Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:23][C@:13]4([C:21]5[C:16](=[N:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][C:7]=3[CH:8]=2)[N:3]=1.[Se](=O)=[O:25]>O1CCOCC1.O>[O:22]=[C:14]1[NH:15][C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[C@:13]21[CH2:12][C:7]1[CH:8]=[C:9]3[C:4](=[CH:5][C:6]=1[CH2:23]2)[N:3]=[C:2]([CH:1]=[O:25])[CH:11]=[CH:10]3
Reactant: Cc1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21

Procedure:
A mixture of (S)-2-methyl-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (1.30 g, 4.31 mmol) and selenium dioxide (718 mg, 6.47 mmol) in dioxane (50 mL) and H2O (5 mL) was heated at reflux for 4 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of CH2 Cl2:MeOH—100:0 to 90:10. Product-containing fractions were combined, toluene was added, and the mixture was concentrated in vacuo to give the title compound. MS: m/z=316 (M+1).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:26](=[O:28])[NH:24][C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(CC)Oc1cc(C)nc2c1[nH]c(=O)n2-c1c(C)cc(C)cc1C

Procedure:
The title compound was prepared by reacting 4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine with triphosgene, NEt3 in THF at room temperature. A white solid was isolated, mp. 184–186° C. Anal. For C21H27N3O2 calc. C, 71.36; H, 7.70; N, 11.89; found: C, 71.09; H, 7.75; N, 11.63.
Reaction SMILES: [C:1]1([CH2:6][C@H:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:8](N(OC)C)=[O:9])[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:22]=[C:23]([Mg]Br)[CH3:24]>C1COCC1>[C:1]1([CH2:6][C@H:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[C:8](=[O:9])[C:23]([CH3:24])=[CH2:22])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C=C(C)[Mg]Br
Reactant: CON(C)C(=O)[C@H](CC1=CCCC1)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C=C(C)C(=O)[C@H](CC1=CCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
To a solution of (S)-tert-butyl (3-(cyclopent-1-en-1-yl)-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (81 g, 0.27 mol) in THF (600 mL) was added freshly prepared prop-1-en-2-ylmagnesium bromide (96.0 mL, 1.08 mol) at 0° C. dropwise. After completion of the addition, the reaction mixture was stirred at 0° C. for 2 h then quenched with saturated aqueous ammonium chloride (500 mL). The resulting mixture was extracted with EtOAc (400 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=100:1) to afford (S)-tert-butyl (1-(cyclopent-1-en-1-yl)-4-methyl-3-oxopent-4-en-2-yl)carbamate as colorless oil (39.3 g, 52% yield).
Reaction SMILES: O[CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]1[CH:19]=[CH:18][C:6]([O:7][CH2:8][C:9]2[O:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1(P([N:40]=[N+:41]=[N-:42])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:40]([CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]1[CH:19]=[CH:18][C:6]([O:7][CH2:8][C:9]2[O:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[N+:41]=[N-:42]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(COc2ccc(C(O)c3ccccc3)cc2)o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(COc2ccc(C(N=[N+]=[N-])c3ccccc3)cc2)o1
Temperature: 100 °C
Yield: 84 %

Procedure:
To a stirred solution of methyl 5-((4-(hydroxy(phenyl)methyl)phenoxy)methyl)-furan-2-carboxylate (325 mg, 0.96 mmol) in toluene (4.5 mL) under nitrogen was added diphenylphosphoryl azide (0.25 mL, 1.15 mmol) followed by DBU (0.17 mL, 1.15 mmol). The reaction was heated at 100° C. for 3 h. The reaction was quenched by the addition of saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate (×2). The combined organic phases were washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified via silica gel chromatography, eluting with 0-25% EtOAc in isohexane, to give the title compound as a colourless oil (293 mg, 84%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25].O>O1CCCC1>[CH3:27][O:26][C:24](=[O:25])[N:10]([CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)Cl
Reactant: CCCCCNCCc1ccccc1Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCN(CCc1ccccc1Br)C(=O)OC
Reaction time: 20 h

Procedure:
4.51 g of N-[2-(2-bromophenyl)ethyl]pentan-1-amine in suspension in 120 cm3 of anhydrous tetrahydrofuran are stirred under an inert atmosphere at 5° C. 2.33 cm3 of triethylamine, then 1.3 cm3 of methyl chloroformate are added to the reaction mixture. This mixture is then stirred for 20 h at a temperature close to 20° C. before being poured over a mixture of water and ice. The phases are stirred for 5 min, then separated. The aqueous phase is extracted 3 times with ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 6.33 g of oil obtained are purified by flash chromatography over silica (column: 200 g; particle size: 15-40 μm; eluent: 20% heptane/80% ethyl acetate). After concentrating the fractions under reduced pressure, 5.45 g of methyl[2-(2-bromophenyl)ethyl]pentylcarbamate are obtained in the form of a colorless oil
Reaction SMILES: [OH:1]C[CH:3]([OH:6])[CH:4]=C.O.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:3]([O-:6])(=[O:15])[CH3:4].[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O-:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: C=CC(O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)[O-]
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
The racemic acetate substrate was prepared by one of two methods. The diol route began with racemic 1,2-dihydroxy-3-butene which could be prepared by reacting EpB with water under neutral conditions or with acid catalysis. The diol was treated with p-toluenesulfonyl chloride (p-TsCl) in pyridine at 4° C. to afford the desired monotosylate contaminated with about 10% of the corresponding ditosylate. The monotosylate could be selectively crystallized to afford pure monotosylate in 61% yield. Hydroxytosylate was acetylated under normal conditions (Ac2O, Et3N, CH2Cl2) to provide the acetoxy-tosylate (the desired racemic acetate) in 93% yield. The diol route is illustrated as follows: ##STR3##
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)[CH2:6][C:7]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[C:30]([CH3:32])=[CH2:31]>C(Cl)Cl>[C:29]([O:12][C:7]1([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:20])([F:21])[F:1])[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1)(=[O:33])[C:30]([CH3:32])=[CH2:31]
Reactant: C=C(C)C(=O)Cl
Reactant: OC1(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC1(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC1
Reaction time: 12 h
Yield: 65 %

Procedure:
43 g of 1-(3,5-bis(trifluoromethyl)benzyl)cyclopentanol and 16.7 g of triethylamine dissolved in 100 mL of methylene chloride was slowly charged into flask equipped with magnetic stirrer and 14.93 mL of methacryloyl chloride in 100 mL of dichloromethane cooled down to 0° C. The resultant mixture slowly warmed up to room temperature and allowed to stir at this temperature for 12 hours. Upon completion of the reaction as confirmed by thin layer chromatography, the mixture was quenched by pouring into 400 mL of deionized water and extracted further into methylene chloride. The methylene chloride extracts were then dried over sodium sulfate, filtered and concentrated in the rotary evaporator affording 34 g of 1-(3,5-bis(trifluoromethyl)benzyl)cyclopentyl methacrylate (˜65%) yield of as an amber oil. The oil was purified further by passing through a silica gel plug eluting with a 60/40 mixture of hexanes/methylene chloride affording 30 g of 1-(3,5-bis(trifluoromethyl)benzyl)cyclopentyl methacrylate (LG1) as pure product. 1H NMR (500 MHz, Acetone-d6): δ 7.97 (s, 1H), 7.76 (s, 2H), 5.99 (s, 1H, vinyl), 5.6 (s, 1H, vinyl), 3.56 (s, 2H), 2.23-1.70 (m, 8H), 1.80 (s, 3H).
Reaction SMILES: ClCCl.B(Br)(Br)Br.[CH3:8][N:9]([CH:28]1[C:36]2[C:31](=[C:32]([OH:37])[CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1)[CH2:10][C:11]1[O:12][C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1.Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C([O-])([O-])=O.[K+].[K+]>ClCCl.CN(C=O)C>[CH3:8][N:9]([CH:28]1[C:36]2[C:31](=[C:32]([O:37][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1)[CH2:10][C:11]1[O:12][C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1
Reactant: CN(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)C1CCc2c(O)cccc21
Reactant: CCOC(=O)CBr
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCC2N(C)Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 0 °C
Reaction time: 4 h
Yield: 60.3 %

Procedure:
To a solution of 1-[N-methyl-N-[(4,5-diphenyloxazol-2.-yl)methyl]amino]-2,3-dihydro-4-methoxy-1H-indene (109 mg) in dichloromethane (2 ml) was added 1M boron tribromide dichloromethane solution (1 ml) at 0° C. After being stirred for 4 hours at 0° C., the solvent was evaporated in vacuo. The residue was extracted with ethyl acetate. The mixture was washed with brine, dried over MgSO4 and evaporated in vacuo to afford crude 1-[N-methyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-hydroxy-1H-indene (109 mg). To a solution of crude 1-[N-methyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-hydroxy-1H-indene (109 mg) and ethyl bromoacetate (80 mg) in DMF (3 ml) was added K2CO3 (80 mg). After being stirred for 24 hours, the solution was extracted with ethyl acetate. The mixture was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-[N-methyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-ethoxycarbonylmethoxy-1H-indene (80 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2].CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C1COCC1.C(Cl)Cl>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][O:25][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:21][CH:22]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCO)cc3)no2)cc1C
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCOS(C)(=O)=O)cc3)no2)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 134.5 %

Procedure:
To a cooled (0° C.) solution of 2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethanol (196 mg, 488 μmol) and DIPEA (84 mg, 732 μmol) in THF (5 mL), methanesulfonyl chloride (126 mg, 976 μmol) is added as a solution in THF (2.5 mL). The reaction mixture is stirred at 0° C. for 1 h, then at rt for 1 h. The mixture is diluted with DCM (100 mL) and washed with brine (3×50 mL). The organic extract is dried over MgSO4, filtered, concentrated and dried to give crude methanesulfonic acid 2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethyl ester (295 mg); LC-MS: tR=0.59 min; [M+1]+=449.71. b) A solution of methanesulfonic acid 2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethyl ester (295 mg, 658 μmol) in 7 N NH3 in methanol (10 mL) is stirred in a sealed vessel at 80° C. for 16 h. The reaction mixture is concentrated and dried to give the title compound (255 mg) as a pale yellow oil; LC-MS: tR=0.64 min; [M+1]+=370.97.
Reaction SMILES: [Cl-:1].[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:28]1([CH:34]=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1(C)C(C)=CC=CC=1>[CH:28]1([CH:34]=[CH:8][C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][Cl:1])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: C(=C1CCCCO1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1CCCCC1
Reactant: [Cl-]
Solvent: Cc1ccccc1C
Product: O=C(C=CC1CCCCC1)CCCCCl
Temperature: 25 °C

Procedure:
2 parts of [(tetrahydro-2H-pyran-2-ylidene)methyl]triphenylphosphonium chloride and 1.2 parts of cyclohexanecarbaldehyde were combined in 45 parts of xylene. This suspension was maintained under a nitrogen atmosphere and was refluxed for about 4 hours until a clear solution formed. After cooling the solution to room temperature, xylene was removed at a temperature of about 60° C. and under reduced pressure, leaving a product mixture. This mixture was separated chromatographically on a silica column using as the elution solvent 50 percent by volume of Skelly B in benzene, to yield 1-cyclohexyl-7-chloro-1-hepten-3-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=1[N:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.C(N(CC)CC)C>S(Cl)(Cl)=O.ClCCl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:16][C:15]=1[N:21]1[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C(O)Cc1ccc(Br)cc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)Cc2ccc(Br)cc2)cc1N1CCN(C)CC1
Reaction time: 1 h
Yield: 53 %

Procedure:
4Bromophenylacetic acid (0.300 g, 1.40 mmol) was suspended in thionyl chloride (10 ml) and heated to reflux with stirring. After 1 h, the reaction mixture was allowed to cool and was evaporated under reduced pressure to give a yellow oil. The oil was then azeotroped with toluene, and the residue dried in vacuo to give the crude acid chloride. Meanwhile 4-methoxy-3-(4-methyl-1-piperazinyl)benzeneamine (EP 0533 267 A1) (0.293 g, 1.33 mmol) was dissolved in dichloromethane (10 ml) and treated with triethylamine (0.195 ml, 1.40 mmol), followed by dropwise addition of a solution of the crude acid chloride in dichloromethane (3 ml). The mixture was stirred at room temperature overnight before being washed with NaHCO3 solution. The organic layer was then dried (Na2SO4), and was evaporated under reduced pressure to give a brown oil. The oil was purified by silica-gel chromatography (5% MeOH/CH2Cl2 as eluant) to give the title compound as a pale yellow oil (0.295 g, 50%), which was converted to its oxalate salt.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[N:9][C:8]([O:11][CH2:12][C@H:13]2[C@@H:18]([OH:19])[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH3:4].C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([C:5]1[N:10]=[N:9][C:8]([O:11][CH2:12][C@H:13]2[C@@H:18]([OH:19])[CH2:17][CH2:16][N:15]([CH3:35])[CH2:14]2)=[CH:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OC[C@@H]2CNCC[C@@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nnc(OC[C@@H]2CN(C)CC[C@@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-piperidin-4-ol (0.27 mmol, 0.14 g) in DCM (1 mL) was added formaldehyde solution (1 mL) followed by sodium triacetoxyborohydride (0.5 g) and continued stirring the reaction mixture for 2 h at room temperature. The reaction mixture was diluted with DCM, separated the organic layer, dried, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography by eluting with DCM (300 mL) followed 10% methanolic solution of ammonia (2 M solution of NH3 in methanol) in DCM to provide (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-1-methyl-piperidin-4-ol which was converted to dihydrochloride salt by treating with 4 N HCl in dioxane. The volatiles were removed under educed pressure, salt was washed with anhydrous ether and solid was dried under high vacuum to provide the title compound (0.121 g). LCMS: m/z 455 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.78 (1H, s), 7.46 (2H, d), 7.12 (2H, d), 4.6-4.73 (1H, m), 4.5-4.58 (2H, m), 4.19 (1H, bs), 3.11-3.53 (6H, m), 2.93 (3H, s), 2.58 (1H, m), 1.99-2.05 (3H, m), 1.8 (2H, m), 1.24-1.60 (11H, m), 0.82 (3H, t).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:15][C:6]2[N:7]=[C:8]([NH:10][C:11]([NH:13][CH3:14])=[O:12])[S:9][C:5]=2[C:4]([CH3:17])([CH3:16])[CH2:3]1.[CH2:19]1[O:24][CH2:23]OCO1.S(=O)(=O)(O)O.[OH-].[Na+]>O>[CH3:1][C:2]1([CH3:18])[CH2:15][C:6]2[N:7]=[C:8]([N:10]3[C:11](=[O:12])[N:13]([CH3:14])[CH2:23][O:24][CH2:19]3)[S:9][C:5]=2[C:4]([CH3:17])([CH3:16])[CH2:3]1
Reactant: C1OCOCO1
Reactant: CNC(=O)Nc1nc2c(s1)C(C)(C)CC(C)(C)C2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1COCN(c2nc3c(s2)C(C)(C)CC(C)(C)C3)C1=O
Temperature: 5 °C
Reaction time: 16 h

Procedure:
Sulfuric acid, 85% concentration (40 grams) was charged into a glass reaction vessel fitted with a mechanical stirrer and a thermometer and was cooled to about 5° C. N-(5,5,7,7-tetramethyl-4,5,6,7-tetrahydrobenzothiazol-2-yl)-N'-methylurea (4.1 grams; 0.015 mole) and s-trioxane (1.4 grams, 0.015 mole) were added portionwise, with stirring, to the cold sulfuric acid. Stirring was continued for a period of about 16 hours at a temperature of about 20°-25° C. The reaction mixture was then diluted 1:1 with water and neutralized with aqueous 40% sodium hydroxide. The neutralized mixture was filtered and the solid obtained was washed with 3-100 ml portions of water and air dried to yield the desired product 3-(5,5,7,7-tetramethyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-5methyltetrahydro-1,3,5-oxadiazin-4-one as a solid having a melting point of 138°-140° C. Elemental analysis: Theory: C: 58.22%; H: 7.49%; N: 13.58%; Found: C:57.53%; H: 7.57%; N: 13.61 %.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([Cl:23])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[CH3:16])[C:6]1=[O:17].CCN(CC)CC.[O:31](S(C(F)(F)F)(=O)=O)[S:32]([C:35]([F:38])([F:37])[F:36])(=O)=[O:33].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:36][C:35]([F:38])([F:37])[S:32]([O:22][C:20]1[CH:19]=[C:18]([Cl:23])[C:3]([CH2:4][CH:5]2[CH2:9][CH2:8][N:7]([C@@H:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]3[CH3:16])[C:6]2=[O:17])=[C:2]([Cl:1])[CH:21]=1)(=[O:33])=[O:31]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C[C@H]1CCCC[C@H]1N1CCC(Cc2c(Cl)cc(O)cc2Cl)C1=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CCCC[C@H]1N1CCC(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)C1=O
Temperature: 0 °C
Yield: 87.4 %

Procedure:
Dissolve 3-(2,6-dichloro-4-hydroxybenzyl)-1-(cis-2-methylcyclohexyl)pyrrolidin-2-one (1.0 g, 2.81 mmol) in DCM (100 mL) and cool to 0° C. under N2. Add DMAP (0.069 g, 0.56 mmol), Et3N (2.84 g, 28.01 mmol), and Tf2O (0.83 g, 2.95 mmol) at the same temperature. Stir the reaction for six hour and then add water (100 mL). Extract the aqueous layer with dichloromethane (3×100 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 20-50% of EtOAc-Hexane) to give 1.2 g (88%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ 7.28 (s, 2H), 4.02 (m, 1H), 3.46 (m, 2H), 3.38 (m, 1H), 3.02 (m, 1H), 2.91 (m, 1H), 2.35 (m, 1H), 2.02 (m, 1H), 1.31-1.87 (m, 9H), 0.92 (d, 3H).
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:32])[NH:11][C@@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([OH:24])[CH2:14][NH:15][CH2:16][C:17]([CH3:23])([CH3:22])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:42]([NH:45][C:46]1[CH:47]=[C:48]([S:52](Cl)(=[O:54])=[O:53])[CH:49]=[CH:50][CH:51]=1)(=[O:44])[CH3:43]>C(Cl)Cl>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:32])[NH:11][C@@H:12]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@H:13]([OH:24])[CH2:14][N:15]([S:52]([C:48]2[CH:49]=[CH:50][CH:51]=[C:46]([NH:45][C:42](=[O:44])[CH3:43])[CH:47]=2)(=[O:54])=[O:53])[CH2:16][C:17]([CH3:22])([CH3:23])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1
Reactant: CC(=O)Nc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCC#N)c1
Yield: 59.1 %

Procedure:
[(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethyl-butylamino)-2-hydroxy-propyl]-carbamic acid (3R,3aS,6aR)hexahydro-furo[2,3-b]furan-3-yl ester (0.020 g, 0.05 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (0.025 ml, 0.13 mmol) and 3-acetamidobenzenesulfonyl chloride (0.012 g, 0.05 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by preparative thin layer chromatography (3% MeOH in CH2Cl2) gave 0.019 g of a white solid. MS(ES): 643 (M+1).
Reaction SMILES: F[C:2]1[C:3]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([S:15][CH3:16])[N:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.[Cu]I>[CH3:25][O:24][C:21]1[N:22]=[CH:23][C:18]([NH:17][C:2]2[C:3]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([S:15][CH3:16])[N:9]=3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(N)cn1
Reactant: CSc1nc(C)nc(-c2nccnc2F)n1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(Nc2nccnc2-c2nc(C)nc(SC)n2)cn1
Temperature: 100 °C
Yield: 76.3 %

Procedure:
A glass microwave reaction vessel was charged with 2-(3-fluoropyrazin-2-yl)-4-methyl-6-(methylthio)-1,3,5-triazine (61 mg, 0.257 mmol), 5-amino-2-methoxypyridine (0.038 mL, 0.309 mmol), copper(I) iodide (5 mg, 0.026 mmol) and N,N-diisopropylethylamine (0.089 mL, 0.514 mmol) in dioxane (1 mL). The reaction mixture was stirred and heated at 100° C. for 24 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 20% EtOAc/CH2Cl2 to give N-(6-methoxypyridin-3-yl)-3-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrazin-2-amine (67 mg, 0.196 mmol, 76% yield) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 11.34 (s, 1H); 8.36 (d, J=1.90 Hz, 1H); 8.26 (s, 2H); 8.00 (dd, J=8.99, 2.56 Hz, 1H); 6.80 (d, J=8.77 Hz, 1H); 3.96 (s, 3H); 2.77 (s, 3H); 2.68 (s, 3H). m/z (ESI, +ve ion) 342.0 (M+H)+.