Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[N:13](CCC#N)[CH:14]=[CH:15][CH:16]=3)[N:5]2[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[NH:13][CH:14]=[CH:15][CH:16]=3)[N:5]2[N:4]=1
Reactant: CSc1ncc2ccc(-c3cccn3CCC#N)n2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1ncc2ccc(-c3ccc[nH]3)n2n1

Procedure:
3-[2-(2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-pyrrol-1-yl]-propionitrile: The above bis-TFA salt (92 mg) was taken up in DCM and washed with dilute, aqueous, NaOH. The organic layer was dried by passing through a plug of Na2SO4 and solvent evaporated to yield 2-methylsulfanyl-7-(1H-pyrrol-2-yl)-pyrrolo[2,1-f][1,2,4]triazine (46 mg, 0.20 mmol) which was taken up in acetonitrile (1.0 mL) and treated with 2-propenenitrile (19 uL, 0.29 mmol) and Triton B (5 μL). The mixture was stirred at RT for 1 h. The reaction was taken up in EtOAc and washed with water and brine. The organic layer was dried by passing through a plug of Na2S0. Solvent was removed by rotary evaporation and the resulting residue was triturated with ether (2×2 mL) to yield 44 mg (78%) of product. HPLC RT: 2.93 min; LC/MS: 284 (M+H); 1H NMR (DMSO-d6): 8.99 (s, 1H), 7.13 (m, 1H), 7.09 (s, 2H), 6.66 (dd, J=3.8, 1.7, 1H), 6.27 (dd, J=3.8, 2.9, 1H), 4.30 (t, J=6.6, 2H), 2.86 (t, 2H, J=6.6), —SMe singlet presumably under DMSO peak.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:9](=S)=[S:10]>C(O)C>[SH:10][C:9]1[NH:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: S=C=S
Reactant: Nc1ccncc1N
Solvent: CCO
Product: Sc1nc2cnccc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of 25 g (0.23 mol) of 3,4-diaminopyridine in 750 mL of ethanol containing 50 mL (63.2 g), 0.83 mol) of carbon disulfide was heated under reflux for 5 hours. The reaction mixture was allowed to cool to room temperature and the beige precipitate which had formed was collected by filtration and allowed to air dry overnight. The product amounted to 33.5 g, m.p.>320° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:23](F)=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].O1CCOCC1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:23]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2ncccc2F)Cc2ccccc2C1
Reactant: C1CCNCC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2ncccc2N2CCCCC2)Cc2ccccc2C1
Reaction time: 0.01 h
Yield: 85.3 %

Procedure:
A 10 mL microwave reaction vessel is charged with 2-[(3-fluoro-pyridine-2-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (359, 488 mg, 1.49 mmol), 1,4-dioxane (1.5 mL) and piperidine (1.51 mL, 15.23 mmol). A stirring bar is added. The reaction vial is crimped sealed. The reaction vial is placed in a Smith Microwave reaction apparatus. The temperature is set for 150° C. with a fixed hold time of 10 min. Pre-stir time is set for 20 sec. The reaction vial is removed from the apparatus. The stirring bar is extracted. The contents of the flask are transferred to a round bottom flask and the solvent removed under reduced pressure. Pumping to a constant weight gives 1.02 g of off white solid. This is dissolved in DCM (10 mL) and applied to an ISCO Companion that is fitted with a 40 g column (silica). The column is eluted with EtOAc/heptanes (5%) for 4 column volumes followed by a linear gradient to 65% EtOAc/heptanes over 10 column volumes and then 90% EtOAc/heptanes for 2 column volumes. 14 mL fractions of UV Active eluent are collected. Fractions 2-10 are combined and evaporated by pumping to constant weight to give white solid (0.5 g, 86%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1
Agent: O=[Pt]
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)cc1
Yield: 94 %

Procedure:
160 Parts of p-nitrobenzotrifluoride is dissolved in 500 parts of ethanol and 1 part platinum oxide catalyst is added. The mixture is placed in a pressure vessel and hydrogen is added at a temperature of 30° C and a pressure of 13.6 atmospheres. The hydrogen pressure is increased to 34 atmospheres during the course of the reaction, which continues until the hydrogen uptake ceases. The excess hydrogen is removed from the reaction vessel under reduced pressure and the catalyst is removed from the mixture by filtration. The solvent is removed from the filtrate under reduced pressure to give 127 parts (94% yield) of p-aminobenzotrifluoride.
Reaction SMILES: Cl.[N:2]1([CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[S:20][C:21]5[C:22]([N:27]=4)=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][C:12]=3[O:11][CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(CC)CC.C[Si]([N:39]=[C:40]=[O:41])(C)C>C(Cl)Cl>[S:20]1[C:21]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:27]=[C:19]1[O:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([CH2:8][N:2]3[CH2:7][CH2:6][N:5]([C:40]([NH2:39])=[O:41])[CH2:4][CH2:3]3)=[CH:10][O:11][C:12]=2[CH:17]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: c1cnc2nc(Oc3ccc4c(CN5CCNCC5)coc4c3)sc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)N1CCN(Cc2coc3cc(Oc4nc5ncccc5s4)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.8 %

Procedure:
To a suspension of 2-(3-piperazin-1-ylmethyl-benzofuran-6-yloxy)-thiazolo[4,5-b]pyridine hydrochloride (122 mg, 0.30 mmol) in DCM (3 mL) was added Et3N (0.21 mL, 1.51 mmol) and the reaction mixture was stirred (rt, 15 min). The resulting solution was treated with trimethylsilyl isocyanate (0.14 mL, 0.91 mmol) and stirred (rt, 4 h). The reaction mixture was concentrated in vacuo and the resulting residue was purified by reverse phase HPLC to afford the title compound as a white solid (55 mg, 44%). MS (ESI): mass calcd. for C20H19N5O3S, 409.47; m/z found, 410.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (dd, J=4.8, 1.6, 1H), 8.02 (dd, J=7.9, 1.6, 1H), 7.77 (d, J=8.5, 1H), 7.59 (d, J=1.9, 2H), 7.29 (dd, J=8.5, 2.1, 1H), 7.21 (dd, J=7.9, 4.8, 1H), 4.43 (s, 2H), 3.66 (d, J=0.7, 2H), 3.47-3.36 (m, 4H), 2.55-2.46 (m, 4H).
Reaction SMILES: CCN(CC)CC.[CH2:8]1[CH:12]2[CH2:13][NH:14][CH2:15][CH:11]2[CH2:10][N:9]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:23]([N:14]1[CH2:13][CH:12]2[CH2:8][N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH:11]2[CH2:15]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccccc3)CC2C1
Temperature: 115 °C

Procedure:
Et3N (0.5 mL) was added into a solution of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.2 g) and benzoyl chloride (0.11 mL) in THF (10 mL). The mixture was heated to 115° C. for 24 hours. The reaction was quenched with water (10 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic phase was dried over MgSO4 and concentrated to give a residue which was purified by silica gel chromatography to give tert-butyl 5-benzoylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.
Reaction SMILES: CC(C)([O-])C.[K+].C(OP([CH2:15]/[C:16](/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])(OCC)=O)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=1[C:39](=[O:42])[CH:40]=O.O>O1CCCC1>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=1[C:39](=[O:42])/[CH:40]=[CH:15]/[C:16](/[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)/C=C(/CP(=O)(OCC)OCC)c1ccccc1
Reactant: COc1ccc(OC)c(C(=O)C=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(/C=C/C(=O)c1cc(OC)ccc1OC)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
1.32 g (11.8 mmol) of potassium tert-butoxide and 30 ml of tetrahydrofuran are mixed together at 25° C. A solution of 3.85 g (11.8 mmol) of ethyl (E)-4-(diethoxyphosphoryl)-3-phenylbut-2-enoate in 30 ml of tetrahydrofuran is then added dropwise. A solution of 3 g (15.4 mmol) of (2,5-dimethoxyphenyl)-2-oxoacetaldehyde dissolved in 30 ml of tetrahydrofuran is added dropwise, at 25° C. The mixture is stirred for 16 hours at 25° C. It is poured into water and extracted with ether. The organic phase is dried (Na2SO4) and the solvents are evaporated off under reduced pressure. The 4 g of product obtained are purified by flash chromatography (80/20 heptane/ethyl acetate) (yellow oil: 0.46 g).
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:11]1[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=[C:2]1[Cl:1]
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Reactant: BrCc1ccccc1Br
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2Br)n(C)c1=O

Procedure:
From 8-Chorotheophylline (10 g, 46.6 mol) and 2-bromobenzyl bromide (12.2 g, 48.93 mol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7])#[N:2].[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=O)=[CH:16][N:15]=1>N1C=CC=CC=1>[F:13][C:14]1[N:15]=[CH:16][C:17]([C:18]2[O:9][N:8]=[C:6]([C:5]3[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=3)[C:1]#[N:2])[N:7]=2)=[CH:21][CH:22]=1
Reactant: N#Cc1cccc(C(N)=NO)c1
Reactant: O=C(Cl)c1ccc(F)nc1
Solvent: c1ccncc1
Product: N#Cc1cccc(-c2noc(-c3ccc(F)nc3)n2)c1
Temperature: 25 °C

Procedure:
3-Cyano-N′-hydroxybenzimidamide (0.322 g, 1 mmol) was dissolved in pyridine 10 mL and 6-fluoronicotinoyl chloride (Frontier Scientific, 0.160 g, 1 mmol) was added. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The cooled reaction mixture was quenched with water (25 mL) and filtered. The solid was further purified with flash column chromatography (5% methanol/dichloromethane) to give the titled product. 1H NMR (300 MHz, DMSO-d6) δ 7.56-7.52 (m, 1H), 7.85 (t, J=7.9 Hz, 1H), 8.15-8.12 (m, 1H), 8.43-8.41 (m, 1H), 8.49 (m, 1H), 8.8-8.74 (m, 1H), 9.11-9.0 (m, 1H) ppm; MS (DCl/NH3) m/z 267 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]([F:30])([F:29])[C:7]([F:28])([F:27])[C:8]([F:26])([F:25])[C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=[O:5])=[O:4].[CH2:31]([CH:33]1[O:35][CH2:34]1)Cl.C[O-].[Na+].[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH2:31][CH:33]1[O:35][CH2:34]1)[S:3]([C:6]([F:30])([F:29])[C:7]([F:27])([F:28])[C:8]([F:25])([F:26])[C:9]([F:23])([F:24])[C:10]([F:21])([F:22])[C:11]([F:19])([F:20])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: ClCC1CO1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(CC1CO1)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
N-methyl-N-glycidyl-perfluorooctanesulfonamide ("epoxide A") was prepared by placing 450 grams N-methyl-perfluorooctanesulfonamide ("amide A") in a two-liter three-necked round-bottom flask and heating to 80° C., 101 grams epichlorohydrin was then added followed by 91 grams methanol. The temperature was reduced to 65° C. before 30 grams 25 wt % sodium methoxide in methanol solution was slowly added keeping the temperature below 70° C. 60 grams 50 wt % aqueous sodium hydroxide solution was slowly added keeping the temperature below 70° C. After addition the reaction was stirred at 65° C. overnight. Water-aspirator vacuum was applied to the flask and excess methanol and epichlorohydrin were removed. 450 grams water was then added to the flask with stirring at 65° to wash the product. The water was decanted after allowing the product to settle. This washing step was repeated a second time. Vacuum was applied to 20 mm Hg and the temperature of the flask was raised to 90° C. to remove volatile materials.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Br:7])=[CH:4][CH:3]=1.[I:10]C1C=CC=CC=1C>>[I:10][C:8]1[CH:9]=[CH:2][CH:3]=[CH:4][C:5]=1[CH2:6][Br:7]
Reactant: BrCc1ccc(I)cc1
Reactant: Cc1ccccc1I
Product: BrCc1ccccc1I

Procedure:
o-Iodobenzyl bromide was prepared by the procedure described by H. A. Sloviter, J. Am. Chem. Soc. 71, p.3360 (1949) for p-iodobenzyl bromide by starting with o-iodotoluene. The crude product was distilled at reduced pressure to yield a liquid product, bp. 85°-92°/0.5 mm Hg, which crystallized spontaneously to yield a solid product having a mp of 42°-49°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH2:11]([CH2:13][NH2:14])[OH:12].Cl.CN(C)CCCN=C=NCC.N=C=N>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:14][CH2:13][CH2:11][OH:12])=[O:8])=[CH:9][CH:10]=1
Reactant: NCCO
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N=C=N
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)NCCO)cc1
Reaction time: 1 h

Procedure:
A solution of 4-aminobenzoic acid (2.7 g, 20 mmol), ethanolamine (1.4 g, 23 mmol), and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (4.19, 21 mmol) in dimethylformamide (60 ml) was stirred overnight at room temperature. More carbodiimide (0.3 g, 2 mmol) was added and after stirring for one hour the reaction mixture was concentrated in vacuo onto silica gel (15 g). Purification by chromatography on silica gel (125 g) eluting with methanol:methylene chloride (3:97 to 1:19) and recrystallization from methanol:ethyl acetate gave, after drying under high vacuum, 4-amino-N-(2-hydroxyethyl)benzamide (1.65 g) as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ: 3.26 (q, J=6 Hz, 2H, NCH2), 3.46 (q, J=6 Hz, 2H, OCH2), 4.68 (t, J=5.5, 1H, OH), 5.58 (br s, 2H, NH2), 6.51 (d, J=8.5 Hz, 2H, Ar), 7.56 (d, J=8.5 Hz, 2H, Ar), 7.94 (br t, J=5.4 Hz, 1H, CONH). Mass spectrum (CI-CH4): 181 (M+1, 100%). Anal. Calculated for C9H12N2O2 : C, 59.99; H, 6.71; N, 15.55. Found: C, 60.05; H, 6.72; N, 15.55.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[N:6]=1.[CH3:12][O:13][CH2:14][C:15](Cl)=[O:16]>N1C=CC=CC=1>[CH3:12][O:13][CH2:14][C:15]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[N:6]=1)=[O:16]
Reactant: Cc1cccc2sc(N)nc12
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Product: COCC(=O)Nc1nc2c(C)cccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-4-methylbenzothiazole (4.9 g) is dissolved in pyridine (100 ml) and thereto is added dropwise methoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting oil is solidified with addition of water. The obtained solids are filtered off and washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (5.2 g) having the following physical properties.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[C:34](Cl)[N:33]=[N:32][C:31]=2[CH2:37][CH2:38][CH2:39][CH3:40])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][O:13][C:34]2[N:33]=[N:32][C:31]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:29][CH:28]=3)[CH:35]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nnc(OCC2CN(C(=O)OC(C)(C)C)C2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (1.5 mmol, 281 mg) in THF (4.0 mL) at 0° C., NaH (60% dispersion in mineral oil, 1.5 mmol, 60 mg) was added and stirring continued for 10 min at room temperature, then 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 1.0 mmol, 352 mg) was added. The resulting mixture was stirred at 50° C. for 1 hour, poured into water, and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The product was purified by column chromatography using 50% ethyl acetate in hexanes to give 3-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-azetidine-1-carboxylic acid tert-butyl ester, which was dissolved in dichloromethane (1.0 mL), added 4.0 M HCl in dioxane (1.0 mL) and stirred at room temperature for 1 hour. Solvents were evaporated to give 6-(azetidin-3-ylmethoxy)-4-(4-benzyloxy-phenyl)-3-butyl-pyridazine dihydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.O.Cl>N1C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(N)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 100 °C
Yield: 77.7 %

Procedure:
After adding 4-nitrobenzoyl chloride (34, 7.534 g, 185.57 mmol) to p-anisidine (33, 5.00 g, 40.60 mmol) dissolved in pyridine (50 mL), the reaction mixture was heated for 2 hours at 100° C. After adding water and aqueous 4 N HCl (300 mL), extracting with ethyl acetate and removing water using sodium sulfate, column chromatography yielded the target compound N-(4-methoxyphenyl)-4-nitrobenzamide (36, 8.594 g, 78%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:12]1[CH:17]=[C:16]([I:18])[C:15]([CH3:19])=[CH:14][N:13]=1)[C:7]([CH:9]1[CH2:11][CH2:10]1)=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:18][C:16]1[C:15]([CH3:19])=[CH:14][N:13]=[C:12]([NH:6][C:7]([CH:9]2[CH2:11][CH2:10]2)=[O:8])[CH:17]=1
Reactant: COc1ccc(CN(C(=O)C2CC2)c2cc(I)c(C)cn2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(NC(=O)C2CC2)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-N-(4-iodo-5-methylpyridin-2-yl)cyclopropanecarboxamide (1.8 g, 3.95 mmol) in DCM (23 mL) was added TFA. The reaction mixture was allowed to stir at rt overnight and then concentrated. The residue was diluted with DCM and aqueous saturated NaHCO3 and the mixture was extracted with DCM. The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give N-(4-iodo-5-methylpyridin-2-yl)cyclopropanecarboxamide (1.0 g, 75%).
Reaction SMILES: Cl.[C:2]([NH2:7])(=[NH:6])[CH:3]([CH3:5])[CH3:4].C[O-].[Na+].C([O:13][C:14](=O)[CH:15]([S:19][CH3:20])[C:16]([CH3:18])=O)C>CO>[CH:3]([C:2]1[N:7]=[C:14]([OH:13])[C:15]([S:19][CH3:20])=[C:16]([CH3:18])[N:6]=1)([CH3:5])[CH3:4]
Reactant: CCOC(=O)C(SC)C(C)=O
Reactant: CC(C)C(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CSc1c(C)nc(C(C)C)nc1O
Reaction time: 4 h
Yield: 43.7 %

Procedure:
A mixture of 19 g (0.15 mole) of isobutyramidine hydrochloride, 35 ml of methanol, 8.1 g (0.15 mole) of sodium methylate and 27 g (0.15 mole) of 2-methylmercaptoacetoacetic acid ethyl ester was stirred for 4 hours at 60°-70°C. The solvent was then distilled off under reduced pressure, the residue was dissolved in warm water and the solution was neutralized with acetic acid. The product which had crystallized out was filtered off. 13 g (44% of theory) of 2-isopropyl-4-hydroxy-5-methylmercapto-6-methylpyrimidine were obtained in the form of a colorless powder of melting point 156°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18](=[O:34])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:12][CH:11]=1)OS(C)(=O)=O.CCN(CC)CC.[OH:43][C@H:44]1[CH2:48][CH2:47][NH:46][CH2:45]1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:35])[CH:4]([C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18](=[O:34])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])=[CH:12][CH:11]=1)[N:46]1[CH2:47][CH2:48][C@H:44]([OH:43])[CH2:45]1
Reactant: COC(=O)C(OS(C)(=O)=O)c1ccc(C=CC(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Reactant: O[C@H]1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-methanesulfonyloxy-acetic acid methyl ester (1.26 g, 2.5 mmol) and Et3N (0.76 g, 7.5 mmol) in CH2Cl2 (15mL) was added (S)-3-hydroxypyrrolidine (0.27 g, 3 mmol). This mixture was stirred overnight at room temperature, then diluted with CH2Cl2 (50 mL), washed with saturated aqueous NaHCO3 solution, water and brine, dried with Na2SO4, filtered, and evaporated to obtain a yellow solid which was directly used in the next reaction without further purification. MS: calc'd 496 (MH+), exp 496 (MH+).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:32]1[C:44]2[C:43](=[CH:45][CH2:46][OH:47])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][CH:33]=1.[CH2:48]([O:50][CH:51]([CH2:57][C:58]1[CH:63]=[CH:62][C:61](O)=[CH:60][CH:59]=1)[C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH3:49]>C1COCC1.O>[CH2:48]([O:50][CH:51]([CH2:57][C:58]1[CH:59]=[CH:60][C:61]([O:47][CH2:46][CH:45]=[C:43]2[C:44]3[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=3[C:37]3[C:42]2=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:62][CH:63]=1)[C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH3:49]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: OCC=C1c2ccccc2-c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCC=C2c3ccccc3-c3ccccc32)cc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Diethyl azodicarboxylate (0.235 ml, 1.49 mmol) was added at 0°C. to a stirred solution of triphenylphosphine (0.392 g, 1.49 mmol) and 2-fluoren-9-ylidene-ethanol (0.208 g, 1.0 mmol) in dry THF (5 ml) and the mixture stirred for 5 min. A solution of ethyl 2-ethoxy-3-(4-hydroxy-phenyl)-propionate (0.356 g, 1.49 mmol) in dry THF (5 ml) was then added, the mixture allowed to warm to room temperature, and stirring continued for 72 h. The resulting mixture was treated with water (50 ml), and the products extracted into dichloromethane (3×20 ml). The extracts were combined, washed with brine, dried (Na2SO4) and evaporated to a yellow gum. This was then purified by column chromatography on silica gel (15% Et2O in petroleum eluent) to give ethyl 2-ethoxy-3-[4-(2-fluoren-9-ylidene-ethoxy)-phenyl]-propionate as a yellow gum; 0.28 g (60%).