Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[CH3:15])=[CH:4][S:5][CH:6]=1.C(P(=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:43]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([C:3]2[C:2](/[CH:43]=[CH:37]/[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:6][S:5][CH:4]=2)=[C:8]([CH3:15])[CH:9]=1)#[N:12]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1cc(C#N)ccc1-c1cscc1Br
Reactant: CCOC(=O)C=[P+]([O-])C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cscc1-c1ccc(C#N)cc1C
Temperature: 150 °C
Reaction time: 8 h
Yield: 386.5 %

Procedure:
To a solution of 4-(4-bromothiophen-3-yl)-3-methylbenzonitrile (2.4 g, 8.7 mmol) and ethyl 2-(tritylphosphinylidene)acetate (2.6 g, 26 mmol) in DMF (10 mL) was added Pd(OAc)2 (194 mg, 0.87 mmol) and PPh3 (228 mg, 0.87 mmol), and the mixture was stirred at 150° C. under nitrogen overnight. The mixture was diluted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, concentrated in vacuo, and purified on silica gel column (PE: EtOAc=20:1) to give (E)-ethyl 3-(4-(4-cyano-2-methylphenyl)thiophen-3-yl)acrylate (Scheme III, 14, X1=4-cyano-2-methylphenyl) (1 g, yield 39%) as yellow oil. 1H NMR (CD3OD 400 MHz): δ 8.03 (d, J=2.8 Hz, 1H), 7.71 (s, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.39-7.34 (m, 2H), 7.28 (d, J=16 Hz, 1H), 6.06 (d, J=16.4 Hz, 1H), 4.15 (q, J=7.2 Hz, 2H), 2.15 (s, 3H), 1.24 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])[C:5]#N.[OH-:17].[Na+].CC([OH:22])C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])[C:5]([OH:22])=[O:17]
Reactant: CC(C)O
Reactant: [OH-]
Reactant: CC(Oc1ccc(C#N)cc1Cl)C(F)(F)F
Agent: [Na+]
Product: CC(Oc1ccc(C(=O)O)cc1Cl)C(F)(F)F
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 3-chloro-4-(2,2,2-trifluoro-1-methylethoxy)benzonitrile (430 mg) in IPA (3 ml) was added a 5M aqueous NaOH solution (1.37 ml), followed by stirring at 80° C. for 24 hours, and a 5M aqueous NaOH solution (1.37 ml) was further added thereto, followed by stirring at 95° C. for 24 hours. The reaction solution was concentrated until the amount was reduced to a half. To the residue was added 12M HCl, and the resulting precipitate was collected by filtration, and then dried to obtain 3-chloro-4-(2,2,2-trifluoro-1-methylethoxy)benzoic acid as a yellow solid.
Reaction SMILES: [H-].[Na+].C([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[N:8]=1)CCC.[H][H].FC(F)(F)S(O[CH2:28][C:29]([F:40])([F:39])[C:30]([F:38])([F:37])[C:31]([F:36])([F:35])[CH2:32][O:33][CH3:34])(=O)=O>O.CN(C)C=O.C1(C)C=CC=CC=1>[CH2:9]([C:12]1[CH:11]=[N:10][C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:28][C:29]([F:39])([F:40])[C:30]([F:37])([F:38])[C:31]([F:35])([F:36])[CH2:32][O:33][CH3:34])=[CH:17][CH:18]=2)=[N:8][CH:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1ccnc(-c2ccc(O)cc2)n1
Reactant: [H][H]
Reactant: COCC(F)(F)C(F)(F)C(F)(F)COS(=O)(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCc1cnc(-c2ccc(OCC(F)(F)C(F)(F)C(F)(F)COC)cc2)nc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Dry sodium hydride (0.5 g, 0.0206 moles) was weighed into a 100 ml flask in a glove bag under dry nitrogen. The flask was then fitted with a magnetic stir bar and a water-cooled condenser with a nitrogen inlet. 20 ml of toluene and 20 ml of anhydrous N,N-dimethylformamide were added, mixing was started, and then 4 g of 4-butyl-2-(4-hydroxyphenyl)pyrimidine (0.0130 moles) was added slowly to control the rate of hydrogen evolution. After stirring at room temperature for 20 minutes, 4.9 g (0.0137 moles) of 2,2,3,3,4,4-hexafluoro-5-methoxypentyl trifluoromethanesulfonate (prepared essentially as in Example 1) was added, and the contents were heated to reflux for 1 hour. After cooling to room temperature, the contents of the flask were poured into a separatory funnel containing 50 ml of water. The funnel was shaken and the two layers formed were allowed to separate. The aqueous layer was extracted twice with 20 ml aliquots of toluene. The organic layers were combined, then were washed three times with 30 ml aliquots of deionized water, dried with anhydrous sodium sulfate, and stripped of solvent using a rotary evaporator. The resulting oil was chromatographed on silica gel, eluting with chloroform, to yield a pale yellow liquid, 5-butyl-2-(4-(2,2,3,3,4,4-hexafluoro-5-methoxypentoxy)phenyl)pyrimidine.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])[N:4]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]=1.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O>[F:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]=[C:2]([C:33]3[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=3)[C:10]=12
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc21
Reactant: OB(O)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc21
Temperature: 95 °C
Yield: 49.3 %

Procedure:
A sealed tube was charged with a solution of 3-bromo-4-(2-fluoro-4-nitrophenoxy)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (480 mg, 1.0 mmol) in toluene (5 mL), pyridin-4-ylboronic acid (246 mg, 2.0 mmol, Lancaster), 0.5 mL of ethanol, and potassium phosphate (1.0 mL, 2 M solution, 2.0 mmol). Argon was bubbled through the mixture for 15 minutes, and the reaction mixture was treated with tetrakis(triphenylphosphine)Pd(0) (58 mg, 0.05 mmol, Strem). The tube was sealed and the mixture was heated at 95° C. for 18 h with vigorous stirring. The reaction mixture was then cooled to room temperature and diluted with EtOAc. The mixture was washed with saturated aq. NaHCO3 solution and brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, eluting with 2% MeOH in dichloromethane) to give the desired product (237 mg, 49%) as a thick brown oil. MS(ESI+) m/z 481.1 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[N:11]2[CH:12]=[C:13]([CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][CH:18]=3)[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1>O>[Cl:5][C:6]1[N:11]2[CH:12]=[C:13]([CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([CH2:21][Cl:3])=[CH:19][CH:18]=3)[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(OCc2cn3c(Cl)cccc3n2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: ClCc1ccc(OCc2cn3c(Cl)cccc3n2)cc1
Reaction time: 1 h
Yield: 52 %

Procedure:
Thionyl chloride (0.597 ml) was added dropwise to a mixture of 4-(5-chloroimidazo[1,2-a]pyridine-2-ylmethoxy)benzylalcohol (1.97 g), triethylamine (1.15 ml) and toluene (50 ml) at 0° C. After stirring for 1 hour, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 5-chloro-2-(4-chloromethylphenoxymethyl)imidazo[1,2-a]pyridine (1.10 g, yield 52%) as colorless crystals. m.p. 114-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[H-].[Na+].[CH2:14](I)[CH2:15][CH3:16].O1C[CH2:21][CH2:20][CH2:19]1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:14][CH2:15][CH3:16])=[O:7])=[C:4]([O:11][CH2:19][CH2:20][CH3:21])[CH:3]=1
Reactant: CCCI
Reactant: O=C(O)c1ccc(Cl)cc1O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOC(=O)c1ccc(Cl)cc1OCCC
Yield: 63 %

Procedure:
The synthesis was carried out according to the method of Example 18-(1). 4-Chlorosalicylic acid (8.5 g), : 60% oil sodium hydride (4.5 g), n-propyl iodide (50 g), tetrahydrofuran (30 ml) and dimethylformamide (25 ml) were used as reagents. The mixture was reacted for 1 hour at 90° C. After the reaction, the mixture was chromatographed on silica gel (hexane-ethyl acetate) to give 7.63 g of a colorless transparent liquid (yield 63%).
Reaction SMILES: [O:1]1[C:5]2=[CH:6][C:7]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=3[CH:14]=[C:4]2[N:3]=[CH:2]1.[Cl:15][CH2:16][CH2:17][CH2:18][S:19][C:20]1[N:21]([CH3:36])[C:22]([C:25]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:26]=2[CH:27]=[CH:28][C:29]([CH3:35])=[N:30]3)=[N:23][N:24]=1>>[ClH:15].[CH3:36][N:21]1[C:22]([C:25]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:26]=2[CH:27]=[CH:28][C:29]([CH3:35])=[N:30]3)=[N:23][N:24]=[C:20]1[S:19][CH2:18][CH2:17][CH2:16][N:11]1[CH2:10][CH2:9][C:8]2[CH:14]=[C:4]3[N:3]=[CH:2][O:1][C:5]3=[CH:6][C:7]=2[CH2:13][CH2:12]1
Reactant: c1nc2cc3c(cc2o1)CCNCC3
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Product: Cc1ccc2c(-c3nnc(SCCCN4CCc5cc6ncoc6cc5CC4)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (0.10 mmol) and 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline and was obtained as a colourless slightly hygroscopic solid (15 μmol)
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:15]([NH:16][C:17]([C:19]2[S:20][C:21]([S:24]([N:27]3[CH:31]=[CH:30][CH:29]=[CH:28]3)(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[O:18])[C@@H:14]2[CH2:32][C@H:11]1[CH2:12][CH2:13]2.[OH-].[Na+]>CO.O1CCCC1.O>[N:27]1([S:24]([C:21]2[S:20][C:19]([C:17]([NH:16][C@H:15]3[C@@H:14]4[CH2:32][C@@H:11]([CH2:12][CH2:13]4)[C@@H:10]3[CH2:9]/[CH:8]=[CH:7]\[CH2:6][CH2:5][CH2:4][C:3]([OH:33])=[O:2])=[O:18])=[CH:23][CH:22]=2)(=[O:26])=[O:25])[CH:31]=[CH:30][CH:29]=[CH:28]1
Reactant: COC(=O)CCC/C=C\C[C@H]1[C@@H]2CC[C@@H](C2)[C@@H]1NC(=O)c1ccc(S(=O)(=O)n2cccc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCC/C=C\C[C@H]1[C@@H]2CC[C@@H](C2)[C@@H]1NC(=O)c1ccc(S(=O)(=O)n2cccc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
To a solution of 350 mg (0.713 mmol) of (5Z)-7-{(1R,2S,3S,4S)-3-[5-(pyrrol-1-ylsulfonyl)thiophen-2-ylcarbonylamino]-bicyclo[2.2.1]hept-2-yl}-5-heptenoic acid methyl ester (I-1a) in 1 ml of methanol and 0.5 ml of tetrahydrofuran was added under ice-cooling 0.5 ml (2.0 mmol) of 4N sodium hydroxide. The mixture was warmed to room temperature and stirred at 25° C. for 2 h. The reaction mixture was diluted with water and washed with ether. The aqueous layer was acidified with 0.5 ml of 5N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane (3:4) to give 234 mg of (5Z)-7-{(1R,2S,3S,4S)-3-[5-(pyrrol-1-ylsulfonyl)-thiophen-2-ylcarbonylamino]-bicyclo[2.2.1]hept-2-yl}-5-heptenoic acid (I-1b) as needles.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([F:22])[CH:15]=[C:16](I)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:26]([OH:29])[C:27]#[CH:28]>C(NCC)C.C(Cl)Cl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([F:22])[CH:15]=[C:16]([C:28]#[C:27][CH2:26][OH:29])[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)cc(F)c21
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)cc(F)c21

Procedure:
A mixture of N-(4-chlorobenzyl)-8-fluoro-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation No. 14 (0.600 g), propargyl alcohol (0.11 mL, 1.90 mmol), CuI (0.048 g, 0.25 mmol), and PdCl2(PPh3)2 (0.178 g, 0.25 mmol) in diethylamine (42.5 mL) and CH2Cl2 (50 mL) are warmed to 65° C. overnight. The reaction mixture is then concentratred in vacuo. Column chromatography (elution with 5-10% MeOH/CH2Cl2) gave the title compound as a solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=O.[CH:17]([C:20]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[C:22]([CH:29]([CH3:31])[CH3:30])[C:21]=1[S:32]([NH:35][NH2:36])(=[O:34])=[O:33])([CH3:19])[CH3:18]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]([F:16])([F:15])[C:3](=[N:36][NH:35][S:32]([C:21]1[C:22]([CH:29]([CH3:30])[CH3:31])=[CH:23][C:24]([CH:26]([CH3:28])[CH3:27])=[CH:25][C:20]=1[CH:17]([CH3:19])[CH3:18])(=[O:33])=[O:34])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN)c(C(C)C)c1
Reactant: O=C(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN=C(c2cccc(C(F)(F)F)c2)C(F)(F)F)c(C(C)C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 49.8 %

Procedure:
2,2,2-Trifluoro-3'-(trifluoromethyl)acetophenone (3.7 g, 0.15 mol) was dissolved in dichloromethane (15 ml, anhydrous) and the solution was cooled to 0° C. Titanium tetrachloride (15 ml, 1.0M in dichloromethane) was added to the solution dropwise and the resulting ochre suspension was stirred at room temperature for 12 h. 2,4,6-Triisopropylbenzenesulfonyl hydrazine (3.8 g, 0.015 mol) was added to the suspension and the reaction mixture was stirred for 2 h. The mixture was quenched with water and the organic phase was separated, washed with brine, dried and the solvent was removed in vacuo. The resulting solid was purified by column chromatography using 10-25% ethyl acetate in hexane as eluant. This afforded the product as a white crystalline solid (3.9 g). 1HNMR (250 MHz, CDCl3) δ 1.10-1.22 (m, 18H, (CH3)2), 2.86 (septet, 1H, C H(CH3)2), 4.02 (septet, 2H, C H(CH3)2), 7.14 (S, 2H, ArH), 7.40-7.48 (m, 2H, ArH), 7.64 (t, 1H, ArH), 7.72-7.80 (m, 1H, ArH), 8.72 (s, 1H, NH).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:20]=[CH:19][C:7]([CH:8]([OH:18])[C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[CH3:3].COC.[Cl:24][C:25]1[CH:35]=[CH:34][C:28]([NH:29][C:30](=[O:33])[CH2:31]O)=[CH:27][CH:26]=1.O1CCCC1>C(O)(=O)C.CCCCCC>[Cl:24][C:25]1[CH:35]=[CH:34][C:28]([NH:29][C:30](=[O:33])[CH2:31][O:18][CH:8]([C:7]2[CH:19]=[CH:20][C:4]([N:2]([CH3:1])[CH3:3])=[CH:5][CH:6]=2)[C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:16])[CH3:17])=[CH:11][CH:10]=2)=[CH:27][CH:26]=1
Reactant: CN(C)c1ccc(C(O)c2ccc(N(C)C)cc2)cc1
Reactant: O=C(CO)Nc1ccc(Cl)cc1
Agent: COC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)c1ccc(C(OCC(=O)Nc2ccc(Cl)cc2)c2ccc(N(C)C)cc2)cc1

Procedure:
A solution of 4,4'-bis(N,N-dimethylamino)benzhydrol, methyl ether, (8.0 g, 0.028 mole), p-chloroglycolanilide (5.23 g, 0.028 mole), 170 ml of tetrahydro-furan, 120 ml of n-hexane, and 4.5 ml of glacial acetic acid was refluxed for about 8.5 hours, replacing solvent as distillate was removed. Color was then discharged by the addition of 20 drops of tetramethylguanidine and the solution was filtered hot. Hexane was added to the filtrate, yielding a light green oil. The oil was removed and the hexane solution, on cooling, gave a light blue solid. The solid was filtered, washed with petroleum ether and dried. Recrystallization from 150 ml methylcyclohexane/40 ml acetone gave a yellow-white, gummy solid. This was recrystallized from VM&P naphtha to give a fine white powder, mp 137.5°-140° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[CH2:7][C:6]=2[NH:5][C:4](=[O:18])[CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].C(OCCO)C.Cl>>[ClH:24].[NH:22]([N:23]=[C:10]1[CH2:9][CH:8]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH2:7][C:6]2[NH:5][C:4](=[O:18])[CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1cc(=O)[nH]c2c1C(=O)CC(c1ccsc1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCOCCO
Product: Cc1cc(=O)[nH]c2c1C(=NNC(=N)N)CC(c1ccsc1)C2
Temperature: 125 °C
Reaction time: 13 h
Yield: 44.2 %

Procedure:
To a mixture of 4-methyl-7-(thiophen-3-yl)-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.155 g) and aminoguanidine hydrochloride (73 mg) were added 2-ethoxyethanol (2 ml) and 2N hydrochloric acid (0.3 ml), and the mixture was stirred at 125° C. for 13 hours and cooled. Precipitated crystals were filtered, washed with ethanol and dried to give 5-guanidinoimino-4-methyl-7-(thiophen-3-yl)-1,2,5,6,7,8-hexahydroquinolin-2-one hydrochloride (Compound 138) (0.093 g) as colorless crystals.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:12][CH:13]1[C:16]23[O:23][CH2:22][O:21][C:17]2=[CH:18][CH:19]=[CH:20][CH:15]3[CH2:14]1.[NH:24]1[CH2:29][CH2:28][CH:27]([N:30]([CH3:36])[C:31](=[O:35])[O:32][CH2:33][CH3:34])[CH2:26][CH2:25]1.N(CCO)(CCO)CCO>C1(C)C=CC=CC=1>[CH2:22]1[O:21][C:17]2[CH:18]=[CH:19][C:20]3[C:13]([CH2:12][N:24]4[CH2:25][CH2:26][CH:27]([N:30]([CH3:36])[C:31](=[O:35])[O:32][CH2:33][CH3:34])[CH2:28][CH2:29]4)=[CH:14][C:15]=3[C:16]=2[O:23]1
Reactant: CC1CC2C=CC=C3OCOC312
Reactant: CCOC(=O)N(C)C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: OCCN(CCO)CCO
Product: CCOC(=O)N(C)C1CCN(CC2=Cc3c2ccc2c3OCO2)CC1

Procedure:
4 g of the compound obtained in Stage H, 2.24 g of the compound obtained in Stage B of Example 6 and 1.7 ml of triethanolamine are refluxed in 40 ml of toluene for 24 hours. The reaction mixture is concentrated, taken up in ethyl acetate, washed with water and then extracted with 1 N hydrochloric acid, and the extract is rendered basic with concentrated sodium hydroxide solution and extracted with methylene chloride. The extract is dried to yield ethyl N-{1-[(3,4-methylenedioxybenzocyclobuten-1-yl)-methyl]-piperid-4-yl)-N-methylcarbamate. 23.5 ml of a 2% solution of fumaric acid in ethanol are added to yield the desired salt.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([Br:18])[CH:12]=2)C(=O)C2=CC=CC=C12.O.NN.Cl>C(O)C>[Br:17][C:15]1[CH:16]=[C:11]([CH:12]=[C:13]([Br:18])[CH:14]=1)[O:10][CH2:9][CH2:8][CH2:7][CH2:6][NH2:5]
Reactant: O=C1c2ccccc2C(=O)N1CCCCOc1cc(Br)cc(Br)c1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCOc1cc(Br)cc(Br)c1
Temperature: 80 °C
Yield: 78.8 %

Procedure:
1-(4′-phthalimidobutoxy)3,5-dibromobenzene (1.0 g, 2.20 mmol) was dissolved in ethanol (45 mL) for 5 minutes under nitrogen. Hydrazine monohydrate (610 mg, 12.1 mmol) was added and the reaction was refluxed at 80° C. for 2 hours. To the reaction aqueous 1M HCl (17.7 mL, 17.7 mmol) was added and refluxed at 105° C. for another 2 hours. The aqueous layer was extracted with dichloromethane (2×150 mL). The organic layers were combined, washed with saturated NaHCO3 (3×), water, and brine, then dried over MgSO4, and filtered. Removal of solvent yielded a yellow oil (560 mg, 78%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([CH:9]=[CH:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[N:3]=1.S(=O)(=O)(O)O.[NH:24]1[C:31](=[O:32])[CH2:30][C:28](=[O:29])[NH:27][C:25]1=[O:26]>C(O)CCCC>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([CH:9]=[CH:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[C:30]3[C:28](=[O:29])[NH:27][C:25](=[O:26])[NH:24][C:31]3=[O:32])=[CH:13][CH:12]=2)[N:3]=1
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: Nc1nc(N)nc(C=Cc2ccc(C=O)cc2)n1
Agent: O=S(=O)(O)O
Solvent: CCCCCO
Product: Nc1nc(N)nc(C=Cc2ccc(C=C3C(=O)NC(=O)NC3=O)cc2)n1
Temperature: 140 °C
Yield: 88 %

Procedure:
To 7.29 g (30 mmol) of 4-[2-(4,6-diamino-[1,3,5]triazin-2-yl)-vinyl]-benzaldehyde suspended in 150 mL of 1-pentanol at 130° C. was cautiously added 75 mL of hot aqueous sulfuric acid (25 mL of concentrated sulfuric acid was added to 50 mL of water with cautious while stirring). The solid dissolved immediately, and a yellow solution was obtained. To this solution, 4.61 g (36 mmol) of powdered barbituric acid was added while stirring vigorously at 140° C. Yellow precipitate appeared immediately. The mixture was slightly refluxed at 140° C. for 10 min then filtrated while it was hot. Solid washed with 50 mL of warm 1-pentanol, then suspended in 300 mL of water and neutralized with saturated aqueous NaHCO3. The solid was collected by filtration and washed with water. Yield: 9.72 g of yellow product. Yield=88%. 1HNMR (400 MHz, DMSO): δ11.519 (s, 1H), 11.375 (s, 1H), 8.378 (s, 1H), 8.234 (d, J=8.0 Hz, 2H), 7.915 (d, J=16.0 Hz, 1H), 7.857 (d, J=8.0 Hz, 2H), 7.101 (br, 4H), 7.047 (d, J=16.0 Hz, 1H). m.p.>350° C. EA found: C, 52.20; H, 3.86; N, 26.12. Calculated for C16H13N7O3.H2O: C, 52.03; H, 4.09; N, 26.55. MS (rel. abundance): M++1 (68), M++2 (13), 242.1 (5), 217.1 (6), 179.0 (15), 157.0 (30), 101.0 (55), 79.1 (100). MS (high resolution, ES+): MH+(352.1158).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:15]([NH2:18])([CH3:17])[CH3:16].[OH-].[Na+]>ClCCl.C(OCC)C.Cl[Ti](Cl)(Cl)Cl>[CH:15]([N:18]=[C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)[CH3:2])([CH3:17])[CH3:16]
Reactant: CC(C)N
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C(C)=NC(C)C)cc1
Temperature: 25 °C

Procedure:
Tetrachlorotitanium (16.85 mL of 1 M, 16.85 mmol) in dichloromethane was added to a solution of ethyl 4-acetylbenzoate (5.4 g, 28.09 mmol) and isopropyl amine (6.644 g, 9.657 mL, 112.4 mmol) in diethyl ether (100 mL) at 0° C. and the reaction mixture allowed to warm to ambient temperature over 15 hours. The reaction mixture was poured into a biphasic mixture of aqueous 0.5 M sodium hydroxide and diethyl ether (4:1, 150 mL) and the layers separated. The aqueous phase was extracted with diethyl ether (×2) and the combined organic phases dried (MgSO4/K2CO3 10:1), filtered and concentrated in vacuo to give ethyl 4-(1-(isopropylimino)ethyl)benzoate as a pale yellow oil (6.7 g, quantitative). 1H NMR (400.0 MHz, DMSO-d6) δ 1.15 (d, J=6.3 Hz, 6H), 1.33 (t, J=7.2 Hz, 3H), 2.25 (s, 3H), 3.88 (sept, 1H), 4.33 (q, J=7.1 Hz, 2H) and 7.91-7.97 (m, 4H) ppm; LC/MS m/z 234.2 [M+H]+.