Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][P:9]([O-:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23]CC)(=[O:22])[CH:20]=[CH2:21].C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[CH2:11]([O:10][P:9]([CH2:21][CH2:20][C:19]([OH:23])=[O:22])([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: C=CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of dibenzylphosphite (2.6 mmol) in 10 mL of THF was added ethyl acrylate (3.0 mmol), K2CO3 (16 mmol), and 0.3 mL of (Bn4NH)2SO4 50% w/w. The reaction mixture was stirred at 45° C. overnight. Water was added. The aqueous layer was extracted with ethyl acetate. Organic layer was collected and dried with MgSO4. Solvent was removed to afford a clear oil 3-bis(benzyloxy)phosphorylpropanoic acid in 90% yield. 1H-NMR (CDCl3, 400 MHz): 7.33 (m, 10H), 4.90-5.10 (m, 4H), 3.61 (s, 3H), 2.50-2.60 (m, 2H), 2.00-2.15 (m, 2H).
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]=1[CH3:3].Cl[C:13]1[C:14](Cl)=[C:15](Cl)[C:16](Cl)=[C:17]2[C:22](=O)[O:21][C:19](=[O:20])[C:18]=12>OCC1CC2CC1C1C2CCC1.CO>[CH:8]1[CH:7]=[C:6]2[CH:5]=[CH:4][C:2]([CH:3]3[C:22](=[O:21])[C:17]4[C:18](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:19]3=[O:20])=[N:1][C:11]2=[CH:10][CH:9]=1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: Cc1ccc2ccccc2n1
Agent: OCC1CC2CC1C1CCCC21
Solvent: CO
Product: O=C1c2ccccc2C(=O)C1c1ccc2ccccc2n1
Temperature: 190 °C
Reaction time: 4 h
Yield: 47.5 %

Procedure:
4.3 g of quinaldine and 8.6 g of tetrachlorophthalic anhydride in 100 ml of 8-hydroxymethyltricyclo[5.2.1.02,6 ]decane [TCD alcohol M®, ex Hoechst] are stirred and heated under nitrogen to 190° C. in a 350 ml glass apparatus equipped with cooler, thermometer, gas inlet pipe and semi-anchor stirrer. The mixture is stirred for 4 hours at 190° C. and the resultant yellow suspension is cooled to 40° C., diluted with 150 ml of methanol and filtered. The filter cake is washed with methanol until colourless and the yellow pigment is dried at 80° C in a vacuum drying cabinet, affording 3.9 g of the yellow quinophthalone pigment of formula ##STR2## which is incorporated in powder form into printing inks and varnishes and gives strong, yellow colorations of good fastness properties.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Br:24])[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][CH:21]([OH:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Br:24])[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC2(CCN(Cc3ccccc3)CC2)Oc2ccc(Br)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1CC2(CCN(Cc3ccccc3)CC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
A mixture of 1′-benzyl-6-bromo-spiro[chromane-2,4′-piperidine]-4-one (3.0 g, 7.8 mmol) and NaBH4 (1.47 g, 38.75 mmol) in MeOH (20 ml) was stirred at RT. After 3 h, the solution was poured into water and the product was extracted with DCM (50 ml). The organic phase was dried over Na2SO4, filtered and evaporated under vacuum to give 1′-benzyl-6-bromo-4-hydroxy-spiro[chromane-2,4′-piperidine] (3.0 g) as a light yellow solid.
Reaction SMILES: [CH2:1]([S:13]([CH:15]([CH2:19][C:20]([OH:22])=[O:21])[C:16]([OH:18])=[O:17])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C(CC(O)=O)C(O)=S)CCCCCCCCCCC.CC[O-].[Na+:46]>C(O)C>[CH2:1]([S:13]([CH:15]([CH2:19][C:20]([O-:22])=[O:21])[C:16]([O-:18])=[O:17])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Na+:46].[Na+:46]
Reactant: CCCCCCCCCCCCS(=O)C(CC(=O)O)C(=O)O
Agent: CCCCCCCCCCCCC(CC(=O)O)C(O)=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCS(=O)C(CC(=O)[O-])C(=O)[O-]
Yield: 97.2 %

Procedure:
Three grams of the sulfoxide of n-dodecylthiosuccinic acid prepared above is dissolved in ethanol and mixed with a solution of 1.4 g of sodium ethylate dissolved in 25 ml of ethanol. The precipitated product is then filtered and dried in vacuo to give 3.3 g of disodium n-dodecylsulfinylsuccinate.
Reaction SMILES: COC1C=C([C@H]2OC(=O)N[C@@H]2C2C=CC=C(C#CC3C=CC=CC=3)C=2)C=CC=1.Br[C:30]1[N:35]=[C:34]([C@@H:36]2[C@@H:40]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)[O:39][C:38](=[O:49])[NH:37]2)[CH:33]=[CH:32][CH:31]=1.[C:50]([C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([F:58])[CH:53]=1)#[CH:51]>>[F:58][C:54]1[CH:53]=[C:52]([C:50]#[C:51][C:30]2[N:35]=[C:34]([C@@H:36]3[C@@H:40]([C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=4)[O:39][C:38](=[O:49])[NH:37]3)[CH:33]=[CH:32][CH:31]=2)[CH:57]=[CH:56][CH:55]=1
Reactant: C#Cc1cccc(F)c1
Reactant: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(Br)n2)c1
Agent: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccccc3)c2)c1
Product: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3cccc(F)c3)n2)c1

Procedure:
Prepared according to the same procedure as (+)-(4R,5R)-5-(3-methoxyphenyl)-4-(3-(phenylethynyl)phenyl)oxazolidin-2-one, starting with optically-enriched (4R,5R)-4-(6-bromopyridin-2-yl)-5-(3-methoxyphenyl)oxazolidin-2-one and 1-ethynyl-3-fluorobenzene. 1H-NMR (CDCl3, 500 MHz) δ 7.81 (d, J=7.9, 7.6, 1H), 7.57 (dd, J=7.9, 0.6, 1H), 7.30-7.45 (M, 5H), 7.13 (m, 1H), 7.04 (m, 2H), 6.95 (m, 1H), 6.00 (bs, 1H), 5.62 (d, J=6.1, 1H), 4.97 (dd, J=5.8, 0.6, 1H), 3.86 (s, 3H). 13C-NMR (CDCl3, 126 MHz) δ 162.5 (d, J=248), 160.2, 159.0, 158.6, 143.5, 139.7, 137.8, 130.20 (d, J=8.6), 130.19, 128.1 (d, J=2.9), 127.4, 123.9 (d, J=10), 120.1, 119.0 (d, J=23), 117.9, 116.8 (d, J=21), 114.8, 111.2, 89.0, 88.7 (d, J=3.8), 83.7, 64.9, 55.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.Cl[S:14]([C:17]1[CH:39]=[CH:38][C:20]([O:21][CH2:22][C:23]([O:25][CH2:26][CH2:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[O:24])=[C:19]([O:40][CH2:41][C:42]([O:44][CH2:45][CH2:46][S:47]([C:50]2[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=2)(=[O:49])=[O:48])=[O:43])[CH:18]=1)(=[O:16])=[O:15]>N1C=CC=CC=1.C1(C)C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][S:14]([C:17]2[CH:39]=[CH:38][C:20]([O:21][CH2:22][C:23]([O:25][CH2:26][CH2:27][S:28]([C:31]3[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=3)(=[O:29])=[O:30])=[O:24])=[C:19]([O:40][CH2:41][C:42]([O:44][CH2:45][CH2:46][S:47]([C:50]3[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=3)(=[O:49])=[O:48])=[O:43])[CH:18]=2)(=[O:15])=[O:16])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)COc2ccc(S(=O)(=O)Cl)cc2OCC(=O)OCCS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2ccc(OCC(=O)OCCS(=O)(=O)c3ccc(C)cc3)c(OCC(=O)OCCS(=O)(=O)c3ccc(C)cc3)c2)c([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 58.3 %

Procedure:
4-Methoxy-2-nitroaniline (2.3 g, 0.014 mol) and 2-(4-tolylsulfonyl)ethyl 4-chlorosulfonyl-2-(2-[4-tolylsulfonyl]ethoxycarbonylmethoxy)phenoxyacetate (Intermediate A16, 9.6 g, 0.014 mol) were dissolved in 40 mL of pyridine and stirred under positive nitrogen pressure. After ca. 16 hr, the mixture was diluted with 50 mL of toluene and 20 mL of dichloromethane and was concentrated at aspirator pressure. The residue was purified on a flash silica gel column (dichloromethane→5:1 dichloromethane:ethyl acetate) to yield 6.7 g (58%) of the title compound.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[S:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C>ClCCl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[N:19]1[CH2:20][CH2:21][N:22]([C:1]([Cl:4])=[S:2])[CH2:23][CH2:24]1
Reactant: S=C(Cl)Cl
Reactant: COc1cc2ncnc(N3CCNCC3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(N3CCN(C(=S)Cl)CC3)c2cc1OC
Reaction time: 2 h
Yield: 51.6 %

Procedure:
To a solution of 3.06 ml (40.1 mmol) of thiophosgene in 100 ml of dichloromethane were slowly added a solution of 10 g (36.5 mmol) of 6,7-dimethoxy-4-(1-piperazinyl)quinazoline obtained by the method described in South African Patent No. 67 06512 (1968) in 100 ml of dichloromethane and 12.4 ml (89.1 mmol) of triethylamine under ice-cooling. The resulting mixture was stirred at the same temperature in an atmosphere of argon for 2 hours. After the solvent was evaporated, the residue was purified by silica gel chromatography to give 6.65 g (52%) of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[CH:20]1([CH2:23][O:24][C:25]2[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=O)[CH2:22][CH2:21]1.[O-]CC.[Na+]>C(O)C>[CH:20]1([CH2:23][O:24][C:25]2[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:26]=2/[CH:27]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:19][CH:18]=[CH:17][N:5]3[C:6](=[O:16])[C:7]=2[C:8]2[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=2)[CH2:21][CH2:22]1
Reactant: COc1cccc(C=O)c1OCC1CC1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C#N)cc2)c1OCC1CC1

Procedure:
The title compound was prepared from Intermediate 4 (180 mg, 0.673 mmol), 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (192 mg, 1.010 mmol) and sodium ethoxide (92 mg, 1.346 mmol) in ethanol (15 ml) according to the procedure described in Example 9 to give 135 mg of the product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.25-0.27 (m, 2H), 0.49-0.51 (m, 2H), 0.90-1.10 (m, 1H), 3.68 (d, J=7.8 Hz, 2H), 3.77 (s, 3H), 6.85 (d, J=15.6 Hz, 1H), 6.96-7.00 (m, 3H), 7.51-7.57 (m, 3H), 7.92 (d, J=7.8 Hz, 2H), 8.01 (d, J=5.1 Hz, 2H), 8.17 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 456.23 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([O:16][CH3:17])[CH2:14][N:13](C(OCC4C=CC=CC=4)=O)[CH2:12]3)=[C:8]([C:28](=[O:30])[NH2:29])[CH:7]=[N:6][N:5]2[CH:31]=1.I[Si](C)(C)C>C(#N)C.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([O:16][CH3:17])[CH2:14][NH:13][CH2:12]3)=[C:8]([C:28]([NH2:29])=[O:30])[CH:7]=[N:6][N:5]2[CH:31]=1
Reactant: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CCOCC
Product: CO[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 135.1 %

Procedure:
A solution of (3R,4S)-benzyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methoxypyrrolidine-1-carboxylate (300 mg, 0.61 mmol) in acetonitrile (5 mL), was added iodotrimethylsilane (123 mg, 0.614 mmol) at 0° C., the mixture was then stirred at rt for 2 h. The mixture was diluted with ether (30 mL), stirred for 1 h, filtered and rinsed with ether to give the hydroiodide salt of 6-bromo-4-(((3R,4S)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (292 mg, 99% yield) as a brown solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.17 (s, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.07 (s, 1H), 4.97-4.88 (m, 2H), 4.56 (br. s., 1H), 4.16-4.09 (m, 1H), 3.67 (dd, J=11.4, 7.7 Hz, 1H), 3.53-3.50 (m, 3H), 3.50-3.45 (m, 1H), 3.40-3.34 (m, 1H), 3.11 (dd, J=11.6, 8.5 Hz, 1H); MS (ES+) m/z: 353.1, 354.0 (M+H); LC retention time: 2.01 min (analytical HPLC Method B).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32]C)=[O:31])=[CH:25][C:24]=2[O:34][CH3:35])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2COCC[Si](C)(C)C)(=[O:11])=[O:10].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][C:24]=2[O:34][CH3:35])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][NH:17]2)(=[O:10])=[O:11]
Reactant: COC(=O)Cc1ccc(Oc2ccc3c(cnn3COCC[Si](C)(C)C)c2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(OC)c1
Agent: Cl
Solvent: CCO
Product: COc1cc(CC(=O)O)ccc1Oc1ccc2[nH]ncc2c1NS(=O)(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of methyl 2-(4-(4-(2,4-dichlorophenylsulfonamido)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yloxy)-3-methoxyphenyl)acetate (45 mg, 0.06 mmol) in ethanol (2 mL) was added 6N aqueous hydrochloric acid (1 mL). The resulting solution was heated at reflux for 3 h. After that time the mixture was cooled to room temperature and concentrated under reduced pressure and the residue taken up in THF (3 mL) and an excess of 2N aqueous lithium hydroxide added. The mixture was stirred at reflux for 1 h, then cooled to room temperature. The mixture was concentrated under reduced pressure. Column chromatography of the residue (1-5% MeOH/DCM with 0.1% AcOH) afforded the product as a cream solid. LC-MS ESI (pos.) m/e: 523 (M+H). 1H NMR (500 MHz) (d6DMSO) δ 11.20 (s, 1H); 10.25 (s, 1H); 7.96 (s, 1H); 7.68 (d, J=8 Hz, 1H); 7.56 (s, 1H), 7.35 (m, 2H); 6.93 (s, 1H), 6.70 (d, J=9 Hz, 1H); 6.61 (d, J=8 Hz, 1H); 6.24 (d, J=9 Hz, 1H); 3.70 (s, 3H); 3.55 (s, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([CH2:11][NH:12][NH2:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:18][C:19](=O)[CH:20]=[C:21]([NH2:25])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:25][C:21]1[NH:13][N:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:15][CH:14]=2)[C:19](=[O:18])[CH:20]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1ccc(-c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(-c3ccccc3)cc2)[nH]1
Reaction time: 8 h

Procedure:
A solution of 29 g of 4-phenylbenzylhydrazine in 60 ml of ethanol was added dropwise, under nitrogen, to a solution of 23.4 g (0.147 mol) of β-amino-β-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid in 100 ml of ethanol. During addition the temperature rose from 22° to 32° C. After standing overnight, the reaction solution was concentrated in vacuo, the precipitate which separated out was dissolved in 2 N sodium hydroxide solution and the alkaline solution was repeatedly extracted with ether. Addition of dilute acetic acid until the mixture reacted weakly acid yielded the compound identified above, which melted at 185°-186° after recrystallisation from ethanol. 13 g (33%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.[Br:25]Br>C(Cl)Cl>[Br:25][CH:9]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:20]
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1

Procedure:
To 1-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)ethanone (1.00 g) in CH2Cl2 containing CHCl3 (1.0 mL) and Cl4 (1.0 mL) was added bromine (0.614 g). After shining light for 1 h, the reaction was quenched with Na2S2O4, extracted with CH2Cl2, dried over Na2SO4 and evaporated to yield the title compound which was used as such for the next step (1.10 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH:17]([F:19])[F:18])[C:10]2[CH2:14][O:13][C:12](=[O:15])[CH:11]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:27]N1C(=O)CCC1=O>C(#N)C>[Br:27][C:11]1[C:12](=[O:15])[O:13][CH2:14][C:10]=1[N:9]([CH2:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:16][CH:17]([F:19])[F:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1C=C(N(Cc2ccc(Cl)nc2)CC(F)F)CO1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1OCC(N(Cc2ccc(Cl)nc2)CC(F)F)=C1Br
Reaction time: 3 h
Yield: 78.6 %

Procedure:
313 mg (1.08 mmol) of 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one (1) are dissolved in 20 ml of acetonitrile, and 166 μl (1.19 mmol) of triethylamine and 386 mg (2.17 mmol) of N-bromosuccinimide are added at room temperature. After 3 hours of stirring, the mixture is concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (2:1) gives 312 mg (63% of theory) of 3-bromo-4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[CH:7][C:8]=1[Cl:9].Cl[CH2:12][CH2:13][CH2:14][OH:15]>>[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[Cl:9])[O:10][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: OCCCCl
Agent: [Na]
Product: OCCCOc1ccc(Cl)c(Cl)c1
Yield: 90 %

Procedure:
Preparation analogously to Example 70 by the reaction of 3,4-dichlorophenol sodium salt with 3-chloro-1-propanol to give 3-(3,4-dichlorophenoxy)-1-propanol (m.p. 40°-43°; yield about 90%), which is converted quantitatively into 3-(3,4-dichlorophenoxy)-propyl 1-methanesulphonate (m.p. 41°-43°) and is reacted with excess 5-amino-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate in boiling ethanol. Isolation as hydrochloride. Yield, after recrystallisation from ethanol: 56%.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)(O)=[O:2].O1CCCC1.C(Cl)(=O)C([Cl:20])=O>>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([Cl:20])=[O:2])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(C(=O)Cl)cc1
Temperature: 2.5 °C

Procedure:
To a thin suspension of 4-carboxybenzaldehyde (600 g, 3.92 mol) in tetrahydrofuran (2664 g, 36.57 mol) was added dimethylformadehyde (11.48 g, 0.16 mol) and the reaction mixture was cooled to 0-5° C. with an ice bath. The reaction mixture was then stirred at 0° C. while oxalyl chloride (608.69 g, 4.70 mol) was added slowly. The reaction mixture was stirred until it was deemed complete by 1HNMR to yield the title compound. The reaction mixture was used in the next step without further manipulation.
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:18]=[C:17]([CH3:19])[C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[C:10]([CH3:20])[CH:9]=2)=O)[S:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:22][OH:23].Cl>N1C=CC=CC=1>[S:5]1[CH:4]=[CH:3][CH:2]=[C:1]1[C:6](=[N:22][OH:23])[C:8]1[CH:18]=[C:17]([CH3:19])[C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[C:10]([CH3:20])[CH:9]=1
Reactant: Cc1cc(C(=O)c2cccs2)cc(C)c1OCC(=O)O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(C(=NO)c2cccs2)cc(C)c1OCC(=O)O
Reaction time: 3 h

Procedure:
4 g of 4-(2-thenoyl)-2,6-dimethyl-phenoxyacetic acid and 4 g of hydroxylamine hydrochloride were dissolved in 30 ml of pyridine and the mixture was kept for 3 hours at reflux. The mixture was then poured into an N aqueous solution of hydrochloric acid and the oxime extracted in ethyl ether. The remaining solid, after evaporation of the solvent, was a mixture of the two isomers of the oxime which melted at 152° C.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][C:7]([CH2:10][OH:11])=[CH:6][CH2:5]1)([CH3:3])=[CH2:2]>C(O)C.[Ni]>[CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: C=C(C)C1CC=C(CO)CC1
Agent: [Ni]
Solvent: CCO
Product: CC(C)C1CCC(CO)CC1

Procedure:
10 g of 4-isopropenyl-cyclohex-1-enylmethanol dissolved in 200 ml of ethanol were hydrogenated at atmospheric pressure in the presence of 200 mg of Raney nickel. The reaction mixture was then filtered, evaporated and finally subjected to a fractional distillation. It was thus isolated a product having bp 75° - 115°/10 Torr. The vapour phase chromatography analysis showed that the isolated product contained 50% of a 60 : 40 (parts by weight) mixture of cis and trans isomers of the desired alcohol.
Reaction SMILES: [OH:1][C@@H:2]([CH:4]1[CH:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])[NH:6][C:5]1=[O:18])[CH3:3]>CO.[Pd]>[OH:1][C@@H:2]([CH:4]1[CH:7]([C:8]([OH:10])=[O:9])[NH:6][C:5]1=[O:18])[CH3:3]
Reactant: C[C@@H](O)C1C(=O)NC1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](O)C1C(=O)NC1C(=O)O

Procedure:
3(b) 500 mg of the benzyl 3-[(R)-1-hydroxyethyl]-2-oxoazetidine-4-carboxylate (prepared as described in above) were dissolved in 5 ml of methanol, and the mixture was hydrogenated in the presence of 100 mg of a 0% w/w palladium-on-carbon catalyst at room temperature for 2 hours. At the end of this time, the catalyst was removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, to give 310 mg of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]1[C:22]2[C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1>>[C:2]1([CH2:1][C:21]2([OH:23])[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:22]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: Cl[Mg]Cc1ccccc1
Product: OC1(Cc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
from benzylmagnesium chloride and 9-fluorenone;
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[O:22])[CH2:8]2)[O:4][N:3]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>C(O)C>[CH2:30]([N:32]([CH2:33][CH3:34])[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[O:22])[CH2:8]2)[O:4][N:3]=1)[CH3:31]
Reactant: CCNCC
Reactant: CCc1ccc(C2CC(c3nc(Cl)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Solvent: CCO
Product: CCc1ccc(C2CC(c3nc(N(CC)CC)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reaction time: 5 h

Procedure:
To a solution of 45.0 mg (0.098 mmol) of the oxadiazole from Example 25A in 0.61 ml of ethanol were added 143 mg (1.96 mmol) of diethylamine, and then the reaction mixture was stirred in the microwave at 80 for 5 h. Another 143 mg (1.96 mmol) of diethylamine were added and the mixture was stirred in the microwave at 80° C. for a further 2 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 35.6 mg (80% of theory)
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH:6]1([C:11]2[C:15]3[N:16]=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH3:29])[NH:18][C:19](=[O:20])[C:14]=3[O:13][N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1>ClCCl>[CH:6]1([C:11]2[C:15]3[N:16]=[C:17]([C:21]4[CH:26]=[C:25]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH3:29])[NH:18][C:19](=[O:20])[C:14]=3[O:13][N:12]=2)[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=S(=O)(O)Cl
Reactant: CCOc1ccccc1-c1nc2c(C3CCCC3)noc2c(=O)[nH]1
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nc2c(C3CCCC3)noc2c(=O)[nH]1
Reaction time: 8 h

Procedure:
0.24 ml (3.6 mmol) of chlorosulfonic acid is introduced while cooling with ice. 130 mg (0.4 mmol) of 3-cyclopentyl-5-(2-ethoxyphenyl)-isoxazolo[4,5-d]pyrimidin-7(6H)-one (example VIII) are added in portions and the mixture is subsequently stirred overnight under reflux; after that, it is diluted with dichloromethane and poured onto ice water. The organic phase is separated off and extraction with dichloromethane takes place again; the organic phases are combined, dried and evaporated.