Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=O)[CH:11]=[C:10]3[CH3:18])[CH:5]=[CH:4][N:3]=[CH:2]1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:12]1[CH:11]=[C:10]([CH3:18])[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:8]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(=O)[nH]c2ccc(Cn3ccnc3)cc12
Product: Cc1cc(Cl)nc2ccc(Cn3ccnc3)cc12
Yield: 12.5 %

Procedure:
A solution of 13 parts of 6-(1H-imidazol-1-ylmethyl)-4-methyl-2(1H)-quinolinone in 55 parts of phosphoryl chloride was stirred for 1 hour at room temperature. After evaporation, the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.75 parts (12.5%) of 2-chloro-6-(1H-imidazol-1-ylmethyl)-4-methylquinoline; mp. 120.6° C. (compound 34).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[S:6][C:7]([CH:10]=[N:11][OH:12])=[CH:8][N:9]=1.[Cl:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[S:6][C:7]([C:10]([Cl:19])=[N:11][OH:12])=[CH:8][N:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(Oc2ncc(C=NO)s2)c(Cl)c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ncc(C(Cl)=NO)s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
To a solution of Example 30C (12 g, 42 mmol) in N,N-dimethyl formamide (80 mL) was added N-chlorosuccinimide (5.6 g, 42 mmol). The mixture was stirred at ambient temperature for 16 hours, water (1000 mL) was added and the resulting suspension was filtered. The solids were dried in a vacuum oven to provide 12.8 g of the title compound (95%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.82 (s, 3H) 7.04 (dd, J=8.82, 2.94 Hz, 1H) 7.26 (d, J=2.94 Hz, 1H) 7.54 (d, J=9.19 Hz, 1H) 7.66 (s, 1H) 12.48 (s, 1H); MS (ESI) m/z 319.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[C:21]([Cl:36])[C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19]C)=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[C:21]([Cl:36])[C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NCc1cccc(O)c1)c1cc(Cl)c(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A mixture of N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine, methyl ester (2.41 g, 4.4 mmol) in methanol (100 mL) and sodium hydroxide (0.35 g, 8.8 mmol) in water (2 mL) was stirred at room temperature overnight and then the solvents were evaporated. The residue was partitioned between water and ethyl acetate and the ethyl acetate layer was discarded. The aqueous layer was acidified with 1 M HCl, and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, and the product started to precipitate. The solvents were evaporated from the organic layer, and dichloromethane/hexanes was added to the residue. The solid was filtered off, dried overnight under high vacuum, and taken up again in dichloromethane/hexanes. The solid was filtered off, and then dried overnight under high vacuum to give N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine (2.10 g, 89%) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13]3[CH:14](O)[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:6][CH:7]=1.[CH:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24].CP(C)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.CC1CCCO1.ClCCl>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]([C:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc2c(n1Cc1cccc(I)c1)C(O)CCC2
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CP(C)C
Solvent: CC1CCCO1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCCc2nc(C(C)C)n(Cc3cccc(I)c3)c21
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of Intermediate 91 (5.7 g) in Toluene (50 mL) and 2-Methyltetrahydrofuran (2-MeTHF) (50 mL) under nitrogen was added triethyl methanetricarboxylate (6.14 mL) followed by trimethylphosphine (2.54 mL). The reaction mixture was then cooled to −78° C. and DIAD (5.68 mL) was added dropwise over 12 min. The reaction mixture was allowed to continue stirring at −78° C. and under nitrogen for a further 40 min. The reaction mixture was then allowed to warm to room temperature and allowed to stir for a further 2 hours while still under nitrogen. The reaction mixture was then concentrated in vacuo before being partitioned between DCM (50 mL) and water (50 mL). The phases were separated and the aqueous layer was washed with further DCM (2×50 mL). The organic phases were combined, filtered through a hydrophobic frit and concentrated in vacuo to give 19.8 g of crude product as an orange oil. The sample was loaded in dichloromethane and purified on by column chromatography (silica) using a 0-100% ethyl acetate-cyclohexane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product 7.67 g as an off-white solid. LC/MS MH+ 611, Rt 3.54 min (5 min run).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:14]O)[CH:10]([CH3:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH:10]([CH3:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=NO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CCC1N
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a 25° C. solution of 1-benzyl-3-methyl-piperidin-4-one oxime in anhydrous THF (20 mL) was added LAH (1.0 M solution THF), (15 mL, 15 mmol). After being stirred at 50° C. overnight, the resultant mixture was quenched with 20% KOH solution. The aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude mixture ((±)-cis:(±)-trans=1:1) 1-benzyl-3-methyl-piperidin-4-ylamine (1). LCMS m/z: 205 (M+H)+. This material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][CH2:17]O.S(=O)(=O)(O)O>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([O:11][CH2:16][CH3:17])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(C(=O)O)c1ccc(N)c([N+](=O)[O-])c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(C)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To the flask of 2-(4-Amino-3-nitrophenyl)propanoic acid residue was added EtOH (200 mL) and catalytic amounts of sulfuric acid (1 mL) at room temperature. The reaction mixture was refluxed for 6 hrs then cooled to room temperature. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo.
Reaction SMILES: Br[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[CH2:12]([NH:19][CH2:20][CH2:21][C:22]1[CH:36]=[CH:35][C:25]([O:26][C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH3:8][N:6]1[C:5](=[O:9])[N:4]([CH3:10])[C:3](=[O:11])[C:2]([N:19]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:20][CH2:21][C:22]2[CH:36]=[CH:35][C:25]([O:26][C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)=[N:7]1
Reactant: Cn1nc(Br)c(=O)n(C)c1=O
Reactant: CCCCCCCNCCc1ccc(OC(C)(C)C(=O)OCC)cc1
Product: CCCCCCCN(CCc1ccc(OC(C)(C)C(=O)OCC)cc1)c1nn(C)c(=O)n(C)c1=O

Procedure:
Compound 112 (oil) is prepared from triazine 1b and from intermediate 14a according to synthesis method 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:19]([CH3:30])[C:20]([CH2:22][NH:23]C(=O)C(C)(C)C)=[O:21])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C>C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[CH:9]=[CH:10][C:11]1=[N:23][CH2:22][C:20](=[O:21])[N:19]([CH3:30])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]1=2
Reactant: CN(C(=O)CNC(=O)C(C)(C)C)c1ccccc1C(=O)/C=C/c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN1C(=O)CN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
65 mg (0.14 mmol) of (E)-N-[[N-[2-[3-(3,4-dichlorophenyl)acryloyl]phenyl]-N-methylcarbamoyl]methyl]pivalamide were dissolved in 5 ml of ethyl acetate saturated with hydrogen chloride and were stirred at room temperature for 30 minutes. The solvent was removed by evaporation and the residue dissolved in 5 ml of methanol and 40 mg (0.04 mmol) of triethylamine added. After 2 hours at room temperature the solvent was removed by evaporation and the residue chromatographed on silica gel using ethyl acetate/petrol 2:1 for the elution. There was obtained 33 mg of (E)-5-(3,4-dichlorostyryl)-1,3-dihydro-1-methyl-2H-benzo-1,4-diazepin-2-one as a pale yellow foam. MS: m/e 344.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-:10].[Na+].Cl>>[Br:1][C:2]1[C:3]([OH:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: [OH-]
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: Cl
Agent: [Na+]
Product: Oc1nc(Cl)ncc1Br
Temperature: 47.5 °C
Reaction time: 0.83 h

Procedure:
50.5 g of 5-bromo-2,4-dichloropyrimidine is mixed with 133 ml of 2N sodium hydroxide solution and stirred for 50 minutes at 45-50° C. After cooling, it is acidified with 21 ml of concentrated hydrochloric acid while being cooled with ice. The precipitate is suctioned off, washed with water and a little methylene chloride and dried at 25-35° C. 17.12 g (36.9% of theory) of the product with a melting point of 136-145° C. (decomposition) is obtained.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([SH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na]>>[CH:8](/[S:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:7]/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: SCc1ccccc1
Agent: [Na]
Product: C(=C\c1ccccc1)\SCc1ccccc1

Procedure:
A solution of phenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the Procedure 2, part A, to form (Z)-styryl benzylsulfide. The title compound was obtained in 65% yield by oxidation of the sulfide according to the Procedure 2, part B. 1HNMR (CDC13) δ4.50 (2H, s), 6.65 (1H, d, JH,H=11.2), 7.18-7.74 (10H aromatic+1H ethylenic).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]([CH3:17])[CH3:16])([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][N:23]([CH2:25][C:26]([NH:28][CH3:29])=[O:27])[CH:24]=1.C(O)(=O)C>C(O)C>[ClH:1].[C:13]([C@@:10]1([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:21]=[N:22][N:23]([CH2:25][C:26]([NH:28][CH3:29])=[O:27])[CH:24]=3)[N:7]=2)[C:9]1=[O:18])#[N:14]
Reactant: CC(C)[C@]1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Reactant: CNC(=O)Cn1cc(N)cn1
Solvent: CC(=O)O
Solvent: CCO
Product: CNC(=O)Cn1cc(Nc2nccc(N3CC[C@@](C#N)(C(C)C)C3=O)n2)cn1
Product: Cl
Yield: 100 %

Procedure:
A solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-isopropyl-2-oxopyrrolidine-3-carbonitrile (55 mg) obtained in Step A of Example 9, 2-(4-amino-1H-pyrazol-1-yl)-N-methylacetamide (38 mg) and acetic acid (13 μL) in ethanol (2 mL) was stirred in a microwave reactor at 150° C. for 1 hr, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol). To a solution of the residue (83 mg) in ethanol (3 mL) was added 1M hydrochloric acid (220 μL), and the solvent was evaporated under reduced pressure. The residue was recrystallized (diisopropyl ether/ethanol) to give the title compound (87 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[CH:24])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Yield: 6 %

Procedure:
3,4-bis(Benzyloxy)-6-ethynylpyridazine (Intermediate 5; 530 mg, 1.68 mmol) and 2-bromo-5-(trifluoromethyl)pyridine (379 mg, 1.68 mmol) were dissolved in tetrahydrofuran (5 ml) to produce an orange solution. The reaction mixture was purged with nitrogen and then triethylamine (1.40 ml, 10.05 mmol), dichlorobis(triphenylphosphine)palladium(II) (58.8 mg, 0.08 mmol) and copper(I) iodide (31.9 mg, 0.17 mmol) were added before it was subjected to microwave irradiation for 1 hour at 80° C. Upon cooling, the mixture was diluted with ethyl acetate and washed with brine. The organic layer was concentrated in vacuo and the crude residue was then purified by silica chromatography (eluting with 0-50% ethyl acetate in petrol) to yield 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (460 mg, 0.10 mmol, 60% yield).
Reaction SMILES: O[C:2]1(C#C)CC(C)CC(C)(C)C1.[CH3:13][C:14]1([CH3:27])[CH2:19][CH:18](C)[CH2:17][C:16]([C:21](=[O:26])[CH2:22][CH2:23][CH:24]=[CH2:25])=[CH:15]1>>[CH3:27][C:14]1([CH3:13])[CH:19]([CH3:2])[CH2:18][CH:17]=[C:16]([C:21](=[O:26])[CH2:22][CH2:23][CH:24]=[CH2:25])[CH2:15]1
Reactant: C=CCCC(=O)C1=CC(C)(C)CC(C)C1
Reactant: C#CC1(O)CC(C)CC(C)(C)C1
Product: C=CCCC(=O)C1=CCC(C)C(C)(C)C1

Procedure:
1-Hydroxy-1-ethynyl-3,3,5-trimethyl-cyclohexane used as starting material for the following preparation was prepared in accordance with W. Ziegenstein, "Aethinylierung und Alkinylierung", p. 9, Verlag Chemie (1963). The conversion into 1-(3,3,5-trimethyl-cyclohex-1-en-1-yl)-pent-4-en-1-one was performed according to the procedure described in pathway I, paragraph (d). The analytical data were as follows:
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][Cl:20])[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)(C)(C)C.[C@H:30]12[CH2:36][C@H:33]([NH:34][CH2:35]1)[CH2:32][O:31]2>>[ClH:20].[C@H:30]12[CH2:36][C@H:33]([N:34]([CH2:19][CH2:18][O:17][C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[O:10][C:9]([C:21]3[N:26]=[CH:25][N:24]5[CH:27]=[CH:28][CH:29]=[C:23]5[CH:22]=3)=[CH:8][C:7]4=[N:6][OH:5])[CH2:35]1)[CH2:32][O:31]2
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Product: Cl
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCN3C[C@@H]4C[C@H]3CO4)cc12

Procedure:
6-[(1S,4S)-2-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 37% overall yield using the method described in example 87, starting from 6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 87B) and (1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]heptane.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([CH2:15][N:16]([CH3:18])[CH3:17])[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:19])C.[NH3:21]>CO>[CH3:17][N:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][C:7]([CH3:19])=[C:6]([CH2:5][C:4]([NH2:21])=[O:3])[C:10]=2[CH:11]=1)[CH3:18]
Reactant: N
Reactant: CCOC(=O)Cc1c(C)oc2ccc(CN(C)C)cc12
Solvent: CO
Product: Cc1oc2ccc(CN(C)C)cc2c1CC(N)=O
Temperature: 70 °C
Reaction time: 72 h
Yield: 90 %

Procedure:
A solution of (5-dimethylaminomethyl-2-methyl-benzofuran-3-yl)-acetic acid ethyl ester (744 mg, 2.70 mmol) in a mixture of methanol (5 mL) and liquid ammonia (40 mL) is stirred for 3 days in an autoclave at 70° C. After careful evaporation of the ammonia, the remaining solvent is evaporated in vacuo to afford the title compound as beige solid (662 mg, 2.42 mmol, 90%). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=7.48 (bs, 1H), 7.42 (s, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.93 (bs, 1H), 3.45 (s, 2H), 3.38 (s, 2H), 2.38 (s, 3H), 2.15 (s, 6H).MS (ES+): 247 (M(C16H14O4)+H)+.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[N:5]1[C:12]([Cl:13])=[N:11][C:9](Cl)=[N:8][C:6]=1[Cl:7].Cl>C(OCC)C.C1(C)C=CC=CC=1>[Cl:7][C:6]1[N:5]=[C:12]([Cl:13])[N:11]=[C:9]([CH2:1][CH3:2])[N:8]=1
Reactant: CC[Mg]Br
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCc1nc(Cl)nc(Cl)n1
Reaction time: 1 h
Yield: 63 %

Procedure:
1.5 equivalent of ethylmagnesium bromide dissolved in diethyl ether (prepared by reacting magnesium with ethyl bromide) are added dropwise to a suspension of one equivalent of cyanuric chloride in toluene, while keeping the temperature of the reaction mixture between 10° and 15° C. After the addition, this mixture is kept at room temperature for one hour. An aqueous solution containing 1.5 equivalent of hydrochloric acid is then added. The two phases are separated, the organic phase is dried over sodium sulfate, then the solvent is removed under reduced pressure. 2,4-dichloro-6-ethyl-1,3,5-triazine is purified by distillation under reduced pressure. Yield: 63%. B.P.: 83° C./17 mbars.
Reaction SMILES: [C:1](=[S:4])([S-:3])[NH2:2].[NH4+].C(O)(C)C.Cl[CH2:11][C:12](=O)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>O>[CH2:17]([O:16][C:14]([CH2:13][C:12]1[N:2]=[C:1]([SH:3])[S:4][CH:11]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(=S)[S-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)Cc1csc(S)n1
Temperature: 25 °C
Yield: 56.7 %

Procedure:
To 180.0 g (1.63 mols) of ammonium dithiocarbamate was added 1.5 liters of isopropyl alcohol, the mixture was stirred and then 268.9 g (1.63 mols) of ethyl 4-chloro-3-oxobutanoate was added dropwise to the mixture. After stirring the resultant mixture for 3 hours under refluxing, 300 ml of water was added to the reaction mixture, the mixture was cooled to room temperature and crystals formed were collected by filtration under a reduced pressure to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate to obtain 188 g (yield 57%) of 4-ethoxycarbonylmethyl-2-mercaptothiazole.
Reaction SMILES: [N+:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O)([O-:3])=[O:2].O.[NH2:14][NH2:15].C(O)(=O)C>C(O)C>[N+:1]([CH2:4][C:5](=[N:14][NH2:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O-:3])=[O:2]
Reactant: O=C(C[N+](=O)[O-])c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: NN=C(C[N+](=O)[O-])c1ccccc1
Yield: 81.1 %

Procedure:
A solution of 2-nitroacetophenone (12.28 g, 0.074 mol) in ethanol (100 mL) was treated with hydrazine hydrate (10.24 g, 0.163 mol) and glacial acetic acid (4.2 mL, 0.074 mol) and the mixture was heated at reflux for 3 hours. The solvent was then evaporated in vacuo. The residue was dissolved in trichloromethane and extracted three times with water to remove the excess of hydrazine hydrate. Evaporation of the organic layer yielded the product (11 g, 0.06 mol, 81%), which was used in the next step without further purification.
Reaction SMILES: O[C:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[CH:3]=1.C(Br)(=O)C([Br:13])=O>ClCCCl.CN(C=O)C>[Br:13][C:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[CH:3]=1
Reactant: O=C(Br)C(=O)Br
Reactant: CC1(C)OC(=O)C=C1O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)C=C1Br
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 86.2 %

Procedure:
To a solution of 4-hydroxy-5, 5-dimethyl-5H-furan-2-one (2.1 g, 16.4 mmol) in DCE (40 mL) and DMF (1.5 mL) at 0° C. was added dropwise oxalyl bromide (3.0 mL, 32 mmol, 2 equiv). The mixture was stirred at room temperature for 4-5 h, and then put in an ice bath. Ice water (100 mL) was added slowly. The mixture was extracted with CH2Cl2 (100 mL). The organic phase was washed with 10% NaHCO3 and again with water, dried over sodium sulfate and evaporated to give the title compound 2.7 g (86% yield).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH2:25]([CH2:27][NH2:28])[OH:26]>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH:28][CH2:27][CH2:25][OH:26])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C=O)ccc1-2
Reactant: NCCO
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(CNCCO)ccc1-2

Procedure:
Following the procedure for 212, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde and ethanolamine were reacted to give 285 isolated as a pale yellow solid (131 mg, 47%). LCMS: RT=6.85 min, [M+H]+=386. 1H NMR δ (ppm) (CDCl3): 8.31 (1 H, d, J=8.11 Hz), 7.89 (1 H, s), 7.12 (1 H, d, J=8.19 Hz), 7.02 (1 H, s), 5.93-5.82 (1 H, m), 4.37 (2 H, t, J=5.06 Hz), 3.81 (2 H, s), 3.66 (2 H, t, J=5.12 Hz), 3.38 (2 H, t, J=5.06 Hz), 2.81 (2 H, t, J=5.11 Hz), 1.60 (6 H, d, J=6.63 Hz). 2 Exchangeable protons not seen.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8]Br)=[CH:5][CH:4]=1.[OH2:13]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([CH:8]=[O:13])=[O:10])=[CH:5][CH:4]=1
Reactant: O
Reactant: COc1ccc(C(=O)CBr)cc1
Product: COc1ccc(C(=O)C=O)cc1

Procedure:
Dimethylslufoxide (50 ml) solution of 4-methyoxyphenacylbromide (9.94 g, 43.4 mmol) and water (1.6 ml, 88.8 mmol) were stirred at 50° C. for 2.5 hr. Water was added and the solution was extracted with ethyl acetate 3 times and washed with brine and then dried over sodium sulfate. Removal of the solvent gave 4-methoxyphenylglyoxal (8.30 g, quant.).
Reaction SMILES: [OH:1][C:2]([CH2:4][O:5][NH:6][C:7](=[O:26])[CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([Cl:25])=[CH:20][N:19]=2)=[CH:13][CH:12]=1)[CH3:9])=O.[N+](=[CH2:29])=[N-].[CH3:30][OH:31]>>[CH3:30][O:31][C:2]([CH2:4][O:5][N:6]([CH3:29])[C:7](=[O:26])[CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([Cl:25])=[CH:20][N:19]=2)=[CH:13][CH:12]=1)[CH3:9])=[O:1]
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)NOCC(=O)O
Reactant: CO
Reactant: C=[N+]=[N-]
Product: COC(=O)CON(C)C(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Reaction time: 0.17 h

Procedure:
To a solution of N-hydroxycarbonylmethoxy-2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]propionamide (Compound No. 37 as obtained in Example 3) (0.38 g) in methanol (1 ml), there was added an etheral solution of diazomethane until the yellow color remained, and the resultant mixture was allowed to stand for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: 88% hexane :12% ethyl acetate) to give N-methoxycarbonylmethoxy-N-methyl-2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]propionamide (0.35 g). Yield, 86%.