Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][C:44]([F:47])=[C:43]([CH3:48])[CH:42]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>CO>[F:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)=[CH:42][C:43]=1[CH3:48]
Reactant: Cc1cc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)ccc1F
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(CCc2cc(O)c(=O)[nH]n2)ccc1F

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[2-(4-fluoro-3-methylphenyl)ethynyl]pyridazine (Intermediate 29) except that the solvent mixture used for the hydrogenation was made up of ethyl acetate and methanol (1:1) and the final material was recrystallised from ethyl acetate.
Reaction SMILES: C([O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([F:12])[C:5]=1[F:13])C.[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([OH:3])=[C:5]([F:13])[C:6]=1[F:12])#[N:9]
Reactant: CCOc1ccc(C#N)c(F)c1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(O)c(F)c1F
Reaction time: 5 h

Procedure:
A solution of 0.1 mol of 4-ethoxy-2,3-difluoro benzonitrile in 100 ml of toluene is slowly added dropwise at room temperature in the course of 30 minutes to a solution of 0.1 mol of aluminium(III) chloride in 100 ml of toluene. The mixture is subsequently heated to boiling for 5 hours and worked up as customary after cooling, m.p.: 145° C.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@@H:13]([NH2:39])[C@@H:14]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=2[C:28]2[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=2[O:37][CH3:38])[CH3:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[S:42](N)(N)(=[O:44])=[O:43]>N1C=CC=CC=1>[F:1][C:2]([F:40])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[NH:39][S:42](=[O:44])(=[O:43])[N:16]([CH2:17][C:18]3[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:19]=3[C:28]3[CH:33]=[C:32]([CH:34]([CH3:35])[CH3:36])[CH:31]=[CH:30][C:29]=3[O:37][CH3:38])[C@H:14]2[CH3:15])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: NS(N)(=O)=O
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN[C@@H](C)[C@H](N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1[C@@H](C)[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)NS1(=O)=O
Temperature: 120 °C

Procedure:
A glass reaction tube was charged with (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propane-1,2-diamine (15.9 mg, 0.0269 mmol), sulfamide (4 mg, 0.0403 mmol), and pyridine (600 μL). The tube was flushed with N2, sealed, and heated at 120° C. for 2 h. The reaction was then cooled to room temperature, diluted with EtOAc (40 mL) and washed with H2O, 1N HCl, and brine (10 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 25% EtOAc/hexanes afforded (3S,4R)-4-[3,5-bis(trifluoromethyl)phenyl]-2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-3-methyl-1,2,5-thiadiazolidine 1,1-dioxide. Rf=0.27 (25% EtOAc/hexanes). LCMS=655.2 (M+1)+. 1H NMR (C6D6, 500 MHz; atropisomers present) δ 6.51-8.19 (m, 9H), 3.64-4.53 (m, 4H), 3.00-3.18 (m, 4H), 2.73 (m, 1H), 1.13-1.20 (m, 6H), −0.03-0.09 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[CH:4][C:5]2[CH2:10][O:9][CH:8]([CH2:11]Br)[O:7][C:6]=2[CH:13]=1.[CH2:15]([NH2:18])[CH2:16][CH3:17]>CCO>[Br:1][C:2]1[C:3]([F:14])=[CH:4][C:5]2[CH2:10][O:9][CH:8]([CH2:11][NH:18][CH2:15][CH2:16][CH3:17])[O:7][C:6]=2[CH:13]=1
Reactant: CCCN
Reactant: Fc1cc2c(cc1Br)OC(CBr)OC2
Solvent: CCO
Product: CCCNCC1OCc2cc(F)c(Br)cc2O1
Yield: 41.1 %

Procedure:
Preparation according to Example 3. 7-bromo-2-(bromomethyl)-6-fluoro-4H-1,3-benzodioxine (0.60 g, 1.84 mmol), propan-1-amine (1.0 ml, 12.2 mmol) and EtOH (3.0 ml) was Heated at 130° C. for 40 min. Twice purification by flash column chroma-tography (EtOAc) gave the pure title compound (0.23 g, 41%). The amine was converted into the hydrochloric acid salt and crystallized from EtOH/DEE. M.p. 182° C. MS m/z (rel. intensity, 70 eV) 305 (M+, 3), 303 (M+, 3), 205 (8), 203 (8), 96 (6), 95 (10), 72 (bp).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:8]2[CH:7]=[CH:6][C:5]([S:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=3)(=[O:12])=[O:11])=[CH:4][C:3]=2[C:1]#[N:2])=[CH:24][CH:23]=1
Reactant: Nc1ccc(O)cc1
Reactant: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1F
Product: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1Oc1ccc(N)cc1

Procedure:
The title compound was prepared according to the method described for Library Protocol 2 using 3-cyano-4-fluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide (Preparation 2), 4-aminophenol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[O:13]1[CH2:14][CH2:15][N:10]([C:4]2[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([C:21]3[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=3)[N:3]=2)[CH2:11][CH2:12]1
Reactant: N#Cc1cc(Cl)nc(N2CCOCC2)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCOCC2)c1
Temperature: 100 °C
Yield: 27.7 %

Procedure:
The nitrile 25B (3.2 g, 14.4 mmol), 4-trifluoromethylphenylboronic acid (3.01 g, 1 mol eq), palladium acetate (65 mg, 0.02 mol eq), cesium carbonate (9.38 g, 2 mol eq), and XPhos (265 mg, 0.04 mol eq) were mixed, placed under a nitrogen atmosphere and dioxane (12 mL) was added. The mixture was heated at 100° C. overnight. After cooling, the mixture was filtered through a celite pad, washed with dioxane (2×30 mL) and concentrated under reduced pressure. The residue was purified by flash chromatography (7/3 Petroleum ether/EtOAc) to afford 26B as yellow solid (1.33 g, 40% Yield). 1HNMR (DMSO, 400 MHz) δ 3.63 (m, 4H, J=1.9), 3.74 (m, 4H, J=2), 7.38 (s, 1H), 7.74 (s, 1H), 7.84 (d, 2H, J=8.1), 8.32 (d, 2H, J=8).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16]SC2SC3C=C([N+]([O-])=O)C=CC=3N=2)[N:14]([CH:30]([C:41]([CH3:43])=[CH2:42])[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[C:13]1=[O:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45]1([S:51](C#N)(=[O:53])=[O:52])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C1(S([O-])=O)C=CC=CC=1.[Na+]>CC(C)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:51]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)(=[O:52])=[O:53])[N:14]([CH:30]([C:41]([CH3:43])=[CH2:42])[C:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])[C:13]1=[O:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccc([N+](=O)[O-])cc2s1
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Yield: 81 %

Procedure:
A 362 mg quantity of benzyl 2-[3-phenoxyacetamido-4-(6-nitrobenzothiazol-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 112 mg of benzenesulfonyl cyanide were dissolved in 3.5 ml of acetone. To the solution was added 3 mg of sodium benzenesulfinate and the mixture was reacted at room temperature for 2 hours. The same subsequent procedure as in Example 5 was followed, producing benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 81%. The NMR spectrum data of the compound thus obtained were identical with those of the compound produced in Example 13.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:10])[CH2:8][CH3:9].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19]>CN(C)C=O>[CH2:7]([S:10][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19])[CH2:8][CH3:9]
Reactant: O=C(c1cccs1)c1ccccc1Cl
Reactant: CCCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1ccccc1C(=O)c1cccs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a cloudy solution of 400 mL of dry dimethylformamide containing 224 g or potassium-t-butoxide, cooled to 0° under a nitrogen atmosphere, was added 18 mL of n-propanethiol dropwise at such a rate to maintain the temperature below 5° C. The resulting mixture was stirred for 5 minutes and then a solution of 44 g of the product of Example 1 dissolved in 100 mL of dimethylformamide was added. The reaction mixture was stirred for 24 hours at room temperature, poured into 2 L of ice-water and extracted with methylene chloride. The organic layer was separated, washed with 1N NaOH (aq), water, and dried (MgSO4). Filtration, followed by concentration of the filtrate in vacuo gave a dark residue which after column chromatography on silica (methylene chloride as eluant) provided 40 g of the subject compound as a red oil.
Reaction SMILES: [C:1]1([S:7][C:8]2[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([CH:25]([CH:29]([CH3:31])[CH3:30])[C:26](O)=[O:27])=[CH:22][C:21]=2[CH:32]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([CH:25]([CH:29]([CH3:30])[CH3:31])[C:26]([O:15][CH2:14][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([S:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:13]=3)=[O:27])=[CH:22][C:21]=2[CH:32]=1
Reactant: OCc1cccc(Sc2ccccc2)n1
Reactant: CC(C)C(C(=O)O)c1cc2cc(Cl)ccc2s1
Product: CC(C)C(C(=O)OCc1cccc(Sc2ccccc2)n1)c1cc2cc(Cl)ccc2s1

Procedure:
Using the procedure of Example 10, (6-phenylthio-2-pyridyl)methanol is reacted with 2-(5-chloro-2-benzothienyl)-3-methylbutanoic acid to give (6-phenylthio-2-pyridyl)methyl 2-(5-chloro-2-benzothienyl)-3-methylbutanoate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]2=[O:16])=[CH:6][CH:5]=1)([O-])=O.N.[H][H]>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]2=[O:16])=[CH:8][CH:9]=1
Reactant: O=c1cnccn1-c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: Nc1ccc(N2CCNCC2=O)cc1

Procedure:
To a solution of 670 mg 1-(4-Nitro-phenyl)-1H-pyrazin-2-one in 100 mL MeOH, 8 g Raney Nickel (washed three times with MeOH) were introduced under a nitrogen atmosphere. Then 10 mL of a 7 M solution of NH3 in MeOH were added. The nitrogen atmosphere was replaced by a hydrogen atmosphere and the mixture was hydrogenated under normal pressure at RT. After 2 h the reaction mixture was filtered through a pad of celite. The solvents were removed under reduced pressure and the residue was subjected to the next reaction step without further purification.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][N:14]=[C:13]2[N:23]([CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[N:24]=[C:25](I)[C:12]=12>>[Cl:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][N:14]=[C:13]2[N:23]([CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[N:24]=[C:25]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:12]=12
Reactant: Clc1c(-c2ccccc2)nnc2c1c(I)nn2CCN1CCCC1
Reactant: OB(O)c1ccccc1
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCN1CCCC1

Procedure:
Compound 13 was synthesised according to Example 1, Step 8 using phenylboronic acid in place of 4-fluorophenylboronic acid and using 4-chloro-3-iodo-5-phenyl-1-(2-pyrrolidin-1-ylethyl)pyrazolo[3,4-c]pyridazine in place of 2-(4-chloro-3-iodo-5-phenyl-pyrazolo[3,4-c]pyridazin-1-yl)-1-[(3R)-3-fluoropyrrolidin-1-yl]ethanone.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[S:25][C:24]([C:26](O)=[O:27])=[C:23]([CH3:29])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[CH3:31][O:32][C:33](=[O:38])[C:34]([NH2:37])([CH3:36])[CH3:35]>>[CH3:31][O:32][C:33](=[O:38])[C:34]([NH:37][C:26]([C:24]1[S:25][C:21]([C:3]([CH2:4][CH3:5])([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=2)[CH2:1][CH3:2])=[CH:22][C:23]=1[CH3:29])=[O:27])([CH3:36])[CH3:35]
Reactant: COC(=O)C(C)(C)N
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)O)s1
Agent: Cl
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)NC(C)(C)C(=O)OC)s1
Yield: 81.3 %

Procedure:
Using the procedure analogous to Example 52, enantiomer 1 of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dirnethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (Example 7) (0.2 g, 0.48 mmol) and 2-amino-2-methyl-propionic acid methyl ester hydrochloride salt (0.018 g, 0.53 mmol) to give the title compound (0.20 g, 0.39 mmol, 71%). 1HNMR (CDC3), δ 0.69 (t, J=7.0 Hz, 6H), 1.01 (s, 9H), 1.60 (s, 6H), 2.02-2.13 (m, 4H), 2.19 (s, 3H), 2.44 (s, 3H), 3.70 (dd, J=8.9, 2.6 Hz, 1H), 3.76 (s, 3H), 3.86 (t, J=8.7, 1H), 4.09 (dd, J=9.4, 2.6 Hz, 1H), 6.28 (s, 1H), 6.59 (s, 1H), 6.73 (d, J=8.4 Hz, 1H), 6.99 (d, J=2.2 Hz, 1H), 7.04 (dd, J=8.4, 2.2 Hz, 1H). LC/MS (m/z): calcd. for C29H44NO5S (M+H)+: 518.7; found: 518.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:2].CCN(CC)CC.[O:22](S(C(F)(F)F)(=O)=O)[S:23]([C:26]([F:29])([F:28])[F:27])(=O)=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:2]
Reactant: CCOC(=O)c1ccc(O)c(C#N)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
Dissolve the ethyl 3-cyano-4-hydroxy-benzoate (22.36 g, 117.1 mmoles) in anhydrous CH2Cl2 (400 mL) at 0° C. Add Et3N (24.3 mL, 175.6 mmoles), DMAP (2.14 g, 17.5 mmol), and dropwise Tf2O (49.5 g, 175.6 mmoles). Stir the mixture at room temperature for 2 hours. Concentrate the mixture under reduced pressure and subject residue to silica gel chromatography eluting hexane/EtOAc 4:1, to obtain 34.99 g of ethyl 3-cyano-4-trifluoromethanesulfonyloxy-benzoate (92% yield). MS(ES): m/z=190.0 [M-H].
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[OH-].[Na+].[Cl:63][CH2:64][C:65](=[O:72])[CH2:66][C:67]([O:69][CH2:70][CH3:71])=[O:68]>>[Cl:63][CH2:64][C@@H:65]([OH:72])[CH2:66][C:67]([O:69][CH2:70][CH3:71])=[O:68]
Reactant: CCOC(=O)CC(=O)CCl
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Product: CCOC(=O)C[C@H](O)CCl
Temperature: 30 °C
Reaction time: 13 h
Yield: 95.7 %

Procedure:
The recombinant E. coil HB101(pNTS1G) obtained in Example 10 was inoculated in 100 ml of a 2×YT medium sterilized in a 500 ml Sakaguchi flask, and cultured with agitation at 37° C. for 13 hours. Glucose, 19.2 g, and 2.5 mg of NADP were added to 40 ml of the resultant culture. The culture was stirred at 30° C. while being adjusted at pH 6.5 with a 5 M sodium hydroxide solution. While stirring, a total of 16.1 g of ethyl 4-chloroacetoacetate was continuously added to the culture at a rate of about 2 g per hour. The reaction was performed for 24 hours. After the reaction, the reaction solution was subjected to extraction using ethyl acetate, the solvent was removed under decompression, and the concentrate was purified by silica gel column chromatography, to obtain 15.6 g of ethyl (S)-4-chloro-3-hydroxybutyrate. The optical purity of the ethyl (S)-4-chloro-3-hydroxybutyrate was analyzed by an HPLC method and found to be 100% e.e. 1H-NMR(CDC13)δ(ppm): 1.33(3H,t), 2.65(2H,d), 3.31(1H,d), 3.60(2H,d), 4.2(3H,m); Column: Chiralcel OB (0.46×25 cm) manufactured by Daicel Chemical Industries, Co., Ltd.; Column temperature: 0° C.; Eluent: n-hexane/2-propanol of 9/1; Flow rate: 0.8 ml/min.; Detection: 215 nm; Elution time: 19.2 minutes for (S), 17.0 minutes for (R).
Reaction SMILES: [F:1][B-](F)(F)F.N#[O+].N[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].ClC1C=CC=CC=1Cl>ClCCl>[F:1][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1c([N+](=O)[O-])ccc2ccccc12
Reactant: F[B-](F)(F)F
Agent: N#[O+]
Solvent: ClCCl
Solvent: Clc1ccccc1Cl
Product: O=[N+]([O-])c1ccc2ccccc2c1F
Reaction time: 0.5 h

Procedure:
To a well stirred slurry of nitrosonium tetrafluoroborate (Aldrich) (10 % molar excess, (cf. David J. Milner, Synthetic Communications (1992) 22 (1), 73-82.)) in dichloromethane at 0° C. is added 1-amino-2-nitronaphthalene. After 30 minutes, ortho-dichlorobenzene is added and the dichloromethane is distilled off, and the dichlorobenzene is heated at 50°-200 ° C. to decompose the diazonium tetrafluoroborate. Removal of solvent and purification of the product by chromatography or crystallization yields 1-fluoro-2-nitronaphthalene.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:24])=[C:19]([S:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>>[Cl:24][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([N:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=4)[CH2:6][CH2:7]3)=[N:13][CH:14]=[N:15]2)=[CH:20][C:19]=1[S:22][CH3:23]
Reactant: CSc1cc2c(Cl)ncnc2cc1Cl
Reactant: Clc1ccc2c(c1)NCC2
Product: CSc1cc2c(N3CCc4ccc(Cl)cc43)ncnc2cc1Cl
Yield: 15 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 15% yield from 6-chloro-indoline and 4,7-dichloro-6-methylsulfanyl-quinazoline. (M.P. 167°-168° C.; LC-MS: 362 (MH+)).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:34])=[C:19]([NH:21][C:22]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][CH:28]=[CH:27]3)=[O:23])[CH:20]=1>C(N(CC)CC)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:34])=[C:19]([NH:21][C:22]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[CH:29][CH:28]=[CH:27]4)=[O:23])[CH:20]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: Cc1ccc(N)cc1NC(=O)c1ccc2ncccc2c1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc(C(F)(F)F)cc2)cc1NC(=O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
Using an analogous procedure to that described in Example 4, 4-trifluoromethylbenzoyl chloride was reacted with N-(5-amino-2methylphenyl)-quinoline-6-carboxamide in the presence of triethylamine. The reaction mixture was stirred at ambient temperature for 18 hours and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound in 52% yield; Mass Spectrum: M+H+ 450.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH:30]([CH2:32][CH2:33][CH:34]([OH:36])[CH3:35])[CH3:31].O>CN(C)C=O>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[C:30]([CH2:32][CH2:33][C:34](=[O:36])[CH3:35])=[CH2:31]
Reactant: CC(O)CCC(C)c1ccc(Cl)cc1Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: C=C(CCC(C)=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A mixture of pyridinium dichromate (49 g) and 2-(2,4-dichlorophenyl)hexan-5-ol (16 g) in dry dimethylformamide (100 ml) was stirred overnight at room temperature then poured into water and extracted with ether. The extracts were washed successively with dilute hydrochloric acid and water, then dried over magnesium sulphate and concentrated under reduced pressure to give almost pure 2-(2,4-dichlorophenyl)hex-1-en-5-one (14.5 g, 91%) as a yellow oil, 1H n.m.r. (CDCl3): δ2.18 (3H,s), 2.4-3.0 (4H,m), 5.15 (1H,s), 5.41 (1H,s), 7.2-7.6 (3H, m).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.[CH3:14][S:15](C)=O.C[Si](C)(C)SC.C(=O)([O-])[O-].[Cs+].[Cs+]>CCOCC>[I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([S:15][CH3:14])[CH:3]=1
Reactant: CS(C)=O
Reactant: O=[N+]([O-])c1cc(I)cc([N+](=O)[O-])c1
Agent: CS[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Product: CSc1cc(I)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-iodo-3,5-dinitrobenzene (15 g, 51 mmole) in 150 mL of DMSO trimethyl(methylthio)silane (10 mL, 70.6 mmol) was added slowly. The resulting reaction mixture turned purple at this point. Cesium carbonate 99.9% (23.13 g, 71.4 mmol) was then added. After stirring at room temperature for 18 h, the reaction mixture was diluted with 150 mL of ether, washed with 400 mL of saturated sodium bicarbonate solution and 150 mL of brine. The combined organic phase were then dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 1-iodo-3-methylsulfanyl-5-nitro-benzene as a yellow solid. The crude material was used in the next step without further purification. HR-EI(+) m/e calcd for C7H6NO2SI (M+) 294.9164, found 294.9164.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[N+:12]([C:3]1[C:2]([OH:11])=[CH:1][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc2c(c1)CCCC2
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc2c(cc1O)CCCC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 5,6,7,8-tetrahydro-2-naphthol (44 g) in 300 ml of acetic acid was added dropwise fuming nitric acid (12 ml in 12 ml of acetic acid) over a period of 30 minutes. The reaction mixture was then stirred for an additional 5 hours at room temperature. After evaporation of the solvent, the crude product was purified by column chromatography (silica gel) to give 16 g of pure product, m.p. 88°-89° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([CH2:12][C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)=[N:6][C:5]=2[S:4][C:3]=1[C:18]([O:20]CC)=[O:19].[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([CH2:12][C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)=[N:6][C:5]=2[S:4][C:3]=1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1sc2nc(Cc3ccsc3)[nH]c(=O)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)O)sc2nc(Cc3ccsc3)[nH]c(=O)c12
Yield: 92.2 %

Procedure:
A mixture of 379 mg of ethyl 5-methyl-4-oxo-2-(thiophen-3-ylmethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate as synthesized in Production Example 1, 3.4 mL of 1N aqueous sodium hydroxide solution and 2.2 mL of ethanol was heated under reflux for 2 hours. After cooling off, the reaction liquid was poured on ice, rendered acidic with diluted hydrochloric acid, and the precipitated crystals were recovered by filtration. After washing with water, the crystals were dried by heating under reduced pressure, to provide 320 mg of 5-methyl-4-oxo-2-(thiophen-3-ylmethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid.