Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[N:21])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:30]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10]([F:30])=[O:11])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[N:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C#N)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C#N)C(=O)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-(2-cyano-phenyl)-propionic acid (2.5 g, 8.6 mmol) and pyridine (0.68 g, 8.6 mmol) were dissolved in dichloromethane (50 mL) at 0° C. Cyanuric fluoride (1.74 mL, 12.9 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 hour and then ice-water was added. The mixture was extracted with dichloromethane (2×). The organic extracts were washed with water, brine, and dried over sodium sulfate. Evaporation of the solvents gave crude [(S)-2-(2-cyano-phenyl)-1-fluorocarbonyl-ethyl]-carbamic acid tert-butyl ester as a yellow solid which was used without further purification in the next step (2.4 g).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[S:11][C:7]=2[CH:6]=1)=[O:4].[N-:15]=[N+:16]=[N-:17].[Na+]>>[N:15]([CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[S:11][C:7]=2[CH:6]=1)=[O:4])=[N+:16]=[N-:17]
Reactant: O=C(CCl)c1ccc2[nH]c(=O)sc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC(=O)c1ccc2[nH]c(=O)sc2c1
Yield: 96 %

Procedure:
Treatment of 6-(2-chloroethanoyl)-3H-benzothiazol-2-one with sodium azide, following the procedure described in Example 6, Step 4, gave 6-(2-azidoethanoyl)-3H-benzothiazol-2-one (6.95 g, 96%):
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[N:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[Cl-].[Cl-].[O:47]=[C:48]1[NH:56][C:51]2=[NH+:52][CH:53]=[CH:54][CH:55]=[C:50]2[N:49]1[CH:57]1[CH2:62][CH2:61][NH2+:60][CH2:59][CH2:58]1>O1CCCC1.ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[N:24][N:25]=[C:20]2[C@H:19]([NH:31][C:33]([N:60]2[CH2:61][CH2:62][CH:57]([N:49]3[C:50]4[C:51](=[N:52][CH:53]=[CH:54][CH:55]=4)[NH:56][C:48]3=[O:47])[CH2:58][CH2:59]2)=[O:34])[CH2:18][CH2:17]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=c1[nH]c2[nH+]cccc2n1C1CC[NH2+]CC1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
Triethylamine (58 μL, 0.417 mmol) was added to a solution of the bis hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-amine (50 mg, 0.119 mmol) and 4-nitrophenyl chloroformate (25 mg, 125 mmol) in tetrahydrofuran (4 mL) at 0° C. After 15 min, 2-oxo-1-piperidinium-4-yl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-4-ium dichloride (52 mg, 0.179 mmol), triethylamine (58 μL, 0.417 mmol) and dichloromethane (3 mL) were added and the mixture allowed to warm to ambient temperature. After 5 h, the reaction was concentrated. Purification by reverse phase HPLC (C-18, 90% water/acetonitrile→100% acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (38 mg). MS 591.2223 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@:17]([CH3:21])([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:22][CH3:23])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C@@H:25]([CH:42]([CH3:44])[CH3:43])[CH2:26][N:27]1[CH2:32][CH2:31][C@:30]([C:34]2[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=2)([CH3:33])[C@@H:29]([CH3:41])[CH2:28]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C1COCC1>[OH:40][C:36]1[CH:35]=[C:34]([C@:30]2([CH3:33])[CH2:31][CH2:32][N:27]([CH2:26][C@@H:25]([NH:24][C:18]([C@@:17]3([CH3:21])[CH2:16][C:15]4[C:10](=[CH:11][C:12]([O:22][CH3:23])=[CH:13][CH:14]=4)[CH2:9][N:8]3[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[O:20])[CH:42]([CH3:43])[CH3:44])[CH2:28][C@@H:29]2[CH3:41])[CH:39]=[CH:38][CH:37]=1
Reactant: COc1ccc2c(c1)CN(C(=O)OC(C)(C)C)[C@@](C)(C(=O)O)C2
Reactant: CC(C)[C@H](N)CN1CC[C@@](C)(c2cccc(O)c2)[C@@H](C)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(C(=O)OC(C)(C)C)[C@@](C)(C(=O)N[C@H](CN1CC[C@@](C)(c3cccc(O)c3)[C@@H](C)C1)C(C)C)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
Compound 2.8 (200 mg, 0.623 mmol), 3-{(3R,4R)-1-[(2S)-2-amino-3-methylbutyl]-3,4-dimethylpiperidin-4-yl}phenol (J) (181 mg, 0.623 mmol) and BOP reagent (275 mg, 0.623 mmol) were dissolved in THF (20 mL). Triethylamine (1 mL) was added and the solution was stirred at room temperature for 3 h. The solution was extracted with CH2Cl2 and saturated NaHCO3 solution. The organic layer was dried and purified by column chromatography to afford 250 mg, (68%) of 2.9.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][N:7]2[CH2:9][CH2:10][CH2:11][C@H:6]2[C:5](=[O:12])[NH:4]1.C(N(CC)CC)C.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:24][C:23]([Si:20]([CH3:22])([CH3:21])[O:1][CH2:2][C@@H:3]1[CH2:8][N:7]2[CH2:9][CH2:10][CH2:11][C@H:6]2[C:5](=[O:12])[NH:4]1)([CH3:26])[CH3:25]
Reactant: O=C1N[C@H](CO)CN2CCC[C@@H]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCC[C@H]2C(=O)N1
Temperature: 25 °C
Reaction time: 14 h
Yield: 66.2 %

Procedure:
To a solution of (3S,8aS)-3-(hydroxymethyl) hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (1.49 g, 8.82 mmol) in dimethylformamide (20 mL) was added triethylamine (2.45 mL, 17.6 mmol) and 4-dimethylaminopyridine (90 mg, 0.882 mmol). The solution was cooled in an ice bath and tert-butyldimethylsilyl chloride (2.66 g, 17.6 mmol) was added. The mixture was warmed to room temperature and stirred for 14 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous portion was extracted twice with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford a pale brown solid which was triturated with ethyl acetate to afford (3S,8aS)-3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl) hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one as an off-white solid (1.74 g, 5.84 mmol, 66% yield). 1H NMR (400 MHz, CDCl3): 6.09-5.90 (m, 1H), 3.86-3.76 (m, 1H), 3.63 (dd, 1H), 3.44 (dd, 1H), 3.25 (t, 1H), 3.10 (ddd, 1H), 2.98-2.90 (m, 1H), 2.68-2.60 (m, 1H), 2.52 (dd, 1H), 2.28-2.18 (m, 1H), 2.06-1.95 (m, 1H), 1.93-1.74 (m, 2H), 0.90 (s, 9H), 0.07 (s, 6H); MS (EI) for C14H28N2O2Si: 285 (MH+).
Reaction SMILES: C(Br)C1C=CC=CC=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.[CH3:21][C:22]1[N:23]=[C:24]([N:32]2[CH2:36][CH2:35][NH:34][C:33]2=[O:37])[S:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH3:21][C:22]1[N:23]=[C:24]([N:32]2[CH2:36][CH2:35][N:34]([CH2:15][C:14]3[CH:17]=[CH:18][C:11]([C:10]([F:20])([F:19])[F:9])=[CH:12][CH:13]=3)[C:33]2=[O:37])[S:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCc1ccccc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C
Yield: 92 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 4-(trifluoromethyl)benzyl bromide to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 92% yield: mp 126-127° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 4.51 (s, 2H), 4.17 (q, J=6.9 Hz, 2H), 4.00 (t, J=8.1 Hz, 2H), 3.47 (t, J=8.1 Hz, 2H), 2.49 (s, 3H), 1.23 (t, J=6.9 Hz, 3H); MS (ES+) m/z 414.1 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=2)=O)=[C:4]1[CH3:23])[CH3:2].C([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35]([C:37]2[C:38](C(O)=O)=NC=CC=2)=O)=[C:27]1[CH3:46])C.C1(NC2C=CC=CC=2)C=CC=CC=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([N:26]([C:27]3[CH:28]=[CH:35][CH:37]=[CH:38][CH:46]=3)[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[C:20](=[O:22])[O:21]2)=[C:4]1[CH3:23])[CH3:2]
Reactant: CCn1c(C)c(C(=O)c2cccnc2C(=O)O)c2ccccc21
Reactant: CCn1c(C)c(C(=O)c2ncccc2C(=O)O)c2ccccc21
Agent: c1ccc(Nc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2(N(c3ccccc3)c3ccccc3)OC(=O)c3cccnc32)c2ccccc21
Reaction time: 8 h

Procedure:
A mixture containing 4.5 g. of an isomer mixture comprising 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-3-pyridinecarboxylic acid and 3-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-2-pyridinecarboxylic acid, 2.5 g. of diphenylamine and 30 ml. of acetic anhydride was stirred 6.5 hours, then treated with one ml. of pyridine and allowed to stand overnight. The reaction mixture was poured into 750 ml. of water and the resulting solid product was purified by column chromatography affording 7(1-ethyl-2-methyl-3-indolyl)-7-(diphenylamino)furo[3,4-b]-pyridine-5(7H)-one as a light orange solid, m.p. 132.5°-136° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed an orange image.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].CC(C)([O-])C.[K+].[CH:18]([Si:21]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[O:22][CH2:23][CH:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)([CH3:20])[CH3:19].O>O1CCCC1>[CH:34]([Si:21]([CH:18]([CH3:20])[CH3:19])([CH:31]([CH3:33])[CH3:32])[O:22][CH2:23][CH:24]1[CH2:29][CH2:28][C:27](=[CH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:26][CH2:25]1)([CH3:35])[CH3:36]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(C)[Si](OCC1CCC(=O)CC1)(C(C)C)C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C=C1CCC(CO[Si](C(C)C)(C(C)C)C(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a solution of 6.37 g (35 mmol) of tri methyl phosphonoacetate in 200 mL of tetrahydrofuran (THF) was added 4.28 g (35 mmol) of potassium tert-butoxide. The reaction mixture was stirred at room temperature for 10 minutes. To the resultant slurry was added a solution of 9.3 g (32.7 mmol) of ketone from step C in 20 mL of THF. The mixture was stirred at room temperature under nitrogen overnight, then poured into water and extracted with three 100 mL portions of ether. The combined organic phases were washed sequentially with water, aqueous saturated sodium bicarbonate, and brine, dried over magnesium sulfate, and concentrated to give 10.8 g (97%) of the title compound as a clear oil which was used without further purification. 1H NMR (500 MHz, CDCl3) δ 5.63 (s, 1H), 3.78 (m, 1H), 3.69 (s, 1H), 3.53 (m, 2H), 2.32 (m, 1H), 2.21(m, 1H), 1.97 (m, 2H), 1.76 (m, 1H), 1.10–1.03 (m 23H).
Reaction SMILES: Cl.[S:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][C:18]([C:20](Cl)=[O:21])=[CH:17][C:16]=2[CH:23]=1.[CH2:24]([NH:31][CH3:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN(CC)CC>C(Cl)Cl>[CH2:24]([N:31]([CH3:32])[C:20]([C:18]1[O:19][C:15]2[CH:14]=[CH:13][C:12]([O:11][C:3]3[S:2][C:10]4[C:5]([N:4]=3)=[N:6][CH:7]=[CH:8][CH:9]=4)=[CH:23][C:16]=2[CH:17]=1)=[O:21])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1cc2cc(Oc3nc4ncccc4s3)ccc2o1
Reactant: CNCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)c1cc2cc(Oc3nc4ncccc4s3)ccc2o1
Yield: 15.1 %

Procedure:
To a solution of 5-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-2-carbonyl chloride hydrochloride (150 mg, 0.43 mmol) in CH2Cl2 (4.3 mL) was added N-benzyl-N-methylamine (55 μL, 0.43 mmol) and Et3N (0.12 mL, 0.86 mmol). The reaction mixture was stirred (rt, 2 h) before additional N-benzyl-N-methylamine (55 μL, 0.43 mmol) was added. The mixture was concentrated and purified by reverse phase chromatography to provide the title product as an orange oil (27 mg, 15%). MS (ESI): mass calcd. for C23H17N3O3S, 415.10; m/z found, 416.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.60 (d, J=3.7, 1H), 8.09 (dd, J=7.9, 1.5, 1H), 7.75 (br s, 1H), 7.66-7.49 (m, 1H), 7.46-7.28 (m, 8H), 5.05-4.62 (m, 2H), 3.45-2.94 (m, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]([NH:14][CH2:15][CH2:16][OH:17])=[S:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[S:13][C:12]([NH:14][CH2:15][CH2:16][OH:17])=[N:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(NC(=S)NCCO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2sc(NCCO)nc2c1
Yield: 82 %

Procedure:
A mixture of 28 parts of N-(2-chloro-5-nitrophenyl)-N'-(2-hydroxyethyl)thiourea, 14.5 parts of potassium carbonate and 225 parts of N,N-dimethylformamide is stirred and refluxed for one hour. After cooling, 300 parts of water are added. The precipitated product is filtered off, washed with water and dried, yielding 20.5 parts (82%) of 2-[(5-nitro-2-benzothiazolyl)amino]ethanol; mp. 183.4° C.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[CH:10][CH:9]=1.[C:17]([N:20]1[CH2:29][C:28]([CH3:31])([CH3:30])[C:27]2[C:22](=[CH:23][C:24]([S:32](Cl)(=[O:34])=[O:33])=[CH:25][CH:26]=2)[CH2:21]1)(=[O:19])[CH3:18].C(OCC)(=O)C>O1CCCC1.O>[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][N:14]2[S:32]([C:24]2[CH:23]=[C:22]3[C:27]([C:28]([CH3:31])([CH3:30])[CH2:29][N:20]([C:17](=[O:19])[CH3:18])[CH2:21]3)=[CH:26][CH:25]=2)(=[O:33])=[O:34])=[CH:10][CH:9]=1
Reactant: CC(=O)N1Cc2cc(S(=O)(=O)Cl)ccc2C(C)(C)C1
Reactant: Clc1ccc2cc[nH]c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1Cc2cc(S(=O)(=O)n3ccc4ccc(Cl)cc43)ccc2C(C)(C)C1
Reaction time: 0.08 h
Yield: 50.9 %

Procedure:
Potassium tert-butoxide (37 mg, 0.33 mmol) was added to a stirred solution of 6-chloroindole (50 mg, 0.33 mmol) in dry tetrahydrofuran (1 ml) under argon at room temperature. After stirring for 5 minutes, a solution of 2-acetyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride (D3) (100 mg, 0.33 mmol) in dry tetrahydrofuran (1 ml) was added and the solution was stirred for a further 3 h. Ethyl acetate (5 ml) and water (5 ml) were added to the reaction mixture, which was then shaken. The layers were separated and the organic phase was washed with brine (5 ml), dried (MgSO4) and concentrated in vacuo to an oil. The oil was purified by column chromatography over silica gel eluting with a gradient of acetone/toluene to afford the title compound (D4) (70 mg, 51%), MS: m/z (MH+) 417/419.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1)#[N:2].[ClH:30].[CH2:31]([OH:33])[CH3:32].O1CCOCC1>>[ClH:30].[CH2:31]([O:33][C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:7][CH:8]=1)=[NH:2])[CH3:32]
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C#N)cc2)CCO3)cc1
Reactant: CCO
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=N)c1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To N-(4-cyanophenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (347 mg) was added a solution of 28% hydrogen chloride/ethanol/dioxane (5 ml). After the resulting mixture was stirred at room temperature for 20 hours, the precipitate was collected by filtration and was washed with ethyl acetate to obtain N-[4-(ethoxycarbonimidoyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide hydrochloride (369 mg) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH:10]([CH2:24][C:25](O)=[O:26])[N:9]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.[NH2:60][CH2:61][C:62]1[CH:63]=[N:64][CH:65]=[CH:66][CH:67]=1>O.C(N(CC)CC)C>[N:64]1[CH:65]=[CH:66][CH:67]=[C:62]([CH2:61][NH:60][C:25](=[O:26])[CH2:24][CH:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]23)[CH:63]=1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(CC(=O)O)c1nnc(C)n1-2
Reactant: NCc1cccnc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(CC(=O)NCc1cccnc1)c1nnc(C)n1-2
Yield: 16.3 %

Procedure:
(±)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (1.0 g) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (1.2 g) are added to dimethylformamide (20 ml), and the mixture is stirred. 3-(Aminomethyl)pyridine (0.30 g) and triethylamine (0.38 g) are added, and the mixture is stirred at room temperature for 6 hours. After the completion of the reaction, water (200 ml) is added and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is crystallized from ethyl acetate and isopropyl ether, and recrystallized from ethanol to give 200 mg of (±)-N-(3-pyridylmethyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetamide 1/2 1759 hydrate as white powdery crystals, melting point 180°-183° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:26])[N:11]([O:22][CH2:23][O:24][CH3:25])[C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:13]=1[OH:14].C(N(CC)CC)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:26])[N:11]([O:22][CH2:23][O:24][CH3:25])[C:12]2([CH2:15][CH2:16][N:17]([O:20][CH3:21])[CH2:18][CH2:19]2)[C:13]=1[O:14][C:37]([CH:34]1[CH2:36][CH2:35]1)=[O:38]
Reactant: O=C(Cl)C1CC1
Reactant: COCON1C(=O)C(c2cc(C)ccc2C)=C(O)C12CCN(OC)CC2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCON1C(=O)C(c2cc(C)ccc2C)=C(OC(=O)C2CC2)C12CCN(OC)CC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
To a solution of 3-(2,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1-methoxymethoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P2ii.2) (200 mg, 0.55 mmol), triethylamine (0.153 ml, 111 mg, 1.10 mmol) and a catalytic amount of 4-dimethylaminopyridine in tetrahydrofuran (6 ml) at 0° C. was added cyclopropanecarboxylic acid chloride (0.066 ml, 75 mg, 0.72 mmol) dropwise. The suspension was stirred at 0° C. for 10 minutes, and at room temperature for one hour. The reaction mixture was evaporated, diluted with ethyl acetate and filtered to remove salts. The filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/hexane 1:2) to afford 200 mg of an oily product. This material was triturated with diethyl ether, filtered and dried. Yield: 190 mg of cyclopropanecarboxylic acid 3-(2,5-dimethyl-phenyl)-8-methoxy-1-methoxymethoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (title compound P1ii.4) as a white solid, mp 114-116° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]1[CH2:16][CH2:15][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=3[C:5]=2[CH2:4]1.C(N(CC)CC)C.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>O1CCCC1.[OH-].[Na+]>[CH3:1][N:2]([CH3:17])[CH:3]1[CH2:16][CH2:15][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][C:26]([F:25])=[CH:27][CH:28]=4)=[CH:10][C:9]=3[C:5]=2[CH2:4]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN(C)C1CCc2oc3ccc(N)cc3c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C1CCc2oc3ccc(NC(=O)c4ccc(F)cc4)cc3c2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.7 %

Procedure:
To a solution of 0.132 gm (0.57 mMol) of N,N-dimethyl-8-amino-1,2,3,4-tetrahydro-2-dibenzofuranamine in 5 mL of tetrahydrofuran were added 1.5 mL of triethylamine followed by 0.10 mL (0.13 gm, 0.85 mMol) of 4-fluorobenzoyl chloride. The resulting mixture was stirred at room temperature for 90 minutes at which time the reaction mixture was diluted with 0.1N aqueous sodium hydroxide. This aqueous solution was extracted with dichloromethane and the organic phases were washed sequentially with water and saturated aqueous sodium chloride. The dichloromethane solution was dried over sodium sulfate and concentrated under reduced pressure. This residue was dissolved in dilute aqueous tartaric acid and then washed with dichloromethane. The aqueous phase made basic with aqueous sodium carbonate and was then extracted with dichloromethane. These dichloro-methane extracts were combined and concentrated under reduced pressure. The residue was subjected to radial chromatography (silica gel, 2 mm), eluting with 5% methanol (containing 5% ammonium hydroxide) in chloro-form. Fractions containing product were combined and concentrated under reduced pressure. The residue was crystallized from toluene/hexane to provide 0.130 gm (64%) of the title compound in two crops.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12]C)=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.COC1C=C(NC=C(C(OCC)=O)C(OCC)=O)C=CC=1>>[OH:12][C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1O
Agent: CCOC(=O)C(=CNc1cccc(OC)c1)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(O)ccc2c1
Temperature: 25 °C
Yield: 90 %

Procedure:
Ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate. To a solution of boiling Dowtherm™ (100 mL) was added diethyl 2-(((3-methoxyphenyl)amino)methylene)malonate (20.0 g, 68.3 mmol). After 15 minutes the reaction was cooled to ambient temperature and poured into hexanes (500 mL). The precipitate was collected by filtration and dried under high vacuum to yield the title compound as a brown solid (15.2 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ 12.09 (d, J=5.9 Hz, 1H), 8.47 (d, J=6.7 Hz, 1H), 8.03 (d, J=9.4 Hz, 1H), 7.04-6.97 (m, 2H), 4.18 (q, J=7.0 Hz, 2H), 3.85 (s, 3H), 1.25 (t, J=7.2 Hz, 4H).