Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C@@H:9]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C@@H:10]([OH:14])[C:11]([NH2:13])=[O:12].CS(O)(=O)=O>C1(C)C(C)=CC=CC=1>[OH:14][C@H:10]1[C:11](=[O:12])[NH:13][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][C@H:9]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc([C@H](Sc2ccccc2N)[C@@H](O)C(N)=O)cc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A mixture of (2S,3S)-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxy-phenyl)propionamide (1.59 g), xylene (8 ml) and methanesulfonic acid (24 mg) is refluxed for 11 hours. After allowed to cool to room temperature, the mixture is stirred to crystallization. The precipitated crystals are collected by filtration, washed with chilled methanol, and dried at 50° C. to give (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (1.41 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11]([OH:24])[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[S:21][C:20]([CH3:22])=[N:19][C:18]=3[CH:23]=2)[CH2:6][CH2:5]1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>COCCOC>[OH:24][C@@H:11]([CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([CH3:22])=[N:19][C:18]=2[CH:23]=1)[CH2:10][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])[CH2:5][CH2:6]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1nc2cc(OCC(O)CN3CCN(CCN)CC3)ccc2s1
Solvent: COCCOC
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCNS(=O)(=O)c4ccccc4)CC3)ccc2s1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-[4-(2-aminoethyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol (60 mg, 0.171 mmol) in DME (6 mL) was cooled to 0° C. and benzene sulfonyl chloride (0.022 mL, 0.172 mmol) was added. The solution was stirred at 0° C. for 5 min and then at RT for 10 min. The reaction mixture was concentrated to an oil and purified via flash column chromatography (9:1 CHCl3/MeOH) to afford (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl) (phenylsulfonyl)amine.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH:11][C:12]2[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:3][CH2:2]1.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH:11][C:12]2[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH:22][C:26]([CH:23]4[CH2:25][CH2:24]4)=[O:27])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc2c(c1)COC(NC1CCOc3ccccc31)=N2
Product: O=C(Nc1ccc2c(c1)COC(NC1CCOc3ccccc31)=N2)C1CC1
Yield: 50 %

Procedure:
Prepared from rac-N2-chroman-4-yl-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 75) (295 mg, 1.0 mmol, HPLC 0.699 min) and cyclopropanecarbonyl chloride (115 mg, 0.55 mmol) according to the procedure described for Example 27. Obtained the title compound as an off-white foam (100 mg, 28%, HPLC 1.353 min), MS (ISP) m/e=364.3 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:28][CH:27]([CH2:29][OH:30])[CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.N1C=CC=CC=1.[O:37](S(C1C=CC(C)=CC=1)(=O)=O)[S:38]([C:41]1[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=1)(=O)=[O:39]>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:28][CH:27]([CH2:29][O:30][S:38]([C:41]4[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=4)(=[O:39])=[O:37])[CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: Nc1nccn2c(C3CC(CO)C3)nc(-c3cccc(OCc4ccccc4)c3)c12
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CC(c3nc(-c4cccc(OCc5ccccc5)c4)c4c(N)nccn34)C2)cc1
Temperature: 25 °C

Procedure:
A solution of {3-[8-amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]cyclobutyl}methanol (23 mg, 0.057 mmol) in dry methylene chloride (3 mL) was charged with pyridine (0.1 mL) and Ts2O (21 mg, 0.063 mmol) at −20° C. under N2 atmosphere. The mixture was slowly warmed to rt overnight. The reaction was quenched with water (1 mL), diluted with ethyl acetate (20 mL), washed with sat. aq. NaHCO3 (10 mL) and brine (2×10 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (eluting with EtOAc:MeOH=98:2→96:4), yielding the title compound as a white solid. Partial trans isomer was removed by chromatography and the ratio of cis and trans isomers raised to 8:1; MS (ES, Pos.): m/z 555 [MH+]. 1H NMR (CDCl3, 400 MHz) δ 2.27-2.35 (m, 2H), 2.41 (s, 3H), 2.55-2.62 (m, 2H), 2.80 (m, 1H), 3.66 (m, 1H), 4.07 (d, J=6.7 Hz, 2H), 5.01 (br s, 2H, NH2), 5.15 (s, 2H), 7.02-7.85 (m, 15H). Anal. Calcd for C31H30N4O4S.1/3H2O: C, 66.41; H, 5.51; N, 9.99. Found: C, 66.43; H, 5.44; N, 10.07.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2([C:36](O)=[O:37])[CH2:35][CH2:34]2)=[O:32])=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([C:33]2([C:36]([NH:1][C:2]3[CH:22]=[CH:21][C:5]([O:6][C:7]4[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)=[O:15])[CH:8]=4)=[CH:4][CH:3]=3)=[O:37])[CH2:35][CH2:34]2)=[O:32])=[CH:28][CH:29]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1)N1CCCC1
Reaction time: 3 h
Yield: 58.8 %

Procedure:
Pyrrolidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (112 mg) and 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (87.4 mg) were dissolved in N,N-dimethylformamide (4 ml), and diisopropylethylamine (0.341 ml) and HBTU (203 mg) were added under a nitrogen atmosphere at room temperature, followed by stirring for 3 hr. The reaction mixture was partitioned after addition of ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml) and brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:7, then ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure, and to the residue (133.0 mg) were added tert-butyl methyl ether (4 ml) and heptane (4 ml) to suspend a solid. The solid was collected by filtration and dried under aeration to provide the titled compound as pale yellow powder (111.1 mg, 62.0%).
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:18]([CH:33]3[CH2:35][CH2:34]3)=[N:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)=[N:21][CH:22]=2)=[CH:11][C:10]=1[CH3:36])([CH3:7])[CH3:6])C.[OH-].[Na+]>C1COCC1.CCO>[CH:33]1([C:18]2[C:17]([CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:37])=[O:3])=[C:10]([CH3:36])[CH:11]=3)=[CH:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=3)[N:19]=2)[CH2:35][CH2:34]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3cccc(C(F)(F)F)c3)nc2C2CC2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(OCc2cnc(-c3cccc(C(F)(F)F)c3)nc2C2CC2)ccc1OC(C)(C)C(=O)O
Reaction time: 7 h

Procedure:
0.240 g (0.466 mmol) of the above prepared 2-{4-[4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester was dissolved in 2.8 ml of THF/EtOH=1/1, treated with 1.40 ml (3 eq.) of 1N NaOH and kept at ambient temperature for 7 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase extracted again with AcOEt; the combined organic layers were washed with water, dried over sodium sulfate, and evaporated to dryness. Recrystallisation from AcOEt/hexane afforded finally 0.196 g of the title compound as white solid of mp. 175–176° C.
Reaction SMILES: [F:1][C:2]([F:41])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([CH2:34][CH:35]([OH:40])[C:36]([F:39])([F:38])[F:37])[C:15]2[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=2)[O:18][CH2:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=2)[C:23]([O:25]CC)=[O:24])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[OH-].[Li+].Cl>O.O1CCCC1>[F:1][C:2]([F:41])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([CH2:34][CH:35]([OH:40])[C:36]([F:37])([F:38])[F:39])[C:15]2[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=2)[O:18][CH2:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=2)[C:23]([OH:25])=[O:24])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: CCOC(=O)c1cccc(COc2cccc(N(Cc3cccc(OC(F)(F)C(F)F)c3)CC(O)C(F)(F)F)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(COc2cccc(N(Cc3cccc(OC(F)(F)C(F)F)c3)CC(O)C(F)(F)F)c2)c1
Yield: 24.9 %

Procedure:
Ex-435A) A solution of ethyl 3-[[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]phenoxy]methyl]benzoate (22.1 mg, 0.04 mmol) and lithium hydroxide (5 mg, 0.12 mmol) in water (1 mL) and tetrahydrofuran (0.5 mL) was heated at 80° C. for 16 h. The reaction mixture was added to 6 N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 5.6 mg (19%) of the desired benzoic acid product as a brown oil. HRMS calcd. for C26H23F7NO5: 562.1464 [M+H]+, found: 562.1418. 1H NMR (acetone-d6) δ3.64 (dd, 1H), 3.95 (m, 1H), 4.454.50 (m, 1H), 4.80 (s, 2H), 5.12 (s, 2H), 6.27-6.63 (m, 4H), 7.06-7.27 (m, 4H), 7.41 (t, 1H), 7.50 (t, 1H), 7.66 (d, 1H), 7.99 (d, 1H), 8.10 (s, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([N:5]2[CH2:6][CH:2]([OH:1])[CH2:3][C@@H:4]2[C:7]([OH:9])=[O:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)[C@H]1CC(O)CN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CC(O)C[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To 10 g (76.30 mmol) of 4-hydroxy-D-proline in 75 ml of water was added 17.45 g (91.6 mmol) of 4-toluenesulfonyl chloride and 17 g (160.2 mmol) of sodium carbonate and the mixture was allowed to stir for 24 hours at room temperature. The reaction was then acidified to pH 1 by the careful addition of 10% aqueous HC1 solution and the product was isolated by filtration. After drying at high vacuum, 18.5 g of product was isolated (85% yield). M.P.=145°-146° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][C:14]#[N:15])[N:12]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:18][CH2:19][N:20]([CH2:22][CH2:23]Cl)[CH3:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]3([C:14]#[N:15])[CH2:23][CH2:22][N:20]([CH3:21])[CH2:19][CH2:18]3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: N#CCc1coc(-c2ccc(F)cc2)n1
Reactant: CN(CCCl)CCCl
Agent: Cl
Product: CN1CCC(C#N)(c2coc(-c3ccc(F)cc3)n2)CC1
Yield: 30 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)acetonitrile and 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride as described in example 16 step 1b (430 mg, yield 30%). 1H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.05-8.00 (m, 2H), 7.41-7.35 (m, 2H), 2.83-2.79 (m, 2H), 2.26-2.18 (m, 7H), 2.04-1.94 (m, 2H). MS (ESI) m/z: Calculated for C16H16FN3O: 285.13. found: 286.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1N2CCN(CC2)C1.[CH2:19]([O:21][C:22]([C:24]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([N:34]=[CH:35][C:36]2[S:37][C:38]([N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[CH:39][CH:40]=2)[S:26][C:25]=1[NH2:46])=[O:23])[CH3:20]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[CH2:32]([O:31][C:29]([C:28]1[C:24]([C:22]([O:21][CH2:19][CH3:20])=[O:23])=[C:25]([N:46]=[CH:9][C:7]2[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[S:26][C:27]=1[N:34]=[CH:35][C:36]1[S:37][C:38]([N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[CH:39][CH:40]=1)=[O:30])[CH3:33]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: CCOC(=O)c1c(N)sc(N=Cc2ccc(N(CC)CC)s2)c1C(=O)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(N=Cc2ccc(N(CC)CC)s2)sc(N=Cc2ccc([N+](=O)[O-])s2)c1C(=O)OCC
Yield: 71.2 %

Procedure:
5-Nitrothiophene-2-carbaldehyde (23 mg) was mixed in toluene under nitrogen at 0° C. with DABCO (16 mg), TiCl4 in solution in toluene (146 μL) and 2-amino-5-[(5-diethylamino-thiophen-2-ylmethylene)-amino]-thiophene-3,4-dicarboxylic acid diethyl ester (56 mg) and refluxed for seven hours. The reaction affords a purple-grey powder (53 mg, 72%) after purification by flash chromatography. 1H-NMR (300 MHz, [D] acetone): δ=8.55 (s, 1H), 8.36 (s, 1H), 8.06 (d, 1H, 3J=4.3 Hz), 7.66 (d, 1H, 3J=4.4 Hz), 7.55 (d, 1H, 3J=4.6 Hz), 6.19 (d, 1H, 3J=4.6 Hz), 4.36 (q, 2H, 3J=7.3 Hz), 4.25 (q, 2H, 3J=7.1 Hz), 3.55 (q, 4H, 3J=7.5 Hz), 1.39 (t, 3H, 3J=7.1 Hz), 1.34 (t, 3H, 3J=7.2 Hz), 1.28 (t, 6H, 3J=7.1 Hz). 13C-NMR (300 MHz, [D] acetone): δ=173.0, 167.5, 164.1, 162.9, 149.7, 143.7, 132.9, 131.6, 131.3, 130.2, 130.1, 129.7, 129.1, 127.6, 114.0, 104.9, 61.4, 60.2, 39.2, 14.2, 13.8, 10.8. +TOF-MS: m/z 563.10838. Calculated for C24H26O6N4S3 563.10872.
Reaction SMILES: [BH4-].[Li+].C[Si](C)(C)Cl.[CH:8]1[CH:9]=[CH:10][C:11]([C@@H:14]([NH2:18])[C:15](O)=[O:16])=[CH:12][CH:13]=1.CO>O1CCCC1>[NH2:18][C@H:14]([C:11]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1)[CH2:15][OH:16]
Reactant: N[C@@H](C(=O)O)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: N[C@@H](CO)c1ccccc1

Procedure:
20 g (920 mmol) of lithium borohydride are dissolved in 420 ml of absolute tetrahydrofuran. 233.5 ml (1.84 mol) of trimethylchlorosilane are added dropwise, while stirring, and 69.5 g (0.46 mol) of (R)-phenylglycine are then added in portions within the space of 4 hours. The reaction mixture is stirred at room temperature overnight. 690 ml of methanol are then added and the mixture is stirred at room temperature for 2 hours and concentrated in vacuo. The residue is dissolved, while stirring, in 690 ml of a 20% aqueous solution of potassium hydroxide. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulphate and concentrated in vacuo.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([C:12]([CH2:14][Br:15])=[O:13])[O:8][CH2:7][C:6]=2[C:5](=[O:16])[CH:4]=[CH:3]1.C(O[CH:21]=[CH:22][CH:23]=[CH2:24])(=O)C>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([C:12]([CH2:14][Br:15])=[O:13])[O:8][CH2:7][C:6]=2[C:5](=[O:16])[C:4]2[C:3]1=[CH:21][CH:22]=[CH:23][CH:24]=2
Reactant: O=C1C=CC(=O)C2=C1C=C(C(=O)CBr)OC2
Reactant: C=CC=COC(C)=O
Solvent: Cc1ccccc1
Product: O=C(CBr)C1=CC2=C(CO1)C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution containing one equivalent of isochromandione (263 mg, 0.92 mmol) from step 1 (example 6) in 25 ml of dry toluene was added three equivalents (2.7 mmol) of acetoxybutadiene. The reaction mixture was stirred overnight under argon at room temperature and then two hours at 60° C. After removal of solvent, the crude product was flash chromatographed (toluene/EtOAc,9:1). The titled orange compound was isolated (192 mg) in 62% yield.
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:12][C@@H:11]([CH2:13][OH:14])[CH2:10][N:9]([C:15]([O-:17])=[O:16])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C1COCC1>[CH:1]1([C@H:7]2[CH2:12][C@@H:11]([CH2:13][O:14][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:10][N:9]([C:15]([O:17][C:1]([CH3:7])([CH3:6])[CH3:2])=[O:16])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C([O-])N1C[C@H](CO)C[C@H](C2CCCCC2)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](COS(C)(=O)=O)C[C@H](C2CCCCC2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of tert-utyl cis-3-cyclohexyl-5-(hydroxymethyl)piperidine-1-carboxylate (431.1 mg) in THF (10 ml) was added TEA (405.0 ml) and MsCl (135.2 ml) at 0° C. After stirring at 0° C. for 1 hour, the insoluble material was filtered off through celite and washed with THF. The filtrate was concentrated to give the crude tert-butyl cis-3-cyclohexyl-5-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate as a pale brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[Br:23]Br>CO>[NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[Br:23]
Reactant: BrBr
Reactant: COC(=O)c1ccc(-c2ccc(N)nn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(Br)c(N)nn2)cc1
Reaction time: 16 h
Yield: 43.6 %

Procedure:
In a 250 mL round bottom flask was placed methyl 4-(6-aminopyridazin-3-yl)benzoate (2.8 g, 12.2 mmol), NaHCO3 (2.05 g, 22.4 mmol) and methanol (100 mL) and to this suspension was added Br2 (1.95 g, 12.2 mmol) drop wise over about 30 minutes at room temperature. The mixture was stirred for 16 h, then filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=2:1) to give methyl 4-(6-amino-5-bromopyridazin-3-yl)benzoate (1.64 g, 43.6%) as a light orange solid. LC-MS: [M+H]+, 309.9, tR=1.397 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:3][CH:2]=1.[H][H]>C(O)C>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccnc1Nc1ccncc1
Solvent: CCO
Product: Nc1cccnc1Nc1ccncc1

Procedure:
A solution of 16.5 g of 2-(4-pyridylamino)-3-nitro-pyridine in 400 ml of 95% ethanol containing 1.6 g of 10% palladized carbon was hydrogenated at 30°-40° C. at atmospheric pressure until 5.8 liters of hydrogen were absorbed and the mixture was filtered to remove the catalyst. The filtrate was evaporated to dryness and the residue was taken up in petroleum ether. The mixture was filtered to obtain 13.5 g (95% yield) of raw product melting at 202°-204° C. which was crystallized from 95% ethanol to obtain 2-(4-pyridylamino)-3-amino-pyridine in the form of a pale yellow, crystalline powder melting at 203°-205° C.
Reaction SMILES: O.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[O:5][S:6]([N:9]=C=O)(=[O:8])=[O:7].C(=O)=O>ClC(Cl)(Cl)Cl>[S:6](=[O:8])(=[O:7])([O:5][C:4]1[C:3]([Cl:2])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:16])[NH2:9]
Reactant: O=C=NS(=O)(=O)Oc1c(Cl)cccc1Cl
Agent: O=C=O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: NS(=O)(=O)Oc1c(Cl)cccc1Cl
Temperature: 0 °C

Procedure:
2.6 ml of water are added dropwise at 30° C. to 40° C. to a solution of 24.4 g of 2,6-dichlorophenoxysulfonyl isocyanate in 200 ml of tetrachloromethane. The mixture is then stirred at room temperature until the evolution of carbon dioxide is complete and cooled to 0° C., the product is filtered off with suction and the residue is then washed with ice-cold tetrachloromethane. After drying in vacuo, 21.4 g of 2,6-dichlorophenyl sulfamate of melting point 108°-110° C. are obtained.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[Cl-].[Li+].C(N(CC)CC)C.CS([Cl:42])(=O)=O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:42][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CO)cc2)CC3)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To a mixture of N-[4-(hydroxymethyl)phenyl]-7-(4methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (2.20 g), lithium chloride (505 mg), triethylamine (1.67 ml), DMAP [4-dimethylaminopyridine] (catalytic amount) and dichloromethane (200 ml) was added methanesulfonyl chloride (645 μl), and the mixture was stirred at room temperature for 42 hours and concentrated under reduced pressure. To the residue was added 0.5N hydrochloric acid (200 ml), and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (973 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[CH2:4][O:5][N:6]=[C:7]([C:13](=[O:15])[CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].S(Cl)([Cl:24])(=O)=O>C(O)(=O)C>[Cl:24][CH2:14][C:13](=[O:15])[C:7](=[N:6][O:5][CH2:4][C:3]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:2]=1[Cl:1])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1Cl)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOCc1ccc(Cl)cc1Cl)C(=O)CCl
Yield: 108.4 %

Procedure:
Ethyl 2-(2,4-dichlorobenzyloxyimino)-3-oxobutyrate (syn isomer, 33.7 g.), sulfuryl chloride (15.7 g.) and acetic acid (35 ml) treated in a similar manner to that of Example A-(2) to give ethyl 4-chloro-2-(2,4-dichlorobenzyloxyimino)-3-oxobutyrate (syn isomer, 40.5 g.).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1[CH2:8]Br.[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11]>O1CCOCC1>[C:10]([N:14]1[CH2:8][C:7]2[S:6][CH:5]=[N:4][C:3]=2[CH2:2]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: BrCc1ncsc1CBr
Reactant: CC(C)(C)N
Solvent: C1COCCO1
Product: CC(C)(C)N1Cc2ncsc2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4,5-bis(bromomethyl)thiazole (1.50 g) synthesized in 1) of Referential Example 109 was dissolved in dioxane (30 ml), and a dioxane solution (10 ml) of tert-butylamine (2.03 ml) was added dropwise to the solution over 1 hour at room temperature. After stirring at room temperature for 5 hours, the reaction mixture was concentrated, and dichloromethane and a saturated aqueous solution of sodium hydrogencarbonate were added to the residue to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:19) to obtain 5-tert-butyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole (407 mg) as a pale yellow oil.