Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:26]COC)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[CH2:30][CH2:31][CH3:32])[CH2:7][C@@H:6]1[CH3:33])=[O:4].[CH3:34][CH:35]([O:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2([CH3:51])[NH:48][C:47](=[O:49])[NH:46][C:45]2=[O:50])=[N:42][CH:43]=1)[CH3:36]>>[F:24][C:22]([F:25])([F:23])[C:17]([C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:46]3[C:45](=[O:50])[C:44]([C:41]4[CH:40]=[CH:39][C:38]([O:37][CH:35]([CH3:34])[CH3:36])=[CH:43][N:42]=4)([CH3:51])[NH:48][C:47]3=[O:49])[C@@H:6]([CH3:33])[CH2:7]2)=[C:12]([CH2:30][CH2:31][CH3:32])[CH:13]=1)([OH:26])[C:18]([F:19])([F:21])[F:20]
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)nc1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)[C@@H](C)C1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc(OC(C)C)cn3)C2=O)[C@@H](C)C1

Procedure:
(S)-2-bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propyl phenyl}-2-methylpiperazin-1-yl)ethanone and 5-[5-(1-methylethoxy)pyridin-2-yl]-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[OH:22])[CH:17]=O.Cl.CO>O>[OH:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1C(=Cc2ccc(O)c(O)c2)CCc2cc(O)ccc21
Temperature: 25 °C
Yield: 72 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 3,4-dihydroxybenzaldehyde 0.85 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for 2.5 hours and cooled to room temperature, and water 357 ml was added. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for six hours under reduced pressure to obtain the desired compound 1.25 g.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:33])[C@H:21]([CH3:32])[NH:22][C:23](=[O:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[F:34]C1C=C(CC(O)=O)C=CC=1>>[F:34][C:29]1[CH:30]=[C:25]([CH2:24][C:23]([NH:22][C@H:21]([C:20]([NH:19][C@@H:3]2[C:2](=[O:1])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C@@H:4]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:33])[CH3:32])=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Product: C[C@H](NC(=O)Cc1cccc(F)c1)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1

Procedure:
A method similar to the one described for (113) was used except that 3-fluorophenylacetic acid (77 mg) was used in place of phenylacetic acid to afford the title compound as a 1:1 mixture with the (2S,3R) diastereomer (140 mg), white solid, m.p.130-140° C. 1H NMR (300 MHz, CDCl3) δ 0.97 (d, 1.5H, J=5 Hz), 1.27 (d, 1.5H, J=5 Hz), 3.45 (two peaks, 2H), 4.52 (m, 0.5H), 4.67 (m, 0.5H), 4.91 (t, 1H, J=6 Hz), 5.12 (t, 1H, J=6 Hz), 5.79 (dd, 1H, J=7 Hz, J=10 Hz), 6.15 (d, 0.5H, J=8 Hz), 6.28 (d, 0.5 Hz, J=8 Hz), 6.63 (d, 0.5 h, J=6 Hz), 6.70 (d, 0.5H, J=7 Hz), 6.86-7.70 (m, 13H), 7.96 (s, 1H). MS APCI, m/z=484 (M+Na). LC/MS: 2.09 min.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].Cl.[CH3:24]NC.C=O.C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([C:18](=[O:22])[C:19](=[CH2:24])[CH2:20][CH3:21])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCCC(=O)c1ccc(OCCCCCC(=O)O)c(Cl)c1Cl
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=C(CC)C(=O)c1ccc(OCCCCCC(=O)O)c(Cl)c1Cl
Temperature: 0 °C

Procedure:
A mixture of 6-(2,3-dichloro-4-butyrylphenoxy)hexanoic acid (9.5 g, 0.026 mole), dimethylamine hydrochloride (15 g, 0.184 mole), paraformaldehyde (2.8 g, 0.09 equiv.) and acetic acid (1 ml) were united and stirred and heated on a steam bath for two hours. The reaction mixture was treated with N,N-dimethylformamide (30 ml) and stirring and heating continued for another hour. The reaction mixture was poured into ice water and the solid that separated was removed by filtration, washed with water and dried. The yield was 9.2 g after recrystallization from butyl chloride the 6-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]hexanoic acid melted at 106°-107° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[NH:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[N:33]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:26])[CH3:23]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C1CCCCC1NC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCCC1N(C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1)C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.333 g, 1.0 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). 2-Cyclohexylamino-cyclohexanecarboxylic acid ethyl ester (0.253 g, 1.0 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.201 g, 1.05 mmol). Then N-methylmorpholine (212 mg, 2.1 mmol) was added. The mixture was stirred at 25° C. for 5 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, 2-{cyclohexyl-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclohexanecarboxylic acid ethyl ester (0.48 g, 0.845 mmol, 84.5%), as a yellow oil. LC-MS (ESI) calcd for C25H36N4O7S2 568.20, found 569.3 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=1[C:22]([F:25])([F:24])[F:23]>>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:15][C:14]=1[C:22]([F:23])([F:24])[F:25]
Reactant: COC(=O)c1cncc(Br)c1
Reactant: Cc1ccc(B(O)O)cc1C(F)(F)F
Product: COC(=O)c1cncc(-c2ccc(C)c(C(F)(F)F)c2)c1

Procedure:
2.2 g (10.3 mmol) of methyl 5-bromonicotinate and 2.5 g (12.4 mmol) of [4-methyl-3-(trifluoromethyl)phenyl]boronic acid were reacted according to the General Method 1A. Yield: 2.6 g (86% of theory)
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:7]=1[C:8](=[O:33])[N:9]([C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:10]2)=[O:4].[CH3:34][NH:35][CH3:36].Cl>CC#N.CCOCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:35]([CH3:36])[CH3:34])=[C:7]2[C:11]=1[CH2:10][N:9]([C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:19])=[O:20])[C:8]2=[O:33]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)CCl)c3C2=O)ccc1OC
Reactant: CNC
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)CN(C)C)c3C2=O)ccc1OC
Temperature: 70 °C

Procedure:
To a solution of (1S)-2-chloro-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (400 mg, 0.78 mmol) in CH3CN (10 ml) was added dimethylamine (2N in MeOH, 1.6 ml, 3.2 mmol). The mixture was heated at 70° C. for 2 hrs. The reaction mixture was concentrated on rota-vap and extracted with water (50 ml) and EtOAc (50 ml). The organic layer was washed with water (50 ml), brine (25 ml), dried over Na2SO4 and concentrated. The resulted oil was purified by chromatography to give an oil which was stirred with HCl in ether (3 ml) to give (1S)-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-dimethylamino-acetamide; hydrochloride as a white solid (300 mg, 68% yield): mp, 198-200° C.; 1H NMR (DMSO-d6) δ 1.32 (t, J=7.5 Hz, 3H, OCH2CH3), 2.87 (s, 6H, N(CH3)2), 3.04 (s, 3H, CH3), 3.74 (s, 3H, CH3), 3.94-4.16 (m, 4H, OCH2CH3+NCHH+CHHSO2), 4.36-4.50 (m, 3H, CHHSO2+CH2NCO), 4.73 (d, J=18 Hz, 1H, CHHN), 5.85-5.91 (m, 1H, NCH), 6.98 (s, 2H, Ar), 7.05 (s, 1H, Ar), 7.69 (d, J=8 Hz, 1H, Ar), 8.18 (d, J=8 Hz, 1H, Ar), 10.21 (bs, 1H, HCl); 10.45 (s, 1H, NHCO); 13C NMR (DMSO-d6) δ 15.17, 23.25, 41.51, 43.86, 46.03, 49.41, 53.88, 56.00, 58.52, 64.41, 112.50, 112.80, 120.23, 121.25, 123.33, 130.22, 133.21, 134.72, 140.60, 148.55, 149.46, 154.53, 167.02, 180.13, Anal Calcd for C24H31Cl2N3O6S+0.41 H2O: C, 50.78; H, 5.65; N, 7.40. Found: C, 50.81; H, 5.55; N, 7.18, H2O, 1.30.
Reaction SMILES: CO[C:3]1[C:8]([O:9][CH:10]([CH3:12])C)=[CH:7][CH:6]=[CH:5][C:4]=1O.[Na].[CH2:15](Cl)C=C(C)C>CCOCC>[O:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:12][CH2:10]1
Reactant: CC(C)=CCCl
Reactant: COc1c(O)cccc1OC(C)C
Agent: [Na]
Solvent: CCOCC
Product: c1ccc2c(c1)CCCO2
Reaction time: 8 h

Procedure:
5.5 g (30 millimoles) of 2-methoxy-3-isopropoxy-phenol are dissolved in 30 ml of ether whereupon 2.1 g of metallic sodium are added in small portions and the mixture is heated to boiling for an hour. To the mixture 3.2 g (30 millimoles) of prenyl chloride are added dropwise and the reaction mixture is heated to boiling for 8 hours. The reaction mixture is worked up in the usual manner. Thus 4.4 g of "chromane" are obtained. This product is dissolved in 60 ml of benzene, 1.2 g of dichloro-dicyano-benzoquinone are added and the reaction mixture is purified as described in Example 3. Thus 3.7 g of the desired compound are obtained in the form of a colorless oil, yield 50%.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:61]([CH3:63])[CH3:62])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:59])[C@H:47]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:48]7[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=7)=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:60]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].[CH3:64][O:65][C:66](N[C@@H](C(C)C)C(O)=O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:61]1[CH2:63][CH2:66][O:65][CH2:64][CH2:62]1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:59])[C@H:47]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:48]7[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=7)=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:60]=2)=[CH:17][N:18]=1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]4)ccc23)[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]4)ccc23)[nH]1)C1CCOCC1

Procedure:
This compound was made in an analogous manner to methyl (R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate, substituting (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid in the first amide coupling. LCMS-ESI+: calculated for C50H52N8O8: 893.00; observed [M+1]+: 894.00.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])=[N:8][C:7](=O)[C:6]=2[CH:20]=1.C(N(CC)CC)C.Cl.[NH:29]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[NH2:30]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])[N:29]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:30]=2)[CH:20]=1
Reactant: O=c1nc(-c2cc(Cl)ccc2O)oc2ccc(Cl)cc12
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1nc(-c2cc(Cl)ccc2O)nc1-c1cc(Cl)ccc1O

Procedure:
6.0 g of chloro-2-(5-chloro-2-hydroxyphenyl)benz[e][1,3]oxazin-4-one (Example 16), 3.0 ml of triethylamine and 3.3 g of ethyl hydrazinoacetate hydrochloride are boiled under reflux for 2 h in 60 ml of ethanol. On cooling, the product precipitates in crystalline form. It is filtered off and washed with ethanol. After drying, ethyl [3,5-bis(5-chloro-2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate is obtained as colorless crystals of m.p. 195-200° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:15](Br)[C:16]#[CH:17]>CN(C)C=O.O>[CH2:17]([O:12][CH2:11][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)[C:16]#[CH:15]
Reactant: OCc1ccc2c(c1)OCCO2
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOCc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 16.6 g of 1,4-benzodioxan-6-methanol in 20 ml of dimethylformamide is added dropwise with stirring to a suspension of 12.5 g of sodium hydride in 75 ml of dimethylformamide. 11.8 g of propargyl bromide are then added dropwise. The mixture is stirred for 3 hours at room temperature, cooled in an ice-bath, decomposed with 20 ml of ice-water, diluted with 150 ml of water and extracted three times with 150 ml of diethyl ether each time. The ether extract is washed with water, dried over sodium sulphate and evaporated. The oily residue is chromatographed on silica gel using benzene as the elution agent. There is obtained 6-[(2-propynyloxy)methyl]-1,4-benzodioxan; nD24 = 1.5487.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[OH-].[K+].Cl.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]Cl>CS(C)=O>[ClH:22].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])[C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 149.9 %

Procedure:
A mixture of 6.72 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 2.58 g of potassium hydroxide and 90 ml of dimethylsulfoxide is stirred at room temperature for one hour. Then, 3.16 g of 2-(dimethylamino)ethyl chloride hydrochloride are added to the mixture, and said mixture is stirred at room temperature for 16 hours. The reaction mixture is poured into ice-water, and the precipitated crystals are collected by filtration and washed with water. The crystals are dissolved in concentrated hydrochloric acid, and the solution is washed with ethyl acetate and then alkalized with potassium carbonate. Then, the solution is extracted with chloroform. The extract is washed with water, dried and then evaporated to remove solvent. The residue is converted to its hydrochloride and then recrystallized from ethanol. 6.65 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are thereby obtained. Recrystallization of the product from a mixture of chloroform, ethanol and ether gives crystals (prisms) melting at 136°-139° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][C:6]1[CH:19]=[C:9]2[NH:10][C:11](=[O:18])[C:12]3[C:17]([N:8]2[N:7]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[C:23]([Zn]C#N)#[N:24]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:18]=[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]2[N:7]=[C:6]([CH2:5][C:4]3[CH:3]=[C:2]([CH:22]=[CH:21][CH:20]=3)[C:23]#[N:24])[CH:19]=[C:9]2[NH:10]1
Reactant: O=c1[nH]c2cc(Cc3cccc(Br)c3)nn2c2ccccc12
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: N#Cc1cccc(Cc2cc3[nH]c(=O)c4ccccc4n3n2)c1

Procedure:
A mixture of Example 61B (0.075 g, 0.212 mmol), dicyanozinc (0.03 g, 0.254 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.024 g, 0.021 mmol) in DMF (2 mL) was heated in a microwave (Personal Chemistry SmithSynthesizer) at 150° C. for 10 minutes. The mixture was evaporated and purified by chromatography on silica gel with 10% MeOH/CH2Cl2 to provide the desired product. 1H NMR (500 MHz, DMSO-d6) δ ppm 4.08 (s, 2 H) 5.76 (s, 1 H) 7.46 (t, J=7.63 Hz, 1 H) 7.53 (t, J=7.63 Hz, 1 H) 7.69 (dd, J=12.36, 7.78 Hz, 2 H) 7.79-7.88 (m, 2 H) 8.02 (d, J=7.93 Hz, 1 H) 8.12 (d, J=7.93 Hz, 1 H) 12.12 (s, 1 H).
Reaction SMILES: C([O-])(=O)C.[CH3:5][O:6][C:7]1[CH:35]=[CH:34][C:10]([CH2:11][P+:12]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.CO.[P:38](=[O:42])([OH:41])([OH:40])[OH:39]>O>[P:38]([O-:42])([O-:41])([O-:40])=[O:39].[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][P+:12]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:34][CH:35]=1.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][P+:12]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:34][CH:35]=1.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][P+:12]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:34][CH:35]=1
Reactant: O=P(O)(O)O
Agent: CC(=O)[O-]
Agent: COc1ccc(C[P+](c2ccc(C)cc2)(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Solvent: CO
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
Into a 2 oz. (59 mL) bottle is placed 1.38 gm of 4-methoxybenzyl-tri-p-tolylphosphonium acetate.acetic acid complex followed by the addition of 1.75 gms of methanol. To another 2 oz. (59 mL) bottle is added 2.2 gms of water and 3.4 gms of 85% phosphoric acid and the contents mixed completely. To the first 2 oz. bottle is placed 0.56 gm of the phosphoric acid solution and the contents mixed completely.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3Cl)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[CH2:39][NH2:40])=[CH:34][CH:33]=1>>[C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3[NH:40][CH2:39][CH:38]([C:35]2[CH:34]=[CH:33][C:32]([CH3:31])=[CH:37][CH:36]=2)[C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: Cc1ccc(C(CN)c2ccc(C)cc2)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(C)cc4)c4ccc(C)cc4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The compound was prepared from (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (Preparation 45) and 2,2-bis(4-methylphenyl)ethanamine (J. Med. Chem., 1969, 12(1), 9) using a similar method to that of Preparation 64.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)=[O:29])=[CH:8][C:7]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CN(C)CCOc1ccc(N)cc1-c1ccnn1C
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1ccnn1C
Yield: 66.4 %

Procedure:
4-(2-Dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (26.0 mg, 0.1 mmol) was treated with 4-fluorophenyl isocyanate (11.8 μL, 0.105 mmol) in a similar manner as described in Example 1.2 to afford Compound 142 as a white solid in 66.4% yield. LCMS m/z (%)=398 (M+H, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.33 (s, 1H), 8.25 (s, 1H), 7.61-7.56 (m, 3H), 8.49 (s, 1H), 7.42 (s, 1H), 7.11-7.04 (m, 3H), 6.24 (s, 1H), 4.11 (t, J=5.85 Hz, 2H), 3.77 (s, 3H), 2.62 (t, J=5.85 Hz, 2H), 2.20 (s, 6H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].N1C=CC=CC=1.[CH3:12][O:13][N:14]=[C:15]([CH:17]([NH:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])[CH3:18])[CH3:16]>C1C=CC=CC=1>[CH3:12][O:13][N:14]=[C:15]([CH:17]([N:19]([C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])[C:3](=[O:4])[CH2:2][Cl:1])[CH3:18])[CH3:16]
Reactant: CON=C(C)C(C)Nc1c(C)cccc1C
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CON=C(C)C(C)N(C(=O)CCl)c1c(C)cccc1C
Yield: 782.7 %

Procedure:
A sample of 54.2 g (0.048 mol) chloroacetyl chloride and a sample of 34.8 g (0.44 mol) pyridine was added over a 25-minute period to a solution of 97.0 g (0.44 mol) 3-(2,6-dimethylphenylamino)-2-butanone O-methyloxime maintained at 45° C. in 500 ml benzene. The pyridine was added slightly faster than the chloroacetyl chloride. The reaction temperature rose to about 50°-58° C. during the addition. The reaction mixture was then cooled, washed with water, washed with 5% aqueous sodium bicarbonate solution, stirred with silica gel, filtered and evaporated under reduced pressure to give 111.5 g of 3-(N-chloroacetyl-2,6-dimethylphenylamino)-2-butanone O-methyloxime, as an oil. The infrared spectrum of the product showed carbonyl absorption at 5.9 micron and O--CH3 absorption at 9.5 micron. The product is tabulated in Table I as Compound No. 5-B.