Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C@@H:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[C@H:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[C@H:19]1[C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])([O:3]C(C)(C)C)=[O:2]>C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1.C(OCC)(=O)C>[C:1]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C@@H:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[C@H:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[C@H:19]1[C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])([OH:3])=[O:2]
Reactant: C=CCOC(=O)[C@H]1[C@H](c2ccc(OC)cc2OCC(=O)OC(C)(C)C)c2cc(OCCC)ccc2[C@@H]1c1ccc2c(c1)OCO2
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CCOC(=O)[C@H]1[C@H](c2ccc(OC)cc2OCC(=O)O)c2cc(OCCC)ccc2[C@@H]1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.7 %

Procedure:
Allyl(1S,2R,3S)-3-(2-carbo-tert-butoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (765 mg, 1.24 mmol) was dissolved in TFA (5 ml) containing a few drops of anisole. The reaction mixture was stirred at RT for 20 min. The solvent was eliminated, the residue was diluted with ethyl acetate, washed with water, brine and dried (MgSO4 anhyd.), filtered and evaporated. The product was purified by column chromatography to provide the title compound (575 mg, 83%) as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7].C([Li])CCC.Cl[Si:14]([CH3:17])([CH3:16])[CH3:15]>CCOCC>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][Si:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: C#CCCCCCl
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)C#CCCCCCl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of 6-chlorohex-1-yne (100 mL, 94.6 g, 0.82 mol) in anhydrous Et2O (500 mL) at −78° C., n-butyllithium (2.5 M in hexane, 360 mL, 0.90 mol) was added over 40 minutes. The resulting mixture was stirred for 30 minutes at −78° C. Chlorotrimethylsilane (125 mL, 1.0 mol) was then added. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was carefully quenched with saturated aqueous NH4Cl (300 mL) at room temperature and extracted with Et2O (2×200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to afford the title compound (144 g, yield 93%). 1H NMR (DMSO-d6, 400 MHz): δ 3.65 (t, 2H), 2.25 (t, 2H), 1.82-1.75 (m, 2H), 1.58-1.51 (m, 2H), 0.12 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([CH3:23])[CH:25]=2)=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: Cc1cccc(CN)c1
Product: Cc1cccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)c1

Procedure:
2′-Methyl-N-(3-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 3-methylbenzylamine using method N. NMR; δH [2H6]—DMSO 9.11,(1H, t), 8.00,(2H, d), 7.90,(1H, dd), 7.77,(1H, d), 7.56-7.51,(3H, m), 7.21,(1H, t), 7.14-7.11,(2H, m), 7.05,(1H, d), 4.47,(2H, d), 2.56,(3H, s), 2.31, (3H, s), 2.29,(3H, s). LCMS; retention time 3.48 min, MH+ 398.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@H:26]4[CH2:30][CH2:29][CH2:28][N:27]4C(OC(C)(C)C)=O)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:38])[NH:6]2.Cl>O1CCOCC1.CO>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:38])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CCCN1
Yield: 61.8 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 11, tert-butyl (2R)-2-[(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-yloxy)methyl]pyrrolidine-1-carboxylate (960 mg, 1.84 mmol) was reacted with hydrogen chloride in dioxane. The solid was dissolved in methanol and absorbed onto an Isolute SCX column which was washed through with methanol and then the product was eluted with 7N ammonia in methanol to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-pyrrolidin-2-ylmethoxy]quinazoline (480 mg, 62%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].Cl[C:34]([O:36][CH3:37])=[O:35]>O1CCCC1>[CH3:37][O:36][C:34]([C:10]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])[CH2:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:24])=[O:35]
Reactant: COc1ccc(C2CCCN(Cc3ccccc3)C2=O)c(OC)c1
Reactant: COC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccc(OC)cc2OC)CCCN(Cc2ccccc2)C1=O
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
A solution of 1 mmol of 1-benzyl-3-(2,4-dimethoxy-phenyl)-piperidin-2-one [597553-90-7] in 20 ml of tetrahydrofuran is cooled to −70° C. and treated drop wise with a solution of 1.2 mmol of lithium diisopropyl-amide in 5 ml of tetrahydrofuran. The mixture is stirred 15 minutes at −70° C. A solution of 1.2 mmol of methyl chloroformate in 5 ml of tetrahydrofuran is added at −70° C. and the reaction mixture is allowed to come to room temperature over a period of 7 hours. The reaction mixture is quenched with water and extracted with tert-butyl methyl ether (3×). The combined organic phases are dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)(O)[CH2:13][CH2:14][CH2:15][CH3:16])[C:6]3[CH2:25][CH2:26][N:27]([CH3:29])[CH2:28][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+]>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)\[CH2:13][CH2:14][CH2:15][CH3:16])[C:6]3[CH2:25][CH2:26][N:27]([CH3:29])[CH2:28][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCCCC(O)(Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CCCC/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(4-fluorophenyl)hexan-2-ol (800 mg, 1.8 mmol) was dissolved in thionyl chloride (5 mL) and the solution was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N-methyl-2-pyrrolidone, stirred for 5 min. at RT, powdered KOH (725 mg, 1.2 mmol) added, and then heated at 100° C. for 3 h. The reaction mixture was cooled to RT and diluted with ice-water to obtain solid product which was filtered and washed with hexane. The product was purified by HPLC. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.70 (m, 2H), 7.50 (m, 1H), 7.36 (m, 2H), 7.0 (m, 2H), 6.85 (m, 1H), 4.40 (m, 2H), 4.20 (m, 2H), 3.60 (m, 1H), 3.50 (m, 1H), 3.38 (m, 1H), 3.05 (m, 1H), 2.90 (s, 3H), 2.70 (m, 1H), 2.30 (m, 1H), 1.35 (m, 2H), 0.9 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:3]=1.[O:23]=[C:24]([C:28]1[N:36]2[C:31]([CH2:32][CH2:33][CH2:34][CH2:35]2)=[CH:30][C:29]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25](Cl)=[O:26].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:25](=[O:26])[C:24](=[O:23])[C:28]4[N:36]5[C:31]([CH2:32][CH2:33][CH2:34][CH2:35]5)=[CH:30][C:29]=4[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:20][CH:21]=3)[CH2:11][CH2:10]2)[CH:3]=1
Reactant: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2n1CCCC2
Reactant: Cc1cc(C)nc(N2CCCN(c3ccc(N)cc3)CC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(N2CCCN(c3ccc(NC(=O)C(=O)c4c(-c5ccccc5)cc5n4CCCC5)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.8 %

Procedure:
To a solution of 4-[4-(4,6-dimethyl-pyridin-2-yl)-[1,4]diazepan-1-yl]-phenyl amine (prepared as described in Reference Example 90, 800 mg, 2.70 mmol) in DCM (30 mL) was added oxo-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetyl chloride (prepared as described in Reference Example 21, 930 mg, 3.24 mmol) and triethylamine (0.75 mL, 5.4 mmol). The mixture was stirred for 2 h at room temperature then concentrated in vacuo to give a residue which was purified by flash chromatography on silica gel (60-120 mesh) eluting with 30% ethyl acetate/n-hexane to afford N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-[1,4]diazepan-1-yl]-phenyl}-2-oxo-2-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetamide (500 mg, 35%) as a yellow solid.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([N:18]=[C:19]=[O:20])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]>C1C=CC=CC=1>[CH3:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[N:1][C:19]([NH:18][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([O:9][CH3:8])[CH:11]=1)=[O:20]
Reactant: COc1ccc(N=C=O)cc1OC
Reactant: CN1CCCC1=N
Solvent: c1ccccc1
Product: COc1ccc(NC(=O)N=C2CCCN2C)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
After dissolving 5.4 g. (0.055 mole) of 2 -imino-1 -methylpyrrolidine in dry benzene, 9.85 g. (0.055 mole) of 3,4 -dimethoxyphenylisocyanate (prepared according to the method of J. G. Lombardino and C. T. Gerber, J. Med. Chem., 7, Jan. 1964, p. 101 ), dissolved in dry benzene, is added dropwise to the solution. The reaction mixture is stirred at room temperature overnight (about 16 hrs.). The solvent is evaporated in vacuo and the residue, which solidifies on cooling, is triturated with anhydrous methanol. Repeated recrystallizations from methanol yields the pure product, 1 -(1 -methyl-2 -pyrrolidylidene)- 3 -(3,4 -dimethoxyphenyl)urea, m.p. = 118-120° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][C@@H:3]1[CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[OH:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@@H:3]1[CH2:15][NH:16][C:17](=[O:18])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@@H](CNC(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CNCC[C@H]1O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a flask containing 1,1-dimethylethyl (3S,4R)-4-hydroxy-3-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-piperidinecarboxylate (E2)(500 mg; 1.37 mmol) was added 20 mL of TFA/DCM (50%). The reaction mixture was stirred for 1 h and then concentrated. The crude product was taken up in chloroform, treated with 500 mg of MP-carbonate resin (2.9 mmol/g) and stirred overnight. After filtration and concentration the product was obtained as its free base (370 mg; 100%).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[C:7]([CH2:11]Br)[C:6]([CH2:13][CH3:14])=[C:5]([CH2:15]Br)[C:4]=1[CH2:17][CH3:18].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[N:21]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[NH2:26][C:22]1[N:21]=[C:20]([NH:19][CH2:2][C:3]2[C:8]([CH2:9][CH3:10])=[C:7]([CH2:11][NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[N:21]=3)[C:6]([CH2:13][CH3:14])=[C:5]([CH2:15][NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[N:21]=3)[C:4]=2[CH2:17][CH3:18])[CH:25]=[CH:24][CH:23]=1
Reactant: CCc1c(CBr)c(CC)c(CBr)c(CC)c1CBr
Reactant: Nc1cccc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1c(CNc2cccc(N)n2)c(CC)c(CNc2cccc(N)n2)c(CC)c1CNc1cccc(N)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
A mixture of 1,3,5-tris(bromomethyl)-2,4,6-triethyl-benzene (0.79 g, 1.8 mmol), 2,6-diamino-pyridine (1.20 g, 11 mmol), and K2CO3 (0.79 g) in CH3CN (100 mL) was stirred at room temperature for 24 h and then heated under reflux for 2 h. After filtration of the reaction mixture and evaporation of CH3CN, the obtained powder was suspended in CHCl3. The suspension was filtrated, the chloroform solution was washed several times with water, dried, and the solvent was removed under reduced pressure. The crude product was crystallized from THF/hexane. Yield 40%. M.p. 164-165° C.; 1H NMR (500 MHz, CDCl3): δ=1.22 (t, 9H, J=7.5 Hz), 2.75 (q, 6H, J=7.5 Hz), 4.05 (t, 3H, J=4.2 Hz), 4.20 (s, 6H), 4.35 (d, 6H, J=4.2 Hz), 5.83-5.86 (m, 6H), 7.24 (m, 3H); 13C NMR (125 MHz, CDCl3): δ=16.9, 23.0, 40.6, 95.9, 96.9, 133.3, 139.4, 143.8, 157.8, 157.9; HR-MS calcd for C30H39N9: 525.3328; found: 525.3322. Rf=0.21 (CHCl3/CH3OH 7:1 v/v).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](Cl)=[N:8][OH:9])=[N:4][O:5][N:6]=1.[CH3:11][O:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:7](=[N:8][OH:9])[NH:15][CH2:14][CH2:13][O:12][CH3:11])=[N:4][O:5][N:6]=1
Reactant: COCCN
Reactant: Nc1nonc1C(Cl)=NO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCCNC(=NO)c1nonc1N
Temperature: 2.5 °C
Yield: 118.8 %

Procedure:
4-Amino-N-hydroxy-1,2,5-oxadiazole-3-carboximidoyl chloride (can be prepared according to Example 1, steps A-B, 200.0 g, 1.23 mol) was mixed with ethyl acetate (1.2 L). At 0-5° C. 2-methoxyethylamine [Aldrich, product #143693] (119.0 mL, 1.35 mol) was added in one portion while stirring. The reaction temperature rose to 41° C. The reaction was cooled to 0-5° C. Triethylamine (258 mL, 1.84 mol) was added. After stirring 5 min, LCMS indicated reaction completion. The reaction solution was washed with water (500 mL) and brine (500 mL), dried over sodium sulfate, and concentrated to give the desired product (294 g, 119%) as a crude dark oil. LCMS for C6H12N5O3 (M+H)+: m/z=202.3. 1H NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1 H), 6.27 (s, 2 H), 6.10 (t, J=6.5 Hz, 1 H), 3.50 (m, 2 H), 3.35 (d, J=5.8 Hz, 2 H), 3.08 (s, 3 H).
Reaction SMILES: CC1(C)CC=C(C2SC=CN=2)C2C=C(C#CC3C=CC=CC=3C(O)=O)C=CC1=2.[CH3:29][C:30]1([CH3:58])[CH2:39][CH:38]=[C:37]([C:40]2[S:41][CH:42]=[CH:43][CH:44]=2)[C:36]2[CH:35]=[C:34]([C:45]#[C:46][C:47]3[CH:57]=[CH:56][C:50]([C:51]([O:53]CC)=[O:52])=[CH:49][CH:48]=3)[CH:33]=[CH:32][C:31]1=2>>[CH3:29][C:30]1([CH3:58])[CH2:39][CH:38]=[C:37]([C:40]2[S:41][CH:42]=[CH:43][CH:44]=2)[C:36]2[CH:35]=[C:34]([C:45]#[C:46][C:47]3[CH:48]=[CH:49][C:50]([C:51]([OH:53])=[O:52])=[CH:56][CH:57]=3)[CH:33]=[CH:32][C:31]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccs2)=CCC3(C)C)cc1
Agent: CC1(C)CC=C(c2nccs2)c2cc(C#Cc3ccccc3C(=O)O)ccc21
Product: CC1(C)CC=C(c2cccs2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(5,6-dihydro-5,5-dimethyl-8-(2-thiazolyl)-2-naphthalenyl)ethynylbenzoic acid (Compound 30a), 70.0 mg (0.17 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-thienyl)-2-naphthalenyl)ethynyl]benzoate (Compound 33a) was converted into the title compound (colorless solid) using 17.8 mg (0.42 mmol) of LiOH in H2O. PMR (d6 -DMSO): δ 1.27 (6H, s), 2.33 (2H, d, J=4.9 Hz), 6.23 (1H, t, J=4.9 Hz), 7.14 (2H, m), 7.38-7.56 (4H, m), 7.61 (2H, d, J=8.3 Hz), 7.92 (2H, d, J=8.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Br[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: COC(=O)c1cccc(O)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)CCCOc1cccc(C(=O)OC)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 84 %

Procedure:
In the same manner as described in Example 38, 0.50 g (1.171 mmol) of the product of Example 37 and 0419 mL (2.927 mmol) of ethyl 4-bromobutyrate provided 0.530 g (84%) of the desired product as a colorless oil. Electrospray Mass Spec: 542.3 (M+H)+
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C1C=CC=CC=1>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:11][CH:12]=1
Reactant: O=C(Cc1ccc(F)cc1)c1ccccc1
Reactant: C1COCCN1
Solvent: c1ccccc1
Product: Fc1ccc(C=C(c2ccccc2)N2CCOCC2)cc1

Procedure:
A mixture of 4-fluorobenzyl phenyl ketone (50g), morpholine (45g) and benzene (100ml) was refluxed overnight with molecular sieve, type 4A, to afford 2-(4-fluorophenyl)- 1-phenyl-1-morpholinoethylene. The latter compound (0.2 mole), cyanoacetamide (0.2 mole), diethylamine (2ml), sulphur (0.2 mole) and ethanol (100 ml) were stirred overnight at room temperature and then added to water. The crude product was recrystallised from ethanol and then from nitromethane to give pure 2-amino-5-(4-fluorophenyl)- 4-phenyl-3-thiophene carboxamide, m.p. 205°-7°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:16]([O-])(=O)/[CH:17]=[CH:18]/[C:19]([O-])=O>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH:17]4[CH2:7][C:6]5[C:19](=[CH:2][CH:3]=[CH:4][CH:5]=5)[CH2:18]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: c1cc2c(cc1N1CCNCC1)CCO2
Reactant: O=C([O-])/C=C/C(=O)[O-]
Product: c1ccc2c(c1)CC(CN1CCN(c3ccc4c(c3)CCO4)CC1)C2

Procedure:
Prepared as described in Example 9, starting from 4-(2,3-dihydrobenzofuran-5-yl)-piperazine. The fumarate of the title compound melts at 180°-182° C. (ethanol).
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.O.[NH2:13][NH2:14]>C(O)(=O)C>[C:4]1(=[O:5])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:6])[NH:14][NH:13]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH][nH]c(=O)c2ccccc12

Procedure:
Compounds of this invention with Formulae I-VIII could be prepared as illustrated by the exemplary reaction in Scheme 20. Reaction of phthalic anhydride with hydrazine hydrate in acetic acid produces 2,3-dihydro-phthalazine-1,4-dione. Chlorination of 2,3-dihydro-phthalazine-1,4-dione and subsequent reaction with an amine, such as N-methyl-p-anisidine, produces the substituted 4-chlorophthalazine, such as (4-chlorophthalazin-1-yl)(4-methoxyphenyl)-amine. The chloro group can then be removed via hydrogenation to produce the substituted phthalazine, such as (4-methoxyphenyl)-methylphthalazin-1-yl-amine.
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:17]2[C@@H:13]([NH:14][O:15][CH2:16]2)[C@H:12]([F:18])[C@H:11]1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)C1C=CC=CC=1.C[O-].[Na+].[Cl-].[NH4+].[C:32](=[O:35])([O-])[OH:33].[Na+]>CO>[CH2:20]([O:19][C@@H:11]1[C@@H:12]([F:18])[C@@H:13]2[N:14]([C:32]([O:33][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:35])[O:15][CH2:16][C@@H:17]2[C@H:10]1[OH:9])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O[C@@H]1[C@H]2CON[C@H]2[C@H](F)[C@H]1OCc1ccccc1)c1ccccc1
Reactant: O=C([O-])O
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: O=C(OCc1ccccc1)N1OC[C@@H]2[C@@H](O)[C@H](OCc3ccccc3)[C@@H](F)[C@@H]21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
The compound (950 mg, 2.66 mmol) synthesized in Example 17 (17f) was dissolved in methanol (10 mL) and sodium methoxide (270 μL, 1.30 mmol) was added thereto, followed by stirring of the mixture at room temperature for 15 minutes. After saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture at 0° C. and the mixture was extracted with ethyl acetate (50 mL), the organic layer was washed with saturated brine (50 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and saturated aqueous sodium hydrogencarbonate (50 mL) and benzyl oxychloroformate (570 μL, 4.00 mmol) were added thereto at 0° C., followed by stirring of the mixture at 0° C. for 1 hour. The organic layer was washed with saturated brine (50 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 1:1, V/V) to obtain the desired title compound (1.00 g, yield 97%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:24][C:25]1[N:29]=[C:28]([NH2:30])[S:27][N:26]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)/[C:13]([NH:30][C:28]2[S:27][N:26]=[C:25]([CH3:24])[N:29]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cc1nsc(N)n1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCCC2)C(=O)O)cc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nsc(NC(=O)/C(=N/OC2CCCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reaction time: 2 h
Yield: 40.2 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclohexyloxyimino-acetic acid (prepared as in Example 9, 112 mg, 0.31 mmol), 3-methyl-[1,2,4]thiadiazol-5-ylamine (36 mg, 0.31 mmol) and N,N-diisopropylethylamine (163 μL, 0.93 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclohexyloxyimino-N-(3-methyl-[1,2,4]thiadiazol-5-yl)-acetamide (57 mg, 40%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C18H21ClN4O4S2 [M+] 456.07, found 457 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.25-1.64 (m, 6H, 3×CH2), 1.73 (m, 2H, 2×CH of CH2), 2.00 (m, 2H, 2×CH of CH2), 2.60 (s, 3 H, ArCH3), 3.31 (s, 3 H, SO2CH3), 4.37 (m, 1 H, OCH), 7.64 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.74 (d, Jm=1.5 Hz, 1 H, Ar), 8.23 (d, Jo=8.2 Hz, 1 H, Ar), 10.35 (s, 1 H, NH).