Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13](=[O:19])[C:14](=O)[CH:15](Br)[CH3:16])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:8][C:7]1[C:2]2[N:3]([C:15]([CH3:16])=[C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:19])[N:1]=2)[CH:4]=[C:5]([CH3:9])[CH:6]=1
Reactant: CCOC(=O)C(=O)C(C)Br
Reactant: Cc1cnc(N)c(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc2c(N)cc(C)cn2c1C
Yield: 29.3 %

Procedure:
A solution of 2,3-diamino-5-methyl-pyridine (2.3 g, 19 mmol) and 3-bromo-2-oxo-butyric acid ethyl ester (4.3 g, 21 mmol) in ethanol (25 ml) was refluxed for 20 h. Sodium carbonate (2.6 g, 25 mmol) was added and the mixture was filtrated and the solids were washed with ethanol. The filtrate and washings were combined and evaporated under reduced pressure. The residue was dissolved in methylene chloride, washed twice with a sodium carbonate solution and twice with water. The organic layer was separated dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using methylene chloride:methanol (9:1) as eluent gave 1.3 g (30%) of the title compound as an oil.
Reaction SMILES: [CH3:1][S:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[N:14]=2)=[CH:10][CH:9]=1)=[O:3].[O-]O.S(=O)(O)[O-:33].[Na+].[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][S:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[N:14]=2)=[CH:10][CH:9]=1)(=[O:33])=[O:3]
Reactant: CS(=O)CCCCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1
Reactant: O=S([O-])O
Agent: [Na+]
Agent: [O-]O
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC(Nc2nccc(-c3ccc(CCCCS(C)(=O)=O)s3)n2)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound of Step D (192 mg, 0.43 mmol) was dissolved in 5 ml TFA and 3 ml DCM. At room temperature 22 mg (0.64 mmol) hydroperoxide 30% were added. This mixture was stirred at room temperature for 4 hours. Afterwards 10 ml 10% sodium bisulfite solution was added and stirring continued for 15 minutes. The solution was basified with 40% NaOH and extracted with EtOAc. The crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:9/1/0.1). Yield: 75 mg (37%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[C@H:10]([O:16][CH2:17][O:18][CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:22]([C:26]1[N:27]=[N:28][C:29](Cl)=[CH:30][C:31]=1[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:34][CH:33]=1)[CH2:23][CH2:24][CH3:25].O>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:29]2[N:28]=[N:27][C:26]([CH2:22][CH2:23][CH2:24][CH3:25])=[C:31]([C:32]3[CH:33]=[CH:34][C:35]([O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:36][CH:37]=3)[CH:30]=2)[C@H:10]([O:16][CH2:17][O:18][CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1CO
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nnc(OC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OCOC)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 44.3 %

Procedure:
To a stirred solution of (±)-cis-4-hydroxymethyl-3-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (4.64 mmol, 1.28 g) in DMF (5 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (13.9 mmol, 0.56 g) and continued stirring for 15 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 2.32 mmol, 0.80 g) in DMF (5 mL). After completion of addition, the reaction mixture was warmed to 50° C. for 2 hours. After cooling to room temperature, the reaction was poured into a mixture of water (100 mL) and ethyl acetate (100 mL). The mixture was shaken and separated. The ethyl acetate layer was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 40 g SiO2 cartridge using a gradient of ethyl acetate/hexanes to provide (±)-cis-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-3-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (0.60 g, 44%). LCMS: m/z 583.9 [M+1].
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=2)[CH:11]=1.[Li+].[OH-]>C1COCC1.CO.O>[F:21][C:2]([F:1])([F:20])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=2)[CH:11]=1
Reactant: CCOC(=O)c1cnc2ccc(COCC(F)(F)F)cn12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc2ccc(COCC(F)(F)F)cn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 6-((2,2,2-trifluoroethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (97) (280 mg, 0.92 mmol) in THF/MeOH/H2O (3:2:1, 5 mL) was treated with 6N LiOH (0.92 mL, 5.52 mmol) and stirred at room temperature for 1 hour. All solvents were removed and 6N HCl was added to adjust pH 5-6. Then the mixture was purified by HPLC to give 6-((2,2,2-trifluoroethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid (98). 1H NMR (400 MHz, d6-DMSO) δ 9.34 (m, 1H), 8.40 (s, 1H), 7.88 (dd, J=0.8, 9.2 Hz, 1H), 7.65 (dd, J=1.6, 9.2 Hz, 1H), 4.83 (s, 2H), 4.18 (q, J=9.6 Hz, 2H). MS m/z 275.1 (M+1)+.
Reaction SMILES: [O:1]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:14]=1[O:21][CH3:22])[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[I-:23].[CH3:24][N+:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[CH3:35].C([O-])(=O)C.[NH4+].C(Cl)(Cl)Cl.CO>C(O)C>[I-:23].[C@@H:2]1([O:1][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:35][C:26]3[CH:27]=[CH:28][C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[N+:25]=3[CH3:24])=[CH:15][C:14]=2[O:21][CH3:22])[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: COc1cc(C=O)ccc1O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: Cc1ccc2ccccc2[n+]1C
Agent: CC(=O)[O-]
Agent: [I-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCO
Product: COc1cc(C=Cc2ccc3ccccc3[n+]2C)ccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 74.4 %

Procedure:
A stirred suspension of 4-formyl-2-methoxyphenyl β-D-galactopyranoside (1c)(0.12 g, 0.37 mmol), 1,2-dimethylquinolinium iodide (0.10 g, 0.37 mmol) and ammonium acetate (0.06 g, 0.8 mmol) in ethanol (10 ml) was heated under reflux to give a heterogeneous mixture which soon turned orange. After 1 h, t.l.c. (chloroform-methanol 5:4) indicated that the aldehyde had been fully converted into an almost non-mobile orange product. The solution was cooled, filtered and the collected material was washed thoroughly with ethanol to give (21c)(0.16 g, 72%) as an orange crystalline solid, m.p. 225° C., [α]D -18° (c1, DMSO).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]=[CH:3]1.C(O)(=O)C.[I:20]N1C(=O)CCC1=O>O>[I:20][C:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]=1
Reactant: COC(=O)c1ccc2[nH]ccc(=O)c2c1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2[nH]cc(I)c(=O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 111.9 %

Procedure:
To a mixture of methyl 4-oxo-1,4-dihydroquinoline-6-carboxylate (1.1 g) and acetic acid (30 mL) was added N-iodosuccinimide (1.1 g), followed by stirring at room temperature for one day. The reaction mixture was diluted with water, and the precipitate was collected by filtration to obtain methyl 3-iodo-4-oxo-1,4-dihydroquinoline-6-carboxylate (1.8 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:7]=1.[N+:19]([O-])([O-:21])=[O:20].[K+]>S(=O)(=O)(O)O>[N+:19]([C:7]1[C:2]([OH:1])=[C:3]([O:17][CH3:18])[CH:4]=[C:5]([N+:14]([O-:16])=[O:15])[C:6]=1[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])([O-:21])=[O:20]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1cc([N+](=O)[O-])c(CCCC(=O)O)cc1O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1cc([N+](=O)[O-])c(CCCC(=O)O)c([N+](=O)[O-])c1O
Temperature: -15 °C

Procedure:
The product from Example 1 (0.77 g) was dissolved in concentrated sulfuric acid and cooled to -15° C. Potassium nitrate (0.31 g) was gradually added to this solution while maintaining the reaction temperature between -15 and -10° C. The resultant mixture was stirred at -15° C. for half an hour and then poured into ice. The solid was washed with water and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[CH2:4][O:5][CH3:6].O.[S-2].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(O)C.O>[CH3:6][O:5][CH2:4][C:3]1[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=1[CH3:1])[NH2:11]
Reactant: COCc1cc([N+](=O)[O-])ccc1C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Product: COCc1cc(N)ccc1C
Yield: 96.9 %

Procedure:
Methyl 2-methyl-5-nitrobenzyl ether (11.5 g) is dissolved in absolute ethanol (125 ml). A solution of sodium sulfide monohydrate (48.3 g) and sodium bicarbonate (16.7 g) in water (75 ml) is added to the alcoholic solution. The resulting mixture is refluxed until thin layer chromatography indicates that the starting material is exhausted. The reaction mixture is then concentrated under vacuum to an oily solid. Methylene chloride is added and the mixture filtered. The methylene chloride layer is separated, dried, and is concentrated under vacuum to yield 9.3 g of a mobile orange liquid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:12][O:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([Sn](C)(C)C)[CH:19]=2)=[CH:2]1.Br[C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42](=[O:43])[NH:41][C:39](=[O:40])[C:38]=12.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:40]=[C:39]1[C:38]2[C:37](=[CH:36][C:35]([C:18]3[CH:19]=[C:14]([O:13][CH2:12][C@@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:10][C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)[CH:15]=[N:16][CH:17]=3)=[CH:34][CH:33]=2)[C:42](=[O:43])[NH:41]1
Reactant: O=C1NC(=O)c2c(Br)cccc21
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cncc([Sn](C)(C)C)c1)Cc1c[nH]c2ccccc12
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COc1cncc(-c2ccc3c(c2)C(=O)NC3=O)c1)Cc1c[nH]c2ccccc12
Temperature: 75 °C
Yield: 73 %

Procedure:
A solution of Example 32A (0.2 g, 0.31 mmol) and 6-bromophthalimide (0.084 g, 0.4 mmol) in DMF (2 mL) was treated with Pd2dba3 (0.04 g, 0.02 mmol), tri-o-tolylphosphine (0.02 g, 0.01 mmol), and triethylamine (0.06 mL, 0.4 mmol). The reaction was heated to 75° C. for 6 hours in a sealed tube and concentrated. The residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide the desired product (0.116 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]=[O:13].O.Cl>CS(C)=O.C(O)C.[OH-].[K+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:12][OH:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: C=O
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1CCO
Temperature: 25 °C
Reaction time: 144 h
Yield: 62.5 %

Procedure:
To a solution of 4-chloro-1-methyl-2-nitro-benzene (171.6 g, 0.5 mole) in DMSO (150 mL) was added paraformaldehyde (30.0 g, 1.0 mole), followed by potassium hydroxide (1.5 g, 0.027 mol) in ethanol (10 mL). The resulting reaction mixture was stirred at room temperature for six days and water (2 L) was added and the mixture neutralized with hydrochloric acid (2 N). The mixture was extracted with ethyl ether (2×1 L) and the combined organic layers were washed with water (1 L), saturated sodium chloride (1 L), dried (sodium sulfate) and concentrated to a yellow solid. Purification by flash column chromatography (silica gel, methylene chloride:hexanes 1:2) provided 63.0 g of the title compound as a yellow solid. 1H NMR (DMSO-d6): 7.90 δ (s, 1H); 7.50 δ (d, 1H); 7.36 δ (d, 1H); 3.90 δ (t, 2H); 3.15 δ (t, 2H); 1.50 δ (broad, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]#[N:14])[C:8](=[O:12])[NH:9][C:10]=1[CH3:11])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CN(C)C=O>[NH2:18][C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([C:13]#[N:14])[C:8](=[O:12])[NH:9][C:10]=2[CH3:11])[N:15]=1
Reactant: Cc1[nH]c(=O)c(C#N)cc1C(=O)CBr
Reactant: NC(N)=S
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
A mixture containing 25.4 g of 5-bromoacetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile, 7.9 g of thiourea and 100 ml of dimethylformamide was heated on a steam bath for 3 hours and then evaporated to dryness. The residual material was diluted with 100 ml of water followed by the addition of 10 ml of concentrated aqueous ammonium hydroxide. The resulting mixture was reacidified with acetic acid and the solid that separated was collected, washed with water and dried. The solid (15.8 g) was suspended in 400 ml of water and the mixture treated with 25 ml of concentrated ammonium hydroxide. The resulting mixture was stirred for 30 minutes and a small quantity of insoluble material was filtered off. The filtrate was concentrated on a rotary evaporator to a volume of about 200 ml and allowed to cool to room temperature. The crystalline precipitate was collected, washed with distilled water and dried in a vacuum oven at 90° C. to produce 7.3 g of 5-(2-amino-4-thiazolyl)-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile, m.p. 294°-296° C. with decomposition.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[N:11]([CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:10][C:9](=[O:20])[NH:8][C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([C:35]([OH:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[OH:38][C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:2]2[N:3]=[C:4]3[N:11]([CH2:12][CH2:13][CH:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:10][C:9](=[O:20])[NH:8][C:5]3=[N:6][CH:7]=2)=[CH:30][CH:31]=1)([CH3:37])[CH3:36]
Reactant: CC(C)(O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C1CN(CCC2CCOCC2)c2nc(Br)cnc2N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)c1ccc(-c2cnc3c(n2)N(CCC2CCOCC2)CC(=O)N3)cc1
Temperature: 120 °C
Yield: 25.9 %

Procedure:
6-Bromo-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.250 g, 0.733 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (0.192 g, 0.733 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane (0.030 g, 0.037 mmol) were combined in dimethylformamide (1.0 mL). Sodium carbonate (0.311 g, 2.93 mmol) in water (0.2 mL) was added and the reaction solution was then heated in a Biotage Emrys Optimizer microwave reactor at 120° C. for 15 min. The cooled reaction solution was filtered through Celite and the filter cake was washed with ethyl acetate. Filtrate and ethyl acetate wash were combined and solvent removed under reduced pressure. The resulting material was purified using Biotage column chromatography (0-5% methanol in ethyl acetate) followed by trituration with dimethylformamide and water to afford the title compound (0.074 g, 0.19 mmol, 25%) 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.24 (s, 1H), 7.98 (s, 1H), 7.89 (d, J=8.39 Hz, 2H), 7.53 (d, J=8.39 Hz, 1H), 5.04 (s, 1H), 4.16 (s, 1H), 3.82 (dd, J=11.1, 2.39 Hz, 2H), 3.61 (t, J=7.59 Hz, 2H), 3.25 (t, J=9.59 Hz, 3H), 1.70 (s, 1H), 1.66 (s, 1H), 1.58 (m, 3H), 1.44 (s, 6H), 1.25 (m, 2H); MS (ESI) m/z 397.2 [M+1]+; mp 210-212° C.
Reaction SMILES: [CH2:1]([S:3]([C:5]1[O:6][C:7]2[C:12]([C:13](=[O:17])[C:14]=1[CH2:15][OH:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH3:2].[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.O>ClCCl.C(OCC)(=O)C>[CH2:1]([S:3]([C:5]1[O:6][C:7]2[C:12]([C:13](=[O:17])[C:14]=1[CH2:15][O:16][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][O:18]1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH3:2]
Reactant: CCS(=O)c1oc2ccccc2c(=O)c1CO
Reactant: C1=COCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCS(=O)c1oc2ccccc2c(=O)c1COC1CCCCO1
Reaction time: 3 h

Procedure:
To 2-ethylsulfinyl-3-hydroxymethyl chromen-4-one (5 g, 19.8 mmol) dissolved in dichloromethane (20 mL) in a 25 mL round bottom flask is added dihydropyran (29.7 mmol) and toluenesulfonic acid (0.99 mol). The reaction mixture is stirred for 3 hours after which it is poured into a separatory funnel and water is added. Ethyl acetate is then added and the layers are separated. The organic layer is washed with water (3×10) and brine and dried over sodium sulfate and filtered. The filtrate is concentrated in vacuo and the residue obtained is purified by silica gel flash chromatography (ethyl ether:hexanes) to yield the above product.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20](OS(C(F)(F)F)(=O)=O)[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCOB1[C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1.C(=O)([O-])O.[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([C:7]2[C:8]3[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([C:43]4[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=4)[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(OS(=O)(=O)C(F)(F)F)cccc1-3
Reactant: c1cncc(B2OCCCO2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(-c2cccnc2)cccc1-3
Temperature: 90 °C
Yield: 82 %

Procedure:
To a suspension of methyl 12-cyclohexyl-4-trifluoromethanesulfonyloxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (130 mg, 0.248 mmol), 3-(1,3,2-dioxaborinan-2-yl)pyridine (53 mg, 0.323 mmol) and sodium hydrogen carbonate (62 mg, 0.744 mmol) in 1,2-dimethoxyethane (2 ml) and water (0.75 ml) was added tetrakis(triphenylphosphine)palladium (16 mg, 0.014 mmol), and the mixture was heated at 90° C. for 3 hr. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2) to give methyl 12-cyclohexyl-4-(pyridin-3-yl)-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (92 mg, yield 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1>>[ClH:22].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:23]2[CH:24]=[C:25]([CH2:29][N:30]3[CH:34]=[CH:33][N:32]=[C:31]3[CH3:35])[N:26]=[N:27][CH:28]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(F)(F)F)c1
Product: COc1cc(-c2cnnc(Cn3ccnc3C)c2)cc(C(F)(F)F)c1
Product: Cl

Procedure:
The title compound, MS: m/e=349.4 (M+H+), was prepared from 2-(3-methoxy-5-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: Cl.C[O:3][C:4](=[O:8])[CH:5]([CH3:7])[NH2:6].[C:9](Cl)(=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O.[OH-].[Na+]>C(Cl)Cl>[C:9]([NH:6][CH:5]([CH3:7])[C:4]([OH:3])=[O:8])(=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)C(C)N
Reactant: CCCCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCCCCCC(=O)NC(C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
30 g (291 mmol) of D,L-alanine methyl ester hydrochloride and 64.77 g (640 mmol) of triethyl)amine are initially charged in 300 ml of dry methylene chloride at 0° C. 43.24 g (291 mmol) of heptanoyl chloride in 50 ml of methylene chloride are added dropwise. The mixture is allowed to warm to RT and stirred at this temperature for 2 h. The precipitate is filtered off and the methylene chloride phase is extracted with saturated sodium bicarbonate solution and wraith saturated sodium chloride solution and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is dissolved in 300 ml of methanol. 300 ml of water, in which 46.55 g (1164 mmol) sodium hydroxide are dissolved, are added to this solution, and the mixture is stirred at RT for 2 h. The mixture is filtered, the methanol is evaporated using a rotary evaporator and the aqueous phase that remains is acidified to pH 1–2 using conc. Hcl. The precipitated product is filtered off and dried. Extraction of the aqueous phase with ethyl acetate gives a second product fraction.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH:8](O)[CH3:9])[CH:2]([CH3:4])[CH3:3].O=S(Cl)[Cl:13]>>[ClH:13].[CH2:1]([NH:5][CH2:6][CH2:7][CH:8]([Cl:13])[CH3:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNCCC(C)O
Reactant: O=S(Cl)Cl
Product: CC(C)CNCCC(C)Cl
Product: Cl

Procedure:
4-Aminobutanol was reacted with butyraldehyde according to Method B9a, Step 1 to afford 2-isopropyltetrahydro,1,3-oxazepine. The 1,3-oxazepine was reduced according to Method B9a, Step 2 to give N-isobutyl-3-hydroxybutylamine. The 3-hydroxybutylamine was reacted with SOCl2 according to Method B9a, Step 3 to give N-isobutyl-3-chlorobutylamine HCl salt. The 3-chlorobutylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyltetrahydro-1,3-thiazepine.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([CH2:13][C:14]([NH2:16])=[NH:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])C.O.[NH2:18]N.[C:20]([NH:23][CH:24]([CH3:32])[C:25](=O)[C:26](OCC)=[O:27])(=[O:22])[CH3:21]>>[CH3:2][O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:13][C:14]1[NH:16][C:26](=[O:27])[C:25]([CH:24]([NH:23][C:20](=[O:22])[CH3:21])[CH3:32])=[N:18][N:15]=1
Reactant: CCOC(=O)C(=O)C(C)NC(C)=O
Reactant: CCOc1cc(CC(=N)N)ccc1OC
Reactant: NN
Agent: Cl
Solvent: O
Product: COc1ccc(Cc2nnc(C(C)NC(C)=O)c(=O)[nH]2)cc1OC

Procedure:
Analogously to Example 10A, 979 mg (4.00 mmol) of 2-(3-ethoxy-4-methoxyphenyl)ethanamidine hydrochloride are reacted with 200 mg (4.00 mmol) of hydrazine hydrate and 1.12 g (6.00 mmol) of ethyl 3-(acetylamino)-2-oxobutanoate to give N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}acetamide.