Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:21]=[N:22][CH:23]=2)[C:19]=1Cl)=[O:13].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:21]=[N:22][CH:23]=2)[C:19]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1])=[O:13]
Reactant: Nc1ccc(I)cc1F
Reactant: COC(=O)c1ccc2cncn2c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To a stirred suspension 2-fluoro-4-iodo aniline (53.95 g, 0.256 mol) and 5-chloro-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (62.0 g, 0.253 mol) in THF (500 mL) under nitrogen at −78° C., a solution of lithium bis(trimethylsilyl)amide (544 mL, 1M solution, 0.544 mol) was added dropwise over 1 hr, maintaining the temperature below −65° C., giving a red/brown solution. After stirring for 30 minutes at −78° C. the reaction mixture was allowed to warm to −30° C. and then quenched with addition water (100 mL). The solvent was removed in vacuo, before diluting with water (500 ml) and the mixture was extracted with 2-methyltetrahydrofuran (2×500 mL). The combined organic extracts were washed with water, then brine, dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was triturated tert-butyl methyl ether (600 mL) to yield product as yellow/brown solid (87.2 g 83%). LCMS (Method B): RT=3.54 min, [M+H]+=412.
Reaction SMILES: CN(C(ON1N=[N:16][C:11]2C=C[CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[C:34]2[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=[N:30][C:29]=2[S:28][C:27]=1[C:49](O)=[O:50].CCN(C(C)C)C(C)C.C(N(C)CCN)(OC(C)(C)C)=O>CN(C=O)C>[CH3:25][C:26]1[C:34]2[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=[N:30][C:29]=2[S:28][C:27]=1[C:49]([NH:16][CH2:11][CH2:10][NH:15][CH3:14])=[O:50]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Agent: CN(CCN)C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNCCNC(=O)c1sc2ncnc(Nc3cccnc3OC3CCOCC3)c2c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
HATU (0.157 g, 0.41 mmol) was added into a mixture of 5-methyl-4-(2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine-6-carboxylic acid (0.145 g, 0.38 mmol) and Hünig's base (65 μL, 0.38 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. N-Boc-N-methylethylenediamine (335 μL, 1.88 mmol) was added, the coolant removed and the reaction mixture stirred at ambient temperature overnight. The solvent was concentrated in vacuo and the crude product dissolved in DCM. The organic layer was washed with water, concentrated in vacuo (10 mL) and trifluoroacetic acid added (3.0 mL). The mixture was stirred at ambient temperature overnight, concentrated in vacuo and purified by ion-exchange chromatography (SCX-2 eluting with hydrochloric acid/MeOH→ammonia/MeOH). Further purification by flash-column chromatography (100% DCM→10% ammonia/MeOH/DCM) yielded the title compound as pale yellow solid (0.043 g, 25%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][CH3:8])(=[O:4])[CH2:2][CH3:3].[CH:10]([CH:12]=[CH2:13])=[O:11].CC1C=C(C)C=C(C)N=1>S(=O)(=O)(O)O>[C:1]([O:5][CH:6]([O:9][C:10](=[O:11])[CH2:12][CH3:13])[CH:7]=[CH2:8])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)OC(=O)CC
Reactant: C=CC=O
Agent: O=S(=O)(O)O
Solvent: Cc1cc(C)nc(C)c1
Product: C=CC(OC(=O)CC)OC(=O)CC
Reaction time: 0.17 h
Yield: 57.6 %

Procedure:
To a solution of 345 g (2.65 mols) propionic anhydride and 1.05 g concentrated sulfuric acid maintained at 45°-50° C was added dropwise 140 g (2.5 mols) acrolein over a period of 15 minutes. The reaction mixture was stirred for an additional 10 minutes. A 2.6 g-sample of 2,4,6-trimethyl-pyridine was then added and the reaction mixture stirred at about 25° C. for about 17 hours. The reaction mixture was then distilled through a short column to give 268 g of the product as a slightly yellow liquid, b.p. 96°-101° C (0.25 mm Hg).
Reaction SMILES: CC1(C)C(C)(C)OB([CH:9]2[CH2:11][CH:10]2[CH2:12][NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)O1.Cl[C:26]1[N:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:32][C:29]1[CH:28]=[N:27][C:26]([CH:9]2[CH2:11][CH:10]2[CH2:12][NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:31][CH:30]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: CC1(C)OB(C2CC2CNC(=O)OCc2ccccc2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCC1CC1c1ncc(F)cn1)OCc1ccccc1
Temperature: 100 °C
Yield: 214.7 %

Procedure:
A mixture of benzyl ((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)methyl)carbamate (500 mg, 1.510 mmol), 2-chloro-5-fluoropyrimidine (45 mg, 0.340 mmol), potassium carbonate (100 mg, 0.724 mmol), and tetrakis(triphenylphosphine) palladium (0) (10 mg, 8.65 μmol) in dioxane (2 mL) and water (0.4 mL) was heated to 100° C. in a sealed vial for 16 h. The mixture was diluted with EtOAc and washed with sat'd sodium carbonate. The EtOAc layer was concentrated to an amber oil. The crude product was purified by silica gel chromatography using 0-30% EtOAc/hexane as the eluent to give benzyl ((2-(5-fluoropyrimidin-2-yl)cyclopropyl)methyl)carbamate as a colorless oil (220 mg, 42%). 1H NMR (400 MHz, CHLOROFORM-d) d 8.45-8.31 (m, 2H), 7.36-7.30 (m, 5H), 5.10 (s, 2H), 4.07 (br. s., 1H, NH), 3.39-3.15 (m, 2H), 2.19 (dt, J=8.5, 4.4 Hz, 1H), 1.78-1.62 (m, 1H), 1.31 (dt, J=8.7, 4.5 Hz, 1H), 1.09-0.95 (m, 1H). LCMS: M+1=302.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[S:5][C:6]=1[CH:7]=O.Cl.NO.[N:16]1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(#N)C.Cl.C(OCC)(=O)C.C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[S:5][C:6]=1[C:7]#[N:16]
Reactant: COC(=O)c1cc(Br)c(C=O)s1
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1cc(Br)c(C#N)s1
Reaction time: 1.5 h
Yield: 94.6 %

Procedure:
To a solution of 16.48 g (66.17 mmol) of methyl 4-bromo-5-formylthiophene-2-carboxylate in 165 mL of acetonitrile was added 5.06 g (72.78 mmol) of hydroxylamine hydrochloride. To this suspension 32.05 mL (397 mmol) of pyridine was added dropwise over a period of 20 min at 20-25° C. After 90 min stirring, neat trifluoroacetic anhydride (22.5 mL, 158.8 mmol) was dropped in over 30 min at room temperature. After 2.5 hours stirring, the reaction mass was poured in a mixture of HCl 0.5 M (200 mL) and ethyl acetate (150 mL); the aqueous layer was extracted again with 150 mL of ethyl acetate. The combined organic extracts were concentrated under reduced pressure and washed again with 120 mL of HCl 1 M. The organic was concentrated under vacuum to afford a raw solid product. This crude material was taken up in 75 mL of ethanol and treated with 75 mL of water under efficient stirring. The resulting suspension was cooled to 0/+4° C., then filtered off to afford 15.4 g of product as light cream solid.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][CH:12]=[C:13](Br)[CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][C@@H:27]2[CH2:29][C@H:24]1[CH2:25][NH:26]2)=[O:22])([CH3:19])([CH3:18])[CH3:17].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:9]1[CH:14]=[C:13]([N:26]2[CH2:25][C@@H:24]3[CH2:29][C@H:27]2[CH2:28][N:23]3[C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH:12]=[N:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: O=C(c1ccccc1)c1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cncc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
In a sealed pressure tube under a nitrogen atmosphere, 3-benzoyl-5-bromopyridine (0.542 g, 2.1 mmol), (1S,4S)-N-(tert-butoxycarb- onyl)-2,5-diazabicyclo[2.2.1]heptane (0.475 g, 2.4 mmol), tris (dibenzylideneacetone)dipalladium (0) (0.04 g, 0.04 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.05 g, 0.08 mmol), sodium tert-butoxide (0.380 g, 3.8 mmol) and anhydrous toluene (20 mL) were stirred at 90° C. for 20 h. The reaction mixture was cooled to room temperature and diluted with water (200 mL) and then extracted with diethyl ether (100 mL). The diethyl ether extract was dried (MgSO4), filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography on silica gel, using a gradient of 50% to 80% ethyl acetate:hexane as eluent, to yield 0.364 g (48%) of a yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]3[CH:48]=[CH:47][C:12]([CH2:13][N:14]([C:32]4[N:36]=[C:35]([C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=5)[O:34][N:33]=4)[CH2:15][CH2:16][C:17]4[CH:31]=[CH:30][C:20]([O:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=4)=[CH:11][CH:10]=3)[N:8]=2)[CH2:3][CH2:2]1.CCO.O.[Li+].[OH-]>C1COCC1>[CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]3[CH:48]=[CH:47][C:12]([CH2:13][N:14]([C:32]4[N:36]=[C:35]([C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:44])([F:45])[F:46])[CH:38]=5)[O:34][N:33]=4)[CH2:15][CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:21][C:22]([CH3:29])([CH3:28])[C:23]([OH:25])=[O:24])=[CH:30][CH:31]=4)=[CH:11][CH:10]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(-c3coc(C4CC4)n3)cc2)c2noc(-c3cccc(C(F)(F)F)c3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(-c3coc(C4CC4)n3)cc2)c2noc(-c3cccc(C(F)(F)F)c3)n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.5 %

Procedure:
To a solution of ethyl 2-{4-[2-([4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]{5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}-2-methylpropanoate (93 mg, 0.14 mmol) in anhydrous THF (1.5 ml) was added EtOH (0.4 ml), water (0.4 ml), and LiOH (31 mg, 1.28 mmol). The mixture was stirred at rt for 12 h. The reaction was quenched with a solution of saturated aqueous KH2PO4, and the aqueous phase was extracted with EtOAc (3×20 ml). The combined organic phases were dried with Na2SO4 and concentrated in vacuo to yield the title compound as a colorless solid (58 mg, 65%). 1H NMR (CDCl3) δ 8.34 (s, 1H), 8.26 (d, 1H, J=7.9), 7.80 (d, 1H, J=7.8), 7.65 (s, 1H), 7.62 (d, 1H, J=8.0), 7.40 (d, 2H, J=8.1), 6.92 (d, 2H, J=8.3), 6.81 (d, 2H, J=8.5), 6.65 (d, 2H, J=8.4), 4.53 (s, 2H), 3.63 (t, 2H, J=6.2), 2.92 (t, 2H, J=6.4), 2.21 (m, 1H), 1.58 (s, 6H), 1.19–1.06 (m, 4H). MS: m/z 633 (M+1).
Reaction SMILES: Br[C:2]12[CH:9]=[CH:8][CH:7]=[CH:6][CH:3]1[CH2:4][CH2:5]2.C([Li])CCC.[C:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:5]1[C:2]2[CH:9]=[CH:8][C:7]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[OH:22])=[CH:6][C:3]=2[CH2:4]1
Reactant: BrC12C=CC=CC1CC2
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccc1)c1ccc2c(c1)CC2
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 42.5 %

Procedure:
3-bromobenzocylcobutene (1.5 g, 8.2 mmol) was dissolved in 50 ml of THF. The solution was cooled to −78° C. To the solution was added butyl-lithium (3.6 mL, 2.0 M in hexanes, 9.0 mmol). After 45 minutes, benzophenone (1.34 g, 7.4 mmol) was added in one portion. The reaction was allowed to warm to room temperature overnight. After normal work-up, the residue was purified by column using 1:1 dichloromethane and hexanes as solvent. 0.9 g of the desired product was obtained (42% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)[CH2:16][CH:17]=[CH2:18])[C:10]2=[O:26])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F-].[Cs+]>COCCOC.C(O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:19]3[CH:24]=[CH:23][C:22]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([C:27]#[N:28])[CH:34]=4)=[CH:21][CH:20]=3)[CH2:16][CH:17]=[CH2:18])[C:10]2=[O:26])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: C=CCC(CN1CCN(c2cc(Cl)cc(Cl)c2)C1=O)c1ccc(I)cc1
Agent: [Cs+]
Agent: [F-]
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCO
Solvent: CCOC(C)=O
Product: C=CCC(CN1CCN(c2cc(Cl)cc(Cl)c2)C1=O)c1ccc(-c2cccc(C#N)c2)cc1
Yield: 49 %

Procedure:
A solution of 1-(3,5-dichloro-phenyl)-3-[2-(4-iodo-phenyl)-pent-4-enyl]-imidazolidin-2-one (0.128 g, 0.255 mmol), 3-cyanophenyl boronic acid (0.113 g, 0.766 mmol, 3 eq), tris(dibenzylidene-acetone)-dipalladium(O) (0.025g, 0.0255 mmol, 10 mol %), triphenylarsine (0.031 g, 0.1 mmol, 40 mol %) and cesium fluoride (0.075 g, 0.51 mmol, 2 eq) in DME (13 mL) and ethanol (3 mL) was microwaved at 50W for 7 h and then at 100W for 1 h. The mixture was diluted with EtOAc (50 mL), filtered through a pad of celite 545® and the filtrate washed with saturated aqueous Na2CO3 solution (25 mL). The aqueous layer was extracted twice with EtOAc (50 mL). The combined organic extracts were washed with saturated aqueous Na2CO3 solution (25 mL) and saturated aqueous sodium chloride solution (25 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated to give a dark oil. Purification by flash column chromatography eluting 15–20% EtOAc/hexanes gave 4′-{1-[3-(3,5-dichloro-phenyl)-2-oxo-imidazolidin-1-ylmethyl]-but-3-enyl}-biphenyl-3-carbonitrile (0.059 g, 0.125 mmol, 49%) as a dark foam. 1H NMR (300 MHz, CDCl3): δ 7.98 (m, 1H), 7.92 (m, 1H), 7.74 (m, 1H), 7.64 (m, 3H), 7.58 (d, 2H), 7.45 (d, 2H), 7.11 (dd, 1H), 5.80 (m, 1H), 5.12 (m, 2H), 3.75 (m, 3H), 3.55 (m, 1H), 4.42 (m, 1H), 3.26 (m, 2H), 2.58 (dd, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([C:10]2[CH:14]=[C:13]([O:15][CH:16]([F:18])[F:17])[N:12]([CH3:19])[N:11]=2)=[CH:5][C:3]=1[NH2:4].C([O-])(=O)C.[Na+].[Br:25]Br>C(O)(=O)C>[Br:25][C:5]1[C:6]([C:10]2[CH:14]=[C:13]([O:15][CH:16]([F:18])[F:17])[N:12]([CH3:19])[N:11]=2)=[C:7]([Cl:9])[CH:8]=[C:2]([Cl:1])[C:3]=1[NH2:4]
Reactant: Cn1nc(-c2cc(N)c(Cl)cc2Cl)cc1OC(F)F
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1nc(-c2c(Cl)cc(Cl)c(N)c2Br)cc1OC(F)F
Reaction time: 8 h

Procedure:
1 g (2.9 mmol) of 2,4-dichloro-5-(5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)aniline and 2.4 g (29 mmol) of sodium acetate were initially charged in 100 ml of glacial acetic acid, and 0.93 g (5.6 mmol) of bromine was added dropwise at room temperature. The reaction mixture was stirred overnight and then concentrated, and the residue was taken up in toluene and washed with 50 ml of 5% by weight strength aqueous sodium hydroxide solution until neutral. The organic phase was dried over magnesium sulfate and concentrated. This gave 1.3 g of the aniline IVa.4. The product that was obtained was identical to the compound obtained according to example 1.1.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([O:24][C@@H:25]2[O:30][C@@H:29]([CH2:31]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:28][CH2:27][CH2:26]2)[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:11][CH:10]=1.[I-].[Na+]>CN(C)C=O.O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([O:24][C@@H:25]2[O:30][C@@H:29]([CH2:31][N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)[CH2:28][CH2:27][CH2:26]2)[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:13][CH:14]=1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OC(c3ccc(Cl)cc3)c3ccc(Cl)cc3Cl)O2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(C(O[C@H]2CCC[C@H](Cn3ccnc3)O2)c2ccc(Cl)cc2Cl)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
114 mg of 55% sodium hydride were added to a solution of 323 mg of imidazole in 10 ml of dimethylformamide, and, after the mixture had been stirred at 80° C. for 30 minutes, it was cooled to room temperature. There were then added 2.20 g of trans-6-[α-(4-chlorophenyl)-2,4-dichlorobenzyloxy]-2-tosyloxymethyltetrahydropyran, dissolved in 15 ml of dimethylformamide, and then 594 mg of sodium iodide were added to the mixture. The resulting mixture stirred under a stream of nitrogen at 90°-95° C. for 4 hours, after which it was cooled, diluted with water and extracted with diethyl ether. The ethereal extract was washed with water and dried over sodium sulphate, after which it was concentrated by evaporation under reduced pressure and the residue was purified by column chromatography through silica gel eluted with a 8:1:0.1 by volume mixture of ethyl acetate, benzene and triethylamine, to give 1.346 g of the title compound as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:16][CH3:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([O:14]C)=[O:13])[O:7][CH2:6][CH2:5]2.O[Li].O>CO.C1COCC1.O>[Br:1][C:2]1[C:3]([O:16][CH3:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([OH:14])=[O:13])[O:7][CH2:6][CH2:5]2
Reactant: COC(=O)C1OCCc2c1ccc(Br)c2OC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(Br)ccc2c1CCOC2C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-bromo-5-(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxylate (650 mg, 2.06 mmol) in 20 mL of MeOH/THF/H2O (2/2/1) was added LiOH.H2O (347 mg, 8.25 mmol), and the mixture was stirred at ambient temperature overnight. The solvents were removed under vacuum, and the residue was added 50 mL of water and extracted with ether. The aqueous layer was then acidified with 4 N HCl to pH=3 in ice bath, and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 6-bromo-5-(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxylic acid.
Reaction SMILES: C([BH3-])#N.[Na+].[I:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.[CH:13](=O)[CH2:14][CH3:15]>CO>[CH2:13]([NH:10][C:9]1[CH:11]=[CH:12][C:6]([I:5])=[CH:7][CH:8]=1)[CH2:14][CH3:15]
Reactant: Nc1ccc(I)cc1
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCNc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Sodium cyanoborohydride (0.63 g) was added to a solution of 4-iodoaniline (2.2 g) and propionaldehyde (0.72 ml) in methanol (15 ml) whilst under an atmosphere of argon. The mixture was stirred at ambient temperature for 72 hours. Sodium cyanoborohydride (0.005 mole) was added and the reaction mixture was stirred for further 48 hours. The pH of the reaction mixture was adjusted to 1 using 2N aqueous hydrocyloric acid. The mixture was filtered and the filtrate was evaporated to yield N-propyl-4-iodoaniline as a solid (1.4 g), NMR: 0.9(3H,t), 1.65(2H,m), 3.1(2H,m), 7.05(2H,d) and 7.67(2H,d).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[CH2:15][O:14][NH:13][C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:20]1([C:26]([O:28][CH3:29])=[O:27])[CH:24]=[CH:23][C:22](=[O:25])[O:21]1>CN(C)C=O.C(OCC)(=O)C.O>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[CH2:15][O:14][N:13]([C:20]3([C:26]([O:28][CH3:29])=[O:27])[CH:24]=[CH:23][C:22](=[O:25])[O:21]3)[C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1CONC1=O
Reactant: COC(=O)C1(Br)C=CC(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C1(N2OC[C@@H](NC(=O)Cc3ccccc3)C2=O)C=CC(=O)O1
Yield: 8.9 %

Procedure:
In 3 ml of anhydrous N,N-dimethylformamide was dissolved 220 mg of (4R)-4-phenylacetamido-3-isoxazolidinone. To the solution were added, under ice-cooling and stirring, 60 mg of sodium hydride (50% mineral oil) and 0.5 ml of anhydrous N,N-dimethylformamide solution dissolving 220 mg of the Compound (26) obtained in Example 26. The reaction solution was stirred for 69 minutes under ice-cooling, which was then poured into a mixture of ethyl acetate and water. The ethyl acetate layer was taken, washed with water and dried (Na2SO4). The solvent was evaporated off, and the residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (2:1→2:3) to give 32 mg of the subject Compound (30) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@:4]([N:9]=[C:10]=[O:11])([CH:6]([CH3:8])[CH3:7])N.[CH2:13]([N:15]([C:18]1[S:19][CH:20]=[C:21]([CH2:23][OH:24])[N:22]=1)[CH2:16][CH3:17])[CH3:14]>ClCCl.CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:9][C:10]([O:24][CH2:23][C:21]1[N:22]=[C:18]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[S:19][CH:20]=1)=[O:11]
Reactant: CCN(CC)c1nc(CO)cs1
Reactant: COC(=O)[C@](N)(N=C=O)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCN(CC)c1nc(COC(=O)N[C@H](C(=O)OC)C(C)C)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
A solution of 5.11 mmol of α-isocyanato-valine methyl ester in 10 ml of dichloromethane was treated with 0.864 g (4.65 mmol) of 2-(N,N -diethylamino)-4-(hydroxymethyl)thiazole and 0.46 mmol of 4-dimethylaminopyridine. The resulting solution was stirred at ambient temperature for 16 h, after which it was diluted with 200 ml of chloroform, washed successively with 10% citric acid, aqueous NaHCO3, and saturated brine. After drying over Na2SO4, the solvent was removed in vacuo, and the residue was chromatographed on silica gel using 1-2% methanol in chloroform to provide 1.31 g (82%) of the desired compound, Rf 0.51 (4% methanol in chloroform) as an oil. 1H NMR (CDCl3)δ0.89 (d, J=7 Hz, 3H), 0.96 (d, J=7 Hz, 3H), 1.24 (t, J=7 Hz, 6H), 2.15 (m, 1H), 3.51 (q, J=7 Hz, 4H), 3.74 (s, 3H), 4.29 (dd, J=8, 4 Hz, 1H), 5.03 (s, 2H), 5.34 (br d, J=8 Hz, 1H), 6.42 (s, 1H). Mass spectrum: (M+H)+ =344.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][CH2:12][O:13][CH3:14].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:21]([S:28][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][CH2:12][O:13][CH3:14])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COCCc1cc([N+](=O)[O-])ccc1Br
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCc1cc([N+](=O)[O-])ccc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
To a solution of 1-bromo-2-(2-methoxyethyl)-4-nitrobenzene (7.8 g, 30 mmol) and Cs2CO3 (14.66 g, 45 mmol) in DMF (100 mL) was added BnSH (4.1 g, 33 mmol) slowly, followed by stirring at room temperature for three hours. Water was added, the precipitate was filtered, washed by water and petroleum to give benzyl(2-(2-methoxyethyl)-4-nitrophenyl)sulfane (8 g, yield 88%). 1H NMR: 400 MHz CDCl3 δ 8.05 (s, 1H), 8.01-7.98 (m, 1H), 7.38-7.28 (m, 6H), 4.23 (s, 2H), 3.64-3.61 (m, 2H), 3.34 (s, 3H), 3.03-2.99 (m, 2H).