Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[CH3:23][N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH2:25][CH2:26][NH2:27].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:27][CH2:26][CH2:25][N:24]([CH3:23])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CN(CCN)c1ccccn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1c(NCCN(C)c2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 100 °C
Reaction time: 3 h
Yield: 47.7 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (400 mg, 1.44 mmol), N-methyl-N-(2-pyridyl)-1,2-ethanediamine (326 mg, 2.16 mmol) and triethylamine (0.300 mL, 2.15 mmol) in anhydrous DMSO (6 mL) was stirred at 100° C. for 3 h. After cooling, the reaction mixture was poured into ice-water (50 mL), the resulting precipitate was collected by filtration and washed with water. The obtained solid was recrystallized from EtOH to give 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[2-[methyl(2-pyridyl)amino]ethylamino]-4-oxoquinoline-3-carboxylic acid (303 mg, 48%) as yellow needles.
Reaction SMILES: FS([O-])(=O)=[O:3].Cl[C:7]1[C:11]([Cl:12])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:9][N+:8]=1[CH3:18]>C([O-])([O-])=O.[K+].[K+]>[Cl:12][C:11]1[C:7](=[O:3])[N:8]([CH3:18])[S:9][C:10]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=S(=O)([O-])F
Reactant: CCOC(=O)c1s[n+](C)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1sn(C)c(=O)c1Cl
Yield: 37.6 %

Procedure:
3,4-Dichloro-5-ethoxycarbonyl-2-methylisothiazolium fluorosulfonate (4.2 g, 0.012 mol) was added to 50 ml of saturated K2CO3 solution. The aqueous phase was extracted wih 3×50 ml of CH2Cl2. The combined extracts were dried (MgSO4), filtered and conc. to yield a solid. Recrystallization from heptane yielded 1.0 g (35%) of 4-chloro-5-ethoxycarbonyl-2-methyl-4-isothiazolin-3-one, mp 142-147.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:31]1[N:36]=[C:35]([C:37]([O:39]C)=[O:38])[CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>CO.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>[N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([C:31]5[N:36]=[C:35]([C:37]([OH:39])=[O:38])[CH:34]=[CH:33][CH:32]=5)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(Br)n1
Reactant: CC1(C)OB(c2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)c1cccc(-c2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)n1
Temperature: 80 °C

Procedure:
A vial containing (R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (Example 64A, 23 mg, 0.056 mmol), methyl 6-bromo-2-pyridinecarboxylate (12 mg, 0.056 mmol), bis(triphenylphosphine)palladium(II) chloride (5 mg, 7 μmol), and K2CO3 (23 mg, 0.17 mmol) in methanol (0.5 mL) was heated to 80° C. for 2 hours and cooled. The mixture was filtered and concentrated. The residue was purified by preparative HPLC on a Phenomenex Luna C8(2) 5 um 100 Å AXIA column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A). Samples were injected in 1.5 mL dimethyl sulfoxide:methanol (1:1). A custom purification system was used, consisting of the following modules: Waters LC4000 preparative pump; Waters 996 diode-array detector; Waters 717+ autosampler; Waters SAT/IN module, Alltech Varex III evaporative light-scattering detector; Gilson 506C interface box; and two Gilson FC204 fraction collectors. The system was controlled using Waters Millennium32 software. Fractions were collected based upon UV signal threshold and selected fractions subsequently analyzed by flow injection analysis mass spectrometry using positive APCI ionization on a Finnigan LCQ using 70:30 methanol:10 mM NH4OH (aqueous) at a flow rate of 0.8 mL/minute. Loop-injection mass spectra were acquired using a Finnigan LCQ running LCQ Navigator 1.2 software and a Gilson 215 liquid handler for fraction injection. The title compound was obtained as the bis trifluoroacetate salt. 1H NMR (300 MHz, CD3OD) δ ppm 1.52-1.68 (m, 1H), 1.74-1.93 (m, 3H), 1.95-2.09 (m, 2H), 2.32-2.47 (m, 1H), 2.64-2.75 (m, 1H), 3.02-3.23 (m, 2H), 3.51-3.76 (m, 3H), 3.79-3.95 (m, 2H), 4.08-4.22 (m, 2H), 7.64 (d, J=8.5 Hz, 1H), 7.99-8.09 (m, 2H), 8.10-8.17 (m, 2H), 8.62 (d, J=1.7 Hz, 1H); MS (DCI/NH3) m/z 409 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC#N.CC#N.CC#N.CC#N.F[P-](F)(F)(F)(F)F.[Cu+]>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][C:6](=[CH:5][C:4]2[CH:19]=[CH:20][CH:21]=[C:2]([O:1][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:3]=2)[CH2:11][CH2:10]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(O)c2)CC1
Reactant: Brc1ccccn1
Agent: [Cu+]
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccccn3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A mixture of tert-butyl 4-(3-hydroxybenzylidene)piperidine-1-carboxylate (0.300 g, Example 57, Step 3), 2-bromopyridine (0.253 mL, 1.50 equiv), cesium carbonate (1.13 g, 2.01 equiv), and tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.048 g, 0.075 equiv) in toluene (9 mL, 0.2 M) was heated to reflux for 12 hours. Additional tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.02 g) and 2-bromopyridine (0.1 mL) were added, and the reaction was heated an additional 6 hours. After cooling to room temperature, the reaction was filtered through Celite, washing the Celite with dichloromethane. The filtrate was concentrated and purified on 60 g silica gel using a gradient eluent consisting of 0-10% ethyl acetate/dichloromethane over 60 minutes to give the title compound as a white solid. 0.483 g, 76% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (9H, s), 2.29 (2H, br. S.), 2.45 (2H, t, J=5.5 Hz), 3.37 (2H, t, J=5.4 Hz), 3.47 (2H, t, J=5.7 Hz), 6.32 (1H, s), 6.76-7.13 (5H, m), 7.32 (1H, t, J=7.7 Hz), 7.67 (1H, t, J=6.5 Hz), 8.18 (1H, br. s.).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11]([O:13][CH3:14])=[O:12])[CH2:8]2.C([N-]C(C)C)(C)C.[Li+].[CH3:23][O:24][CH2:25][CH2:26]Br>O1CCCC1>[CH3:23][O:24][CH2:25][CH2:26][C:2]1([C:11]([O:13][CH3:14])=[O:12])[CH:1]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]1[CH2:4]3)[CH2:8]2
Reactant: COC(=O)C1C2CC3CC(C2)CC1C3
Reactant: COCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCC1(C(=O)OC)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 56A (0.314 g) in tetrahydrofuran (5 mL) was added dropwise lithium diisopropylamide (1.401 mL) at −78° C. The reaction mixture was stirred for 60 minutes and 2-bromoethyl methyl ether (0.562 g) was added. The reaction mixture was slowly warmed up to room temperature, stirred at room temperature overnight, quenched with saturated aqueous NH4Cl solution (2 mL), and extracted with ether. The combined organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromotography (silica 40 g, 0%-30% ethyl acetate/hexanes).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([Cl:22])=[CH:17][C:16]=2[C:23]2[N:27]([CH3:28])[CH:26]=[N:25][N:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([Cl:22])=[CH:17][C:16]=2[C:23]2[N:27]([CH3:28])[C:26]([CH2:26][N:27]([CH3:28])[CH3:23])=[N:25][N:24]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cnnc1-c1cc(Cl)c(F)cc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Solvent: CN(C)C=O
Product: CN(C)Cc1nnc(-c2cc(Cl)c(F)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 25 mL pear-shaped flask was charged with 4-tert-butyl-N-[4-chloro-5-fluoro-2-(4-methyl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide (prepared according to general procedure C) (75 mg, 0.18 mmol), N,N-dimethylmethyleneiminium iodide (43 mg, 0.23 mmol), and DMF (0.44 mL). The flask was heated to 100° C. and stirred overnight. The following day, the solvent was evacuated in vacuo and the residue was purified via HPLC to afford 4-tert-butyl-N-[4-chloro-2-(5-dimethylaminomethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-5-fluoro-phenyl]-benzenesulfonamide as a white powder: 1H NMR (400 MHz, CD3OD) δ 7.60 (d, 1H), 7.48-7.54 (m, 4H), 7.28 (d, 1H), 3.70 (s, 2H), 3.46 (s, 3H), 2.36 (s, 6H), 1.33 (s, 9H), MS (ES) M+H expected 480.2, found 480.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[Mg].[B:11]([O:20]C(C)C)([O:16]C(C)C)[O:12]C(C)C.S(=O)(=O)(O)O>O1CCCC1>[F:9][C:4]1[CH:3]=[C:2]([O:12][B:11]([OH:20])[OH:16])[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: Fc1ccc(Br)cc1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: OB(O)Oc1ccc(F)c(F)c1
Temperature: -65 °C
Reaction time: 1 h

Procedure:
A Grignard reagent solution prepared from 46.8 g of 1-bromo-3,4-difluorobenzene and 6 g of magnesium in 150 ml of tetrahydrofuran is added dropwise at -65° C. under nitrogen to a solution of 72.8 ml of triisopropyl borate in 200 ml of tetrahydrofuran. The mixture is stirred at -65° C. for 1 hour, warmed to 14°-20° C., treated dropwise with 100 ml of 10 percent (v/v) sulphuric acid, left to stand overnight and the separated salt is filtered off. The aqueous phase of the filtrate is separated and extracted with diethyl ether. The organic phases are combined, washed with sodium chloride solution, dried over sodium sulphate and evaporated. After boiling with hexane the residue gives 22.1 g of colourless 3,4-difluorophenylboric acid m.p. 275°-277.5° C. (sublimed).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:15][CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)[C:4]=2[C:5]([N:8]=CN(C)C)=[N:6][CH:7]=1.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[S:42](Cl)(=[O:44])=[O:43]>>[NH2:8][C:5]1[C:4]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)=[CH:14][S:15][C:3]=2[C:2]([NH:1][S:42]([C:38]2[S:37][CH:41]=[CH:40][CH:39]=2)(=[O:44])=[O:43])=[CH:7][N:6]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1cc(-c2csc3c(N)cnc(N=CN(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2csc3c(NS(=O)(=O)c4cccs4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-[4-(7-amino-4-{[(dimethylamino)methylene]amino}thieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide and 2-thiophenesulfonyl chloride using General Procedure G followed by General Procedure M. 1H NMR (DMSO-d6, 400 MHz) δ 9.70 (br, 1H), 9.49 (s, 1H), 7.97 (d, 1H), 7.80 (m, 1H), 7.70 (d, 1H), 7.58 (d, 1H), 7.47 (s, 1H), 7.40 (m, 1H), 7.37 (s, 1H), 7.34 (m, 2H), 7.17 (s 1H), 7.14 (d, 1H), 7.07 (m, 2H), 5.35 (br, 2H), 4.03 (s, 3H), 3.90 (s, 3H); MS; (M−H)− 588.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C([BH3-])#N.[Na+]>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]2[O:13][CH2:12][C:11](=[O:22])[N:10]([CH2:9][CH2:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][CH2:34][C:32]4[CH:31]=[CH:30][C:27]5[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=5[N:33]=4)[CH2:3][CH2:4]3)[C:15]=2[CH:16]=1
Reactant: COc1ccc2c(c1)N(CC[C@H]1CC[C@H](N)CC1)C(=O)CO2
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccc2c(c1)N(CC[C@H]1CC[C@H](NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)CO2

Procedure:
4-[2-(Trans-4-aminocyclohexyl)ethyl]-6-methoxy-2H-1,4-benzoxazin-3(4H)-one (Intermediate 74) (310 mg, 1.73 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (1.73 mmol) and sodium cyanoborohydride were reacted as described under Example 21 to give 110 mg (24%) product.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:7][N:6]=[CH:5]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:7]1[N:6]=[CH:5][N:4]2[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:2][CH2:3]2
Reactant: OCCn1cncc1-c1ccccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc2c(c1)OCCn1cncc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a stirred solution of 2-(1-(2-hydroxyethyl)-1H-imidazol-5-yl)phenol (103.0 mg, 0.5 mmol) and PPh3 (157.0 mg, 0.6 mmol) in THF (4 mL) at 0° C., was added DEAD (0.22 mL, 40% solution in toluene, 0.75 mmol). The resulting yellow solution was allowed to warm to rt and stirred overnight. The solvent was removed under reduced pressure and the crude residue was purified by flash column chromatography on silica gel to afford the desired product in 84% yield. 1H NMR: 4.35-4.45 (m, 4H), 6.94-7.05 (m, 2H), 7.11-7.19 (m, 1H), 7.43 (d, 1H, J=0.8 Hz), 7.49 (s, 1H), 7.67 (dd, 1H, J=1.6, 8.0 Hz).
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][CH:15]=[C:14]([C:21](O)=[O:22])[CH:13]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:25][NH:26][O:27][CH3:28].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(=O)([O-])O.[Na+].C(#N)C>[CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][CH:15]=[C:14]([C:21]([N:26]([CH3:25])[O:27][CH3:28])=[O:22])[CH:13]=4)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNOC
Reactant: O=C(O)c1ccc2[nH]c(=O)c3cnc(C4CCCCC4)n3c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc2[nH]c(=O)c3cnc(C4CCCCC4)n3c2c1
Reaction time: 24 h

Procedure:
1-Cyclohexyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxyic acid as synthesized in Example 103, 6.23 g, N,O-dimethylhydroxyamine hydrochloride 2.15 g, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 5.75 g, 1-hydroxybenzotriazole monohydrate 3.97 g, acetonitrile 51 mL and N,N-diisopropylethylamine 7.3 mL were mixed and stirred for 24 hours. The reaction liquid was poured in saturated aqueous sodium hydrogencarbonate solution and extracted with tetrahydrofuran and ethyl acetate. The organic layer was washed twice with saturated brine and dried over magnesium sulfate. After distilling the solvent off, the residue was heat-suspended in 200 mL of acetone and purified, to provide 3.36 g of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([CH3:15])[CH:8]=1)[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.O>ClCCCl>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][C:2]([CH3:1])([CH3:16])[C:3]2=[O:5])=[CH:8][C:9]=1[CH3:15]
Reactant: COc1ccc(CC(C)(C)C(=O)O)cc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCCl
Product: COc1cc2c(cc1C)CC(C)(C)C2=O
Reaction time: 2 h

Procedure:
A mixture of 9.0 g of 2,2-dimethyl-3-(4-methoxy-3-methylphenyl)propanoic acid and 20 mL of oxalyl chloride was prepared and allowed to stir for 2 hours. The volatiles were then removed by evaporation under reduced pressure. The residue was dissolved in 30 mL of carbon disulfide and the solution was added with stirring to a mixture of 7.4 g of aluminum chloride and 30 mL of carbon disulfide. The mixture was allowed to react for 2 hours and was then diluted with 200 mL of 1,2-dichloroethane. Water was added slowly with stirring and, after 2 hours, the mixture was extracted with dichloromethane. The extract was dried over sodium sulfate and concentrated by evaporation under reduced pressure. The residue was distilled to obtain the title compound as a colorless liquid boiling at 90°-95° C. under 1 mm Hg (133 Pascals) pressure.
Reaction SMILES: [BH4-].[Na+].C(O)(=O)C(O)=O.[C:9]([CH2:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=1[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:27](OCC)=[O:28])#[N:10].CO.Cl>C1COCC1.O.ClCCl>[OH:28][CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22][C:13]1[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=1[CH2:11][C:9]#[N:10]
Reactant: CCOC(=O)CCNCCc1cc(OC)c(OC)cc1CC#N
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CC#N)c(CCNCCCO)cc1OC
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
To a suspension of 10.8 g of NaBH4 (284 mmol, 11 eq.) in 110 mL of THF there is added, at several points over a period of time, ethyl N-{2-[2-(cyanomethyl)-4,5-dimethoxyphenyl]ethyl}-β-alaninate oxalate (10.6 g, 25.9 mmol). Stirring is carried out for 30 minutes at ambient temperature, and then 23.1 ml of methanol (570 mmol, 22 eq.) are poured in dropwise. The mixture is heated for 16 hours at 60° C., and is then hydrolysed using 100 mL of 5N hydrochloric acid. There are then added 100 mL of dichloromethane and 200 mL of demineralised water. After separation of the phases, 50 ml of 10N sodium hydroxide solution are added (pH>10) to the aqueous phase and extraction is carried out using 3×70 mL of dichloromethane. The organic phases are combined and washed with 2×75 mL of saturated aqueous NaCl solution and then dried over MgSO4. After carrying out drying in vacuo, there are obtained 6.15 g of a colourless oil corresponding to the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]#[CH:12].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][SH:18].[Na]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[CH:11]=[CH:12]\[CH:11]([S:18][CH:17](/[CH:12]=[CH:11]\[C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])[C:16]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=1[O:14][CH3:13])[C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(CS)c(OC)c1
Reactant: C#Cc1ccc(OC)cc1OC
Agent: [Na]
Product: COc1ccc(/C=C\C(SC(/C=C\c2ccc(OC)cc2OC)c2ccc(OC)cc2OC)c2ccc(OC)cc2OC)c(OC)c1

Procedure:
A solution of 2,4-dimethoxyphenylacetylene (0.02 mol), 2,4-dimethoxybenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,4-dimethoxystyryl-2,4-dimethoxybenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.I[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:17]
Reactant: OCCc1ccc(Cl)cc1
Reactant: CCOC(=O)CI
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)COCCc1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 78.1, 2-(4-chloro-phenyl)-ethanol was reacted with ethyl iodoacetate in the presence of silver trifluoromethanesulfonate and 2,6-di-tert-butylpyridin to give [2-(4-chloro-phenyl)-ethoxy]-acetic acid ethyl ester as colorless liquid. MS: m/e=243.2 [M+H+].
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:9]([CH3:10])=[CH:8][C:7](=[O:11])[CH2:6][S:5]1(=[O:13])=[O:12].[CH3:14]I>O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:3][N:4]1[C:9]([CH3:10])=[CH:8][C:7](=[O:11])[CH:6]([CH3:14])[S:5]1(=[O:12])=[O:13]
Reactant: CC1=CC(=O)CS(=O)(=O)N1C
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC1=CC(=O)C(C)S(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.6 %

Procedure:
A solution of 1.6 g of sodium hydroxide in 20 ml of water was added dropwise at 5°-12° with vigorous stirring to a solution of 3.5 g of 2,3-dimethyl-1,2-thiazin-5(6H)-one 1,1-dioxide, 6.8 g of tetrabutylammonium hydrogen sulfate and 1.9 ml (0.03 mol) of methyl iodide in 40 ml of methylene chloride. The mixture was thereafter stirred vigorously at room temperature for 15 minutes. The organic phase was separated, the aqueous phase was extracted twice with 15 ml of methylene chloride and the combined organic phases were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The oily residue was chromatographed on 300 g of silica gel with chloroform/n-heptane/ethanol (10:10:1) as the elution agent. The uniform fractions were combined and evaporated. After triturating the residue with ether there were obtained 1.8 g of 2,3,6-trimethyl-2H-1,2-thiazin-5(6H)-one 1,1-dioxide in the form of colorless crystals, m.p. 73°-75°.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([SH:17])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].[C:18]1([S:24]([CH2:27][CH2:28][CH:29]2[CH:32]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:31][C:30]2=[O:43])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.C(OCC)C>[C:18]1([S:24]([CH2:27][CH2:28][CH:29]([CH:32]([S:17][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH3:7])[CH:10]=2)[CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:30]([OH:43])=[O:31])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc(S)cc1OC
Reactant: O=C1OC(CCCCc2ccccc2)C1CCS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(SC(CCCCc2ccccc2)C(CCS(=O)(=O)c2ccccc2)C(=O)O)cc1OC
Yield: 78.4 %

Procedure:
To a vigorously stirring suspension of cesium carbonate (0.88 g, 2.69 mmol) in anhydrous DMF (10 mL) under a nitrogen atmosphere is added 3,4-dimethoxythiophenol (0.45 g, 2.69 mmol) in a dropwise fashion. The white heterogeneous mixture is stirred for 15 minutes then a solution containing (-)-3-(2-benzenesulfonylethyl)-4-(4-phenylbutyl)-oxetan-2-one (0.50 g, 1.34 mmol) in anhydrous DMF (4 mL) is added. The pale yellow heterogeneous mixture is stirred at room temperature for 2.5 hours then partitioned between water (50 mL) and diethyl ether (50 mL). Aqueous HCl (1 N, 5 mL) is added and the layers are separated. The aqueous phase is extracted with diethyl ether (2×20 mL) and the combined organic extracts are washed with water (10×10 mL), brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated to afford a pale yellow oil. The crude product is chromatographed on silica gel (CH2Cl2 →CH2Cl2 :MeOH, 19:1) to afford a colorless oil which is dissolved in diethyl ether (100 mL) and washed with water (10×30 mL) to remove residual DMF. The organic phase is washed with brine (30 mL), dried over anhydrous MgSO4, filtered and concentrated to afford (-)-2-(2-benzenesulfonylethyl)-3-(3,4-dimethoxyphenyl-sulfanyl)-7-phenylheptanoic acid (0.57 g, 78%) as a white foam. TLC analysis [hexane/EtOAc, 2:1, Rf (lactone)=0.65, Rf (acid)=0.05]. [α]23D -35.3° (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.31-1.70 (m, 6H), 2.00 (m, 1H), 2.30 (m, 1H), 2.56 (m, 3H), 2.95 (m, 1H), 3.25 (m, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 6.77 (d, J=8.2 Hz, 1H), 6.95 (m, 2H), 7.15 (m, 3H), 7.25 (m, 2H), 7.55 (m, 2H), 7.65 (m, 1H), 7.90 (m, 2H) ppm. Mass spectrum (FAB) m/z 542 (M)+.