Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C1C(=CC=CC=1)O.C(OO)(C)(C)C.C1(C)C=CC=CC=1.[C:24]1([S:30]([CH:33]([CH2:44][CH:45]=[C:46]([CH3:54])[CH2:47][CH2:48][CH:49]=[C:50]([CH3:53])[CH:51]=[O:52])[CH:34]=[C:35]([CH3:43])[CH2:36][CH2:37][CH:38]=[C:39]([CH3:42])[CH:40]=[O:41])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:24]1([S:30]([CH:33]([CH2:44][CH:45]=[C:46]([CH3:54])[CH2:47][CH2:48][CH:49]=[C:50]([CH3:53])[CH2:51][OH:52])[CH:34]=[C:35]([CH3:43])[CH2:36][CH2:37][CH:38]=[C:39]([CH3:42])[CH2:40][OH:41])(=[O:32])=[O:31])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C=O)=CCCC(C)=CCC(C=C(C)CCC=C(C)C=O)S(=O)(=O)c1ccccc1
Agent: CC(C)(C)OO
Agent: O=C(O)c1ccccc1O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=CCCC(C)=CCC(C=C(C)CCC=C(C)CO)S(=O)(=O)c1ccccc1)CO
Reaction time: 1.5 h
Yield: 44 %

Procedure:
To a stirred suspension of SeO2 (0.54 g, 4.82 mmol, 2 equiv) and salicylic acid (0.34 g, 2.41 mmol, 1 equiv) in CH2Cl2 (20 mL) at 0° C. was added a 3.0 M solution of t-butyl hydrogen peroxide (TBHP) in toluene (5.0 mL, 14.46 mmol, 6 equiv). The mixture was stirred at that temperature for 1.5 h, and a solution of the compound (J) (1.00 g, 2.41 mmol, 1 equiv) in CH2Cl2 (5 mL) was slowly added for 10 min. The reaction mixture was stirred at 0° C. for 3 h, diluted with CH2Cl2 (30 mL), washed with 10% NaOH solution (10 mL×3) and then saturated Na2S2O3 solution (10 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the diol compound (K) (0.47 g, 1.06 mmol) in 44% yield, together with the hydroxyl-aldehyde (0.13 g, 0.29 mmol, 12% yield), which was derived from further oxidation. Both of these two compounds can provide the dialdehyde of the Chemical Formula 3 after the Swern oxidation reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OC1CCOCC1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)C1CCOCC1
Yield: 61.4 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg, 0.661 mmol) obtained in Example 5 and tetrahydro-4H-pyran-4-ol (0.13 ml, 1.36 mmol) were dissolved in toluene (10 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (330 mg, 1.37 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, cyanomethylenetri-n-butylphosphorane (200 mg, 0.829 mmol) was added thereto. Under an argon atmosphere, the mixture was heated under reflux for 14 hours. The reaction mixture was then allowed to cool down. The residue obtained by concentrating the mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with hexane, whereby the title compound (157 mg, 0.406 mmol, 61%) was obtained as a white powder.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:11]2[C@@:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])([N:7]=[C:8]([NH2:12])[S:9][CH2:10]2)[CH2:5][O:4]1.S(=O)(=O)(O)O.[N+:25]([O-])([OH:27])=[O:26].[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl>[F:19][C:14]1[CH:15]=[CH:16][C:17]([N+:25]([O-:27])=[O:26])=[CH:18][C:13]=1[C@:6]12[CH2:5][O:4][C@H:3]([CH2:2][F:1])[C@H:11]1[CH2:10][S:9][C:8]([NH2:12])=[N:7]2
Reactant: O=[N+]([O-])O
Reactant: NC1=N[C@@]2(c3ccccc3F)CO[C@H](CF)[C@H]2CS1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: NC1=N[C@@]2(c3cc([N+](=O)[O-])ccc3F)CO[C@H](CF)[C@H]2CS1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
(4aS,5S,7aS)-5-(fluoromethyl)-7a-(2-fluorophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (45.85 g, 161.26 mmol) was dissolved in TFA (192 mL), and the solution was cooled to 0° C. Sulfuric acid (conc., 33.65 mL, 161.26 mmol) was added, followed by fuming nitric acid (7.78 mL, 185.44 mmol) dropwise over 25 mins. After stirring at 0° C. for 30 mins, the reaction mixture was poured onto ice (500 g)/CHCl3 (500 mL) and basified to pH 12 with 6N NaOH (aq.). The two layers were separated and the aqueous layer was extracted with CHCl3 (2×500 mL). The combined organic extracts were dried over MgSO4 and concentrated to give the product as a light orange foam (52.11 g, 98%). 1H NMR (400 MHz, CDCl3) δ ppm 2.80 (dd, J=13.26, 3.92 Hz, 1H) 3.03 (dt, J=7.77, 3.82 Hz, 1H) 3.08 (dd, J=13.39, 3.28 Hz, 1H) 3.85 (dd, J=8.84, 2.27 Hz, 1H) 4.49-4.67 (m, 4H) 7.22 (dd, J=10.99, 8.97 Hz, 1H) 8.16-8.23 (m, 1H) 8.43 (dd, J=6.82, 2.78 Hz, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:28]
Reactant: Cc1ccsc1C(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccsc1C(=O)NCCCSc1ccncc1
Yield: 84.5 %

Procedure:
In 100 ml of benzene was suspended 3.00 g (21.1 mmol) of 3-methyl-2-thiophenecarboxylic acid, oxalyl chloride [7.36 ml (84.4 mmol)] was added and the mixture was refluxed for 2 hours. After cooling, the solvent was distilled off to obtain 3.40 g of 3-methylthenoyl chloride (yield: quant.). To a solution of 1.50 g (6.23 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.61 ml (18.7 mmol) of triethylamine in 60 ml of methylene chloride, 1.20 ml (7.48 mmol) of the 3-methylthenoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder was washed with ether and dried to obtain 1.54 g of the desired compound (yield: 84.5%, pale yellow powder).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:13])([C:10]([OH:12])=[O:11])[NH:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)CC)(C)C.[C:23](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1[C:3]([NH:13][C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:10]([OH:12])=[O:11])[NH:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC1=C(C)C(N)(C(=O)O)NC=C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC1=C(C)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)(C(=O)O)NC=C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.7 %

Procedure:
1.70 g of methyl 2-amino-4-methoxy-picolinic acid (compound C6) are dissolved in 44 ml of dichloromethane. Subsequently, 1.92 ml of diisopropylethylamine, 690 mg of tetrabutylammonium iodide, and 3.12 g of trityl chloride are added. The solution is stirred for 48 h at room temperature. Thereafter, the mixture is extracted three times each with 50 ml of sat sodium hydrogencarbonate solution. The organic layer is dried using sodium sulphate, filtered with suction and concentrated in vacuum. The crude product (5.38 g) is purified by chromatography (eluent: toluene/ethyl acetate 5:1) to afford 3.49 g of the title compound as a colorless oil. TSP-MS: 425.2 [MH+]. TLC: Rf=0.37 (toluene/ethyl acetate 5:1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:15])[CH2:7][C:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[O:9].[CH2:16]([O:18][C:19](=[O:22])[CH2:20]Br)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:22])[CH2:20][CH:7]([C:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[O:9])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:15])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: O=C(CC(=O)c1cccs1)c1cccs1
Product: CCOC(=O)CC(C(=O)c1cccs1)C(=O)c1cccs1

Procedure:
Following a procedure analogous to that described in Example (2b), 1,3-di-(2-thienyl)-1,3-propanedione was alkylated by reaction with bromoacetic acid ethyl ester to form 3,3-di-(2-thienoyl)-propionic acid ethyl ester, which was reacted with phenylhydrazine in accordance with a procedure analogous to that set out in Example (2c) to form 1-phenyl-3,5-di-(2-thienyl)-pyrazol-4-acetic acid ethyl ester. This substance was saponified by a procedure analogous to that described in Example (1b). 1-Phenyl-3,5-di-(2-thienyl)-pyrazol-4-acetic acid, melting at 216°-218° C., was obtained in a yield of 56% based on the propanedione starting material.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:20])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[S:10](=[O:16])(=[O:15])[CH2:9][CH2:8][CH:7]2[CH2:17][O:18][CH3:19])(=[O:3])C.Cl[O-].[Na+].S([O-])([O-])=[O:25].[Na+].[Na+]>O1CCOCC1>[CH3:19][O:18][CH2:17][CH:7]1[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=[C:4]([C:1]([OH:25])=[O:3])[C:5]=2[CH3:20])[S:10](=[O:16])(=[O:15])[CH2:9][CH2:8]1
Reactant: COCC1CCS(=O)(=O)c2c(C)cc(C(C)=O)c(C)c21
Reactant: O=S([O-])[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1COCCO1
Product: COCC1CCS(=O)(=O)c2c(C)cc(C(=O)O)c(C)c21
Yield: 75 %

Procedure:
To a solution of 0.32 g (1.1 mmol) of 6-acetyl-4-methoxymethyl-5,8-dimethylthiochroman-1,1-dioxide in 1 ml of dioxane was added 3.8 ml of a sodium hypochlorite aqueous solution, and the mixture was allowed to react at 0° C. for 1 hour and further allowed to react at room temperature overnight. A 20 wt % sodium sulfite aqueous solution was added to the reaction mixture, and the mixture was washed with ethyl acetate. An aqueous layer was acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution, and an organic layer was dried over anhydrous sodium sulfate and filtered. Then, the solvent was distilled off under reduced pressure to give 0.24 g (yield 75%) of the titled compound as a crude product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2([C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=3)[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:13][C:14]3([C:21]4[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=4)[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)[C:29]2=[O:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCC(CNCCNc2ccc(F)c(F)c2)(c2ccc(I)cc2)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(CN2CCN(c3ccc(F)c(F)c3)C2=O)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.9 %

Procedure:
To a stirred solution of N-(3,4-difluoro-phenyl)-N′-[4-(4-iodo-phenyl)-1-methyl-piperidin-4-ylmethyl]-ethane-1,2-diamine (0.36 g, 1.0 mmol) in THF (10 mL) at 0° C. was added TEA (0.91 mL, 6.5 mmol, 6.5 eq.) and triphosgene (0.195 g, 0.65 mmol, 0.65 eq.). The mixture was stirred at room temperature for 4 h, diluted with EtOAc (25 mL) and washed with saturated brine (2×25 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation to give a yellow oil. The crude product was purified by flash column chromatography by eluting with 2% MeOH/CH2Cl2 to give 1-(3,4-difluoro-phenyl)-3-[4-(4-iodo-phenyl)-1-methyl-piperidin-4-ylmethyl]-imidazolid in-2-one (0.023 g, 0.045 mmol, 5%) as a pale foam. MS (ESI): 512.1/513.1 (M+H), impurity peak 690.9/692.0.
Reaction SMILES: C=O.S(=O)(=O)(O)O.[CH2:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])([OH:20])[C:12]1=[O:27])[CH:9]=[CH2:10].[C:28]([O-])(=[O:30])C.[Na+]>C(O)(=O)C.O>[CH2:8]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:28][OH:30])=[CH:17][CH:18]=2)[C:13]([CH2:21][C:22]([N:24]([CH3:25])[CH3:26])=[O:23])([OH:20])[C:12]1=[O:27])[CH:9]=[CH2:10]
Reactant: CC(=O)[O-]
Reactant: C=CCN1C(=O)C(O)(CC(=O)N(C)C)c2ccccc21
Agent: C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CCN1C(=O)C(O)(CC(=O)N(C)C)c2cc(CO)ccc21
Temperature: 80 °C
Yield: 113 %

Procedure:
To a suspension of para-formaldehyde (36.2 g, 1.13 mol) in 150 ml of glacial acetic acid, sulfuric acid (22.2 g, 0.226 mol) is added and the mixture heated at 80° C., until a clear solution has been formed. To this, during 45 minutes a solution of 2-(1-allyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide (example 26) (62 g, 226 mmol) in a mixture of glacial acetic acid (350 mL) and water (10 mL) is added. The red reaction mixture is stirred for another hour at 80° C., and by then all of the starting material is consumed (HPLC). Sodium acetate (46.3 g, 564 mmol) is added, and after stirring for 5 minutes an orange suspension forms. The solvent is removed on the rotavapor, and to the residue water (about 250 mL) is added. Extraction with chloroform (2×200 mL), drying the organic layer and removal of the solvent leaves the crude title product (77.7 g, quant.) as a red oil. After chromatographic purification white crystals, mp=125° C. 1H-NMR (CDCl3, 300 MHz) δ 2.71, 2.94 (AB, 2H, 2J=16.1 Hz, CH2CONMe2); 2.83, 2.84 (2 s, 3H each, N(CH3)2); 4.19, 4.25 (ABAtlyl, 2H, 2J=16.4 Hz, 3J=5.3 Hz, NCH2); 4.47 (s, 2H, CH2OH); 5.12 (dd, 1H, 2J=1.2 Hz, 3J=10.3 Hz, cis CH═CH2), 5.51 (dd, 1H, 3J=17.3 Hz, trans CH═CH2); 5.75 (ddtr, 1H, CH═CH2); 6.21 (br s, 1H, OH); 6.70 (d, 1H, 3J=7.9 Hz, H-7); 7.15 (dd, 1H, 4J=1.5 Hz, H-6); 7.37 (d, 1H, H-4). 13C-NMR (CDCl3, 75 MHz) δ 35.71, 37.84 (N(CH3)2); 38.87 (CH2CONMe2); 42.67 (NCH2); 64.80 (CH2OH); 74.46 (C-3); 109.36 (C-7); 117.73 (CH═CH2); 123.43 (C-4); 128.63 (C-6); 131.00 (C-9); 131.33 (CH═CH2); 136.35 (C-5); 141.89 (C-8); 170.53 (C-11); 176.36 (C-2).
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>C(O)C>[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[N:9][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[CH:13][CH:12]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=Cc1ccc(O)cc1
Solvent: CCO
Product: CC(N=Cc1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
9.96 g (0.082 mole) of (R)-(+)-1-phenylethylamine and 10.54 g (0.086 mole) of p-hydroxybenzaldehyde were dissolved in 140 ml of ethyl alcohol, and the resulting solution was stirred under reflux for 2 hours. The reaction mixture was cooled to room temperature, and the crystalline material thus formed was separated by filtration to give 13.0 g of (-)-N-(p-hydroxybenzylidene)-1-phenylethylamine. Yield: 70.4%. m.p. 176°-178° C.; α!D22 -120.7° (C 1.0, MeOH) NMR-spectral data (δ ppm, DMSO-d6) 1.50 (d) 3H; 4.50 (q) 1H; 6.7-7.8 (m) 9H; 7-7.8 (broad) 1H; 8.34 (s) 1H
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[S:9]([CH2:12][C:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:23][CH3:24])[C:16]([C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[H][H]>[Pd].C1COCC1.C(O)C>[CH:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH2:3][CH:2]2[S:9]([CH2:12][C:13]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:23][CH3:24])[C:16]([C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:10]
Reactant: [H][H]
Reactant: COC(=O)c1c(CS(=O)(=O)C2CC3C=CC2CC3)ccc(-c2ccoc2)c1OC
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1c(CS(=O)(=O)C2CC3CCC2CC3)ccc(-c2ccoc2)c1OC
Yield: 11.1 %

Procedure:
A mixture of methyl 6-(bicyclo[2.2.2]oct-5-ene-2-ylsulphonylmethyl)-3-(furan-3-yl)-2-methoxybenzoate (Intermediate 170, 0.26 g) and palladium on carbon (10%, 0.01 g) in THF (15 ml) and ethanol (10 ml) was stirred in an atmosphere of hydrogen (balloon) for 1 hour. The mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate in cyclohexane with a gradient of 10-50% to give methyl 6-(bicyclo[2.2.2]octane-2-ylsulphonylmethyl)-3-(furan-3-yl)-2-methoxybenzoate (0.029 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][NH:20][CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:23][N:24]([CH:31]([CH3:33])[CH3:32])[CH2:25]/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][N:20]([C:28](=[O:29])/[CH:27]=[CH:26]/[CH2:25][N:24]([CH:31]([CH3:33])[CH3:32])[CH3:23])[CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(Nc2ncnc3sc4c(c23)CNC4)cc1Cl
Reactant: CC(C)N(C)C/C=C/C(=O)O
Agent: Cl
Product: CC(C)N(C)C/C=C/C(=O)N1Cc2sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c3c2C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-(3,4-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 25A (65 mg, 0.19 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (52 mg, 0.27 mmol) to yield 34 mg (37%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([Cl:17])[CH:12]=1)=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([Cl:17])[CH:12]=2)=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccnc(Cl)c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccnc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 133 mg of (2-Amino-5-chloro-phenyl)-(2-chloro-pyridin-4-yl)-methanone and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.26 (s, 9H), 7.18 (dd, 5.2 Hz, 1.6 Hz), 7.25 (m, 1H), 7.32 (m, 1H), 7.41 (d, 2H, J=6.4 Hz), 7.54 (dd,1H, J=9.2 Hz, 2.4 Hz), 7.67 (m, 2H), 7.77 (d,1H, J−8.8 Hz), 8.55 (d, 1H, J=5.2 Hz), 10.09 (s, 1H). MS: m/z463.0 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([OH:29])[CH2:24]2)[CH:3]=1.[NH3:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:30])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([OH:29])[CH2:24]2)[CH:3]=1
Reactant: N
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCC[C@H](O)C3)c12
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCC[C@H](O)C3)c12

Procedure:
Prepared analogously to example 1.4 from 5.6 g racemic racemic 4-[4-Fluoro-2-((trans)-3-hydroxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and 100 ml ammonia (0.5 M in THF).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:20]=[CH:19][C:18]([C:21]4[O:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:37][C:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[O:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=3)=[CH:19][CH:20]=2)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2
Reactant: c1ccc2c(-c3ccc(-c4nc5ccccc5o4)cc3)c3ccccc3cc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Brc1c2ccccc2c(-c2ccc(-c3nc4ccccc4o3)cc2)c2ccccc12
Reaction time: 25 h
Yield: 83.3 %

Procedure:
In a 1 L Meyer flask, 3.3 g (8.8 mmol) of 2-[4-(9-anthryl)phenyl]benzoxazole, 50 mL of toluene, and 200 mL of ethyl acetate were placed. Into the solution, 1.6 g (8.8 mmol) of N-bromosuccinimide was added little by little. This solution was stirred under air for 25 hours. After a certain period, the solution was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline, and then, the organic layer was dried with magnesium sulfate. The obtained mixture was gravity filtered, and the filtrate was condensed to give an oily substance. The oily substance was purified by silica gel column chromatography (toluene:hexane=5:1) to give a solid. The solid was recrystallized with toluene/methanol, giving 3.3 g of the target yellow powder in a yield of 82%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:14]([N:16]=[C:17](SC)[S:18][CH3:19])#[N:15]>C(O)C>[C:14]([NH:16][C:17](=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1)[S:18][CH3:19])#[N:15]
Reactant: CSC(=NC#N)SC
Reactant: COc1cccnc1CSCCN
Solvent: CCO
Product: COc1cccnc1CSCCN=C(NC#N)SC
Reaction time: 8 h

Procedure:
A solution of 2-[2-aminoethylthiomethyl]-3methoxypyridine (2.1g in ethanol (15 ml) was added over one hour to a stirred solution of dimethyl N-cyanodithioimidocarbonate (1.5 g) in ethanol (15 ml). The mixture was allowed to stand overnight and nitrogen was bubbled through for one hour. The crystalline precipitate was recrystallised from ethanol/ether to yield N-cyano-N'-[2-((3-methoxy-2-pyridyl)methylthio)ethyl]-S-methylisothiourea (2.2 g), m.p. 102°-103°.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([OH:16])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][NH2:18]>CCO>[C:2]1([C:1]2[C:9]3[CH:13]=[CH:12][S:11][C:10]=3[C:14](=[O:16])[NH:17][N:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccsc1C(=O)O
Reactant: NN
Solvent: CCO
Product: O=c1[nH]nc(-c2ccccc2)c2ccsc12
Temperature: 25 °C

Procedure:
To 3-benzoylthiophene-2-carboxylic acid (1.00 g, 4.31 mmol) and EtOH (15 mL) was added hydrazine (1.35 ml, 43.1 mmol). A water condenser was attached to the reaction flask and the mixture was heated to reflux under nitrogen for 3.5 hours. The reaction was cooled to RT, the resulting solids filtered and washed with water, and dried to yield 4-phenylthieno[2,3-d]pyridazin-7(6H)-one as a white solid. MS m/z=229 [M+1]+. Calc'd for C12H8N2OS: 228.27.
Reaction SMILES: [Cl:1][C:2]1[C@@H:6]([OH:7])[C:5]([Cl:9])([Cl:8])[C@:4]([OH:13])(C(O)=O)[CH:3]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].O>C(O)(=O)C>[Cl:1][C:2]1[C@@H:6]([OH:7])[C:5]([Cl:9])([Cl:8])[C:4](=[O:13])[CH:3]=1
Reactant: O=C(O)[C@]1(O)C=C(Cl)[C@@H](O)C1(Cl)Cl
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: O
Solvent: CC(=O)O
Product: O=C1C=C(Cl)[C@@H](O)C1(Cl)Cl
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
The (1R,4R)-acid (4) (200 mg, 0.8 mmol) was added portionwise over 10 min to lead tetraacetate (500 mg, 1.13 mmol) in acetic acid (5 ml) containing water (0.05 ml) at 80°. After a further 5 min, water (25 ml) was added and the cooled mixture extracted with ether (3×25 ml). The combined ether solutions were extracted with 5% aqueous sodium bicarbonate until the washings were alkaline (pH 7.5-8), then washed with water (10 ml), dried (MgSO4), and evaporated under reduced pressure. Short path distillation (bath temp. 60°/0.1 mmHg) gave the (4R)-enone (6) (160 mg, 98%) as a colourless oil, [α]35725 +1547° (c 5.66×10-2, EtOH), [α]25225 -11,280° (c 2.26×10-3, EtOH), [θ]33325 +8407° (c 5.66×10-2, EtOH), [θ]24025 -45,025° (c 2.26×10-3, EtOH) (Found: C, 29.8; H, 1.65; Cl, 51.3; C5H3Cl3O2 requires C, 29.8; H, 1.5; Cl, 52.8%).