium cyanide in 20 ml. of dimethyl sulfoxide is treated dropwise with a solution of 4.12 g. (.01 mole) of the diazonium tetrafluoroborate salt of 6-(aminophenylthio)-2-(methoxycarbonylamino) imidazo [1,2-a] pyridine obtained in Example 15 in 10 ml. of dimethyl sulfinate. An exotherm is observed and external cooling is necessary. The reaction mixture is stirred at room temperature for 1 hour, diluted with water and the solids collected by filtration. The solids are washed with water, dried and recrystallized from dimethylformamide-ethanol (50/50) to yield 6-(p-cyanophenylthio)-2-(methoxycarbonylamino) imidazo [1,2-a] pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2>CCO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1cc(Cl)c2[nH]ccc2c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(Cl)c2[nH]ccc2c1
Reaction time: 3 h
Yield: 99.7 %

Procedure:
Pd/C (DeGussa catalyst) (192 mg) was added to a solution of 7-chloro-5-nitro-1H-indole (Synthesis 2004, 4, 610-618) (765 mg, 3.9 mmol) in EtOH (15 mL) at room temperature and the reaction mixture was stirred under hydrogen atmosphere (1 atm.) for 3 hours. The catalyst was then filtered off on a celite pad and the filtrate was evaporated under reduced pressure to give a dark oil. This crude material was purified by flash chromatography (0% to 20% of MeOH in DCM) to give 648 mg (60% yield) of 7-chloro-1H-indol-5-ylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:14]CC2C=CC(OC)=C(OC)C=2)[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH2:14])[C:10]([F:11])([F:12])[F:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(CNC(c2ccc(Cl)c(Cl)c2)C(F)(F)F)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(c1ccc(Cl)c(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
To a solution of 146 (4.11 g, 10.43 mmol) in DCM (50 mL) was added TFA (2.410 ml, 31.28 mmol) and reaction was stirred for 18 hr at RT. The reaction mixture was concentrated and dissolved in DCM. A solution of HCl (20 mL, 2M Et2O) was added and the solvent was decanted from the solids. The solids were dissolved in 15% MeOH/DCM and saturated NaHCO3 was added. The organic layer was separated and concentrated. The residue was triturated with EtOAc and allowed to stand. The resulting solids were filtered to afford 1.904 g (74.8%) of 1-(3,4-dichlorophenyl)-2,2,2-trifluoroethanamine (148).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[CH2:4][NH:5][C:6]1[S:7][CH2:8][C:9](=[O:11])[N:10]=1.[CH2:17]([O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:30]=O)[CH:28]=2)[N:23]=[C:22]([NH:32][CH3:33])[N:21]=1)[CH3:18].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:30][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([NH:32][CH3:33])[N:21]=[C:20]3[O:19][CH2:17][CH3:18])[C:9](=[O:11])[N:10]=1
Reactant: Cc1cccc(Cl)c1CNC1=NC(=O)CS1
Reactant: CCOc1nc(NC)nc2ccc(C=O)cc12
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOc1nc(NC)nc2ccc(C=C3SC(NCc4c(C)cccc4Cl)=NC3=O)cc12
Temperature: 150 °C

Procedure:
To a suspension of 2-(2-chloro-6-methyl-benzylamino)-thiazol-4-one (example 18a, 40.8 mg, 0.16 mmole), and 4-ethoxy-2-methylamino-quinazoline-6-carbaldehyde (example 12f, 45.5 mg, 0.20 mmole) in 2 mL of toluene in a microwave tube were added benzoic acid (2.0 mg, 0.016 mmole) and piperidine (1.5 mg, 0.02 mmole). The reaction mixture was heated to 150° C. with microwave for 30 min. The reaction mixture was then cooled to r.t. and the solid was filtered off, washed with toluene, MeOH and ether to give 2-(2-chloro-6-methyl-benzylamino)-5-(4-ethoxy-2-methylamino-quinazolin-6-ylmethylene)-thiazol-4-one as a light brown solid: 45.9 mg (61.3%), MS: m/e 468 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[O:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[CH2:11]2)[CH:7]=1.[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]2[N:35]=[C:36]([CH:38]=O)[N:37]=[C:30]2[N:29]=1.B.CNC.Cl>CO.O>[Cl:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[O:15][C:14](=[O:16])[CH:13]([CH2:38][C:36]3[N:37]=[C:30]4[N:29]=[C:28]([CH3:27])[CH:33]=[C:32]([CH3:34])[N:31]4[N:35]=3)[C:12](=[O:17])[CH2:11]2)[CH:7]=1
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Agent: B
Agent: CNC
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound was prepared by treating a suspension of 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione (350 mg, 0.917 mmol) and 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxaldehyde (described in Step 3 of example B(75)) (242 mg, 1.375 mmol, 1.5 equiv, from Step 3 of Example B(75)) in MeOH (10 mL) with dimethylamine borane (65 mg, 1.1 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 18 h. A 1 M solution of HCl (3 mL) was added to the reaction mixture to acidify to a pH of 3. The mixture diluted with water and extracted with dichloromethane containing 10% methanol (3×10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to a white amorphous foam. The foam was chromatographed on silica gel, eluting with 2% methanol in dichloromethane affording a white solid. This solid was recrystallized from ethyl acetate/hexanes to give 100 mg (19%) of the product as a fine white powder. Isolated as a monohydrate.
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:12])C.C(OO)(=O)C.O.O.O.C([O-])(=O)C.[Na+]>O>[N+:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O-:12])=[O:9]
Reactant: CC(=O)O
Reactant: ON=Cc1ccccc1
Agent: CC(=O)OO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])Cc1ccccc1
Temperature: 80 °C

Procedure:
184.1 g. (1.51 mole) of benzaldehyde oxime and 185 ml. of glacial acetic acid are placed in a 3 liter 3 neck flask. The mixture is stirred and heated to 80° C. A solution of 344.1 g. (1.65 mole) of 36.6% peracetic acid and 19 g. of sodium acetate trihydrate is added at a rate such that the temperature is maintained between about 80° and about 90° C. Stirring is continued at about 85° C. for about 3 1/2 hours until there is no oxime. The reaction mixture is chilled to 25° C. and one liter of water is added and the mixture stirred well and the oil which forms, is separated. The aqueous layer is extracted twice with 200 ml. of methylene chloride. The aqueous extract is combined with the oil layer and washed twice with 600 ml. of water and once with 600 ml. of 5% sodium bicarbonate solution, washed again with 400 ml. of water, and dried over sodium sulfate and concentrated to a light orange oil. The yield is 173.5 g. (84%) of 97% pure material by GC.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[NH:11]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:12]([C:22]([OH:24])=O)[CH2:13][S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:32][C@@H:33]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl.CN1CCOCC1.CCN=C=NCCCN(C)C>O.CN(C=O)C>[NH:11]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:12]([C:22]([NH:32][C@@H:33]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:24])[CH2:13][S:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@H](N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CCOC(=O)[C@H](NC(=O)[C@H](CSCc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
HOBt (1.90 g) was added to a DMF solution (50 ml) of Boc-Cys(Bzl)-OH (4.34 g) and D-Phg-OEt hydrochloride (3.00 g), to which were added N-methylmorpholine (1.65 ml) and WSC (4.00 g) at 0° C. The reaction mixture was stirred at 0° C. for 20 minutes and was further stirred at room temperature for 80 minutes, to which water was added, and extracted with AcOEt. The organic phase was washed with saturated saline, dried with magnesium sulfate anhydride, and then filtered and concentrated. The residue was purified by silica gel chromatography (h-hexane/AcOEt=4/1→2/1) to obtain Boc-Cys(Bzl)-D-Phg-OEt.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[N+](N[C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:26](=[O:37])[CH:25]=2)=[CH:18][N:17]=1)([O-])=O>N1C=CC=CC=1>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:26](=[O:37])[CH:25]=2)=[CH:18][N:17]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccn(Cc2ccccc2)c(=O)c1
Solvent: c1ccncc1
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2ccn(Cc3ccccc3)c(=O)c2)c(=O)[nH]1

Procedure:
2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamine (1.28 g) and 2-nitroamino-5-(1-benzyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (2.47 g) were refluxed in pyridine (12 ml) for 20 hours. The reaction mixture was evaporated under reduced pressure and the glassy residue washed with hot water. The mixture was allowed to cool and the water was decanted to give the title compound as a residue. This residue was taken up in isopropanol, treated with ethanolic HCl, evaporated under reduced pressure and crystallised from ethanol-methanol to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(1-benzyl-2-oxopyridin 4-ylmethyl)pyrimidin-4-one as a trihydrochloride salt (3.23 g): recrystallisation gave material with m.p. 185.5°-189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Si](C)(C)C)[O:10][C:3]=12.[F-].[K+].[I:17]C1CC(=O)NC1=O.C(OC(=O)C)C>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([I:17])[O:10][C:3]=12
Reactant: O=C1CC(I)C(=O)N1
Reactant: C[Si](C)(C)c1cc2nccc(Cl)c2o1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccnc2cc(I)oc12
Temperature: 60 °C
Reaction time: 14 h

Procedure:
7-Chloro-2-trimethylsilanyl-furo[3,2-b]pyridine (185 g, 0.23 mol) is dissolved in ACN under nitrogen atmosphere. Then KF (47.6 g, 0.82 mol) and Iodosuccinimide (553.1 g, 0.25 mol) are added. The reaction mixture is stirred at 60° C. for 14 h and then cooled to room temperature. To the reaction mixture is added acetic acid ethyl ester (5 l) and water (5 l). The organic layer is separated, washed with sodiumthiosulfate (5 l) solution, then extracted with NaHCO3 solution and washed with brine. The organic layer is dried over Na2SO4. The drying agent is filtered and the solvent is removed in vacuum; yield: 133 g 7-chloro-2-iodo-furo[3,2-b]pyridine; HPLC/MS: 2.34 min, [M+H]=280;
Reaction SMILES: [CH:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].C(=O)([O-])O.[Na+].[CH2:23]([O:32][C:33](Cl)=[O:34])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CC(N(C)C)=O>[CH2:23]([O:32][C:33]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]2[OH:3])[C:11](=[O:12])[N:13]=1)=[O:34])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: Nc1ccn(C2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Reactant: CCCCCCCCCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
In 120 ml of dimethylacetamide, 6.0 g of arabinofuranosylcytosine is dissolved and to the resultant solution are added 4.15 g of sodium hydrogen carbonate and 7.66 g of nonyloxycarbonyl chloride. The mixture is then allowed to react under stirring at 20 to 25° C. for 2 hours. After the reaction, the solvent is removed under reduced pressure and the residue is dissolved in a small amount of ethanol. Water is then added to the resultant solution and the precipitated solids are collected by filtration, followed by drying. The white powders obtained are washed thoroughly with ethyl ether to obtain 3.8 g of N4 -nonyloxycarbonyl-1-β-D-arabinofuranosylcytosine (Yield:37%).
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][C@H:6]([CH3:13])[CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])C.CO.C(Cl)(Cl)Cl>[OH-].[Na+]>[CH3:13][C@H:6]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)C[C@H](C)CCCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)CCC[C@@H](C)CC(=O)O
Yield: 60 %

Procedure:
Hydrolysis: 400 mg. (2 mmol) of 3(R),7-dimethyl octanoic acid ethyl ester was refluxed in 6N NaOH (1 ml.) and methanol (4 ml.) for 2 hours. It was worked up as in Example 10 to give 207 mg. (60% yield) of 3(R),7-dimethyl octanoic acid (R-(+)-dihydrocitronellic acid), [α]D25 +6.81° (c=5.039, CHCl3).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]3[CH2:20][CH2:19]3)[N:13]=2)[CH:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].N#N>CN1CCCC1=O.CN(C1C=CN=CC=1)C>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:20][CH2:19]2)[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: NC(=O)c1nnc(Cl)cc1Nc1cccc(C2CC2)n1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(C3CC3)n2)c(C(N)=O)nn1
Temperature: 150 °C

Procedure:
To a stirred solution of 6-chloro-4-(6-cyclopropylpyridin-2-ylamino) pyridazine-3-carboxamide (104 mg, 359 mmol) in N-methyl-2-pyrrolidinone (5 mL) was added DMAP (47 mg, 377 μmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (154 mg, 718 μmol). The mixture was heated to 150° C. for 1.5 days, then a stream of N2 was blown into the flask while heating at 140° C. to evaporate the volatile solvents. The residue obtained was then purified by chromatography (silica, 50 μm, 60 g, Analogix, 97:2.75:0.15 to 84:15.2:0.8 dichloromethane:MeOH:NH4OH, 30 min) to afford tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-cyclopropylpyridin-2-ylamino)pyridazin-3 ylamino)cyclohexylcarbamate (126 mg, containing some residual NMP) as a brown viscous oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 11.43 (br. s., 1H) 8.17 (br. s., 1H) 8.03 (br. s., 1H) 7.44 (br. s., 1H) 7.03 (br. s., 1H) 6.80 (br. s., 1H) 6.60 (br. s., 1H) 5.76 (br. s., 1H) 5.49 (br. s., 1H) 3.82 (br. s., 1H) 3.24 (br. s., 1H) 2.03 (br. s., 1H) 1.32-1.91 (m, 8H) 1.45 (s., 9H) 1.05 (d, J=16.62 Hz, 4H). LCMS (EI/CI) m/z: 468 [M+H]. This was used directly in the next step without further purification.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:4]=1[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C([O:24][C:25]1[CH:34]=[CH:33][C:28]([O:29][CH2:30][CH2:31]Br)=[CH:27][C:26]=1[CH3:35])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[OH:24][C:25]1[CH:34]=[CH:33][C:28]([O:29][CH2:30][CH2:31][N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:3]=3[F:2])[CH2:11][CH2:10]2)=[CH:27][C:26]=1[CH3:35]
Reactant: Cc1cc(OCCBr)ccc1OCc1ccccc1
Reactant: Cc1ccc(CC2CCNCC2)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(CC2CCN(CCOc3ccc(O)c(C)c3)CC2)c(F)c1

Procedure:
The title compound was prepared from 4-(2-fluoro-4-methylbenzyl)piperidine hydrochloride (311.7 mg, 1.28 mmol), 2-(4-benzyloxy-3-methylphenoxy)ethyl bromide (411 mg, 1.28 mmol) and potassium carbonate (444 mg, 3.2 mmol) in two steps as white-off solid (244 mg), mp 165-167° C. 1H NMR (CD3OD) 1.503 (m, 2 H), 1.848 (m, 3 H), 2.076 (s, 3 H), 2.223 (s, 3 H), 2.560 (m, 2 H), 2.932 (m, 2 H), 3.389 (m, 2 H), 3.526 (m, 2 H), 4.141 (t, J=5.1 Hz, 2 H), 6.758 (s, 1 H), 6.667 (s, 1 H), 6.788-6.858 (m, 3 H), 7.109 (m, 1 H). Anal. Calcd for C22H29ClFNO2 : C, 67.08; H, 7.42; N, 3.98. Found: C, 66.85; H, 7.44; N, 3.46.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][CH:8]2[N:10](C(OC(C)(C)C)=O)[CH:4]([CH2:5][O:6][CH2:7]2)[CH2:3]1.C(O[CH:23](N(C)C)[N:24](C)C)(C)(C)C.NO.Cl.Cl>O1CCOCC1>[CH:8]12[NH:10][CH:4]([CH2:5][O:6][CH2:7]1)[CH2:3][C:2]1[O:1][N:24]=[CH:23][C:9]2=1
Reactant: CC(C)(C)OC(=O)N1C2COCC1CC(=O)C2
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: Cl
Agent: NO
Solvent: C1COCCO1
Product: c1noc2c1C1COCC(C2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of tert-butyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (482 mg, 2 mmol) and tert-butoxy-N,N,N′,N′-tetra-methyl-methanediamine (522 mg) in dioxane (10 mL) was stirred at 60° C. for 16 h. The solvent was removed in vacuo, and the residue was dissolved in EtOH (10 mL). To it NH2OH.HCl (462 mg, 3 mmol) was added. After stirring at room temperature for 2 h, 12 N HCl (1 mL) was added and refluxed for 2 h. The reaction mixture was concentrated to give 5,10-Dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene 105a as an oil (yield 100%), which was used without further purification. MS: calc'd (MH+) 167, measured (MH+) 167.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2].[N:16](OC(C)(C)C)=O>C(O)(=O)C.O.C(OC(=O)C)(=O)C>[C:1]([N:4]1[C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:16]1)(=[O:3])[CH3:2]
Reactant: COC(=O)Cc1ccccc1NC(C)=O
Reactant: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1nn(C(C)=O)c2ccccc12
Temperature: 90 °C
Yield: 85.2 %

Procedure:
Methyl (2-acetamidophenyl)acetate (24.3 g, 0.12 mol) and acetic anhydride (24.3 ml, 0.26 mmol) were dissolved in acetic acid (60 ml). To the resulting solution, tert-butyl nitrite (90% purity, 18.6 ml, 0.14 mol) was added dropwise over 20 minutes under stirring at 90° C. After completion of the dropwise addition, the reaction mixture was stirred at 90° C. for further 1 hour. The reaction mixture was cooled to room temperature and then, poured in water (500 ml), followed by stirring for 1 hour. The crystals thus precipitated were collected by filtration under reduced pressure and dissolved in chloroform. The chloroform solution was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent, whereby methyl 1-acetylindazole-3-carboxylate (22.3 g, 85%) was obtained as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN(C(C)C)C(C)C.[CH3:55][O:56][CH2:57][CH2:58][CH2:59][NH2:60].Cl>CN(C=O)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:60][CH2:59][CH2:58][CH2:57][O:56][CH3:55])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: COCCCN
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.2 %

Procedure:
Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (4.00 g, 13.06 mmol), EDCI (3.76 g, 19.59 mmol), and HOBT hydrate (3.00 g, 19.59 mmol) in DMF (39.6 mL) and treated with Hunig's base (6.82 mL, 39.2 mmol). Then 3-methoxypropan-1-amine (2.005 mL, 19.59 mmol) was added and the reaction mixture was stirred at ambient temperature for 24 h. The reaction mixture was then diluted with water (200 mL) and acidified with HCl (aq., 1N) until pH=5 and stirred to give a fine suspension. The solid was collected by filtration, suspended in MeOH (150 mL), and heated to reflux for 8 hours, the slowly cooled to ambient temperature. The solid was collected by filtration and dried in vacuum to give the title compound (4.25 g, 11.26 mmol, 86% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78 (quin, J=6.63 Hz, 2H) 3.30-3.37 (m, 2H) 3.40 (t, J=6.32 Hz, 2H) 7.79 (d, J=8.34 Hz, 2H) 8.14 (d, J=6.57 Hz, 2H) 8.31-8.69 (m, 3H) 8.71 (t, J=5.31 Hz, 1H) 8.91 (s, 1H) 13.54 (br. s., 1H). MS [M+H]378.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([O:14][CH3:15])[C:11]([OH:13])=O.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=1[F:26]>>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([CH2:17][NH:16][C:11](=[O:13])[CH:10]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[O:14][CH3:15])=[C:19]([F:26])[CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(CN)c(F)c1
Reactant: COc1ccc(C(OC)C(=O)O)c(F)c1
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2F)c(F)c1

Procedure:
(RS)-(2-Fluoro-4-methoxy-phenyl)-methoxy-acetic acid (example 15.1) was coupled with 4-aminomethyl-3-fluoro-benzonitrile according to general procedure B to give (RS)-N-(4-cyano-2-fluoro-benzyl)-2-(2-fluoro-4-methoxy-phenyl)-2-methoxy-acetamide. Yellow oil. MS 347.3 ([M+H]+)