Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.Cl.[Cl:9][C:10]1[CH:11]=[C:12]([OH:30])[CH:13]=[C:14]([NH:16][C:17]2[C:18]3[C:25]4[CH2:26][CH2:27][NH:28][CH2:29][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:15]=1.Cl.[O:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:9][C:10]1[CH:11]=[C:12]([OH:30])[CH:13]=[C:14]([NH:16][C:17]2[C:18]3[C:25]4[CH2:26][CH2:27][N:28]([C:5](=[O:7])/[CH:4]=[CH:3]/[CH2:2][N:35]5[CH2:36][CH2:37][CH2:38][O:32][CH2:33][CH2:34]5)[CH2:29][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:15]=1
Reactant: Oc1cc(Cl)cc(Nc2ncnc3sc4c(c23)CCNC4)c1
Reactant: O=C(O)/C=C/CBr
Reactant: C1CNCCOC1
Agent: Cl
Product: O=C(/C=C/CN1CCCOCC1)N1CCc2c(sc3ncnc(Nc4cc(O)cc(Cl)c4)c23)C1

Procedure:
In analogy to Example 130, the title compound was prepared from (2E)-4-bromobut-2-enoic acid (84 mg, 0.41 mmol), 3-chloro-5-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol hydrochloride from Example 65A (100 mg, 0.27 mmol) and 1,4-oxazepane hydrochloride (60 mg, 0.43 mmol) to yield 30 mg (22%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:8][CH3:9])[NH:5][C:6]=1[Br:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CN=C1>CN(C=O)C.CCOC(C)=O.CCCCCC>[CH2:19]([O:18][CH2:17][N:3]1[C:2]([Br:1])=[C:6]([Br:7])[N:5]=[C:4]1[CH2:8][CH3:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCc1nc(Br)c(Br)[nH]1
Reactant: ClCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCc1nc(Br)c(Br)n1COCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85 %

Procedure:
To a mechanically stirred solution of 4,5-dibromo-2-ethylimidazole (25.4 g, 0.1 mole,) in anhydrous DMF (250 mL) was treated with K2CO3 (69.1 g, fw=138.2, 0.5 moles, 5 equiv.) followed by dropwise addition of benzyl chloromethyl ether (18.5 g, 0.11 moles, 93% pure, TCI, fw=156.61) and stirred overnight at room temp under nitrogen for 20 h. TLC (30:70 EtOAc/hexane) revealed absence of starting material imidazole (Rf=0.2) along with formation of product (Rf=0.71). The reaction mixture was filtered, washed the solid with dichloromethane and the combined filterate was evaporated under reduced pressure and purified the crude (47 g) by flash column chromatography (dichloromethane eluent) to afford 31.75 g (85%) of colorless oil. Mass spectrum (m/z=375, M+H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])([CH3:3])[CH3:2].S(Cl)([Cl:18])=O>ClCCl>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:18])=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)ccc1OC(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)Cl)ccc1OC(C)C
Temperature: 30 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
To a stirring solution of 4-isopropoxy-3-methoxy-benzoic acid (40.0 g, 190.3 mmol) in anhydrous dichloromethane (400 mL) at room temperature was slowly added thionyl chloride (27.8 mL, 381 mmol). The reaction was then transferred from a room temperature water bath to an oil bath that was then warmed to 30° C. The solution was allowed to stir overnight at 30° C. The reaction mixture was allowed to cool to room temperature prior to the addition of additional thionyl chloride (10.0 mL, 137 mmol). The reaction was allowed to stir at 40° C. for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure, azeotrophing with toluene to provide 4-isopropoxy-3-methoxy-benzoyl chloride (44.3 g) as a yellow oil. The product was used in the next step without further purification.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:11])([F:10])[F:9])(=O)=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C(C)=CC=CC=1>[F:9][C:8]([F:11])([F:10])[CH2:7][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1C
Product: FC(F)(F)CNc1ccccc1

Procedure:
2.5 g (10.7 mmol) 2,2,2-trifluoroethyl trifluoromethanesulphonate were added to 2.0 g (21.5 mmol) aniline in 50 mL xylene and the mixture was refluxed for 2 days. After cooling, the mixture was filtered, washed with DIPE and the filtrate was evaporated down i.vac. The residue was purified by flash chromatography. The product fractions were combined and evaporated down i.vac.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[N:6][C:5]=1[F:11].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)=[N:6][C:5]=1[F:11]
Reactant: COC(=O)c1ccc(F)nc1F
Reactant: NCc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NCc2ccc(Cl)cc2)nc1F
Reaction time: 2 h

Procedure:
To 2,6-difluoro-nicotinic acid methyl ester (60, 2.00 g, 0.0116 mol) in N,N-dimethylformamide (20.0 mL), under an atmosphere of nitrogen at −40° C., was added p-chlorobenzylamine (61, 2.60 mL, 0.0214 mol). The reaction was stirred at −40° C. to −20° C. for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane to give compound (62, 2.0 g, 58.7%).
Reaction SMILES: [NH:1]1[C@@H:6]2[CH2:7][CH2:8][CH2:9][C@@H:5]2[CH2:4][O:3][C:2]1=[O:10].F[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[CH:14][N:13]=1>>[F:26][C:22]1[CH:21]=[C:20]([C:19]#[C:18][C:15]2[CH:16]=[CH:17][C:12]([N:1]3[C@@H:6]4[CH2:7][CH2:8][CH2:9][C@@H:5]4[CH2:4][O:3][C:2]3=[O:10])=[N:13][CH:14]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C1N[C@@H]2CCC[C@@H]2CO1
Reactant: Fc1cccc(C#Cc2ccc(F)nc2)c1
Product: O=C1OC[C@H]2CCC[C@H]2N1c1ccc(C#Cc2cccc(F)c2)cn1
Yield: 13.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, step 4 using (4aS,7aR)-hexahydro-cyclopenta[d][1,3]oxazin-2-one (66 mg, 0.47 mmol) (Example 1, step 2) and 2-fluoro-5-((3-fluorophenyl)ethynyl)pyridine (100 mg, 0.47 mmol) to yield 22 mg (14%) of the title compound as a colorless oil; MS: m/e=337.4 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:19])[CH2:18][CH2:17][CH2:16][C:5]2([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6]2)[CH2:4]1.[N-:20]=[N+:21]=[N-:22].[Na+]>CS(C)=O.O>[N:20]([CH2:2][C:3]1([CH3:19])[CH2:18][CH2:17][CH2:16][C:5]2([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6]2)[CH2:4]1)=[N+:21]=[N-:22]
Reactant: CC(C)(C)CN1CC2(CCCC(C)(CBr)C2)OC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)CN1CC2(CCCC(C)(CN=[N+]=[N-])C2)OC1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a solution of 7-(bromomethyl)-7-methyl-3-neopentyl-1-oxa-3-azaspiro[4.5]decan-2-one (11.3 g, 34.1 mmol) in DMSO (171 mL) was added sodium azide (2.89 g, 44.4 mmol). The reaction flask was placed behind a blast shield and heated to 80° C. for 4 days. The temperature was increased to 100° C. After 16 h, additional sodium azide (0.665 g, 10.23 mmol) was added to the reaction. After 19 h, the reaction was cooled to rt and diluted with water (300 mL). The product was extracted into EtOAc (2×300 mL). The combined organics were washed with water (3×400 mL). The organic layer was dried over MgSO4, filtered, and concentrated to provide the title compound (10.0 g, 95% crude yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 3.33 (q, J=8.53 Hz, 2H), 3.09 (s, 2H), 3.06 (d, J=14.00 Hz, 1H), 2.94 (d, J=14.05 Hz, 1H), 1.96-2.05 (m, 1H), 1.83-1.96 (m, 1H), 1.69 (dt, J=2.04, 14.24 Hz, 1H), 1.59-1.65 (m, 1H), 1.47 (d, J=14.05 Hz, 1H), 1.26-1.44 (m, 3H), 1.15 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1.O=[C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]([C:34]([OH:36])=[O:35])[CH2:26]1.C(O)(=O)C.C([O-])(=O)C.[Na+]>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:25]2\[CH2:26][CH:27]([C:34]([OH:36])=[O:35])[C:28]3[C:33]\2=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:22][CH:23]=1
Reactant: O=C1CC(C(=O)O)c2ccccc21
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C2\CC(C(=O)O)c3ccccc32)cc1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (500 mg), 3-oxo-1-indancarboxylic acid (284 mg), acetic acid (0.276 ml), sodium acetate (264 mg) and ethanol (20 ml) was heated to reflux for 18 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-1-indancarboxylic acid (522 mg, yield 69%) as colorless crystals. m.p. 148-149° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([C:35]([O:37][CH3:38])=[O:36])[CH:34]=1>>[F:28][C:29]1[CH:34]=[C:33]([CH:32]=[C:31]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7](=[O:8])[NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:12][CH:11]=3)[CH:21]=2)[CH:30]=1)[C:35]([O:37][CH3:38])=[O:36]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: COC(=O)c1cc(F)cc(B(O)O)c1
Product: COC(=O)c1cc(F)cc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 35 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and (3-fluoro-5-(methoxycarbonyl)phenyl)boronic acid to afford a white solid. UPLC-MS (Condition 3), tR=1.18 min, m/z=520.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6), δ ppm 1.67-1.75 (m, 1H) 1.77-1.89 (m, 1H) 2.81-2.90 (m, 1H) 3.13-3.27 (m, 2H) 3.33-3.45 (m, 1H) 3.88 (s, 3H) 4.13-4.20 (m, 1H) 4.82 (d, J=1.00 Hz, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.54-7.63 (m, 1H) 7.65-7.73 (m, 1H) 7.74-7.79 (m, 1H) 7.84 (d, J=9.38 Hz, 2H) 8.03 (d, J=2.35 Hz, 1H) 8.75 (d, J=2.35 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[N:23]([CH2:26][C:27](O)=[O:28])=[N+:24]=[N-:25].C([O-])(O)=O.[Na+].C(Cl)CCl>CN(C=O)C>[N:23]([CH2:26][C:27](=[O:28])[NH:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[N+:24]=[N-:25]
Reactant: CC(C)(C)OC(=O)NCCCOCCOCCOCCCN
Reactant: [N-]=[N+]=NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCCOCCOCCOCCCNC(=O)CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
To a 25 mL round bottomed flask equipped with a magnetic stir bar, rubber septum, and argon inlet containing tert-butyl 3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propylcarbamate (amine, 160 mg, 0.5 mmol), 2-azidoacetic acid (56 mg, 0.55 mmol, in 50% DCM solution), NaHCO3 (168 mg, 2 mmol), and 1 mL DMF was added EDC (115 mg, 0.6 mmol). The mixture was stirred at rt for 3 h and concentrated in vacuo. The crude product was purified by silica chromatography (gradient 5% to 90% EtOAc in hexane) to afford compound 141 as a clear oil (130 mg, 65%). MS (ESI) m/z 426 (M+Na+).
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Br)=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH4+:12].[OH-]>C1COCC1.C(Cl)Cl.Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH2:12])[C:5]2=[N:4][CH:3]=1
Reactant: Brc1cncc2ncc(Br)n12
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1nccn2c(Br)cnc12
Temperature: 50 °C
Yield: 50 %

Procedure:
To a solution of 3,5-dibromo-imidazo[1,2-a]pyrazine (D) (500 mg, 1.8 mmol) in THF (4 ml) was added NH4OH (4 ml). The mixture was heated at 50° C. in sealed tube overnight. Additional NH4OH (4 ml) was added to the reaction mixture and was heated at 50° C. in sealed tube overnight. The mixture was then cooled to rt, diluted with DCM (200 ml) and 1N HCl (50 ml). The organic layer was washed with 10N NaOH, brine, dried and concentrated. The residue was purified on a silica gel column to afford 190 mg (yield 50%) of 3-bromo-imidazo[1,2-a]pyrazin-8-ylamine.
Reaction SMILES: C(O[CH:4]=[CH:5][C:6](O)([C:16]([F:19])([F:18])[F:17])[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]#[N:9])C.[NH3:21]>>[C:10]1([C:7]2[C:8]([NH2:9])=[N:21][CH:4]=[CH:5][C:6]=2[C:16]([F:19])([F:18])[F:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N
Reactant: CCOC=CC(O)(C(C#N)c1ccccc1)C(F)(F)F
Product: Nc1nccc(C(F)(F)F)c1-c1ccccc1
Temperature: 125 °C
Yield: 57.7 %

Procedure:
50 g of 5-ethoxy-3-hydroxy-2-phenyl-3-trifluoromethylpent-4-enenitrile were mixed with 600 g of aqueous ammonia (25%), and the resulting mixture was heated to 125° C. in an autoclave for 24 h. Subsequently, the reaction mixture was cooled and the resulting biphasic mixture was extracted repeatedly with dichloromethane. The combined organic phases were concentrated by rotary evaporation and the product was subsequently recrystallized from heptane. 24.1 g of 3-phenyl-4-trifluoromethylpyridin-2-ylamine (52% over both stages) were thus isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[C:8]([CH3:13])[CH:7]=1)[CH3:2].[Li]CCCC.CN([CH:23]=[O:24])C>C1COCC1>[CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:23]=[O:24])=[C:8]([CH3:13])[CH:7]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)Nc1ccc(Br)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)Nc1ccc(C=O)c(C)c1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of (4-bromo-3-methyl-phenyl)-carbamic acid ethyl ester (210 mg) in THF (4 mL) was added n-BuLi (0.71 mL, 2.5 M solution in hexane) at −78° C. The mixture was stirred at −78° C. for 40 min, then DMF (0.31 mL) was added. The mixture was stirred at −78° C. for 40 min and then warmed up to room temperature. The reaction mixture was quenched with saturated NH4Cl aqueous solution (11 mL) and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, EtOAc:Hexane=5:95 to 40:60) to give (4-formyl-3-methyl-phenyl)-carbamic acid ethyl ester: MS (ESI): m/z 206 (M+1); 1H NMR (CDCl3, 400 MHz) δ 10.14 (s, 1H), 7.75 (d, 1H), 7.39 (dd, 1H), 7.32 (s, 1H), 6.92 (s, 1H), 4.25 (q, 2H), 2.65 (s, 3H), 1.32 (t, 3H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]=[CH:11][C:12](=[O:15])[CH2:13][CH3:14])=[CH:4][C:3]=2[O:2]1.[CH2:16]=O.Cl.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]=[CH:11][C:12](=[O:15])[CH:13]([CH3:16])[CH2:14][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:4][C:3]=2[O:2]1
Reactant: C=O
Reactant: C1COCCN1
Reactant: CCC(=O)C=Cc1ccc2c(c1)OCO2
Agent: Cl
Product: CC(CN1CCOCC1)C(=O)C=Cc1ccc2c(c1)OCO2

Procedure:
A mixture of 20 g of 1-(3,4-methylenedioxyphenyl)-1-pentene-3-one (0.1 mole), 3 g of paraformaldehyde (0.1 mole) and 12.2 g of morpholine hydrochloride (0.1 mole) in 100 cm3 of absolute alcohol adjusted to a pH of 3 is refluxed for 9 hours. The alcohol is removed and the product is taken up in water. The product is then extracted with chloroform, and the basic, aqueous phase is taken and re-extracted with benzene. A yellow oil is obtained which can be used for the reduction of Example 6.
Reaction SMILES: [F:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[NH:15]1[CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(#N)C>[N:15]1([S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([F:1])(=[O:4])=[O:3])(=[O:13])=[O:12])[CH2:18][CH2:17][CH2:16]1
Reactant: C1CNC1
Reactant: O=S(=O)(F)c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=S(=O)(F)c1ccccc1S(=O)(=O)N1CCC1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
In a flask was placed 9.24 g of 2-fluorosulfonylbenzenesulfonyl chloride and 200 ml of dry acetonitrile. The resultant solution was cooled to 0° C. An addition funnel was charged with 2 g of azetidine, 4.95 ml of triethylamine and 50 ml of acetonitrile. This solution was added dropwise to the first solution. After stirring overnight the solvent was evaporated under reduced pressure. The residue was partitioned between dichloromethane and 1N hydrochloric acid. The organic layer was separated, dried and concentrated to give 9.80 g of a solid, m.p. 93° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1(O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.S(=O)(=O)(O)O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:10]2([CH3:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC1(O)CCCCC1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC1(c2cc(F)ccc2O)CCCCC1
Temperature: 25 °C
Reaction time: 50 h
Yield: 61.3 %

Procedure:
4-Fluorophenol (41.8 g, 373 mmol) and 1-methylcyclohexanol (63.8 g, 560 mmol) dissolved in 600 mL of dried CH2Cl2, were treated with concentrated sulfuric acid (98%, 22.3 mL, 418 mmol). The mixture was stirred at room temperature for 50 hours. The reaction mixture was then extracted by CH2Cl2 (250 mL×3). The organic layer was washed with saturated a.q NaHCO3., dried over MgSO4, and evaporated under vacuum. The residue was purified by column chromatography on silica gel to give 4-fluoro-2-(1-methylcyclohexyl)phenol as a dark green oil −47.6 g. 1H NMR (400 MHz, CDCl3) δ 7.00 (dd, J=3.2, 11.2 Hz, 1H), 6.76-6.71 (m, 1H), 6.62-6.59 (m, 1H), 5.27 (brs, 1H), 2.13-2.07 (m, 2H), 1.70-1.37 (m, 8H), 1.32 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[O:8])[CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]([Si](C)(C)C)([F:18])[F:17]>CN(C)C=O>[F:15][C:16]([F:18])([F:17])[CH:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)[OH:8]
Reactant: Cn1cc(C=O)cn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(C(O)C(F)(F)F)cn1
Yield: 47.1 %

Procedure:
According to Reference Example 8-2, by use of 1-methyl-1H-pyrazole-4-carbaldehyde (300 mg, 2.72 mmol) dissolved in N,N-dimethylformamide (4.5 mL), potassium carbonate (75 mg, 0.54 mmol) and (trifluoromethyl)trimethylsilane (0.442 mL, 2.99 mmol), the mixture was stirred and reacted at room temperature for 3 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=10/1) was performed to give 2,2,2-trifluoro-1-(1-methyl-1H-pyrazol-4-yl)ethanol (Compound DJ) (231 mg, yield: 47%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1N=[C:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[N:8]=C(C(Cl)(Cl)Cl)[N:6]=1.Cl>>[Cl:12][C:11]([Cl:14])([Cl:13])[C:9]#[N:8].[Cl:1][CH2:2][CH2:3][CH2:4][C:5]#[N:6]
Reactant: ClCCCc1nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n1
Agent: Cl
Product: N#CC(Cl)(Cl)Cl
Product: N#CCCCCl

Procedure:
The 2-amino-4-cyclopropyl-triazines of formula I can also be prepared, starting from a 2-(γ-chloropropyl)4,6-bis-(trichloromethyl)-1,3,5-triazine, which is obtained by condensation of 2 moles of trichloroacetonitrile and one mol of γ-chlorobutyronitrile in the presence of hydrogen chloride. ##STR6##
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]3[CH2:17][CH:16]3[CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)[CH:8]=[CH:7]1.CN([CH:25]=[O:26])C>>[CH3:20][N:19]([CH2:18][CH:16]1[CH2:17][CH:15]1[C:12]1[CH:13]=[C:14]2[C:9]([C:8]([CH:25]=[O:26])=[CH:7][NH:6]2)=[CH:10][CH:11]=1)[CH3:21]
Reactant: CN(C)CC1CC1c1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CC1CC1c1ccc2c(C=O)c[nH]c2c1
Reaction time: 0.25 h

Procedure:
Phosphorous oxychloride (0.23 g, 1.47 mmol) was added to dimethylformamide (2 mL) at room temperature with stirring. After 15 min, [2-(1H-indol-6-yl)-cyclopropylmethyl]-dimethyl-amine (0.35 g, 1.64 mmol) in DMF (3 mL) was added dropwise. After 20 h, the reaction was quenched with ice and 1 N NaOH. The solution was extracted with methylene chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 6-(2-dimethylaminomethyl-cyclopropyl)-1H-indole-3-carbaldehyde of an oil (0.25 g, 63%) that was used for the next reaction without purification. 1H NMR (CDCl3): δ9.84 (s, 1H), 8.14 (d, J=8.4 Hz, 1H), 7.97 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.05 (s, 1H), 2.64 (s, 1H), 2.56 (s, 7H), 1.91 (m, 1H), 1.27 (m, 1H), 1.06 (m, 1H), and 0.92 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([CH:8]1[O:10][CH2:9]1)Cl>>[O:10]1[CH2:9][CH:8]1[CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: ClCC1CO1
Product: C1CCN(CC2CO2)C1

Procedure:
By using pyrrolidine (3 ml) and (±)-epichlorohydrin (2.9 ml) as starting materials, the title compound (2.10 g) was obtained in the same manner as that of Reference Example 33.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@:7]3([O:30][C@@H:8]3[C@H:9](O)[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:28][C@@H:13]3[C:14]32[O:27][CH2:26][CH2:25][O:24]3)[CH2:6]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:51]>N1C=CC=CC=1.C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@:7]3([O:30][C@@H:8]3[C@@H:9]([Cl:51])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:28][C@@H:13]3[C:14]32[O:27][CH2:26][CH2:25][O:24]3)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@]4(C)[C@@H]([C@@H]5C[C@@H]5C45OCCO5)[C@@H]3[C@@H](O)[C@H]3O[C@]32C1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@]4(C)[C@@H]([C@@H]5C[C@@H]5C45OCCO5)[C@@H]3[C@H](Cl)[C@H]3O[C@]32C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 24 g of 3β-acetoxy-5,6β-epoxy-17,17-ethylenedioxy-15β,16β-methylene-5β-androstan-7β-ol in 48 ml of pyridine and 48 ml of carbon tetrachloride was combined with 28 g of triphenylphosphine and stirred for 1.5 hours at room temperature. The reaction mixture was diluted with methylene chloride, washed with water, dried, and evaporated. The residue was chromatographed on silica gel, thus producing 21.5 g of 3β-acetoxy-7α-chloro-5,6β-epoxy-17,17-ethylenedioxy-15β,16β-methylene-5β-androstane, mp 169°-170° C. (diisopropyl ether).