Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].Cl[C:10]1[CH:15]=[CH:14][N+:13]([O-:16])=[C:12]([CH3:17])[C:11]=1[CH3:18]>CS(C)=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:10]1[CH:15]=[CH:14][N+:13]([O-:16])=[C:12]([CH3:17])[C:11]=1[CH3:18]
Reactant: COCCCO
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCCCOc1cc[n+]([O-])c(C)c1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 18.9 %

Procedure:
2.0 g (22 mmol) of 3-methoxypropanol was dissolved in 50 ml of dimethyl sulfoxide to obtain a solution. 2.7 g (66 mmol) of sodium hydride was added to this solution at a room temperature. The obtained mixture was stirred at 60° C. for one hour and cooled to a room temperature by allowing to stand, followed by the addition of 3.0 g (19 mmol) of 4-chloro-2,3-dimethylpyridine N-oxide. The obtained mixture was stirred at 40° C. for one hour. After the completion of the reaction, the reaction mixture was distilled to remove the dimethyl sulfoxide. The obtained residue was purified by silica gel column chromatography to obtain 760 mg of 4-(3-methoxypropoxy)-2,3-dimethylpyridine N-oxide.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][CH2:8][CH:7]2[CH:5]([O:6]2)[CH2:4][O:3]1.O.O.O.O.O.O.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(#N)C>[OH:6][CH:5]1[CH2:4][O:3][C:2]([CH3:1])([CH3:10])[O:9][CH2:8][CH:7]1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CC1(C)OCC2OC2CO1
Reactant: C1CNCCN1
Solvent: O
Solvent: CC#N
Product: CC1(C)OCC(O)C(N2CCNCC2)CO1
Yield: 20.4 %

Procedure:
14.4 g (0.1 mol) of 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (J. Org. Chem. 41, 2469 [1976]) are heated under reflux in 100 ml of acetonitrile with 20 g (0.1 mol) of piperazine hexahydrate for 8 hours and the 1,4-bis-(6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-piperazine precipitated [melting point: 235°-237° (from isopropanol)] is filtered off with suction. The mother liquor is concentrated and the residue is purified by chromatography on 200 g of silica gel with methylene chloride/methanol (9:1) as the mobile phase, the main component being eluted towards the end of the chromatography with methylene chloride/methanol (4:1). 4.7 g of 1-(6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-piperazine are obtained as an oil; Rf value=0.05 (on silica gel; methylene chloride/methanol (9:1)].
Reaction SMILES: [C:1]([N:5]1[C:18](=[O:19])[N:8]2[CH:9]=[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[NH:11][C:12](=O)[C:7]2=[N:6]1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[C:1]([N:5]1[C:18](=[O:19])[N:8]2[CH:9]=[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:11]=[C:12]([Cl:22])[C:7]2=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cn2c(=O)n(C(C)(C)C)nc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1cn2c(=O)n(C(C)(C)C)nc2c(Cl)n1
Reaction time: 16 h

Procedure:
A solution of 5.90 g the product of Step D in phosphoryl chloride (100 mL) was heated to 110° C. After 16 h, the reaction mixture was cooled and the excess phosphoryl chloride was removed by distillation at reduced pressure (15 mm Hg). The residue was dissolved in chloroform and carefully poured onto 200 g of ice. After the ice had melted, the layers were separated and the aqueous was extracted with chloroform. The combined organic layers were washed with sat. sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to yield 2-tert-butyl-8-chloro-6-tert-butyl-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one as a yellow solid. MS (M+H+)=283.3.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25]Br>>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25][N:15]1[CH2:16][C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:20])[CH:12]=2)[C:14]1=[O:19]
Reactant: Clc1ccccc1CCBr
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3ccccc3Cl)C2=O)cn1
Yield: 25 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 2-chlorophenethyl bromide. Yield: 25%. MS M+H calculated 414.13. found 414.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.250M.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[C:6]1([S:12]([C:15]#[N:16])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl([O-])(=O)(=O)=O.[Li+]>>[C:6]1([S:12]([C:15]2[CH:4]=[CH:3][CH:2]=[CH:1][N:16]=2)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: C/C=C/C=O
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: O=S(=O)(c1ccccc1)c1ccccn1
Temperature: 110 °C
Yield: 89.7 %

Procedure:
First, 8.05 g (113 mmol) of crotonaldehyde (2-butenal) and 9.17 g (54.9 mmol) of benzenesulfonyl cyanide were introduced to a 3-necked flask (50 ml volume) equipped with a thermometer, a magnetic stirrer, a Dean-Stark water type distilling receiver, and a condenser tube. Toluene (15 ml) as a solvent and butanol (1.5 ml) were added, and then 589 mg (5.55 mmol) of lithium perchlorate was added. Next, the mixture was heated under reflux for 15 hours while agitating at an internal temperature of 110° C. in a nitrogen atmosphere, and separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystal were dried for 2 hours in vacuo to give 10.8 g of 2-benzenesulfonylpyridine having the following properties as colorless crystals (purity of 99%, yield of 89% based on benzenesulfonyl cyanide).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([N+:13]([O-])=O)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:13][C:12]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: [H][H]
Reactant: COC(=O)c1cnc(OC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(OC)c(N)c1
Yield: 92.7 %

Procedure:
A solution of methyl 6-methoxy-5-nitronicotinate (5.4 g) in ethyl acetate (120 mL) is hydrogenated using 5% palladium on carbon (1 g) as catalyst. When hydrogen uptake ceased the mixture is filtered through a pad of diatomaceous earth and the filtrate evaporated. The residue is triturated with n-pentane and methyl t-butyl ether to give methyl 5-amino-6-methoxynicotinoate (4.3 g) as a light-brown solid, m.p. 108–9° C. [Elemental analysis:—C, 52.99; H, 5.49; N, 15.25%. calculated:—C, 52.74; H, 5.53; N, 15.38%.]
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC)=O.O[N:34]1[C:38](=[O:39])[CH2:37][CH2:36][C:35]1=[O:40]>CN(C)C=O>[CH2:8]([O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][N:34]1[C:38](=[O:39])[CH2:37][CH2:36][C:35]1=[O:40])=[O:25])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCCCCNC(=O)OCc1ccccc1)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
Triethylamine (0.63 ml, 4.52 mmol) is added to a solution of 6-(benzyloxycarbonylamino)hexanoic acid (1.00 g, 3.77 mmol) in dimethylformamide (20 ml) and the mixture is left to stir at ambient temperature and under argon for 30 minutes. The solution is cooled to 0° C. and ethyl chloroformate (0.43 ml, 4.52 mmol) is added dropwise. After two hours at ambient temperature, N-hydroxysuccinimide (0.52 g, 4.52 mmol) is added and the mixture is left to stir overnight at ambient temperature. The mixture is evaporated to dryness before taking up the residue in water to which ethyl acetate is added. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered and evaporated to dryness before purification on a silica gel column with an ethyl acetate/pentane mixture (75/25 v/v) as eluent. The fractions, once evaporated, give 1.13 g of succinimidyl 6(benzyloxycarbonylamino)hexanoate in the form of an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[CH:30]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:47])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][N:21]4[C:30]([Br:47])=[C:31]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:32]=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(-c5ccccc5)cn4cc3-c3ccccc3)cc2)CCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(-c5ccccc5)c(Br)n4cc3-c3ccccc3)cc2)CCC1
Yield: 59.6 %

Procedure:
To a solution of compound 5-2 (110 mg, 0.2 mmol) in CHCl3 (5 mL) was added NBS (40 mg 0.22 mmol.) and the mixture was heated to reflux for 1 hrs. After cooling, the mixture was diluted with 15 mL of DCM, the combined organic phase was washed with 0.1N HClaq and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 71 mg of 5-4.
Reaction SMILES: [Mg].BrCCBr.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10](Br)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.C([Mg]Cl)(C)C.[CH2:26]([O:33][C:34](=[O:45])[NH:35][CH:36]([CH3:44])[CH2:37][C:38](N(OC)C)=[O:39])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([C:38](=[O:39])[CH2:37][CH:36]([NH:35][C:34](=[O:45])[O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:44])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1
Reactant: CON(C)C(=O)CC(C)NC(=O)OCc1ccccc1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(CC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC(=O)OCc1ccccc1
Temperature: 75 °C
Reaction time: 14 h

Procedure:
To a stirred suspension of magnesium turnings (1.55 g; 63.76 mmol) in THF (50 mL) under an atmosphere of N2 was added 1,2-dibromoethane (135 uL). The mixture was heated to 75° C. and 3,5-bis(trifluoromethyl)bromo benzene (4.59 mL; 26.79 mmol) was slowly added to maintain a gentle reflux. The reaction was heated at gentle reflux for 2.5 h and then cooled to room temperature. In a separate flask, isopropyl magnesium chloride (18 mL; 36 mmol) was added dropwise to a stirred solution of benzyl-{3-[methoxy(methyl)amino]-1-methyl-3-oxopropyl}carbamate (Step B; 5 g; 17.86 mmol) in THF (30 mL) at −20° C. The resultant solution was stirred at −20° C. for 40 min prior to dropwise addition of the Grignard solution. The reaction was allowed to warm to room temperature and stirred for 14 h. The reaction was quenched with 1 N HCl (100 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-10% acetone/hexanes gradient) to afford benzyl {3-[3,5-bis(trifluoromethyl)phenyl]-1-methyl-3-oxopropyl}carbamate as a white solid. LCMS=434.2 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.39 (s, 2H), 8.07 (s, 1H), 7.37-7.29 (m, 5H), 5.16-5.04 (m, 3 h), 4.31-4.23 (m, 1H), 4.16-4.10 (m, 1H), 3.19 (dd, J=16.8, 6.5 Hz, 1H), 1.34 (d, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]([OH:13])=[CH:5][CH:4]=1)#[N:2].[ClH:14].[CH3:15][OH:16]>>[ClH:14].[CH3:15][O:16][N:2]=[CH:1][C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]([OH:13])=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc(C#N)ccc1O
Reactant: CO
Agent: Cl
Product: CON=Cc1ccc(O)c(C(=O)OC)c1

Procedure:
In 450 ml of anhydrous methanol, was suspended 44.0 g of methyl 5-cyanosalicylate. While being cooled in ice and stirred, the suspension was saturated with dried gaseous hydrogen chloride. The suspension was further stirred for 2 days at room temperature, then the resulting solution was concentrated to about 200 ml at a low temperature under reduced pressure, and admixed with ethyl acetate to precipitate colorless crystals. The crystals were collected by filtration and dried to obtain 41.0 g of methyl 5-methoxyiminomethylsalicylate hydrochloride.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.[CH3:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]([OH:41])[CH2:34][N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[CH:27][C:25]=2[N:26]=1>CCO>[CH:7]1([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:38]2[CH2:39][CH2:40][N:35]([CH2:34][C@@H:33]([OH:41])[CH2:32][O:31][C:28]3[CH:29]=[CH:30][C:24]4[S:23][C:22]([CH3:21])=[N:26][C:25]=4[CH:27]=3)[CH2:36][CH2:37]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: BrCCCCOC1CCCC1
Reactant: Cc1nc2cc(OCC(O)CN3CCNCC3)ccc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCCCOC4CCCC4)CC3)ccc2s1

Procedure:
A solution of (4-bromobutoxy)cyclopentane (400 mg, 1.81 mmol) in EtOH (5 mL) was treated with DIEA (0.64 mL, 3.62 mmol) and 1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol as prepared in Example 3A (557 mg, 1.81 mmol). The solution was stirred at reflux 15 hours. Upon cooling, the product was concentrated and purified by flash column chromatography (10% MeOH/EtOAc) to yield (2R)-3-[4-(4-cyclopentyloxybutyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[NH:30][C:31](=[NH:36])[CH2:32][CH2:33][O:34][CH3:35]>>[CH3:35][O:34][CH2:33][CH2:32][C:31]1[N:36]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][S:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:30]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: COCCC(=N)NO
Product: COCCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 600 mg (1.43 mmol) of the compound from Example 25A and 232 mg (1.58 mmol) of N-hydroxy-3-methoxypropanimidamide were reacted Yield: 398 mg (53% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30])([O-:25])=[O:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1)=[O:30])([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(NC(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a stirring solution of tert-butyl (3-aminophenyl)carbamate (2.00 g, 9.6 mmol) and triethylamine (1.40 mL, 10 mol) in dry tetrahydrofuran (27.3 mL) at 0° C. was slowly added a solution of 3-nitrobenzoyl chloride (1.87 g, 10.1 mmol) in tetrahydrofuran (7.8 mL). The resulting mixture was slowly warmed up to rt and stirred for one additional hour at rt. The reaction mixture was treated with Na2CO3 (aq). The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as a white powder (3.4 g, 99%). LCMS for C18H19N3O5 (M-tBu+H)+: m/z=302.0. 1H NMR (400 MHz, CD3OD): δ 8.79 (t, J=2.0 Hz, 1H), 8.43 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 8.31 (ddd, J=6.4, 2.4, 1.2 Hz, 1H), 7.87 (t, J=2.1 Hz, 1H), 7.77 (t, J=8.0 Hz, 1H), 7.60 (ddd, J=8.0, 4.0, 2.4, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.19 (d, J=1.2 Hz, 1H), 1.52 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][OH:15]>>[CH3:14][O:15][C:3]([C:2]1[N:11]=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:12][CH3:13])[CH:4]=2)[S:10][C:7]=1[CH3:6])=[O:12]
Reactant: COc1cc(NC(N)=S)ccc1Cl
Reactant: CO
Product: COC(=O)c1nc(Nc2ccc(Cl)c(OC)c2)sc1C
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 8.7 g (40.1 mmol) 1-(4-chloro-3-methoxyphenyl)-thiourea and 7.5 g (0.44 mmol) α-methylchloropyruvate (J. Chem Soc. Perkin 1, 1982, 2, 159) in 140 ml methanol was heated under reflux for 5 h, cooled to room temperature and volatiles were removed. The residue was dissolved in dichloromethane and washed successively with 25% aq. ammonia and water. Water phases were extracted thrice with dichloromethane, the organic phases were pooled, dried with MgSO4 and the solvent removed in vacuo. The residue was purified by chromatography on silica gel with heptane/ethyl acetate (1:2) to give 6.2 g (50%) of the title compound as colorless solid.
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH2:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(CN)OC
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCNCC(OC)OC
Yield: 78.1 %

Procedure:
Hexyl iodide (50 mmol, 7.38 ml) was added to a mixture of 2-amino acetaldehyde dimethyl acetal (100 mmol, 11 ml) and potassium carbonate (50 mmol, 6.9 g) in DMF (10 ml) at 0° C. Stirring was continued for 16h before diluting with ethyl acetate (200 ml), and ffitering the solution through a plug of celite. Concentration in vacuo was follwed by column chromatography (eluant ethyl acetate) to give N-hexyl 2-amino acetaldehyde dimethyl acetal (7.39 g, 78%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH2:10].C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:40]([C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:19]3[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:29][CH:28]=1)[C:32]([CH3:44])=[C:33]2[CH3:43])=[O:41]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCc1ccc(Cl)cc1Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccc(Cl)cc3Cl)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (2,4-dichlorophenyl)methanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 557/559 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[C:22]([N:29]1[CH2:32][CH:31]([CH:33]=[O:34])[CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH:33]([CH:31]4[CH2:32][N:29]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:30]4)[OH:34])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Product: COC(=O)c1nc2n(c1C(O)C1CN(C(=O)OC(C)(C)C)C1)C1CC(C1)c1cc(F)c(Br)cc1-2
Yield: 63 %

Procedure:
Methyl 10-bromo-3-((1-(tert-butoxycarbonyl)azetidin-3-yl)(hydroxy)methyl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was prepared similarly according to the procedure in Example 9. Methyl 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with 1-boc-3-azetidinecarboxaldehyde to afford 479 mg (63% yield) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:16][C:15]3=[CH:17][NH:18][C:13]4[C:14]3=[C:9]([CH:10]=[CH:11][N:12]=4)[C:8]2=[O:19])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:27]([CH2:29][C:30](ON1C(=O)CCC1=O)=[O:31])#[N:28]>CCO>[O:31]=[C:30]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH2:16][C:15]3=[CH:17][NH:18][C:13]4[C:14]3=[C:9]([CH:10]=[CH:11][N:12]=4)[C:8]2=[O:19])[CH2:5][CH2:6]1)[CH2:29][C:27]#[N:28]
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Reactant: O=C1c2ccnc3[nH]cc(c23)CN1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#CCC(=O)N1CCC(N2Cc3c[nH]c4nccc(c34)C2=O)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23.3 %

Procedure:
4-(Piperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one (34 mg, 0.133 mmol) and triethylamine (0.055 mL, 0.398 mmol) were dissolved in EtOH (4 mL) and cooled to 0° C. and allowed to stir for 10 min. Then 2,5-dioxopyrrolidin-1-yl 2-cyanoacetate (29 mg, 0.159 mmol) dissolved in EtOH (1 mL) was added dropwise and the mixture was allowed to stir for 30 min at 0° C. The solution was concentrated in vacuo and purified via preparative HPLC eluting with 10% to 40% B in A and gave 10 mg of the title compound as its TFA salt. 1H NMR (400 MHz, CD3OD) δ 7.60 (m, 1H), 7.43 (m, 1H), 4.98 (s, 2H), 4.84-4.88 (m, 1H), 4.68-4.72 (m, 1H), 3.89-3.95 (m, 3H), 3.33 (m, 1H), 2.80-2.88 (m, 1H), 1.86-2.05 (m, 4H). [M+H] found 324.
Reaction SMILES: C([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25]/[CH:26]=[CH:27]/[C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[CH:29]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.Cl>CO>[NH:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25]/[CH:26]=[CH:27]/[C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)[CH:29]=1
Reactant: COC(=O)c1ccc(/C=C/Cc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(F)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(/C=C/Cc2ncc[nH]2)cc1-c1ccc(F)cc1
Yield: 63 %

Procedure:
A solution of methyl 4-[(E)-3-(1-tritylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate (5.78 g; 6.5 mmol), acetic acid (5 ml) and 12N HCl (5 ml) in methanol (100 ml) was refluxed for 1 hour 30 minutes. After evaporation to dryness, the residue was neutralised with aqueous NH4 OH, extracted with dichloromethane, evaporated and purified by flash chromatography, eluting with dichloromethane/ethanol (98/2) to give methyl 4-[(E)-3-(imidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate. Yield: 63%
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:33]1C(N)=C2C(C=C(Br)C=C2)=N1)C1C=CC=CC=1>>[CH2:1]([N:8]1[C:16]([NH2:33])=[C:15]2[C:10]([CH:11]=[C:12]([B:17]3[O:18][C:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[O:21]3)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1c2ccc(Br)cc2nn1Cc1ccccc1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Product: CC1(C)OB(c2ccc3c(N)n(Cc4ccccc4)nc3c2)OC1(C)C

Procedure:
This compound was prepared in a manner similar to the procedure described for the preparation of 2-benzyl-6-(4,4,5,5-tetramethyl-{1,3,2]dioxaborolan-2-yl)-2H-indazole (Intermediate C, step 2), using 2-benzyl-6-bromo-2H-indazol-3-ylamine in place of 2-benzyl-6-bromo-2H-indazole. 1H-NMR (300 MHz, CD2Cl2) 7.95 (s, 1H), 7.44 (dd, 1H), 7.63 to 7.29 (m, 3H), 7.29 to 7.17 (m, 3H), 5.51 (s, 2H), 3.88 (broad s, 2H), 1.36 (s, 12H).