Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH2:26]([C:29]1[NH:30][CH:31]=[CH:32][N:33]=1)[CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:30]3[CH:31]=[CH:32][N:33]=[C:29]3[CH2:26][CH2:27][CH3:28])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: CCCc1ncc[nH]1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccccc2OC)o1
Temperature: 125 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (500 mg), 2-propylimidazole (1.10 g), potassium carbonate (1.38 g) and N,N-dimethylformamide (10 ml) was stirred at 120-130° C. for 4 hours. The reaction mixture was poured into water (100 ml), the resulting solid precipitate was filtered, air-dried and recrystallized from acetone-hexane to give 4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-(2-propyl-1-imidazolyl) oxazole as pale yellow prisms (233 mg, 39%). Melting point 89-90° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6](=[O:19])[C:5]2([CH3:21])[CH3:20].[C:22]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:21][C:5]1([CH3:20])[C:4]2[C:8](=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:3]=2)[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1=[O:19]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Product: CCCCCN1C(=O)C(C)(C)c2cc(NC(=O)CCc3ccccc3)c([N+](=O)[O-])cc21
Yield: 99.7 %

Procedure:
N-(3,3-Dimethyl-6-nitro-2-oxo-1-pentyl-2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionamide (1.17 g) is synthesized from A8 (807 mg) and freshly prepared 3-phenyl-propionyl chloride (0.5 ml; 3,3 mmol) as described in Example 1a.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1N=[C:13]([O:15]C)[CH:12]=[CH:11]N=1>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:6]2[CH:7]=[CH:2][C:12]([CH:13]=[O:15])=[CH:11][CH:5]=2)[N:3]=1
Reactant: Clc1cccnn1
Reactant: COc1ccnc(Cl)n1
Product: O=Cc1ccc(-c2cccnn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 13 by substituting 3-chloropyridazine (prepared as described in WO 9724124) for the 2-chloro4-methoxypyrimidine of Reference Example 13. MS 185 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:10]=2[N:9]([CH3:19])[C:8](=[O:20])[CH2:7]1)[CH3:2].[CH2:22]([N:29]=[C:30]=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCOC(C)=O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([NH:18][C:30]([NH:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:31])[CH:16]=[CH:17][C:10]=2[N:9]([CH3:19])[C:8](=[O:20])[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CN1CC(=O)N(C)c2ccc(N)cc2C1=O
Reactant: O=C=NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CC(=O)N(C)c2ccc(NC(=O)NCc3ccccc3)cc2C1=O
Yield: 98.2 %

Procedure:
To a solution of (7-amino-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetic acid ethyl ester (0.65 g, 2.23 mmol) in DMF (5 ml) was added benzylisocyanate (0.5 g, 3.75 mmol) and DMAP (5 mg). After 2 h at 60° C. the reaction mixture was poured into AcOEt (70 ml), washed with aqueous KHSO4 (0.1 N) and water. After drying over Na2SO4 and evaporation of the solvents the residue was purified by chromatography (dichloromethane/MeOH 19:1) to give [7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid ethyl ester (930 mg, 2.19 mmol): mp. 151° C.; MS (EI): 424 (M)+.
Reaction SMILES: [I:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH:19](OC)(OC)OC>CO>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[I:1]
Reactant: COC(OC)OC
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1I
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1I

Procedure:
2-iodo-3-nitro-benzoic acid (61 g, 208 mmol, prepared as described in Org. Syn. Coll. Vol. 1, 56-58, and 125-127), sulfuric acid (40.8 g, 416 mmol), and trimethyl orthoformate (88.4 g, 833 mmol) were dissolved in 500 mL dry MeOH. The reaction was refluxed under argon for 20 h. The reaction mixture was concentrated to 100 mL then partitioned between saturated NaHCO3(aq) and CH2Cl2. The layers were separated and the aqueous layer extrated three times with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The yellow solid was crystallized from CH2Cl2/hexanes yielding 2-iodo-3-nitro-benzoic acid methyl ester, 57.8 g (90%) as a yellow solid: m.p.64.0-64.5° C.; 1H NMR (300 MHz, CDCl3) 3.99 (s, 3H), 7.54 (app t, J=7.8 Hz, 1H), 7.70 (dd, J=8.1, 1.8 Hz, 1H), 7.77 (dd, J=7.8, 1.8 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH:9]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH2:27]1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13](=[O:15])[NH:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][N:29]([CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:30][CH2:31]2)[CH2:11][S:10][CH:9]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C(c2cccnc2)SC[C@H]1C(=O)O
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CCP(=O)(C#N)CC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(c2cccnc2)SC[C@H]1C(=O)NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A mixture of 500 mg (1.61 mmole) of 3-t-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4(R)-carboxylic acid, 500 mg (1.61 mmole) of 1-(3-aminopropyl)-4-(diphenylmethyl) piperazine (prepared as described in Preparation 16'), 263 mg (1.61 mmole) of diethylphosphoryl cyanide, 163 mg (1.61 mmole) of triethylamine and 10 ml of tetrahydrofuran was stirred at room temperature overnight. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, diluted with water and extracted with methylene chloride. The solvent was then removed by evaporation under reduced pressure, and the resulting residue was subjected to column chromatography through alumina, using ethyl acetate as the eluent, to afford 840 mg (yield 89%) of the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(O[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)C.C(OC1C=CC=CC=1)(=O)C1C=CC=C(C(OC2C=CC=CC=2)=O)C=1>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(=O)Oc1ccccc1
Agent: O=C(Oc1ccccc1)c1cccc(C(=O)Oc2ccccc2)c1
Product: O=C(Oc1ccccc1)c1ccc(O)cc1
Temperature: 180 °C
Reaction time: 8 h

Procedure:
138 g. (1 mole) of p-hydroxybenzoic acid, 170 g. (1.25 moles) of phenyl acetate and 39.75 g. (0.125 mole) of diphenyl isophthalate are placed in a four-necked resin kettle equipped as in Example 3. The mixture is heated to 180°C, and HCl is then bubbled through the resulting melt for 8 hours, during which the temperature is held at 180°C for 6 hours and subsequently at 200°C for 2 hours. Phenyl p-hydroxybenzoate is produced thereby. The HCl flow is discontinued, and 30.6 g. (0.250 mole) of hydroquinone and 500 g. of a polyaromatic ether heat transfer medium (b.p above 400°C) are added. The temperature is then raised to 280°C where it is held for 1 hour, raised to 300°C where it is held for 2 hours, and raised to 320°C where it is held for 5 hours. The mixture is cooled and acetone is added. The product is recovered by filtration, washed with acetone, extracted with acetone overnight in a Soxhlet extractor, and dried in vacuum at 110°C. The product is a linear copolyester consisting essentially of moieties of Formulas II, III and IV in a ratio of about 8:1:1, wherein the moiety of Formula III is isophthaloyl and the moiety of Formula IV is para-dioxyphenylene, and the average number of moieties in the copolyester chain is about 10.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:8]([CH:9]=O)=[CH:7][N:6]=[CH:5][CH:4]=1.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:26][N+:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[NH2:35].N12CCCN=C1CCCCC2>C(O)C>[F:33][C:31]1[C:30]([F:34])=[CH:29][C:28]2[N:27]([N:26]=[C:9]([C:8]3[CH:7]=[N:6][CH:5]=[CH:4][C:3]=3[C:2]([F:12])([F:11])[F:1])[N:35]=2)[CH:32]=1
Reactant: O=Cc1cnccc1C(F)(F)F
Reactant: Nc1cc(F)c(F)c[n+]1N
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: Fc1cc2nc(-c3cnccc3C(F)(F)F)nn2cc1F

Procedure:
4-(trifluoromethyl)nicotinaldehyde was added to a solution of 1,2-diamino-4,5-difluoropyridinium 2,4,6-trimethylbenzenesulfonate (47-4; 0.2 g, 0.000579 mol) in ethanol (20 mL) while stirring, followed by the addition of 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction mixture was stirred for 12 h at RT. It was then concentrated under vacuum, diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The collected organic parts were concentrated under vacuum to afford the crude product, which was purified by silica gel column chromatography to afford the title compounds. 1H NMR (400 MHz, DMSO) δ 8.20 (s, 1H), 9.09-9.06 (m, 1H), 9.03-9.02 (d, J=4 Hz, 1H), 7.99-7.77 (d, J=8 Hz, 1H), 7.61-7.55 (m, 1H). HPLC purity-99.13%, MS (M+1): 301.1.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:3][CH2:2]1.Cl.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH:32]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH2:32][CH2:31][N:30]([C:8]([C:7]3[CH:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=[CH:14][C:6]=3[O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)=[O:10])[CH2:29][CH:28]=2)=[CH:23][CH:22]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)O)c1
Agent: Cl
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)N2CC=C(c3ccc(Cl)cc3)CC2)c1

Procedure:
According to the procedure described for the synthesis of example 4, step f, the title compound has been synthesized from 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (CAS: 845616-03-7) and 4-(4-chloro-phenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride (commercial). MS (m/e): 446.0 (MH+, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>CN(C=O)C.C(OCC)(=O)C>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: Clc1ccccc1CBr
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2Cl)CCCC1=O
Reaction time: 0.08 h
Yield: 53.5 %

Procedure:
40% Methanolic Triton B (2.42 mL, 5.3 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (873.7 mg, 3.59 mM) in 10 mL of DMF at 25° C. After 5 minutes, 2-chlorobenzyl bromide (1.11 g, 5.39 mM) was added and the resultant mixture stirred at room temperature for 72 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, once with saturated brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purified by crystallization from ethyl acetate to afford 706.3 mg (53%) of the 9-[(2-chlorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a yellow solid. 1H NMR (DMSO-d6) δ7.6 (m, 2H), 7.4-7.1 (m, 4H), 6.5 (d, 1H, J=8 Hz), 5.6 (s, 2H), 3.8 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.4 (t, 2H, J=6 Hz), and 2.1 (m, 2H). IR (CDCl3, cm−1) 3050, 2950, 1725, 1655, 1462, 1446, 1435, 1288 and 1120. MS (ES) m/e 368, 370.
Reaction SMILES: O[C:2]1([C:38]2[CH:43]=[CH:42][C:41]3[O:44][CH2:45][O:46][C:40]=3[CH:39]=2)[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=2)[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH2:24][CH2:25][O:26]CC2C=CC=CC=2)=[C:3]1[C:34]([O:36][CH3:37])=[O:35].C(O)C>C(OC(=O)C)C>[OH:26][CH2:25][CH2:24][O:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH3:14])[CH:6]=2)[CH:2]([C:38]2[CH:43]=[CH:42][C:41]3[O:44][CH2:45][O:46][C:40]=3[CH:39]=2)[CH:3]1[C:34]([O:36][CH3:37])=[O:35]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCOCc1ccccc1)=C(C(=O)OC)C2(O)c1ccc2c(c1)OCO2
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCO)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Reaction time: 48 h
Yield: 81.1 %

Procedure:
A mixture of methyl (1SR)-1-hydroxy-3-[2-(2-benzyloxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxy phenyl)-5-propoxyindene-2-carboxylate (88 g, 0.141 moles) 10% palladium on carbon (21 g), 0.65 L of absolute ethanol and 0.65 L of ethylacetate was hydrogenated at 50 psi, 55° C. for 48 hrs. The catalyst was filtered off, and the filtrate concentrated in vacuo to give an amorphous glass. Crystallization from 350 mL of absolute ethanol gave 59.5 g (81%) of white solid; m.p. 165°-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[N:7]([NH:12][CH3:13])[C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5].C(=O)(O)[O-].[Na+].[Br:23][CH2:24][C:25](Br)=[O:26]>ClCCl>[CH3:13][N:12]([N:7]1[C:8]([CH3:11])=[CH:9][CH:10]=[C:6]1[C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[Cl:1])[C:25](=[O:26])[CH2:24][Br:23]
Reactant: CNn1c(C)ccc1C(=O)c1ccccc1Cl
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2ccccc2Cl)n1N(C)C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A stirred slurry of 2-(2-chlorobenzoyl)-1-methylamino-5-methylpyrrole (18.7 g, 75 mmol) and sodium bicarbonate (14.2 g, 170 mmol) in 100 ml of dichloromethane was treated with a solution of bromoacetyl bromide (15.2 g, 90 mmol) in 30 ml of dichloromethane over 30 minutes and stirred at room temperature overnight. The reaction mixture was quenched with 100 ml of H2O, separated, washed with H2O and brine, dried (MgSO4), filtered, and evaporated. The resultant oil was purified by HPLC (silica, 1:1 ethyl actate-hexane) to give an oil which crystallized from ether to give 22.7 g (82%) of needles, m.p. 108°-109°.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]4[CH2:20][CH2:19][CH:17]([CH:18]=3)[N:16](C3C=CC(OC)=CC=3)[CH2:15]4)=[CH:10][CH:11]=2)[N:6]([CH3:29])[C:5]1=[O:30].CC#N.OS(O)(=O)=O.I(O)(=O)(=O)=O>O>[CH:17]12[CH2:19][CH2:20][CH:14]([C:13]([C:9]3[N:8]=[C:7]4[N:6]([CH3:29])[C:5](=[O:30])[N:4]([CH2:3][C:2]([CH3:31])([CH3:32])[CH3:1])[C:12]4=[CH:11][CH:10]=3)=[CH:18]1)[CH2:15][NH:16]2
Reactant: COc1ccc(N2CC3CCC2C=C3c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)cc1
Agent: O=S(=O)(O)O
Agent: [O-][I+3]([O-])([O-])O
Solvent: O
Solvent: CC#N
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CCC3CN4)nc21
Temperature: 50 °C

Procedure:
1-(2,2-Dimethylpropyl)-5-[2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]oct-5-en-5-yl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2-4, 339 mg, 0.78 mmol, 1.0 equiv) was added to CH3CN (7 mL) and water (7 mL) To this suspension was added aqueous H2SO4 (0.78 mL, 0.78 mmol, 1.0 equiv, 1.0 M) followed by periodic acid in one portion (179 mg, 0.78 mmol, 1.0 equiv). The reaction contents were heated to 50° C. for 18 h. Following this duration,
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][NH2:22].[C:23]([OH:27])(=[O:26])[CH:24]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][N:22]=[CH:24][C:23]([OH:27])=[O:26]
Reactant: O=CC(=O)O
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccncc1
Product: CC1=C(CCON=CC(=O)O)c2cc(F)ccc2/C1=C\c1ccncc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-pyridyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with glyoxylic acid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH:14]=[O:15])[CH:13]=1)[N:10]([CH2:16][CH3:17])[CH2:9][CH2:8][C:7]2([CH3:19])[CH3:18])([CH3:3])[CH3:2].[CH3:20][Mg]Br>C1COCC1>[CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH:14]=[O:15])[CH:13]=1)[N:10]([CH2:16][CH2:17][CH3:20])[CH2:9][CH2:8][C:7]2([CH3:19])[CH3:18])([CH3:2])[CH3:3]
Reactant: CCN1CCC(C)(C)c2cc(C(C)C)cc(C=O)c21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(C=O)c21
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6-isopropyl-4,4-dimethyl-1-ethyl-1,2,3,4-tetrahydro-quinoline-8-carbaldehyde (Intermediate 7, 2.00 g, 9.00 mmol) and 35 ml of anhydrous THF under argon at −78° C. was slowly added 3 M solution of methyl magnesium bromide in THF (7.5 ml, 22.5 mmol). The resulting solution was stirred at −78° C. for 45 minutes. The reaction was quenched with saturated NH4Cl and the product was extracted with diethyl ether. The organic extract was washed with water, and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography using 5% ethyl acetate in hexane to yield the title compound as light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([SH:8])[N:3]=1.IC.[C:11]([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:11])[N:3]=1
Reactant: Cc1ccnc(S)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nccc(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
A mixture of compound 4-methylpyrimidine-2-thiol (500 g, 3.05 mol), iodomethane (611 g, 4.27 mol) and K2CO3 (915 g, 6.71 mol) in THF (4 L) was stirred at room temperature for 18 h. The suspension was filtered and the solid was washed with ether (500 mL×2). The filtrate was concentrated and dried in vacuum to give compound 2 (380 g, 89.2%) as a yellow oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C:16]([O-:18])=[O:17])C(O)=CC=C(C)C=1.[K+].C(=O)=O>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:16]([OH:18])=[O:17])=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: Cc1ccc(O)c(C(=O)[O-])c1
Agent: O=C=O
Agent: [K+]
Product: O=C(O)c1ccc(O)cc1
Yield: 79.6 %

Procedure:
A pressure vessel was charged with 4.73 g of phenol, 23.52 g of potassium para cresolate being in a dry powder form and 54 ml of a high boiling point light oil fraction (160° to 230° C./10mmHg) . Reaction was carried out at a carbon dioxide pressure of 4 kg/cm2 (G) and at 250° C. for one hour. An analysis of the reaction mixture after conversion to acid form showed a para-hydroxybenzoic acid yield of 79.6% on the basis of phenol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:20])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH2:15][CH2:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=C(S(O[CH2:34][C@H:35]2[O:37][CH2:36]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:20][CH2:34][C@@H:35]2[CH2:36][O:37]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH2:15][CH2:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCc2c(O)ccc(OCc3ccccc3)c2N1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1CCc2c(OC[C@@H]3CO3)ccc(OCc3ccccc3)c2N1
Yield: 82.1 %

Procedure:
A mixture of 8-(benzyloxy)-5-hydroxy-3,4-dihydro-2(1H)-quinolinone (0.20 g, 0.743 mmol), (S)-(+)-glycidyl 3-nitrobenzenesulfonate (0.193 g, 0.743 mmol) and potassium carbonate (0.113 g, 0.817 mmol) in 2-butanone (10 mL) was heated at reflux for 16 hours. The solvent was removed in vacuo and the residue purified by flash chromatography (chloroform-methanol, 50:1) to yield the title compound (0.210 g, 0.61 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([CH:23]=[CH:24][N:25]=3)[N:22]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[Br:31]Br>CC(O)=O>[C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([C:23]([Br:31])=[CH:24][N:25]=3)[N:22]=2)[CH2:15][CH2:16]1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccc3nccn3n2)CC1
Solvent: CC(=O)O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccc3ncc(Br)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 104 mg (0.25 mmol) of (S)-tert-butyl(1-(4-(imidazo[1,2-b]pyridazin-6-yl)piperazin-1-yl)-4-methyl-1-oxopentan-2-yl)carbamate dissolved in 5 mL of AcOH was added bromine (48 mg, 0.3 mmol) and the resulting mixture was stirred at room temperature. After 0.25 hr, the reaction was done, and concentrated by rotavap and then by high vacuum pump to obtain 139 mg (100% yield) of mono-acetic acid salt of the desired product.
Reaction SMILES: C(O[C:4](=[O:15])[C:5](=[CH:11]OCC)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.[C:17]([NH2:20])(=[NH:19])[CH3:18]>>[CH3:18][C:17]1[N:20]=[C:4]([OH:15])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][N:19]=1
Reactant: CC(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Product: CCOC(=O)c1cnc(C)nc1O
Yield: 67 %

Procedure:
The title compound was prepared by (a) reaction of diethylethoxymethylenemalonate (6 g, 28 mmol) with acetamidine hydrochloride (3 g, 31 mmol) to afford 67% of ethyl 2-methyl-4-hydroxypyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of ethyl 2-methyl-4-hydroxypyrimidine-5-carboxylate (2.8 g, 15 mmol) with POCl3 (46 g, 300 mmol) to afford 28% of ethyl 4-chloro-2-methylpyrimidine-5-carboxylate, (c) reaction of ethyl 4-chloro-2-methylpyrimidine-5-carboxylate (0.25 g, 1.25 mmol) with hydrazine (0.2 g, 6.3 mmol) to afford 96% of 4-hydrazino-2-methylpyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of 4-hydrazino-2-methylpyrimidine-5-carboxylate (0.24 g, 1.2 mmol) with citraconic anhydride (0.16 g, 1.44 mmol) to afford 70% (0.24 g) of the title compound (m.p. 98-99° C.) in analogy to Example 21.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)([O-])[O-].[K+].[K+].[C:15]1([CH:21](Br)[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[C:15]1([CH:21]([S:1][C:2]2[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=2)[NH2:5])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(Br)c1ccccc1
Reactant: Nc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Sc1cccc(N)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-mercaptoaniline (1 g) and potassium carbonate (1.21 g) in N,N-dimethylformamide (20 mL) was added 1-phenylethyl bromide (1.2 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/1) to give the title compound (1.78 g).