Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[S:38][C:39]([C:42]([NH:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[CH:40][N:41]=1>>[C:45]([NH:44][C:42]([C:39]1[S:38][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[N:41][CH:40]=1)=[O:43])([CH3:48])([CH3:47])[CH3:46]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)(C)NC(=O)c1cnc(Br)s1
Product: C[C@@H](c1ccc(-c2ncc(C(=O)NC(C)(C)C)s2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromo-N-tert-butylthiazole-5-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.351 min, m/z=558.1; 1H NMR (CDCl3) 1.13 (s, 3H), 1.16 (s, 3H), 1.49 (s, 9H), 1.51 (d, 3H), 2.15-2.32 (m, 5H), 2.41 (m, 1H), 2.89 (m, 1H), 3.72 (m, 1H), 5.70 (m, 1H), 5.78 (m, 1H), 7.02 (m, 2H), 7.34 (m, 5H), 7.70 (m, 2H), 8.08 (m, 1H)
Reaction SMILES: [OH-].[K+].CS(C)=O.[N:7]1([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:23]4[NH:24][C:25]5[C:30]([CH:31]=4)=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:21][N:22]=3)[N:19]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:32]I>O>[N:7]1([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:23]4[N:24]([CH3:32])[C:25]5[C:30]([CH:31]=4)=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:21][N:22]=3)[N:19]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: c1ccc2[nH]c(-c3nnc4ccc(N5CCCCCC5)nn34)cc2c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(-c2nnc3ccc(N4CCCCCC4)nn23)cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of potassium hydroxide (98 mg) and DMSO (5 ml), 6-azepan-1-yl-3-(1H-indol-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (501 mg) was added, and the mixture was stirred at room temperature for 30 minutes, and then combined with methyl iodide (0.15 ml) and then stirred for further 2 hours at room temperature. The reaction mixture was combined with water, and the resultant solids were collected by filtration, washed with a solvent a mixture of water and methanol, and then purified by silica gel column chromatography (eluent: chloroform: methanol=99:1). The resultant crude crystals were recrystallized from ethanol to obtain 6-azepan-1-yl-3-(1-methylindol-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (40 mg) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]([CH:27]2[CH2:29][CH2:28]2)[NH2:26])=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([NH:26][CH2:16][CH2:15][C:2]2([OH:1])[CH2:3][CH2:4][C:5]3([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10]3)[CH2:13][CH2:14]2)[CH:27]2[CH2:29][CH2:28]2)=[CH:23][CH:24]=1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: N[C@H](c1ccc(Br)cc1)C1CC1
Product: CC1(C)COC2(CCC(O)(CCN[C@H](c3ccc(Br)cc3)C3CC3)CC2)OC1
Yield: 71 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-(4-bromophenyl)(cyclopropyl)methanamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 71% of theory; LC (method 1): tR=1.64 min; Mass spectrum (ESI+): m/z=452/454 (Br) [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH:8](O)[C:7]=2[CH:18]=1.[ClH:19]>O1CCOCC1>[Cl:19][CH:8]1[C:7]2[CH:18]=[C:3]([S:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH:12]=[CH:11][C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]1=2
Reactant: Cl
Reactant: CSc1ccc2c(c1)C(O)c1ccccc1C=C2
Solvent: C1COCCO1
Product: CSc1ccc2c(c1)C(Cl)c1ccccc1C=C2

Procedure:
A solution of 18 g. (0.071 mole) of 3-methylmercapto-5H-dibenzo[a,d]cyclohepten-5-ol in 90 ml. of dry dioxane is cooled in an ice-bath and saturated with dry hydrogen chloride. A solid separates and when precipitation appears to be complete, the mixture is stirred with 150 ml. of petroleum ether and the product collected, washed with petroleum ether, and dried in a vacuum desiccator over potassium hydroxide. The yield of 5-chloro-3-methylmercapto-5H-dibenzo[a,d]cycloheptene is 16 g. (84%), m.p. 135°-138°C. The melting point is unchanged by recrystallization from cyclohexane.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:11])=[C:4]([NH2:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[C:12](O)(=[O:16])[C:13](O)=[O:14].C(O)C>Cl>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]2[C:3]=1[NH:11][C:12](=[O:16])[C:13](=[O:14])[NH:10]2
Reactant: Nc1cc(F)c(F)c(F)c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2cc(F)c(F)c(F)c2[nH]c1=O
Reaction time: 8 h
Yield: 4 %

Procedure:
To a brown solution of 3,4,5-trifluoro-1,2-phenylenediamine (285 mg, 1.75 mmol) in aqueous 2N HCl (10 mL) is added oxalic acid (221 mg, 1.75 mmol). The brown mixture is brought to reflux and stirred under N2 overnight. The mixture is filtered to yield 139 mg (37%) of crude title compound. An analytical sample is prepared by dissolving 42 mg of this brown powder in 2.5 mL boiling ethanol. Upon cooling, brown rod-like crystals were formed which are filtered and dried in vacuo to yield 15 mg (36%) of pure title compound: 1H NMR (DMSO-d6), 6.91 (m, 1H), 12.02 (s, 1H), 12.19 (s, 1H); analysis calculated for C8H3F3N2O2 : C, 44.46; H, 1.40; N, 12.96. Found: C, 44.42; H, 1.16; N, 12.76.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2].Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[O:13][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1Oc1cccc(O)c1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Oc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Yield: 101.2 %

Procedure:
In 120 ml of acetone were dissolved 8.0 g of 3-(2-nitrophenoxy)phenol and 7.5 g of ethyl 2-bromopropionate followed by addition of 7.2 g of potassium carbonate. The mixture was refluxed for 5 hours and, after cooling, the insoluble matter was filtered off. The filtrate was concentrated to give 11.6 g of the title compound as a light brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:14]([O-])=O)[C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].CO>[Pd].O1CCCC1>[NH2:14][C:5]1[C:6]([OH:13])=[C:7]([CH:12]=[C:3]([C:1]#[N:2])[CH:4]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(C#N)cc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(C#N)cc(N)c1O
Temperature: 50 °C
Reaction time: 4 h
Yield: 78.1 %

Procedure:
To a mixture of 2.71 g of methyl 5-cyano-2-hydroxy-3-nitrobenzoate in a 60 ml of methanol and 40 ml of tetrahydrofuran was added palladium on carbon (500 mg, 10% wet). This suspension was purged with, and stirred under, an atmosphere of hydrogen (via balloon) for 4 h at 50° C. The mixture was then filtered through a plug of Celite, eluting with ethyl acetate (75 ml). The eluent was concentrated in vacuo and the residue was taken up in ethyl acetate (50 ml) and methanol (as needed to dissolve) and was then filtered through a plug of silica gel. The eluent was concentrated in vacuo again and purified via column chromatography using a Biotage Horizon, 65i column, eluting with 1 column volume of 100% hexanes followed by a gradient of 0 to 100% ethyl acetate in hexanes over 10 column volumes, followed by 2 column volumes of 100% ethyl acetate to provide the title compound (1.83 g, 78%). Mass spectrum (ESI) 190.9 (M−1).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:67])[C@@H:22]([NH:56]C(OCC1C=CC=CC=1)=O)[CH2:23][S:24][CH2:25][C@H:26]([O:42][C:43](=[O:55])[NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:27][O:28][C:29](=[O:41])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>C(Cl)Cl>[NH2:56][C@@H:22]([CH2:23][S:24][CH2:25][C@H:26]([O:42][C:43](=[O:55])[NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:27][O:28][C:29](=[O:41])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:21](=[O:67])[NH:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8]
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)NCCCCCCCCCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(O)O)OC(=O)NCCCCCCCCCC
Temperature: 32 °C
Reaction time: 8 h

Procedure:
To a solution of (14R,18R)-14-(benzyloxycarbonylamino)-18-(decylcarbamoyloxy)-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12,22-diazadotriacontylphosphonic acid diethyl ester (1 eq) in DCM at 0° C. (0.1 M) was added trimethylsilyl bromide (10 eq). The reaction mixture was stirred at 32° C. overnight then cooled to room temperature, diluted with DCM and concentrated. The crude material was dried under high vacuum for 2 hours then purified by reverse phase high performance liquid chromatography (HPLC) with a C4 column eluting with a gradient of 40-100% MeCN/10 mM NH4OAc (95:5) in 10 mM NH4OAc (pH 9) to afford (14R,18R)-14-amino-18-(decylcarbamoyloxy)-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12,22-diazadotriacontylphosphonic acid as a white solid. 1H NMR (DMSO-d6): δ 8.49 (t, 1H), 7.32 (m, 2H), 4.78 (m, 1H), 4.01(m, 2H), 3.0-3.6 (m, 18H), 2.88 (m, 4H), 2.52-2.81 (m, 5H), 1.54 (m, 2H), 1.34 (m, 4H), 1.12-1.24 (m, 28H), 0.81 (t, 6H). LRMS [M+H]=801.5.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][C:5]([F:10])=[C:4]([Cl:11])[N:3]=1.P(Br)(Br)[Br:13].C(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:13][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:11])=[C:5]([F:10])[CH:6]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc(F)c(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Fc1cc(CBr)c(Cl)nc1Cl
Temperature: 25 °C
Yield: 88 %

Procedure:
To a stirred mixture of alcohol 1A (3.52 g, 17.9 mmol) in CHCl3 (100 mL) under argon was added 1M PBr3 in CH2Cl2 (18.0 mL, 18.0 mmol). The reaction mixture was heated to reflux for 15 minutes, cooled to room temperature, then poured into a mixture of ice and saturated NaHCO3 solution (200 mL). The pH was adjusted to basic by addition of solid NaHCO3. The aqueous layer was extracted with EtOAc. The combined EtOAc extracts were washed with brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 1B (4.11 g, 88%). HPLC Rt=2.78 min. (Column: YMC ODS-A 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:21][CH2:20]O[CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:22]1(C2CCC(=O)CC2)C=CC=CC=1.N1CCOCC1.[O-2].[Al+3].[O-2].[O-2].[Al+3]>>[CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:21][CH2:20][CH2:22][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CN[C@H]1CC[C@H](c2ccc(CN3CCOCC3)cc2)CC1
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: [Al+3]
Agent: [O-2]
Solvent: C1COCCN1
Product: CN[C@H]1CC[C@H](c2ccc(CN3CCCCC3)cc2)CC1

Procedure:
cis/trans-N-methyl-4-[4-(morpholinomethyl)phenyl]cyclohexylamine, from 4-phenylcyclohexanone and morpholine; colourless solid; Rf values 0.26 and 0.48 (aluminium oxide, petroleum ether/ethyl acetate=5:1, v:v)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O-:13])=[O:12].[Na+].C(=O)([O-])O.[Na+].C1(=O)[O:25][C:23](=[O:24])[CH:22]=[CH:21]1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])(=[O:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)[O-])c1
Reactant: O=C1C=CC(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)CCS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 100 °C
Reaction time: 5 h
Yield: 80.9 %

Procedure:
36 g of sodium 2-chloro-5-nitrobenzenesulphinate, 12.6 g of solid sodium hydrogen carbonate and 22.5 g of maleic anhydride are heated at 100° C. in 250 ml of water for 3 hours. After cooling down, a further 12.6 g of sodium hydrogencarbonate and 22.5 g of maleic anhydride are then added. After a further 5 hours of stirring at 100° C., the cooled, weakly acid reaction mixture is filtered with suction. The filter is cake at 50° C. in 300 ml of water, and the suspension is cooled down to 20° C. and is filtered again with suction. Drying gives 35.1 g of 3-(2-chloro-5-nitrophenylsulphonyl)-propionic acid.
Reaction SMILES: CCCC(O[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])CC.[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([CH3:27])[C:25]=1[OH:26])[CH:21]=O>>[CH2:9]([O:10][C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[CH:8]=[CH:21][C:20]2[CH:19]=[C:18]([CH3:17])[C:25]([OH:26])=[C:24]([CH3:27])[CH:23]=2)=[CH:16][CH:15]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CCCC(CC)OCC(=O)c1ccccc1
Product: CCCCCCOc1ccc(C(=O)C=Cc2cc(C)c(O)c(C)c2)cc1

Procedure:
This compound was synthesized from 4-hexyloxyacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1)=[O:6].Cl.[NH2:21][C@H:22]([C:27]([NH2:29])=[O:28])[CH2:23][CH2:24][S:25][CH3:26].C(N(CC)CC)C>CCO>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][C:10]2([NH:29][C:27](=[O:28])[C@H:22]([CH2:23][CH2:24][S:25][CH3:26])[NH:21]2)[CH2:9][CH2:8]1)=[O:6]
Reactant: CSCC[C@H](N)C(N)=O
Reactant: COc1ccc(C(=O)N2CCC(=O)CC2)c(OC)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCC3(CC2)NC(=O)[C@H](CCSC)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(2,4-dimethoxybenzoyl)piperidin-4-one (1.4 g, 5.1 mmol), (S)-methioninamide hydrochloride (950 mg, 5.1 mmol) and triethylamine (520 mg, 5.1 mmol) in EtOH (40 ml) was heated under reflux for 2.5 h and stirred at RT for a further 16 h. After removal of the solvent, water (25 ml) and CH2Cl2 (25 ml) were added to the residue and it was rendered basic using conc. sodium hydroxide solution. The aqueous phase was extracted with CH2Cl2 (3×20 ml) and the combined organic phases were dried over Na2SO4. After removal of the solvent and drying in vacuo, the product 8-(2,4-dimethoxybenzoyl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5]decan-2-one was obtained in a yield of 1.9 g (95%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([NH:30]N)=[CH:24][C:23]=2[O:22]1>C(O)(=O)C>[O:29]1[C:28]2[CH:27]=[CH:26][C:25]([N:30]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:24][C:23]=2[O:22][CH2:21]1
Reactant: NNc1ccc2c(c1)OCO2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Solvent: CC(=O)O
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccc2c(c1)OCO2
Yield: 301.7 %

Procedure:
3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) (0.2 g; 0.74 mmol) and 3,4-methylenedioxyphenylhydrazine (0.136 g; 0.89 mmol) are dissolved in a sealed tube in acetic acid (4 ml) and irradiated at 180° C. for 10 min. The solvent of the reaction mixture is removed and the crude product is purified by preparative HPLC yielding 0.80 g (30%) of the final product. MS: M=359.0 (M+H)+
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].[N+:18]([C:21]1[N:25]=[CH:24][NH:23][N:22]=1)([O-:20])=[O:19]>CN(C=O)C.O>[CH:10]([C:7]1[CH:8]=[CH:9][C:2]([N:23]2[CH:24]=[N:25][C:21]([N+:18]([O-:20])=[O:19])=[N:22]2)=[C:3]([CH:6]=1)[C:4]#[N:5])=[O:11]
Reactant: O=[N+]([O-])c1nc[nH]n1
Reactant: N#Cc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(C=O)ccc1-n1cnc([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 44.9 %

Procedure:
To a stiffing solution of 2-fluoro-5-formylbenzonitrile (0.5 g, 3.3 mmol) in DMF (25 mL) were added K2CO3 (0.68 g, 4.95 mmol) and 3-nitro-1,2,4 triazole (0.45 g, 4.2 mmol) and the resultant reaction mixture was stirred at ambient temperature for 14 h. After completion of reaction (TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined EtOAc layer was washed with water and brine then dried over Na2SO4 and concentrated under reduced pressure to afforded the title compound as a pale yellow solid (0.36 g, 45%): mp 170-172° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.12 (s, 1H), 9.61 (s, 1H), 8.69 (s, 1H), 8.45 (d, J=9.3 Hz, 1H), 8.23 (d, J=9.3 Hz, 1H); ESIMS m/z 242.3 ([M−H]−); IR (thin film) 2238, 1705, 1551, 1314 cm−1.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:20][C:9]2[N:10]([CH3:19])[C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]2[N:10]([CH3:19])[C:9]3[CH2:20][CH:6]([CH2:4][OH:3])[CH2:7][C:8]=3[C:16]=2[CH:15]=1
Reactant: CCOC(=O)C1Cc2c(n(C)c3ccc(OC)cc23)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c1c(n2C)CC(CO)C1
Yield: 74.1 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-7-methoxy-4-methylcyclopent[b]indole-2-carboxylic acid ethyl ester (2.0 g, 0.007 mole) in 30 ml of dry tetrahydrofuran, was added lithium aluminum hydride (1M solution in tetrahydrofuran, 15 ml, 0.015 mole). After stirring at reflux for three hours, the mixture was cooled, quenched with 5 ml of saturated ammonium chloride solution and then diluted with 50 ml of ether. The mixture was filtered, and the filtrate concentrated to a yellow oil (~2 g). This oil was eluted on a silica gel column with 10% ethyl acetate/dichloromethane via HPLC. The desired fractions were combined and concentrated to give the product as a thick yellow oil (1.2g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=Cc1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N=Cc2cccnc2)cc1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (33 g, 200 mmol), pyridine-3-carbaldehyde (24.0 g, 220 mmol) and p-toluenesulfonic acid (760 mg, 4 mmol) in toluene (600 mL) was heated to reflux for 12 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[(pyridin-3-ylmethylene)-amino]-benzoic acid ethyl ester (51 g, quant.) as a light yellow solid: LC/MS m/e calcd for C15H14N2O2 (M+H)+: 255.29, observed: 255.4.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)[CH3:2].C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCC1.Cl>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=C(O)CC(=O)O
Reactant: CCc1ccc(C=O)cc1
Agent: Cl
Solvent: C1CCNC1
Solvent: c1ccncc1
Product: CCc1ccc(C=CC(=O)O)cc1
Temperature: 0 °C
Yield: 96.5 %

Procedure:
A solution of 4-ethylbenzaldehyde (26.0 g, 0.2 mol), malonic acid (41.6 g, 0.4 mol), pyrrolidine (3 ml), and pyridine (80 ml) was heated in an 85° C. oil bath for 16 hr. The reaction mixture was poured over crushed ice (800 ml), and then made acidic with 12N HCl (100 ml). The white precipitate was filtered, suspended in 1N HCl, and filtered again. The white precipitate was washed with water and air dried to give 4-ethyl cinnamic acid (34.0 g, 96.6).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[N:8]=[C:7]([S:11][CH3:12])[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].[Na].[C:15](Cl)(=[O:17])[CH3:16]>O1CCCC1>[C:15]([N:8]1[C:7]([S:11][CH3:12])=[N:6][C:5](=[O:13])[N:4]([CH:1]([CH3:3])[CH3:2])[C:9]1=[O:10])(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: CSc1nc(=O)n(C(C)C)c(=O)[nH]1
Agent: [Na]
Solvent: C1CCOC1
Product: CSc1nc(=O)n(C(C)C)c(=O)n1C(C)=O

Procedure:
To 9.0 parts sodium 3-isopropyl-6-methylthio-s-triazine-2,4(1H,3H)-dione prepared as in Example 10 in 100 parts tetrahydrofuran can be added 3.1 parts acetyl chloride. The reaction can be refluxed for 5 hours and the solvent evaporated. Methylene chloride can be added to the residue and the solution can be washed with 1N sodium hydroxide and brine. After drying and evaporation of the solvent, the residue can be recrystallized from chlorobutane.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][O:6][CH:5]([CH2:8][OH:9])[O:4][CH2:3]1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][N+:17]([O-:20])=[C:16]([CH3:21])[C:15]=1[CH3:22]>CS(C)=O>[CH3:1][C:2]1([CH3:10])[CH2:7][O:6][CH:5]([CH2:8][O:9][C:14]2[CH:19]=[CH:18][N+:17]([O-:20])=[C:16]([CH3:21])[C:15]=2[CH3:22])[O:4][CH2:3]1
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: CC1(C)COC(CO)OC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(OCC2OCC(C)(C)CO2)cc[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
The (5,5-dimethyl-1,3-dioxan-2-yl)methanol (2 g, 13.7 mmol) obtained in the step (1b) was mixed with sodium hydride in oil (822 mg, 20.6 mmol as the content was regarded as 60%) and dimethylsulfoxide (20 ml). The mixture was stirred at room temperature for 30 minutes. To the reaction mixture, 4-chloro-2,3-dimethylpyridine 1-oxide (2.16 g, 13.7 mmol) was added and stirred at 50° C. overnight, and further allowed to stand still for one day at room temperature. After dimethylsulfoxide was distilled off, methanol and NH silica gel were added to the residue and then methanol was distilled off. The mixture of the reaction mixture and NH silica gel was purified by silica gel column chromatography (NH silica gel: 200 g, elution solvent: ethyl acetate/heptane=1/1 to 4/1→methanol/ethyl acetate=1/9) to obtain the title compound (3.1 g, yield: 84.6%) as a light yellow oil.