Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]#[C:15][P:16]([O:25][CH3:26])([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:17])=[C:12]([CH:27]([CH3:29])[CH3:28])[CH:11]=[C:10]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:9]=2)=[CH:4][CH:3]=1.CC(O)=[O:38].[N+](=C)=[N-]>C1COCC1.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]#[C:15][P:16]([O:25][CH3:26])([CH2:18][C@@H:19]([OH:38])[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:17])=[C:12]([CH:27]([CH3:28])[CH3:29])[CH:11]=[C:10]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: COC(=O)CCCP(=O)(C#Cc1c(C(C)C)cc(-c2ccccc2)nc1-c1ccc(F)cc1)OC
Agent: C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C[C@H](O)CP(=O)(C#Cc1c(C(C)C)cc(-c2ccccc2)nc1-c1ccc(F)cc1)OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.5 %

Procedure:
A mixture of (S)-3-[[1,1-Dimethylethyl)diphenylsilyl]oxy]-4-[[[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]butanoic acid, methyl ester (750 mg, 1.00 mmol) tetra-n-butylammonium fluoride (1.0M in THF, 3.50 mmol), and HOAc (330 mg, 5.50 mmol) in THF (12 ml) was stirred at room temperature for 15 hours. The solution was partitioned between 5% KHSO4 and EtOAc. The layers were shaken and separated and the EtOAc layer was washed again with 5% KHSO4. The pooled aqueous washings were back-extracted twice with EtOAc. The combined EtOAc layers were washed with brine and dried (Na2SO4). Filtration and removal the solvent afforded a yellow oil. The oil was dissolved in Et2O and treated with excess diazomethane for 20 minutes. The excess diazomethane was destroyed by the addition of HOAc and the solvent was removed in vacuo. The residue was chromatographed (flash, Merck SiO2, 40% acetone in hexane followed by 1:1 acetone:hexane) to afford (S)-4-[[[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester (446 mg, 88%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][NH:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][N:13]([C:25]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:32])[C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3
Reactant: O=C(Cl)c1cccnc1
Reactant: Clc1cnc2nc1Nc1cccc(c1)NCc1cccc(c1)N2
Agent: Cl
Product: O=C(c1cccnc1)N1Cc2cccc(c2)Nc2ncc(Cl)c(n2)Nc2cccc1c2
Yield: 60 %

Procedure:
The desired compound was prepared as a white powder according to the procedure of Example C22, step F, using 6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene and nicotinoyl chloride hydrochloride as the starting materials in 60% yield. LCMS for C23H18ClN6O (M+H)+: m/z=429.0. 1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.15 (s, 1H), 8.40 (s, 1H), 8.14 (s, 2H), 7.89 (s, 1H), 7.62 (s, 1H), 7.23 (m, 4H), 7.10 (m, 4H), 4.85 (m, 2H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>CCCCCC.C1COCC1>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([B:15]([OH:20])[OH:16])[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
n-Butyllithium in n-hexane (925.0 mL, 1.59 M) was added dropwise to a mixture of THF (1,000 mL) and 1-bromo-3-methoxybenzene (T-1) (250.0 g, 1.34 mol) at −70° C. under an atmosphere of nitrogen. After the addition had been completed, the reaction mixture was stirred at the same temperature for 1 hour. Triisopropyl borate (300.9 g, 1.60 mol) was added dropwise, and then the mixture was warmed slowly to room temperature. The stirring was continued at room temperature for 18 hours, and the reaction mixture was poured into 6M-hydrochloric acid. The mixture was extracted with ethyl acetate (500 mL) four times, and the organic layer was washed with water. After the organic layer had been dried over anhydrous magnesium sulfate, the organic solvent was distilled off under reduced pressure. The residue was sufficiently washed with heptane to leave colorless solids (156.1 g) of 3-methoxyphenylboronic acid (T-2).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][Sn:8]([CH3:11])([CH3:10])[CH3:9])=O)C.[NH2:12][NH2:13]>C(O)C>[NH:12]([C:4]([CH2:6][CH2:7][Sn:8]([CH3:11])([CH3:10])[CH3:9])=[O:3])[NH2:13]
Reactant: NN
Reactant: CCOC(=O)CC[Sn](C)(C)C
Solvent: CCO
Product: C[Sn](C)(C)CCC(=O)NN
Reaction time: 2 h
Yield: 69.9 %

Procedure:
A mixture of 8 g (30 mmoles) of 2-(ethoxycarbonyl)ethyltrimethylstannane (compound 47), 5 ml of 95% hydrazine (150 mmoles) in 10 ml of ethanol was refuxed for 2 hours. The volatiles were removed at reduced pressure. Distillation of the crude product afforded 5.26 g of 2-(hydrazinocarbonyl)ethyltrimethylstannane, b.p. 92°-98° C. (0.07 mm), compound 42 of Table I. The infrared spectrum of the distillate showed the following characteristic absorptions: 3300 cm-1 (N-H), 1660 cm-1 and 1530 cm-1 ##STR21## and 760 cm-1 (--Sn(CH3)3). A gas chromatogram of the sample showed a single peak on a 6 feet × 1/8 inch commercially obtained column packed with 10% of silicone gum rubber on silanized diatomaceous earth. The NMR spectrum exhibited the following proton absorptions: a broad singlet at 752 Hz (1 proton) assigned to N-H, a singlet at 388 Hz (2 protons) assigned to NH2, a triplet centered at 235 Hz (2 protons) assigned to ##STR22## a triplet centered at 98 Hz (2 protons) assigned to CH2 -Sn, and a singlet centered at 6 Hz (9 protons) assigned to Sn(CH3)3.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.[CH:11]1([C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)[CH2:13][CH2:12]1.CN1CCOCC1.C(#N)C.CO>CN(C)C=O.Cl>[CH:11]1([C:14]2[N:15]=[CH:16][N:17]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=3)[CH:18]=2)[CH2:13][CH2:12]1
Reactant: c1nc(C2CC2)c[nH]1
Reactant: O=C(O)c1cc(F)ccn1
Agent: Cl
Solvent: CO
Solvent: CN1CCOCC1
Solvent: CC#N
Product: O=C(O)c1cc(-n2cnc(C3CC3)c2)ccn1
Temperature: 35 °C
Reaction time: 20 h
Yield: 79.9 %

Procedure:
A mixture of 4-fluoropicolinic acid (400 mg, 2.84 mmol) and 4-cyclopropyl-1H-imidazole (322 mg, 2.98 mmol) were dissolved in N,N-dimethylformamide, and N-methylmorpholine (0.36 ml, 3.28 mmol) was added. The reaction was warmed to 35° C., and stirred for 20 hours. The solvent was then removed under reduced pressure to afford a viscous oily residue. This residue was dissolved in 1N hydrochloric acid (5 mL), and the aqueous layer was extracted with ethyl acetate (2×5 mL). The aqueous layer was concentrated under reduced pressure to afford a yellow solid. To this residue was added 5 mL of acetonitrile/methanol (20:1) and the mixture was sonicated to afford a fine suspension of solids. The solids were collected by filtration, washed several times with acetonitrile, and dried on the filter funnel. The yellow solids were collected to afford 520 mg (69% yield) of 4-(4-cyclopropyl-1H-imidazol-1-yl)picolinic acid as the hydrochloride salt. M+1=230.1
Reaction SMILES: C(O[CH:4](OCC)[N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])C.[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].CN1CCN(C)C1=O>Cl[Sn](Cl)(Cl)Cl.CCOCC>[C:20]([C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[N:17]=[CH:4][N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])#[N:21]
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Reactant: N#Cc1ccccc1N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CN1CCN(C)C1=O
Product: N#Cc1ccccc1N=CN1CCNC1=N[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 130.4 %

Procedure:
0.05 g of SnCl4 was added to a mixture of 2.0 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 1.02 g of o-aminobenzonitrile and 5 ml of 1,3-dimethyl-2-imidazolidinone, followed by agitation at room temperature for 10 minutes. Ether was added to the reaction mixture, and the resultant crystals were collected by filtration and dried to give 2.9 g of 1-(2-cyanophenyliminomethyl)-2-nitroimino-imidazolidine.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1.N1C=CC=CC=1>C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([NH:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)=[O:4]
Reactant: COc1ccc(CCN)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(CCNC(=O)C(F)(F)F)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
32.2 ml (0.23 mol) of trifluoroacetic acid were added dropwise to a solution of 22.3 ml (0.15 mol) of 2-(4-methoxyphenyl)ethylamine and 24.7 ml (0.23 mol) of pyridine in 125 ml of absolute THF cooled to 5° C., and the resulting solution was stirred at RT for 3 h. The reaction solution was then poured onto 750 ml of ice, and the deposited precipitate was filtered off with suction and dried at 40° C. in a high vacuum. 36.3 g of the title compound were obtained as a beige solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cn(Cc2ccccc2)nc1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cn(Cc2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
A mixture of (1-benzyl-3-benzyloxy-1H-pyrazol-4-yl)methanol (14.70 g), active manganese dioxide (30.00 g) and tetrahydrofuran (200 ml) was stirred at room temperature for 2 hrs. Manganese dioxide was filtered off and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1-benzyl-3-benzyloxy-1H-pyrazole-4-carbaldehyde (13.10 g, yield 90%). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 85–86° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](C4SC(C5C=CC=CC=5)=CN=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[C:64]([C:66]([C:71]1[CH:79]=[CH:78][C:74](C(Cl)=O)=[CH:73][CH:72]=1)([CH2:69][CH3:70])[CH2:67][CH3:68])#[N:65]>>[C:64]([C:66]([C:71]1[CH:72]=[CH:73][C:74]([C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([C:12]3[CH:11]=[C:10]4[C:15]([CH2:16][N:8]([C@@H:3]([CH:2]([CH3:38])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])[C:9]4=[O:37])=[CH:14][CH:13]=3)=[CH:18][CH:19]=2)=[O:25])=[CH:78][CH:79]=1)([CH2:67][CH3:68])[CH2:69][CH3:70])#[N:65]
Reactant: CCC(C#N)(CC)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: CCC(C#N)(CC)c1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)cc2)cc1
Yield: 49 %

Procedure:
The compound of example 632 was prepared analogous to the compound of example 611 by reaction of compound of example 6 with 4-(3-cyanopentan-3-yl)benzoyl chloride.
Reaction SMILES: [Na+:1].[CH2:2]([N+:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([CH3:24])([CH2:17][CH2:18][CH2:19][S:20]([OH:23])(=[O:22])=[O:21])[C:5]=1/[CH:25]=[CH:26]/NC1C=CC=CC=1)[CH3:3].[I-].[C:35]([CH2:38][CH2:39][CH2:40][C:41]1([CH3:53])[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[N+:43]([CH2:50][CH3:51])=[C:42]1[CH3:52])([OH:37])=[O:36].N1C=CC=CC=1.CCOCC>C(O)(=O)C.C(OC(=O)C)(=O)C>[Na+:1].[C:35]([CH2:38][CH2:39][CH2:40][C:41]1([CH3:53])[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:43]([CH2:50][CH3:51])/[C:42]/1=[CH:52]/[CH:26]=[CH:25]/[C:5]1[C:6]([CH3:24])([CH2:17][CH2:18][CH2:19][S:20]([OH:23])(=[O:21])=[O:22])[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([S:13]([OH:16])(=[O:15])=[O:14])[CH:8]=2)[N+:4]=1[CH2:2][CH3:3])([OH:37])=[O:36]
Reactant: CC[N+]1=C(C)C(C)(CCCC(=O)O)c2ccccc21
Reactant: CC[N+]1=C(/C=C/Nc2ccccc2)C(C)(CCCS(=O)(=O)O)c2cc(S(=O)(=O)O)ccc21
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CCN1/C(=C/C=C/C2=[N+](CC)c3ccc(S(=O)(=O)O)cc3C2(C)CCCS(=O)(=O)O)C(C)(CCCC(=O)O)c2ccccc21

Procedure:
500 mg (1 mmol) 1-ethyl-3-methyl-2-((E)-2-phenylamino-vinyl)-5-sulfo-3-(3-sulfo-propyl)-3H-indolium sodium salt 2 and 387 mg (1 mmol) 3-(3-carboxypropyl) -2,3-dimethyl-1-ethyl-3H-indolium iodide 3 salt were dissolved in a mixture of 10 ml acetic acid and 10 ml acetic anhydride. Subsequently, 5 ml pyridine was added. The solution was stirred under reflux for 15 minutes. After cooling to room temperature (about 20° C. to about 22° C.), 20 ml ether was added. The precipitate that was obtained, which was a mixture of the diastereomers 4.1 and 4.2, was extracted by suction, washed with ether, and dried. The residue was purified by column chromatography: RP-18: methanol/water 1/1.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH:8]1[NH:12][C:11](=[O:13])[CH2:10][CH2:9]1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC.O1CCCC1>[C:14]([N:12]1[CH:8]([O:7][CH3:6])[CH2:9][CH2:10][C:11]1=[O:13])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC1CCC(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC1CCC(=O)N1C(=O)c1ccccc1
Yield: 41.5 %

Procedure:
20.8 cm3 of a 1.5M solution of butyllithium in hexane is added at -70° C. to a solution of 3.8 g of 5-methoxy pyrrolidin-2-one in 160 cm3 of tetrahydrofuran. This temperature is maintained for 20 minutes, then 4.69 g of benzoyl chloride in solution in tetrahydrofuran is added. After allowing to return to ambient temperature, the mixture is concentrated to dryness and chromatographed on silica (eluent: hexane-ethyl acetate 1-1). 3 g of expected product is obtained. m.p. =92°-94° C. crystallized from isopropyl ether.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][C@@:8]2([CH3:28])[N:12]3[C:13]([C:16](O)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)[C:9]2=[O:27])=[CH:5][CH:4]=1)#[N:2].[C:31]([O:35][C:36]([C:38]1([NH2:41])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[C:31]([O:35][C:36]([C:38]1([NH:41][C:16]([C:13]2[N:12]3[C@@:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:30][CH:29]=4)([CH3:28])[C:9](=[O:27])[N:10]([C:19]4[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=4)[C:11]3=[N:15][CH:14]=2)=[O:17])[CH2:39][CH2:40]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)C1(N)CC1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)O)n21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)CC1
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (3.3 g, 7.48 mmol), 1-amino-cyclopropane-carboxylic acid tert-butyl ester (1.8 g, 11.4 mmol) and HATU (4.27 g, 11.2 mmol) were dissolved in anhydrous DMF (20 mL). The mixture was stirred for 15 min. Et3N (2.95 mL, 20.4 mmol) was then added to the reaction. After 30 min, the crude reaction was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (10% to 30% EtOAc/Hexanes) to give 1-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid tert-butyl ester (3.8 g, 6.55 mmol, 87.5%) as a white solid, m/z 580.5 [M+1]+.
Reaction SMILES: [OH:1][C:2]([C:5]1([C:11]#[N:12])[CH2:9][CH:8]=[C:7]([CH3:10])[CH2:6]1)([CH3:4])[CH3:3].ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[OH:1][C:2]([C:5]1([C:11]#[N:12])[CH2:9][CH:8]2[C:7]([CH3:10])([O:21]2)[CH2:6]1)([CH3:4])[CH3:3]
Reactant: CC1=CCC(C#N)(C(C)(C)O)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC12CC(C#N)(C(C)(C)O)CC1O2
Reaction time: 8 h
Yield: 111.1 %

Procedure:
To a stirred mixture of 11.65 g of 1-(1-hydroxy-1-methylethyl)-3-methyl-3-cyclopentene-1-carbonitrile in 700 ml of methylene chloride and 210 ml of aqueous sodium bicarbonate was added portionwise at 25°-35° C. 15.3 g of 85% m-chloroperbenzoic acid. After stirring overnight, the phases were separated and the organic phase was washed successively with 200 ml of 1N sodium hydroxide, 200 ml of water and 200 ml of saturated aqueous sodium chloride, dried (MgSO4), and concentrated in vacuo to leave 14.2 g of a colorless oil, as a 1.2;1.0 mixture of diastereomeric epoxides. These diastereomers were separated by flash silica gel column chromatography using 2:8:40 tetrahydrofuran/ethyl acetate/hexane as eluent to give 5.1 g of the less polar (1α,3β,5α) isomer as a colorless oil and using 2:15:33 ratio of the same solvents to give 5.4 g of the more polar (1α,3α,5α)isomer as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:19])[NH:4][C:5](=[S:18])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:7]=1[NH2:8].[CH:20](O)=O>>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:6]2[C:7]3[N:8]=[CH:20][NH:1][C:2]=3[C:3](=[O:19])[NH:4][C:5]2=[S:18])=[CH:15][CH:14]=1
Reactant: COc1ccc(Cn2c(N)c(N)c(=O)[nH]c2=S)cc1
Reactant: O=CO
Product: COc1ccc(Cn2c(=S)[nH]c(=O)c3[nH]cnc32)cc1
Temperature: 100 °C
Yield: 16 %

Procedure:
5,6-Diamino-1-(4-methoxybenzyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.83 g, 3.0 mmol) was dissolved in formic acid (3.0 mL) and the resulting solution heated at 100° C. for 1 h. The excess formic acid was removed under reduced pressure and the residue dissolved in 10% potassium hydroxide solution (8 mL) and heated at 100° C. for 15 minutes. The reaction mixture was neutralized with 10% acetic acid and the resulting precipitate collected by filtration. The precipitate was recrystallised from ethanol: dimethylformamide and the isolated crystals dissolved in 1M potassium hydroxide solution, precipitated by neutralization with 10% acetic acid and collected by filtration. After drying, the title compound (0.14 g, 16%) was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.[C:7]([NH:12][NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:12]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][N:13]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)NNC(=O)OCC
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCCCN1C(=O)OCC
Temperature: 25 °C
Yield: 69.4 %

Procedure:
1,4-Dibromobutane (81.4 mL, 0.682 mol) is added over 1 hour to a mixture of 1,2-dicarbethoxyhydrazine (100 g, 0.568 mol) and potassium carbonate (158 g, 1.14 mol) in acetonitrile (600 mL). The resultant reaction mixture is refluxed for 6 hours, cooled to room temperature, and filtered. The filtrate is concentrated in vacuo to obtain a yellow liquid which is distilled under reduced pressure to give the title product as a colorless liquid (90.8 g, bp 115°-120° C. at 0.9 mm Hg).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1I>>[CH3:10][N:11]([CH3:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)c1ccccc1I
Reactant: NC(=O)c1ccccc1
Product: CN(C)c1ccccc1NC(=O)c1ccccc1
Yield: 94.7 %

Procedure:
Using general procedure A, benzamide (150 mg, 1.24 mmol) was coupled with N,N-dimethyl-2-iodoaniline (160 μL, 1.05 mmol). The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 7:1; 15 mL fractions). Fractions 8-15 provided 239 mg (95% yield) of the product as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 9.42 (br s, 1H), 8.57 (dd, J=7.8, 1.4 Hz, 1H), 7.98-7.92 (m, 2H), 7.62-7.51 (m, 3H), 7.26 (dd, J=7.8, 1.4 Hz, 1H), 7.22 (td, J=7.8, 1.4 Hz, 1H), 7.12 (td, J=7.8, 1.4 Hz, 1H), 2.74 (s, 6H).
Reaction SMILES: [CH2:1]([N:3]([C:19]1[N:24]=[N:23][C:22]([C:25](N)=[O:26])=[CH:21][CH:20]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2].[OH-:28].[Na+]>C(O)CCC>[CH2:1]([N:3]([C:19]1[N:24]=[N:23][C:22]([C:25]([OH:28])=[O:26])=[CH:21][CH:20]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: [OH-]
Reactant: CCN(Cc1ccccc1NCc1ccccc1)c1ccc(C(N)=O)nn1
Agent: [Na+]
Solvent: CCCCO
Product: CCN(Cc1ccccc1NCc1ccccc1)c1ccc(C(=O)O)nn1
Yield: 45 %

Procedure:
6-(N-Ethyl-N-(2-(benzylamino)benzyl)amino)pyridazine-3-carboxamide (0.49 g) in n-butanol was treated with sodium hydroxide pellets (140 mg) and heated at gentle reflux for 9 hours. The reaction was allowed to cool, was evaporated to dryness and the residue taken into water and acidified with acetic acid. The mixture was extracted with ethyl acetate (×2) and the extracts dried and evaporated to give a gum which was purified by MPLC to give the title compound as a brown foam (220 mg, 45%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=O)=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1.[CH:18]1([CH2:21][CH2:22][NH2:23])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][CH2:22][NH:23][C:14]([C:10]2[S:9][C:8]([N:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][C:4]3=[O:17])=[N:12][C:11]=2[CH3:13])=[O:16])[CH2:20][CH2:19]1
Reactant: NCCC1CC1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCCC1CC1
Yield: 64 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with 2-cyclopropylethanamine, the title compound was obtained as a colorless solid in 64% yield: mp 234-236° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.58 (d, J=8.0 Hz, 1H), 8.16 (t, J=5.6 Hz, 1H), 6.25 (dd, J=8.0, 2.6 Hz, 1H), 5.81 (d, J=2.5 Hz, 1H), 3.26-3.20 (m, 2H), 2.50 (s, 3H), 1.40-1.34 (m, 2H), 0.76-0.59 (m, 1H), 0.39-0.33 (m, 2H), 0.03-0.01 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 167.8, 161.8, 161.6, 153.9, 149.4, 132.6, 124.2, 104.3, 98.0, 39.9, 34.4, 17.4, 9.0, 4.6; MS (ES+) m/z 320.2 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)C(C)C)(C)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][NH:5][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: COCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a stirred solution of 2-methoxyethylamine (2.67 mL, 31.0 mmol) in anhydrous methylene chloride (100 mL) and N,N-diisopropylethyl amine (8.54 mL, 51.7 mmol) at 0° C. was slowly added methanesulfonyl chloride (2.0 mL, 25.8 mmol). The reaction mixture was slowly warmed to room temperature and stirred overnight. The mixture was concentrated and the residue was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to afford the product as a colorless oil (2.8 g, 71%). 1H NMR (300 MHz, CDCl3) δ 4.66 (br s, 1H), 3.54 (t, 2H, J=4.8 Hz), 3.39 (s, 3H), 6.37-3.29 (m, 2H), 3.00 (s, 3H).