Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[O:6]=[C:7]1[C:16](=[O:17])[NH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([S:18](Cl)(=[O:20])=[O:19])[CH:13]=2)[NH:8]1.C(O)(=O)C>O>[CH3:1][O:2][CH2:3][CH2:4][NH:5][S:18]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:6])[C:16](=[O:17])[NH:15]2)(=[O:19])=[O:20]
Reactant: COCCN
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2[nH]c1=O
Solvent: CC(=O)O
Solvent: O
Product: COCCNS(=O)(=O)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Reaction time: 48 h
Yield: 63 %

Procedure:
To a solution of 7.51 g (0.1 mole) of 2-methoxyethylamine in 20 ml of water 5.21 g (0.02 mole) of 1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxalinesulfonyl chloride are added in small portions, under stirring, and the mixture is stirred at room temperature for 16 hours. It is allowed to stand further for 2 days, and then 15 ml of acetic acid and 10 ml of water are added to it. The separated crystals are filtered, washed successively with water and acetone, dried, dissolved in a slight amount of hot dimethyl sulfoxide and precipitated from the solution with water. Thus 3.80 g (63%) of 1,2,3,4-tetra-hydro-N-(2-methoxy-ethyl)-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: 264-267° C.
Reaction SMILES: [CH2:1]([O:6][N:7]=[C:8]([C:14](=O)[CH2:15]Cl)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:18][C:19]([NH2:21])=[S:20].O.O.O.C([O-])(=O)C.[Na+].C(O)C>O>[NH2:21][C:19]1[S:20][CH:15]=[C:14]([C:8](=[N:7][O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:18]=1
Reactant: CCCCCON=C(C(=O)CCl)C(=O)OCC
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCON=C(C(=O)OCC)c1csc(N)n1
Yield: 52.1 %

Procedure:
Ethyl 2-pentyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 51.1 g.), thiourea (14.7 g.), sodium acetate trihydrate (26.4 g.), ethanol (175 ml.) and water (125 ml.) were treated in a similar manner to that of Example F -(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetate (syn isomer, 28.7 g.), mp 86° to 88° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[C:4](O)=O.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[NH2:32][NH:33][C:34]([NH2:36])=[O:35].[OH-].[K+].[NH4+].[Cl-]>CC#N>[CH3:1][O:2][C:3]([C:4]1[NH:36][C:34](=[O:35])[NH:33][N:32]=1)([CH3:7])[CH3:8]
Reactant: COC(C)(C)C(=O)O
Reactant: NNC(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: COC(C)(C)c1n[nH]c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
2-Methoxyisobutyric acid (0.50 g, 4.23 mmol) was dissolved in MeCN (8.5 mL). 1H-Benzo[d][1,2,3]triazol-1-ol (20% hydrate) (0.65 g, 4.23 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.81 g, 4.23 mmol) were added and the mixture was stirred at RT for 2 h. Semicarbazide hydrochloride (0.47 g, 4.23 mmol) was added and the mixture was stirred for an additional 12 h. Organic solvent was removed in vacuo and the residue was suspended in water (85 mL). Potassium hydroxide (0.48 g, 8.5 mmol) was added and the mixture was stirred at RT until complete dissolution of solids. The mixture was then stirred at 100° C. for 12 h and then allowed to cool to RT. The solution was saturated with solid NH4Cl and extracted with EtOAc (8×50 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford 3-(2-methoxypropan-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.35 g, 52.6%) as an amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 11.44 (s, 1H), 11.28 (s, 1H), 2.96 (s, 3H), 1.36 (s, 6H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1.[CH3:17][OH:18]>ClCCl>[CH3:17][O:18][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: CO
Reactant: O=c1c(CCl)c[nH]c2c([N+](=O)[O-])cccc12
Solvent: ClCCl
Product: COCc1c[nH]c2c([N+](=O)[O-])cccc2c1=O

Procedure:
A suspension of 3-chloromethyl-1,4-dihydro-8-nitro-4-oxoquinoline (2 g) in dichloromethane (70 ml) and methanol (30 ml) was refluxed for 15 minutes and concentrated in vacuo. The crystalline residue was suspended in hot methanol (30 ml), and the mixture was allowed to stand to ambient temperature. The resulting precipitates were collected by filtration to give 1,4-dihydro-3-methoxymethyl-8-nitro-4-oxoquinoline (1.5 g).
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([NH2:18])[CH2:13][CH2:12]2.N12CCCN=C1CCCCC2>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([NH:18][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])[CH2:13][CH2:12]2
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NC1CCc2cc(Br)ccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
At 0° C. and under protective atmosphere, a solution of 2-propanesulfonyl chloride (11.87 mL, 121 mmol) in DCM (121 mL) was added gradually to a solution of 5-bromo-2,3-dihydro-1H-inden-1-amine (12.8 g, 60.4 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.83 mL, 32.1 mmol) in dichloromethane (300 mL). The reaction was stirred at rt overnight. The reaction mixture was washed with 1N KHSO4 (1×) and sat NaHCO3 (2×) before being dried on Na2SO4 and solvent evaporated in vacuo to afford a green oil. Purification by column chromatography (25% EtOAc in hept) afforded the title compound as a white solid (6.0 g, 18.9 mmol, 31%). MS (ESI): m/z [M−H]− 317.0.
Reaction SMILES: [C:1]1([C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[C:13]([C:20]([OH:22])=O)[N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[C:44]12([NH2:54])[CH2:53][CH:48]3[CH2:49][CH:50]([CH2:52][CH:46]([CH2:47]3)[CH2:45]1)[CH2:51]2>CN(C=O)C.C(OCC)(=O)C>[C:44]12([NH:54][C:20]([C:13]3[N:12]=[C:11]([C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)[N:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=34)=[O:22])[CH2:51][CH:50]3[CH2:49][CH:48]([CH2:47][CH:46]([CH2:52]3)[CH2:45]1)[CH2:53]2
Reactant: O=C(O)c1nc(-c2cccc3ccccc23)n2ccccc12
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(NC12CC3CC(CC(C3)C1)C2)c1nc(-c2cccc3ccccc23)n2ccccc12
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
To a solution of 3-naphthalen-1-yl-imidazo[1,5-a]pyridine-1-carboxylic acid (55 mg, 0.19 mmol) in DMF (5 mL) was added EDC (161 mg, 0.84 mmol), HOBt, (90 mg, 0.67 mmol) and Et3N (0.23 mL, 1.68 mmol). The mixture was allowed to stir for 10 min. and adamantylamine (93 mg, 0.62 mmol) was added. The mixture was stirred for 15 h then diluted with ethyl acetate (30 mL) and washed with water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (67 mg, 84%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:7]=1[F:22])[CH3:2].C(N(CC)CC)C.Br[CH2:41][CH2:42][OH:43]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:41][CH2:42][OH:43])[CH2:20][CH2:21]2)[C:7]=1[F:22])[CH3:2]
Reactant: OCCBr
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OC2CCNCC2)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OC2CCN(CCO)CC2)c1F
Temperature: 50 °C

Procedure:
A solution of 300 mg (RS)-(4-cyano-phenylamino)-[5-ethoxy-2-fluoro-3-(piperidin-4-yloxy)-phenyl]-acetic acid ethyl ester described in example 11.2 in 10 ml THF was treated with 0.19 ml triethylamine, 0.82 ml 2-bromoethanol and 25 mg tetrabutylammonium iodide. The reaction mixture was heated to 50° C. for 6 hrs, then evaporated. The residue was taken up in water and extracted with EtOAc. The crude product was purified by chromatography on silica with dichloromethane/MeOH 9:1 to give 175 mg (RS)-(4-cyano-phenylamino)-{5-ethoxy-2-fluoro-3-[1-(2-hydroxy-ethyl)-piperidin-4-yloxy]-phenyl}acetic acid ethyl ester. MS: 486.4 ([M+H]+).
Reaction SMILES: [Br-:1].[NH:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=[N+:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.BrBr>C(Cl)(Cl)Cl>[Br-:1].[Br:1][C:5]1[CH:4]=[C:3]([CH:7]=[N+:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[NH:2][CH:6]=1
Reactant: C(c1ccc[nH]1)=[N+]1CCCC1
Agent: BrBr
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: Brc1c[nH]c(C=[N+]2CCCC2)c1

Procedure:
To a solution of 91.0 g of 1-(pyrrol-2-ylmethylene)pyrrolidmium bromide (0.397 mole) in 1300 ml of absolute chloroform is added dropwise with stirring and ice-cooling 63.4 g of bromine (0.397mole). A solid precipitates during addition. After the reaction mixture has been stirred at room temperature for 64 hours, the solvent is evaporated in vacuo and the residue is recrystallized from 3:1 chloroform-acetonitrile to give as an off-white solid 1-(4-bromopyrrole-2-ylmethylene)pyrrolidinium bromide; m.p. 226°-228° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][N:17]=[C:16]3[NH:20][N:21]=[CH:22][C:15]=23)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[N+](C1C=CC(N=C=O)=CC=1)([O-])=O.[O:35]([C:42]1[CH:47]=[CH:46][C:45]([N:48]=C=O)=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[O:35]([C:42]1[CH:43]=[CH:44][C:45]([NH:48][C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:19]=[CH:18][N:17]=[C:16]4[NH:20][N:21]=[CH:22][C:15]=34)[CH2:12][CH2:13]2)=[O:7])=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ncc23)CC1
Agent: O=C=Nc1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)N1CCN(c2ncnc3[nH]ncc23)CC1

Procedure:
The target compound was produced in the same manner as in Example 2, except that 4-(6-purinyl)-1-piperazinecarboxylic acid tert-butyl ester was replaced with 4-(4-pyrazolo[3,4-d]pyrimidinyl )-1-piperazinecarboxylic acid tert-butyl ester produced in Reference Example 10, and that 4-nitrophenyl isocyanate was replaced with 4-phenoxyphenyl isocyanate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[C:17]([N+:19]([O-])=O)[CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])([O-])=O.[K+].[K+].[O-]S(S([O-])=O)=O.[Na+].[Na+].[H-].[Na+]>CN(C=O)C.CCOC(C)=O.C1(C)C=CC=CC=1.O.CCO>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[O:1][C:2]3[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=3[C:4](=[O:6])[NH:19][C:17]=2[CH:18]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2cc(Br)ccc2Oc2ccccc21
Temperature: 40 °C
Reaction time: 2 h
Yield: 9 %

Procedure:
A mixture of a methyl 2-hydroxybenzoate (1.0 mL, 10.0 mmol), 5-bromo-2-fluoronitrobenzene (0.62 mL, 5.0 mmol) and Cs2CO3 (3.3 g, 10.0 mol) in DMF (12 mL) was stirred at 40° C. for 2 h. The mixture was diluted with EtOAc and washed with 2 M aqueous NaOH-solution. To the EtOAc-phase was added EtOH, H2O, K2CO3 (2.8 g, 20 mmol) and Na2S2O4 (3.5 g, 20 mmol) and the resulting mixture was stirred vigorously for 1 h. The aqueous phase was removed and the organic phase was washed with 1 M aqueous NaOH-solution and then concentrated. The residue was taken up in DMF (1 mL) and then toluene (4 mL) and NaH (60 mg, 1.5 mmol, 60% in mineral oil) were added and the resulting mixture was stirred at 80° C. over night, then quenched by addition of saturated aqueous NH4Cl-solution. The resulting mixture was diluted with EtOAc, washed with 2 M aqueous NaOH-solution, dried (Na2SO4), concentrated, filtered through a short SiO2-column, concentrated and crystallised from heptane:EtoAc to give 130 mg of the title compound (189JO56). MS (ESI) 290 (MH+). Purity for MH+ (UV/MS) 100/100.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[OH-].[K+].[CH2:14](Br)[CH3:15]>CS(C)=O.O>[CH2:14]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:15]
Reactant: CN(CCO)c1ccccc1
Reactant: CCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOCCN(C)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.5 %

Procedure:
To a solution of the product from step 1 (850 mg, 506 mmol) in DMSO (4 mL) and KOH (1.2 g, 22.0 mmol) was added ethyl bromide (0.85 mL, 11.4 mmol). After stirring 1.5 hours at ambient temperature, the reaction mixture was diluted with water and the product extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered and concentrated to afford the title compound as a yellow oil (950 mg, 95%). MS (ES+) m/z 180 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[CH:2].C(N(CC)CC)C.Cl[C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][N:24]=[C:23]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)[N:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:25]2[C:26]([C:27]([F:29])([F:28])[F:30])=[CH:21][N:22]=[C:23]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([N:38]4[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]4)=[CH:36][CH:37]=3)[N:24]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1cccc(C(=O)OC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C#Cc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Temperature: 120 °C
Yield: 57.3 %

Procedure:
To a nitrogen de-gassed solution of methyl 3-ethynylbenzoate (I31) (0.105 g, 0.655 mmol) in dry DMF (6 mL) were added triethylamine (0.308 mL, 2.18 mmol) followed by tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I3) (0.250 g, 0.546 mmol), triphenylphosphine (0.021 g, 0.082 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.038 g, 0.055 mmol) and Cu(I)I (0.016 g, 0.082 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes, concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I32) (0.182 g, 57% yield) as an orange solid; 1H NMR (400 MHz, d6-DMSO) δ 10.28 (br s, 1H), 8.78 (s, 1H), 8.16-8.03 (m, 2H), 7.90 (d, J=7.8 Hz, 1H), 7.69 (t, J=7.9 Hz, 1H), 7.55 (d, J=9.0 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 3.90 (s, 3H), 3.50-3.41 (m, 4H), 3.11-2.99 (m, 4H), 1.42 (s, 9H). LCMS Method C: rt 6.82 min; m/z 582.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([CH3:12])[CH2:9][CH2:10]I)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH:21]2[CH2:24][NH:23][CH2:22]2)=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([CH3:12])[CH2:9][CH2:10][N:23]1[CH2:24][CH:21]([O:20][C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:26][CH:25]=2)[CH2:22]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](CCI)NC(=O)OC(C)(C)C
Reactant: Clc1ccc(OC2CNC2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](CCN1CC(Oc2ccc(Cl)cc2)C1)NC(=O)OC(C)(C)C

Procedure:
A solution of ((R)-3-iodo-1-methyl-propyl)-carbamic acid tert-butyl ester (0.038 mg, 0.13 mmol), 3-(4-chloro-phenoxy)-azetidine hydrochloride (0.030 g, 0.13 mmol) and triethylamine (0.073 ml, 0.52 mmol) in DMF (1 ml) is stirred at room temperature for 18 hours. The reaction mixture is partitioned between ethylacetate and a saturated solution of sodium bicarbonate. The organic phase is washed with water and brine, dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography using 1:1 ethylacetate:hexane as eluent to afford {(R)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-methyl-propyl}-carbamic acid tert-butyl ester. [M+H] 355.33
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1O.C(C(C#N)=C(C#N)C#N)#N>CC(N(C)C)=O>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]2[O:9][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: Nc1ccccc1O
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: N#CC(C#N)=C(C#N)C#N
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(-c2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Resin-bound 4-carboxybenzaldehyde (subn. 0.60 mmol/g, 400 mg, 0.24 mmol) was treated with a solution of 2-aminophenol (262 mg, 2.4 mmol) in DMA (3 mL). The suspension was shaken at room temperature for 24 h. Tetracyanoethylene (307 mg, 2.4 mmol) was added, and the mixture stirred at room temperature for an additional 24 h. The resin was filtered, washed with DMA and DCM, and dried under high vacuum. The benzoxazole was cleaved from the solid support with 20% (v/v) TFA in DCM (2×5 mL, 15 min) and the combined filtrates were evaporated to give the title compound. 1H NMR (CD3OD) δ 7.36-7.45 (m, 2H), 7.62-7,67 (m, 111), 7.72-7.77 (m, 1H), 8.17 (d, 2H, J=8.3 Hz), 8.29 (d, 2H, J=8.3 Hz). MS (API-ES+) m/z 240 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:27][NH2:28])(=[O:26])[CH3:25]>>[C:24]([NH:27][N:28]=[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]1[CH:16]=[C:17]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:18]([OH:19])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=1)(=[O:26])[CH3:25]
Reactant: CC(C)(C)c1cc(C(=O)c2ccccc2)cc(C(C)(C)C)c1O
Reactant: CC(=O)NN
Product: CC(=O)NN=C(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
3,5-di-t-butyl-4-hydroxybenzophenone and acetohydrazide were treated in the same way as in Example 7 to give 3,5-di-t-butyl-4-hydroxybenzophenone acetylhydrazone.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=O)=[C:6]([F:10])[C:5]([N:11]=[N:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:4]([F:18])[CH:3]=1.C1(P(=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:42]([O:41][C:39](=[O:40])[CH:38]=[CH:8][C:7]1[C:2]([Br:1])=[CH:3][C:4]([F:18])=[C:5]([N:11]=[N:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:6]=1[F:10])[CH3:43]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c(Br)cc(F)c(N=NN2CCCC2)c1F
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1c(Br)cc(F)c(N=NN2CCCC2)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 0.3 1 three necked flask fitted with a magnetical stirrer and dropping funnel under inert atmosphere, 6.62 g (20.8 mmol, 1 eq) of 6-bromo-2,4-difluoro-3-(pyrrolidin-1-ylazo)-benzaldehyde a9 are dissolved in THF (100 ml) and cooled down to 0° C. Ethyl (triphenylphosphoranylidene)acetate (9.43 g, 1.3 eq) is then added under efficient stirring, the temperature raising to 10° C. The mixture is kept under stirring one hour at 0° C., and then overnight at room temperature. The mixture is concentrated to dryness, the residue suspended in diethyl ether, the triphenylphospine oxide is filtered off and the filtrate concentrated to dryness. The residue is purified by PrepLC on silicagel (CH2Cl2/pentane: 50/50 (v/v)) to give 4.17 g of pure of 3-[6-bromo-2,4-difluoro-3-(pyrrolidin-1-ylazo)-phenyl]-acrylic acid ethyl ester a10 (47%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:20]([NH2:22])=[O:21].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:35][C:36](OC)=O)[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([CH:26]=[C:25]([O:24][CH3:23])[C:30]=1[O:31][CH3:32])[CH2:35][C:36]1[NH:22][C:20](=[O:21])[C:3]2[N:4]=[N:5][N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:2]=2[N:1]=1
Reactant: CC(O)C(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Reactant: COC(=O)Cc1cc(OC)c(OC)c(OC)c1
Product: COc1cc(Cc2nc3c(nnn3C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)cc(OC)c1OC

Procedure:
Analogously to the procedure of Example XI, the title compound is prepared from 10 mg (0.024 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-[1,2,3]triazole-4-carboxamide and 20 mg (0.107 mmol) of methyl 3,4,5-trimethoxyphenylacetate.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:16][C:17]#[N:18])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)=O)C.CCN(CC)CC>N.CCO.C1(C)C=CC=CC=1.[Ni]>[O:13]1[C:9]2([CH2:14][CH2:15][C:6]3([CH2:16][CH2:17][NH:18][C:4]3=[O:3])[CH2:7][CH2:8]2)[O:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)C1(CC#N)CCC2(CC1)OCCO2
Agent: [Ni]
Agent: N
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1NCCC12CCC1(CC2)OCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
To a stirred solution of 8-cyanomethyl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (12 g, 47.3 mmol) in a mixture of NH3-EtOH (200 ml, 7:93) was added Raney-Ni (4.16 g, 70.95 mmol) under nitrogen atmosphere at 25° C. The reaction mixture was then hydrogenated at 40° C. in an autoclave under 400 psi H2 pressure for 16 h. After the completion of reaction, the mixture was filtered through a bed of celite, and the filtrate was evaporated under reduced pressure. The crude material thus obtained (10 g, 38.9 mmol) was dissolved in dry toluene (100 ml) and to the stirred solution was added Et3N (10 ml, 71.14 mmol) under a nitrogen atmosphere at 25° C. The mixture was then heated under reflux for 24 h. After the completion of reaction, it was cooled to 25° C., the precipitated white solid was filtered, washed with hexane (3×50 ml), dried under vacuum to give the title compound (7.3 g) as a white solid. MS (m/e): 212.2 [MH+].
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]=[CH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:18]1([CH2:17][CH2:16][CH:15]=[CH:14][C@H:11]2[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=CCCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@H](C=CCCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 0.47 g of trans-[4-(4-phenyl-but-1-enyl)-cyclohexyl]-carbamic acid tert-butyl ester in 4 mL of dichloromethane at 0° C. and under nitrogen was added 2 mL of trifluoroacetic acid. The reaction was aged for 1 hour, concentrated under reduced pressure. The resulting oil dissolved in methylene chloride and concentrated to give an oil which was utilized in the next step without purification: LCMS (M+1)=230.
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:23])[N:12]([CH3:22])[C:13]3[C:18]([C:19]=2O)=[CH:17][C:16]([F:21])=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:21])[CH:17]=2)[N:12]([CH3:22])[C:11](=[O:23])[C:10]=1[C:8]#[N:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)c(C(=O)NC2CCCCC2)c(O)c2cc(F)ccc21
Product: Cn1c(=O)c(C#N)c(Cl)c2cc(F)ccc21
Yield: 56 %

Procedure:
A solution of Compound 44 (2 g, 6.28 mmol) in 20 ml neat phosphorus oxychloride was heated at 90° C. for 5 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 0.80 g (56%) of yellow solids. M.P. 258° C. 1H NMR (DMSO-d6): δ 3.67 (s, 3H), 7.78-7.89 (m, 3H). EIMS m/z 259 (M+23).