Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][NH2:25]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:25][CH2:24][CH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH3:15])#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: COc1ccccc1CCN
Solvent: CO
Product: COc1ccccc1CCN=C(NC#N)c1cccnc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.2 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 2-(2-methoxyphenyl)ethylamine (0.44 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform methanol (100:1). The eluted fractions were concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from chloroform-hexane to give the title compound (0.50 g, 1.8 mmol, yield: 68%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([OH:17])=O)[C:12]=2[CH3:14])[S:7](=[O:19])(=[O:18])[CH2:6][CH2:5]1.[CH2:20]([N:22]1[C:26]([OH:27])=[CH:25][CH:24]=[N:23]1)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C>[CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([C:25]3[CH:24]=[N:23][N:22]([CH2:20][CH3:21])[C:26]=3[OH:27])=[O:17])[C:12]=2[CH3:14])[S:7](=[O:19])(=[O:18])[CH2:6][CH2:5]1
Reactant: CCn1nccc1O
Reactant: CON=C1CCS(=O)(=O)c2ccc(C(=O)O)c(C)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(=NOC)CCS3(=O)=O)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
0.9 Gram (3.2 mmol) of the 4-methoxyimino-5-methylthiochroman-6-carboxylic acid-1,1-dioxide and 0.44 g (3.9 mmol) of 1-ethyl-5-hydroxypyrazol were dissolved in 5 ml of t-amyl alcohol, and 0.81 g (3.9 mmol) of DCC(dicyclohexyl-carbodiimide) was added at room temperature. The mixture was stirred at room temperature for 2 hours, then, 0.74 g (5.4 mmol) of potassium carbonate was added, and the mixture was allowed to react at 90° C. for 8 hours. After the reaction, the solvent was distilled off, ethyl acetate was added, and the mixture was extracted with a 5% potassium carbonate aqueous solution. An aqueous layer was neutralized with concentrated hydrochloric acid, and extracted with ethyl acetate. The extract was washed with a saturated sodium hydroxide aqueous solution, dried over sodium sulfate and concentrated to give 0.88 g (yield 72%) of 4-methoxyimino-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl) carbonylthiochroman-1,1-dioxide.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[N:7][N:8]=[CH:9]2)([O-])=O.O.NN>C(O)C.C1COCC1.[Ni].O>[CH:9]1[C:10]2[C:5](=[C:4]([NH2:1])[CH:13]=[CH:12][CH:11]=2)[CH:6]=[N:7][N:8]=1
Reactant: O=[N+]([O-])c1cccc2cnncc12
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cccc2cnncc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.8 %

Procedure:
A reaction vessel was charged with the 5-nitrophthalazine (1.9 g, 10.9 mmol) prepared above, dissolved in a mixture of 60 mL of ethanol:THF (5:1). Hydrazine hydrate (2.5 g, 25 mmol) was added to the reaction mixture followed by a catalytic amount of Raney nickel as a slurry in water. The reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was then passed through a pad of silica gel/celite which was washed with ethanol. The ethanol fractions were combined and evaporated to yield 1.2 g (79%) of the title compound of formula (Z).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:10])=[C:6](N)[C:7]=1[Cl:8].C(N=C=S)(C)C.[CH:17]1([N:23]=[C:24]=[N:25]C2CCCCC2)[CH2:22]CCC[CH2:18]1.C1(C)C=CC=CC=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:10][C:24]([NH:23][CH:17]([CH3:22])[CH3:18])=[N:25][C:4]=2[CH:3]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Nc1ccc(Cl)c(Cl)c1N
Agent: CC(C)N=C=S
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 80 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
5,6-Dichloro-1,2-phenylenediamine (0.61 g, 3.4 mmol), and isopropyl isothiocyanate (0.39 g, 3.8 mmo) were combined in anhydrous pyridine (10 mL) and were heated to 80° C. for 15 min. Dicyclohexylcarbodiimide (1.06 g, 5.14 mmol) was then added and the resulting mixture was allowed to stir at 100° C. for 5 h. Toluene (30 mL) was added and the mixture was concentrated by rotary evaporation leaving a brown residue. The product was flilrer purified by silica gel chromatography using 6.5:3:0.5 ethyl acetatelhexane/triethylamine to afford a gummy solid which was recrystallised from acetonitrile to give 0.46 g (60%) of a tan solid; m.p. 218-220° C. Anal. Calcd for C10H11Cl2N3 : C, 49.20; H, 4.54; N, 17.21. Found: C. 49.31; H, 4.59; N, 17.33.
Reaction SMILES: [CH2:1]([N:3]([Si](C)(C)C)[CH2:4][CH3:5])[CH3:2].[F:10][C:11]([F:17])([F:16])[S:12]([O-:15])(=[O:14])=[O:13].[CH3:18][NH+:19]1[CH2:23][CH2:22][N:21]([CH3:24])[CH:20]1Cl>C(Cl)(Cl)Cl>[F:10][C:11]([F:17])([F:16])[S:12]([O-:15])(=[O:14])=[O:13].[CH3:18][NH+:19]1[CH2:23][CH2:22][N:21]([CH3:24])[CH:20]1[N:3]([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: CN1CC[NH+](C)C1Cl
Reactant: CCN(CC)[Si](C)(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCN(CC)C1N(C)CC[NH+]1C
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
0.62 g (4.27 mmol) of N,N-diethyltrimethylsilylamine are added over the course of a few minutes at room temperature with stirring to 1.0 g (3.54 mmol) of 1,3-dimethyl-2-chloroimidazolidinium trifluoromethanesulfonate in 15 ml of chloroform. The reaction mixture is stirred for 30 minutes at room temperature and for 30 minutes at 40-50° C. The volatile constituents are distilled off, and the residue obtained is dried at 50° C. under reduced pressure (7.0 Pa), giving 1.11 g of 1,3-dimethyl-2-diethylaminoimidazolidinium trifluoromethanesulfonate as an oil, corresponding to a yield of 98.2%.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])C.[OH-].[Na+]>CO>[CH3:17][CH:16]([CH3:18])[CH2:15][CH2:14][N:7]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cn1CCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCn1cc([N+](=O)[O-])cc1C(=O)O
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 100.7 %

Procedure:
1-(3-Methyl-butyl)-4-nitro-1H-pyrrole-2-carboxylic acid ethyl ester (1.44 g) was dissolved in 50 ml of methanol and 25 ml of 20% aqueous NaOH was added. The reaction mixture was stirred at 50° C. for 1.5 h until there was no starting material checked by TLC. The reaction mixture was concentrated to about 20 ml, 200 ml of water was added. The resulting solution was neutralized with 5 M hydrochloric acid to pH 2 and the precipitates formed were collected by filtration, washed with water and dried to give 1-(3-methyl-butyl)-4-nitro-1H-pyrrole-2-carboxylic acid (1.29 g, 99%). 1H NMR (DMSO-d6) δ13.12 (br. s, 1H), 8.27 (d, 1H), 7.26 (d, 1H), 4.36 (t, 2H), 1.59 (dd, 2H), 1.50 (dt, 11H), 0.88 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:25]=[C:5]2[NH:6][C:7]([CH3:24])=[C:8]([C:22]#[N:23])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=3[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]2[N:3]=1.[C:26]1(=O)[O:31][C:29](=[O:30])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.C(N(CC)CC)C>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[N:4]3[N:3]=[C:2]([N:1]4[C:29](=[O:30])[C:28]5[C:27](=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:26]4=[O:31])[N:25]=[C:5]3[NH:6][C:7]([CH3:24])=[C:8]2[C:22]#[N:23])=[C:11]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:12]=1)#[N:17]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC1=C(C#N)C(c2ccc(C#N)cc2S(C)(=O)=O)n2nc(N)nc2N1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1=C(C#N)C(c2ccc(C#N)cc2S(C)(=O)=O)n2nc(N3C(=O)c4ccccc4C3=O)nc2N1

Procedure:
Under argon, (rac)-2-amino-7-[4-cyano-2-(methylsulfonyl)phenyl]-5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (60 mg, 0.17 mmol) together with phthalic anhydride (50.02 mg, 0.34 mmol, 2.0 eq.) was suspended in a mixture of toluene (4 ml) and pyridine (2 ml), triethylamine (4.7 μl, 0.034 mmol, 0.2 eq.) was added and the mixture was heated under reflux for 2 h. The reaction mixture was then concentrated under reduced pressure. From the residue, the product was precipitated by addition of ethanol (2 ml) in an ultrasonic bath. The precipitate was filtered off and dried under high vacuum. This gave 67 mg (75.6% of theory) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.Cl[C:35]([CH2:37][O:38]C(=O)C)=[O:36]>>[OH:38][CH2:37][C:35]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)=[O:36]
Reactant: CC(=O)OCC(=O)Cl
Reactant: O=C(NCC1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: O=C(NCC1CCCN(C(=O)CO)C1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-3-ylmethyl)-amide (example A145) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:22]=[N:21][C:9]2[O:10][C:11]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=3[NH:13][C:14](=[O:15])[C:8]=2[CH:7]=1)([O-:5])=[O:4].[CH3:23]I>CN(C)C=O>[N+:3]([C:6]1[CH:22]=[N:21][C:9]2[O:10][C:11]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:12]=3[N:13]([CH3:23])[C:14](=[O:15])[C:8]=2[CH:7]=1)([O-:5])=[O:4]
Reactant: Cc1ccc2c(c1)Oc1ncc([N+](=O)[O-])cc1C(=O)N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)Oc1ncc([N+](=O)[O-])cc1C(=O)N2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (0.73 g, 0.015 mol of a 50% dispersion in mineral oil) in dimethylformamide (75 ml) under argon was added in one portion 3-Nitro-9-methylpyrido[2,3-b][1,5]benzoxazepin-5(6H)-one (3.75 g, 0.014 mol). Methyl iodide (1.3 ml. 0.021 mol) was added, and the resulting solution was stirred overnight at room temperature. The mixture was diluted with ice Water, and the precipitated product was collected and washed with water and pet ether. The crude product was recrystallized from ethyl acetate to give 3.14 g (79% of theory) of the product as a pale yellow solid. m.p. 197°-198° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH2:14])[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].Br[CH2:16][C:17]([C:19]1[N:20]=[CH:21][S:22][CH:23]=1)=[O:18]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:14][CH2:16][CH:17]([OH:18])[C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: O=C(CBr)c1cscn1
Reactant: COC(=O)c1ccc(CC(C)N)cc1
Product: COC(=O)c1ccc(CC(C)NCC(O)c2cscn2)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2-(4-carbomethoxyphenyl)-1-methylethylamine with 4-bromoacetyl-thiazole, followed by reduction and purification of the base on a silica gel plate using ethyl acetate/methanol=8:2 as eluant.
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[C:20](Br)[C:19](=[O:24])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH3:31])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[CH3:56][Si:57]([C:60]#[CH:61])([CH3:59])[CH3:58]>[Cu]I.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.CN(C)C=O>[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[C:20]([C:61]#[C:60][Si:57]([CH3:59])([CH3:58])[CH3:56])[C:19](=[O:24])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH3:31])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c(C)n(-c2ccccc2)c(=O)c1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c(C)n(-c2ccccc2)c(=O)c1C#C[Si](C)(C)C
Temperature: 120 °C
Yield: 53.2 %

Procedure:
A mixture of 5-bromo-2,4-dimethyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (2a, 60.0 mg, 0.124 mmol), N,N-dimethylformamide (0.6 mL), copper(I) iodide (4.5 mg, 0.024 mmol), bis(triphenylphosphine)palladium(II) chloride (9.1 mg, 0.013 mmol), triphenylphosphine (20.0 mg, 0.0762 mmol), N-ethylethanamine (0.6 mL, 6 mmol) and (trimethylsilyl)acetylene (0.052.6 mL, 0.372 mmol) was flushed with Argon and heated under microwave irradiation for 30 min at 120° C. It was evaporated in vacuo, transferred to 20 g silica gel column with 1,2-dichloroethane and separated by flash chromatography with gradient heptane-ethyl acetate to give 2,4-dimethyl-6-oxo-1-phenyl-5-trimethylsilanylethynyl-1,6-dihydro-pyridine-3-carboxylic acid [(S) -cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (33 mg; yield=53%) as a pale yellow-brown solid. LC-MS (m/z) 501.7 (MH+); tR=1.94 (method C).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[Cl:12][CH2:13][C:14]#[C:15][CH2:16]O>>[Cl:12][CH2:13][C:14]#[C:15][CH2:16][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([I:11])=[N:6]1
Reactant: OCC#CCCl
Reactant: Fc1ccc2[nH]nc(I)c2c1
Product: Fc1ccc2c(c1)c(I)nn2CC#CCCl
Yield: 58 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and 4-chloro-2-butyn-1-ol in 58% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:14])[O:10][C:11](=[O:13])[NH:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].IC.O(C(C)C)[CH:20](C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:14])[O:10][C:11](=[O:13])[N:12]([CH3:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)OC(C)C
Reactant: COc1cccc2[nH]c(=O)oc(=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc2c1c(=O)oc(=O)n2C
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a stirred and cooled (<10° C.) solution of 9.65 parts of 5-methoxy-2H-3,1-benzoxazine-2,4(1H)-dione in 54 parts of N,N-dimethylformamide were added portionwise 2.64 parts of a sodium hydride dispersion 50%. After stirring for 1 hour in an ice bath. 7.81 parts of iodomethane were added dropwise at <15° C. When the reaction mixture was solidified, 45 parts of N,N-dimethylformamide were added and a sodium hydride dispersion 50% was further added dropwise. Upon complete addition, stirring was continued overnight while the reaction mixture was allowed to reach room temperature. The reaction mixture was poured into ice water and 2,2'-oxybispropane was added. The precipitated product was filtered off, washed with water and dried, yielding 8.37 parts (80.7%) of 5-methoxy-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione; mp. 215.8° C. (interm. 2)
Reaction SMILES: Cl.[CH2:2]([N:5]([CH2:32][CH2:33][CH3:34])[C:6]([N:8]1[C:12]2[CH2:13][C@@:14]3([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29]C)[CH:24]=4)[C@H:19]([CH2:20][C:11]=2[C:10]([CH3:31])=[CH:9]1)[CH2:18][N:17]([CH2:21][CH3:22])[CH2:16][CH2:15]3)=[O:7])[CH2:3][CH3:4].B(Br)(Br)Br>>[CH2:2]([N:5]([CH2:32][CH2:33][CH3:34])[C:6]([N:8]1[C:12]2[CH2:13][C@@:14]3([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=4)[C@H:19]([CH2:20][C:11]=2[C:10]([CH3:31])=[CH:9]1)[CH2:18][N:17]([CH2:21][CH3:22])[CH2:16][CH2:15]3)=[O:7])[CH2:3][CH3:4]
Reactant: CCCN(CCC)C(=O)n1cc(C)c2c1C[C@]1(c3cccc(OC)c3)CCN(CC)C[C@H]1C2
Agent: BrB(Br)Br
Agent: Cl
Product: CCCN(CCC)C(=O)n1cc(C)c2c1C[C@]1(c3cccc(O)c3)CCN(CC)C[C@H]1C2

Procedure:
0.56 g (1.15 mmol) of (±)-trans-dipropylaminocarbonyl-6-ethyl-3-methyl-8a-(3-methoxyphenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline hydrochloride were treated with 0.65 ml (7 mmol) of boron tribromide as described in example 2. The residue was purified by flash chromatography (AcOEt/MeOH/conc. NH4OH 75:25:2.5). The crude product was crystallised from acetone yielding 0.075 g of the title compound. M.p.=151°-153° C.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][S:5]1.[C:19]([O:23][C:24]([N:26]([CH:39]([CH3:41])[CH3:40])[CH2:27][CH:28]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:29](O)=[O:30])=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:28]([C:29]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[S:5][CH2:6][C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:14][CH2:15]2)=[O:30])[CH2:27][N:26]([CH:39]([CH3:40])[CH3:41])[C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:33][CH:34]=1
Reactant: C[C@@H]1SCc2ncnc(N3CCNCC3)c21
Reactant: CC(C)N(CC(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)SC3)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of (S)-5-methyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (0.5 g, 1.62 mmol) and 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.7 g, 2.05 mmol) in DCM (40 mL) were added HBTU (1.0 g, 2.64 mmol) and triethylamine (1.38 mL, 9.88 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed, and the residue was dissolved in ethyl acetate (200 mL) and washed with brine (5×100 mL) and water (3×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with Hexane/ethyl acetate (2:1-0:1) to give tert-butyl 2-(4-chlorophenyl)-3-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.63 g, 70%). 1H NMR (CDCl3, 400 MHz) δ 8.50 (d, J=5.6 Hz, 1H), 7.31-7.23 (m, 4H), 4.76 (m, 1H), 4.18 (m, 3H), 4.92-3.25 (m, 10H), 1.48 (m, 12H), 0.99 (m, 3H), 0.69 (m, 3H). MS (APCI+) [M+H]+ 561.
Reaction SMILES: [O:1]1[C@H:7]2[C@@H:2]1[C:3]([CH3:18])([CH3:17])[O:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([O:15][CH3:16])=[CH:8][C:6]=12.Cl([O-])(=O)(=O)=O.[Li+].[Cl-].[NH4+:26]>O1CCOCC1>[CH3:16][O:15][C:9]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]2[O:4][C:3]([CH3:18])([CH3:17])[C@H:2]([OH:1])[C@@H:7]([NH:26][CH2:2][CH2:7][C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:5]=3)[C:6]=2[CH:8]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@@H]1O[C@H]21
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@H](O)[C@H]2NCCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of (3R*,4R*)-3,4-epoxy-6-methoxy-2,2-dimethyl-7-nitro-3,4-dihydro-2H-1-benzopyran (2.50 g, 9.95 mmol) in 1,4-dioxane (5.0 mL), lithium perchlorate (1.06 g, 9.95 mmol) and 42-(phenylethyl)amine (1.50 mL, 11.9 mmol) were added at room temperature and the mixture was stirred at 80° C. for 1 hour. Upon the completion of the reaction, an aqueous solution of saturated ammonium chloride was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=6/4) and the aimed product was obtained as orange amorphous substance (quantitative yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15]C)=[O:14])=[CH:7][C:6]2=[O:17].[OH-].[Na+]>>[CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=[O:14])=[CH:7][C:6]2=[O:17]
Reactant: COC(=O)c1cc(=O)c2cc(SC)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: CSc1ccc2[nH]c(C(=O)O)cc(=O)c2c1
Yield: 84.8 %

Procedure:
Treatment of methyl 6-methylthio-4-oxo-1,4-dihydroquinoline-2-carboxylate (2.0 g) with sodium hydroxide (1.29 g), as described in Example 1c, gave 6-methylthio-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (1.6 g), m.p. 256°-257° C. δ (360 MHz, DMSO-d6) 2.55 (3H, s, CH3S), 6.65 (1H, s, 3-H), 7.62 (1H, dd, 7-H), 7.83 (1H, d, 5-H) and 7.90 (1H, d, 8-H). (Found: C, 54.08; H, 4.19; N, 5.72% C11H9NO3S.0.5H2O requires C, 54.09; H. 4.13; N. 5.72%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[C:11]#[CH:12]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH:12]=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C#CC(=O)OCC
Reactant: COc1ccccc1N
Solvent: CCO
Product: CCOC(=O)C=CNc1ccccc1OC
Yield: 49.7 %

Procedure:
o-Anisidine (57 ml, 0.5 mol) and ethyl propiolate (51 ml, 0.5 mol) were heated together under reflux in ethanol (200 ml) for 3 hours. The solvent was evaporated to afford ethyl 3-(2-methoxyphenylamino)acrylate as a yellow oil (55 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:11][O:10]1.[Na].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.ClCCl.CO>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH3:13])[CH2:11][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: CC(c1ccncc1)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CC(c1ccncc1)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Treatment of the product of part (i) (1.02 g) with 1H-1,2,4-triazole sodium salt (0.71 g) in N,N-dimethylformamide (10 ml) by the method of Example 1(ii), followed by chromatography of the crude product on silica gel using dichloromethane/methanol (97:3) as eluant, first gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (0.22 g), m.p. 161°-163° (from ether).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24](OCC)=[O:25])=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][OH:25])=[CH:22][N:21]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a solution of ethyl 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carboxylate (2.44 g) in tetrahydrofuran (50 mL) was added lithium aluminum hydride (0.17 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. Sodium sulfate decahydrate (1.48 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated to give {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methanol as colorless crystals (2.20 g, yield 98%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 127-128° C.