Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][S:6][C:7]1[NH:8][C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[N:11]=1.[H-].[Na+].CI.[C:24](OCC)(=O)C>CN(C)C=O.O>[CH3:24][N:11]1[C:10](=[O:12])[C:9]([CH3:14])([CH3:13])[N:8]=[C:7]1[S:6][CH2:5][C:4]1[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=1[N:2]([CH3:1])[CH3:19]
Reactant: CN(C)c1ccccc1CSC1=NC(=O)C(C)(C)N1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN1C(=O)C(C)(C)N=C1SCc1ccccc1N(C)C
Reaction time: 0.25 h

Procedure:
To a solution of 0.5 g of 2-(2-dimethylaminobenzylthio)-5,5-dimethylimidazolin-4-one in 20 mL of N,N-dimethylformamide, there was added 60% sodium hydride in 0.09 g of mineral oil at -10° C. After the mixture was stirred for 15 minutes, 1 mL of methyl iodide was added to the mixture, and the stirring was continued for one hour. To the reaction mixture, there were added 100 mL of ethyl acetate (AcOEt) and 100 mL of water. The AcOEt layer was separated. The separated AcOEt layer was washed three times with 50 mL of brine, dried over magnesium sulfate (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography (using CHCl3 as a developing solvent), to give the desired compound in the form of a syrup. The yield of this compound was 0.41 g with a yield ratio of 78.1%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][SH:11](=[O:13])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH:45]([N:58]1[CH2:61][CH:60](O)[CH2:59]1)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>O1CCCC1>[CH:45]([N:58]1[CH2:61][CH:60]([N:10]([CH2:9][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[SH:11](=[O:13])=[O:12])[CH2:59]1)([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=[SH](=O)NCc1cc(F)cc(F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[SH](=O)N(Cc1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 20 h
Yield: 60.2 %

Procedure:
N-(1-Benzhydrylazetidin-3-yl)-N-(3,5-difluorophenyl)methylsulfonamide may be obtained by carrying out the procedure as in Example 13 (method 2) in the following manner: 0.86 g of N-(3,5-difluorophenyl)methylsulfonamide, 3.28 g of triphenylphosphine and then 2 ml of diethyl azodicarboxylate are added successively to a solution of 2 g of 1-benzhydrylazetidin-3-ol in 100 cm3 of tetrahydrofuran. An increase in the temperature, which passes from 22° C. to 29° C., as well as the formation of a precipitate immediately following the addition of the diethyl azodicarboxylate are observed. After 20 h at 22° C., the precipitate is removed by filtration and the filtrate is concentrated to dryness at 40° C. under 2.7 kPa. The residue is triturated with 5 cm3 of methanol for 20 minutes at 21° C., providing 1.07 g of N-(1-benzhydrylazetidin-3-yl)-N-(3,5-difluorophenyl)methylsulfonamide in the form of a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:17]([O:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24](=[O:27])[CH2:25]Cl)([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([CH2:25][C:24]([C:23]3[CH:28]=[CH:29][CH:30]=[C:21]([O:20][CH:17]([CH3:19])[CH3:18])[CH:22]=3)=[O:27])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)Oc1cccc(C(=O)CCl)c1
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Product: CC(C)Oc1cccc(C(=O)CN2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
Prepare by the method of example 3.1 using 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (2 mmol) and 3-isopropoxy-phenacyl chloride (2 mmol). Chromatograph on silica gel to give the title compound. Rf =0.44 (silica gel, 5% methanol/dichloromethane).
Reaction SMILES: CO[C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][OH:6].C([Li])CCC.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]=[O:25].[Cl-].[NH4+]>CCOCC.CCCCCC>[OH:6][CH2:5][C:4]1[CH:3]=[CH:10][CH:9]=[C:8]([O:11][CH3:12])[C:7]=1[CH:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1)[OH:25]
Reactant: COc1ccc(OC)c(CO)c1
Reactant: O=Cc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cccc(CO)c1C(O)c1ccccn1
Temperature: -20 °C
Reaction time: 1 h
Yield: 11.7 %

Procedure:
To a mixture of 10 g (0.059 mol) of 2,5-dimethoxybenzyl alcohol in 250 ml of ether cooled to -20° C. was added in portions 12.75 ml (0.127 mol) of n-butyllithium (10M) in hexane over a 10 min period, and the reaction mixture was allowed to warm to room temperature and stirred 1 hr. The above reaction mixture was cooled to -20° C., 7.58 g (0.07 mol) of pyridine-2-carboxaldehyde was added to the mixture, and the resulting reaction mixture was allowed to warm to room temperature (a brown precipitate formed) and stirred for 1 hr. Ammonium chloride solution (60 ml) was added, the mixture was extracted with ethyl acetate, the combined organic layer was washed with brine, dried over sodium sulfate, and concentrated. The diol was purified by chromatography on silica eluting with ethyl acetate/hexane (9:1) to afford 1.7 g (10.5%) of 2-[(2',5'-dimethoxy-6'-hydroxymethyl)benzyl]pyridine (Formula XIII: R1 =R7 =H; R2 =2',5'(OCH3)2), as a white solid, m.p. 102°-104° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1)[CH3:2].[CH2:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH:20]=[O:21])[CH2:15][CH2:14]1)[CH3:12].Cl>C1COCC1>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][CH:20]([OH:21])[CH2:19][CH:16]2[CH2:17][CH2:18][CH:13]([CH2:11][CH3:12])[CH2:14][CH2:15]2)=[CH:4][CH:5]=1)[CH3:10]
Reactant: CCC1CCC(CC=O)CC1
Reactant: C#Cc1ccc(CC)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCc1ccc(C#CC(O)CC2CCC(CC)CC2)cc1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
4-Ethylphenylacetylene (1.3 g) was dissolved in THF (20 ml), followed by dropwise adding an n-butyllithium-hexane solution (1.61M, 0.62 ml) under ice cooling with stirring, further stirring the reaction solution under ice cooling for 30 minutes, dropwise adding a solution of 2-(4-ethylcyclohexyl)acetaldehyde (1.5 g) in THF (10 ml) , raising the temperature of the reaction solution up to room temperature after completion of the addition, stirring it for 5 hours, adding dilute hydrochloric acid (5 ml) to the resulting raw solution, extracting with ethyl acetate (50 ml), washing the organic layer with water, drying over anhydrous MgSO4 and concentrating under reduced pressure, to obtain a brown oil, which was then recrystallized from an ethyl acetate-heptane mixed solution, to obtain white crystals of 1-(4-ethylphenyl)-4-(4-ethylcyclohexyl)-1-butyn-3-ol (2.3 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[NH:8][C:7]2=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.C(N(C(C)C)C=O)(C)C.Cl.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34].C(N(CC)CC)C.[CH2:44]([NH2:47])[CH:45]=[CH2:46]>O>[CH2:44]([NH:47][C:9]1[N:8]=[C:7]([NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1)[CH:45]=[CH2:46]
Reactant: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: NCC(F)(F)F
Reactant: C=CCN
Agent: CC(C)N(C=O)C(C)C
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCNc1nc(NCC(F)(F)F)c2cc([N+](=O)[O-])ccc2n1
Reaction time: 0.5 h
Yield: 12.6 %

Procedure:
To 250 mg (1.21 mmol) of 6-nitroquinazoline-2,4(1H,3H)-dione were added 5.00 ml (53.64 mmol) of phosphorus oxychloride and 0.18 ml (1.21 mmol) of diisopropylformamide, and the resulting mixture was subjected to heating under reflux for 24 hours. After phosphorus oxychloride was removed in vacuo, the mixture was dissolved in 5 ml of acetonitrile, followed by addition of 328 mg (2.42 mmol) of 2,2,2-trifluoroethylamine hydrochloride and 1.69 ml (12.10 mmol) of triethylamine under ice cooling and stirring under ice cooling for 30 minutes. To the reaction solution was added water, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, 1.50 ml (20.00 mmol) of allylamine was added thereto, followed by stirring overnight, adding water to the reaction solution, extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 50 mg (12.6%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].[CH3:14][CH:15]([CH3:21])[CH2:16][CH:17]([NH:19][OH:20])[CH3:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[N+:19]([CH:17]([CH2:16][CH:15]([CH3:21])[CH3:14])[CH3:18])[O-:20])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: CC(C)CC(C)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOc1cc(C=[N+]([O-])C(C)CC(C)C)ccc1OC

Procedure:
3-Ethoxy-4-methoxybenzaldehyde (12.0 g, 0.0666 mol) and N-(4-methylpent-2-yl)hydroxylamine (9.36 g, 0.0799 mol) were mixed into benzene (200 mL) with p-toluenesulfonic acid monohydrate (1.0 g, 5.26 mol.). The mixture was refluxed for 16 hours under an argon atmosphere with a Dean-Stark trap to remove the generated water. The solution was rotary evaporated, dissolved in ethyl acetate, washed with 5% aqueous sodium hydroxide solution, dried over magnesium sulfate, filtered and concentrated. The title compound was obtained as a white solid (17.07 g, 91.8% yield). m.p. 87.2° C. (Rf=0.31 on a silica gel plate using hexanes;EtOAc,, 1:1, v/v, as an eluant). The N-(4-methyl-2-pentyl)hydroxylamine precursor was obtained by sodium cyanoborohydride reduction of 4-methyl-2-pentanone oxime in methanol, with hydrochloric acid catalysis.
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[CH3:16][N:17]([CH3:33])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:32])[C:24]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:25]=2[N:26]=1.FC(F)(F)C(O)=O>C(Cl)Cl.C(Cl)(Cl)Cl.N>[CH3:33][N:17]([CH3:16])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:32])[C:24]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:25]=2[N+:26]=1[O-:6]
Reactant: Cc1ccc2c(c1)nc(NCCN(C)C)n[n+]2[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)[n+]([O-])c(NCCN(C)C)n[n+]2[O-]
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 34.2 %

Procedure:
Hydrogen peroxide (70%, 1.1 mL, ca. 22.9 mmol) was added dropwise to a stirred solution of trifluoroacetic anhydride (3.2 mL, 22.9 mmol) in DCM (20 mL) at 5° C. The mixture was stirred at 5° C. for 5 min, warmed to 20° C., stirred for 10 min, and cooled to 5° C. The mixture was added to a stirred solution of 1-oxide 2 (566 mg, 2.3 mmol) and trifluoroacetic acid (353 μL, 4.6 mmol) in CHCl3 (20 mL) at 5° C. and the mixture stirred at 20° C. for 16 h. The solution was carefully diluted with dilute aqueous NH3 solution (20 mL) and the mixture extracted with CHCl3 (5×50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 3 (207 mg, 34%) as a red solid, mp (MeOH/EtOAc) 187-189° C.; 1H NMR δ 8.19 (d, J=9.0 Hz, 1 H, H-8), 8.05 (d, J=1.7 Hz, 1 H, H-5), 7.44. (br s, 1 H, NH), 7.29 (dd, J=9.0, 1.7 Hz, 1 H, H-7), 3.58-3.64 (m, 2 H, CH2N), 2.57-2.61 (m, 2 H, CH2N), 2.56 (s, 3 H, CH3), 2.28 [s, 6 H, (CH3)2]; 13C NMR δ 149.9, 148.0, 138.2, 129.3, 128.8, 121.4, 116.0, 57.4, 45.2 (2), 38.8, 22.3. Anal. Calcd for C12H17N5O2: C, 54.7; H, 6.5; N, 26.6. Found: C, 54.3: H, 6.7; N, 26.8%.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][NH2:15].[BH4-].[Na+]>CO.ClCCl>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:15][CH3:14])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CNC1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 1-N—BOC-3-pyrrolidinone (3.0 g) in methanol (30 ml) was added a solution of freshly prepared methylamine (0.75 g) in methanol (3.1 ml). The reaction mixture was stirred for 1 hour and then sodium borohydride (0.61 g) was added. After stirring for 4 hours the reaction mixture was then diluted with dichloromethane, washed with sodium bicarbonate solution, dried (Mg2SO4) and the solvent removed in vacuo to give 3-methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (3.18 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)=[O:5])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:29]=[CH:30][C:31]=1[Cl:32])[O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClC(Cl)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([NH:15][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([O:20][C:19]3[CH:29]=[CH:30][C:31]([Cl:32])=[C:17]([Cl:16])[CH:18]=3)[CH:22]=2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: O=Cc1cccc(Oc2ccc(Cl)c(Cl)c2)c1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccc(Cl)c(Cl)c3)c2)cc1
Reaction time: 12 h
Yield: 85.8 %

Procedure:
To a mixture of (+)-(trans)-ethyl-2-(4-aminophenyl)cyclopropanecarboxylate (III-1b) (0.099 g, 0.482 mmol) in dichloroethane (3.0 mL) was added 3-(3,4-dichlorophenoxy)benzaldehyde (0.116 g, 0.434 mmol). The mixture was stirred for 12 h followed by addition of sodium triacetoxyborohydride (0.140 g, 0.660 mmol). The mixture was stirred for 6 h at RT. Water was added (10 mL), and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×10 mL). The combined organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography (EtOAc/hexanes) to give the title compound (0.17 g, 85%, mixture of ethyl and methyl ester). 1H NMR (400 MHz, CDCl3) δ 7.35-7.31 (m, 2H), 7.14 (d, J=7.5 Hz, 1H), 7.05-7.00 (m, 2H), 6.92-6.87 (m, 3H), 6.81 (dd, J=8.8 Hz, 2.7 Hz, 1H), 6.52 (d, J=8.4 Hz, 2H), 4.31 (s, 2H), 4.14 (q, J=7.1 Hz, 2H), 2.42 (m, 1H), 1.77 (m, 1H), 1.51 (m, 1H), 1.28-1.20 (t+m, 4H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][O:7][CH2:6][O:5][CH2:4]1.O[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:14]1(=[O:15])[N:10]([O:1][CH2:2][CH:3]2[CH2:8][O:7][CH2:6][O:5][CH2:4]2)[C:11](=[O:20])[C:12]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]12
Reactant: OCC1COCOC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCC1COCOC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
A mixture of 5-hydroxymethyl-1,3-dioxane (3.90 g, 33 mmol), N-hydroxyphthalimide (6.46 g, 39.6 mmol) and triphenylphosphine (10.39 g, 39.6 mmol) in tetrahydrofuran (150 ml) was cooled to O° C. and stirred during the addition of diethyl azodicarboxylate (6.24 ml, 39.6 mmol). The solution was then stirred for 16 h at 25° C. and evaporated to dryness. The residue was triturated twice with ether, evaporated to dryness then chromatographed in chloroform/methanol (40:1) to give 5-phthalimidooxymethyl-1,3-dioxane (6.63 g, 76.3%) as a white solid; m.p. 98-106° C.: νmax (KBr) 1780, 1735, 1470, 1400, 1160 cm-1 ; δH (CDCl3) 2.20(1H, m, CH), 4.07(4H, m, OCH2CHCH2O), 4.37(2H, d, J6.88 Hz, CH2ON), 4.86(2H, m, OCH2O), 7.8I(4H, m, C6H4); Found: C,59.31; H, 5.03; N, 5.31%; C13H13NO5 requires: C, 59.31; H, 4.98; N, 5.32%; m/z 264(MH+, 100%).
Reaction SMILES: [CH2:1]([CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH2:1]([CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][O:11][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCCCC(CO)CCCCCCCC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC(CCCCCCCC)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 107.8 %

Procedure:
2-Octyl-1-dodecanol (20 ml, 56.14 mmol) and anhydrous triethylamine (16 ml, 112.28 mmol) were dissolved in dry dichloromethane (60 ml). The solution was cooled to 0° C. and methanesulfonyl chloride (5.2 ml, 67.36 mmol) in dry dichloromethane (40 ml) added dropwise. After completion of the addition, the mixture was stirred at 0° C. for 3 hours and then refrigerated (2-8° C.) overnight. The reaction mixture was poured on ice (500 grams), allowed to warm to room temperature, and extracted with ether (3×150 ml). The organic phase was washed consecutively with water (150 ml), 2% H2SO4 (150 ml), water (150 ml), saturated sodium bicarbonate (150 ml) and again with water (150 ml). The organic phase was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure, yielding 22.8 grams of methanesulfonic acid 2-octyl-dodecyl ester as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:22][C:23]([CH3:25])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:23]([CH3:25])[CH3:22])=[CH:20][CH:21]=1)([O-:3])=[O:2]
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1ccc(CNCc2ccc([N+](=O)[O-])cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N(Cc1ccc([N+](=O)[O-])cc1)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of bis(4-nitrobenzyl)amine (50 mg, 0.174 mmol) and acetone (51.1 μL, 0.696 mmol) in methanol (752 μL)/acetic acid (39.6 μL)/CH2Cl2 (79 μL) was stirred at room temperature for 1 hour. The reaction was cooled to 0° C. and sodium cyanoborohydride (32.8 mg, 0.522 mmol) was added. The mixture was stirred at 0° C. for 1 hour, and allowed to warm to rt and stirred overnight. The reaction was concentrated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, 50% EtOAc/hexane) afforded the title product (42.8 mg, 75%). MS (ESI) m/z 329.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[CH3:21][NH:22][CH2:23][C:24]1[N:28]=[CH:27][N:26]([CH3:29])[N:25]=1>C(N(CC)CC)C.CN(C=O)C.CO>[ClH:1].[ClH:1].[CH:17]1([C:3]2[C:2]([N:22]([CH3:21])[CH2:23][C:24]3[N:28]=[CH:27][N:26]([CH3:29])[N:25]=3)=[N:7][N:6]3[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Reactant: CNCc1ncn(C)n1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ncn(C)n1)c1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Product: Cl
Temperature: 100 °C
Yield: 55.6 %

Procedure:
A mixture of 6-chloro-7-cyclobutyl-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (100 mg, 0.35 mmol) and N-methyl-N-(1-methyl-1H-1,2,4-triazol-3-ylmethyl)amine (150 mg, 1.2 mmol) in triethylamine (1 ml) and dry DMF (1 ml) was stirred and heated at 100° C. in a sealed tube for 16 hours. Upon cooling the volatiles were removed in vacuo, and the residue was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The aqueous was further extracted with dichloromethane (x2). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 2%→5% methanol-dichloromethane to give the free base as on oil. Treatment with a solution of hydrogen chloride in methanol gave the title compound (40 mg, 30%) as a pale yellow solid. 1H NMR (360 MHz, d6-DMSO) δ 1.86-1.92 (1H, m), 1.96-2.04 (1H, m), 2.20-2.32 (2H, m), 2.40-2.46 (2H, m), 2.97 (3H, s), 3.83 (3H, s), 4.42 (2H, s), 7.54-7.60 (3H, m), 8.26 (1H, s), 8.36 (2H, br d, J=8 Hz), 8.48 (1H, s); MS (ES+) m/e 374 [MH]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[CH:9]=2)[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3]1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3]1
Reactant: COC(=O)c1ccc2c(-c3ccccc3)cn(C)c2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(-c2ccccc2)c2ccc(C(=O)O)cc21
Reaction time: 4 h

Procedure:
A mixture of compound 16c (517 mg, 1.95 mmol) and LiOH (187 mg, 7.80 mmol) in THF/MeOH/H2O (4/4/4 mL) was stirred for 4 h. A 15% citric acid solution (20 mL) was added, and the mixture was then extracted with EtOAc (3×). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue, compound 16d, was dried under reduced pressure for 18 h.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:9]=[O:10])[CH2:3][CH2:2]1.S(=O)(=O)([OH:20])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:16])[F:17])[C:9]([OH:20])=[O:10])[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)O
Reactant: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (12 g, 50 mmol) and sulfamic acid (7.3 g, 75 mmol) were dissolved in glacial acetic acid (50 ml) and the solution added with a solution of sodium chlorite (8.2 g, 75 mmol) in water (15 ml). The reaction mixture was stirred at room temperature for 1 hr then water (300 ml) was added so obtaining the precipitation of a solid that was filtered and dried at 40° C. under vacuum (12 g, 48 mmol, 97% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[CH3:11][CH2:12][CH2:13][CH2:14][CH:15]([CH:17]([CH3:19])C)C.[CH3:20][CH2:21]CC(CC(C)C)C.CC(CC(C(C)C)C)C>>[CH:1]([C:4]1[CH:9]=[C:8]([CH2:20][CH2:21][CH2:19][CH2:17][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])[CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2]
Reactant: CCCC(C)CC(C)C
Reactant: CCCCC(C)C(C)C
Reactant: CC(C)c1ccccc1O
Agent: CC(C)CC(C)C(C)C
Product: CCCCCCCCCc1ccc(O)c(C(C)C)c1
Yield: 266.4 %

Procedure:
2-Isopropylphenol (272.6 g, 2.0 mol), tripropylene (131.74 g), and Amberlyst 15 (8.55 g) were stirred for 7 h at 125° C. Work-up and in vacuo distillation as given for 1b gave 2-isopropyl-4-nonylphenol (239.4 g, 96.4% purity by GC area %) in 46% yield.