Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[OH:18][C:12]1[CH:17]=[CH:16][C:15]([C:4]2([C:15]3[CH:16]=[CH:17][C:12]([OH:18])=[CH:13][CH:14]=3)[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:1][C:2]2=[O:3])=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: O=C1Nc2ccccc2C1=O
Product: O=C1Nc2ccccc2C1(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 85 °C
Yield: 82 %

Procedure:
147 g of isatin and 470 g of phenol were brought together and heated to 85° C. Hydrogen chloride gas dried over sulphuric acid is then passed in at 85° C., during which the reaction temperature rises to 115° C. This temperature is maintained and hydrogen chloride is passed in for a further 5 hours. The resulting crystal paste is stirred into 500 ml of benzene and the crystals, colored light yellow, which are thereupon obtained are filtered off and dried. After recrystallization from acetone/chloroform and drying in a water pump vacuum at 90° C., 260 g (82% yield) of colorless crystals are obtained. Melting point 267° C.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[C:30](O)=[O:31].C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3](=[O:20])[CH:2]([NH:1][C:30]([C:22]2[O:21][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH:23]=2)=[O:31])[N:8]=1
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (80 mg, 0.297 mmol), benzofuran-2-carboxylic acid (48 mg, 0.297 mmol), and EDC (56.9 mg, 0.297 mmol) were combined in CH2Cl2 (3 ml) and the pH adjusted to 9.5 with triethylamine (41 μl, 0.297 mmol). After stirring 30 minutes at 25° C., the reaction was concentrated and chromatographed on silica gel (3% MeOH in CH2Cl2) to give the title compound as a white solid from CH2Cl2 /Et2O: (m.p. 289°-291°).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[C:9]([CH2:20][CH3:21])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34]([C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:11][N:10]=[C:9]([CH2:20][CH3:21])[C:8]=4[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])=[CH:14][CH:15]=3)=[CH:33][CH:32]=2)[CH2:29][CH2:30]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CCc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(CC)c4NC(=O)OC(C)(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using the following starting materials: [5-(4-bromo-phenyl)-3-ethyl-isoxazol-4-yl]-carbamic acid tert-butyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:4][CH:3]=1.CNCCNC.[Na+].[I-:22]>O1CCOCC1.[Cu]I>[I:22][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CC(=O)NC(C)Cc1ccc(Br)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)NC(C)Cc1ccc(I)cc1
Temperature: 120 °C
Reaction time: 70 h

Procedure:
To 6.00 g (23.4 mmol) N-(1-(4-bromophenyl)propan-2-yl)acetamide (I44.1) in 65 mL dioxan are added 0.45 g (2.34 mmol) CuI, 0.50 mL (4.70 mmol) N,N′-dimethylethylendiamine and 7.02 g (46.9 mmol) NaI. The reaction mixture is stirred at 120° C. for 70 h. The mixture is allowed to cool to r.t. and half of the solvent is removed in vacuo. EtOAc and diluted aq. ammonia solution are added and the layers are separated. The aq. layer is once more extracted with EtOAc. The organic layers are combined, dried with Na2SO4 and the solvent is removed in vacuo. The crude product is triturated with diethylether and dried at 50° C. in vacuo.
Reaction SMILES: C(OC([N:8]([C:17]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23])[NH:9]C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:29]>C(OCC)(=O)C>[ClH:29].[NH:8]([C:17]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23])[NH2:9]
Reactant: CCOC(=O)C1(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC(=O)NC1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(NN)CC(=O)NC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
To a solution of ethyl 3-[N,N′-bis(tert-butyloxycarbonyl)hydrazino]-2,5-dioxopyrrolidine-3-carboxy late (5.77 g) in ethyl acetate (20 ml) was added a solution of 4M hydrogen chloride in ethyl acetate (25 ml) and the mixture was stirred at room temperature for 24 hours. The resulting precipitates were collected by filtering and washed with ethyl acetate to give the desired product (3.02 g, 76%) as powder. The desired product was identified to be a monohydrochloride salt thereof by the results of elementary analysis and X-ray crystallographic analysis.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([S:40](CCC(OC)=O)(=[O:42])=[O:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:49][CH3:50])=[O:5])[CH3:2].[OH-].[Na+].Cl.C(OCC)(=[O:56])C>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:37])([F:39])[F:38])[CH:29]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:31]=3)[C:22]([S:40]([OH:41])(=[O:42])=[O:56])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:49][CH3:50])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(S(=O)(=O)CCC(=O)OC)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(S(=O)(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(2-methoxycarbonyl-ethanesulfonyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (141 mg) and 2N aqueous NaOH solution (384 μl) are dissolved in ethanol (3 ml), and the mixture is stirred at 50° C. for 30 minutes. To the reaction solution is added 2N aqueous HCl solution (385 μl), and stirred overnight. To the reaction mixture is added ethyl acetate, and the organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=9:1→4:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-sulfopyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (64 mg). MS (m/z): 662 [M−H]−.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49].NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:41])[NH:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49])=[CH:33][CH:32]=3)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)CO
Agent: CC(C)(N)C(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCCC(=O)NC(C)(C)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1-propanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-propionamide, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[C:17]([CH2:18][N:19]([CH3:31])[CH2:20][CH2:21][N:22](C)[C:23](=O)OC(C)(C)C)=[CH:16][N:15](C3CCCCO3)[N:14]=2)[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40].CC#N>Cl>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[C:17]([CH2:18][N:19]([CH3:31])[CH2:20][CH2:21][NH:22][CH3:23])=[CH:16][NH:15][N:14]=2)[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1c(Cl)cc(-c2nn(C3CCCCO3)cc2CN(C)CCN(C)C(=O)OC(C)(C)C)cc1Cl
Agent: Cl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CNCCN(C)Cc1c[nH]nc1-c1cc(Cl)c(OC(C)C)c(Cl)c1
Reaction time: 0.17 h
Yield: 46.7 %

Procedure:
A solution of tert-butyl N-[2-[([3-[3,5-dichloro-4-(propan-2-yloxy)phenyl]-1-(oxan-2-yl)-1H-pyrazol-4-yl]methyl)(methyl)amino]ethyl]-N-methylcarbamate (210 mg, 0.38 mmol, 1.00 equiv) in 3N hydrochloric acid (20 mL) was stirred at 40° C. overnight. The resulting solution was washed with 3×10 mL of dichloromethane. The aqueous layer was concentrated under vacuum and the crude product was purified by Prep-HPLC with the following conditions (2#-Waters 2767-2(HPLC-08)): Column, Xbridge Shield RP 18, 5 um, 19*150 mm; mobile phase, water with 50 mmol CF3COOH and CH3CN (10.0% CH3CN up to 28.0% in 2 min, up to 46.0% in 10 min, up to 100.0% in 1 min, down to 10.0% in 1 min); Detector, UV 254 nm to yield 106.4 mg (47%) of ([3-[3,5-dichloro-4-(propan-2-yloxy)phenyl]-1H-pyrazol-4-yl]methyl)(methyl)[2-(methylamino)ethyl]amine bis(trifluoroacetic acid) salt as a yellow oil. 1H-NMR (300 MHz, D2O): δ 7.94 (s, 1H), 7.56 (s, 2H), 4.89-4.52 (m, 1H), 4.44 (s, 2H), 3.29 (s, 4H), 2.62 (d, J=4.5 Hz, 6H), 1.32 (d, J=6.3 Hz, 6H) ppm. LCMS (method D, ESI): RT=1.28 min, m/z=371.0 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>O>[C:11]1([C:2]2[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[CH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cnc(Br)c(C)c1C
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cnc(-c2ccccc2)c(C)c1C

Procedure:
10.2 g (0.051 mol) of 2-bromo-3,4,5-trimethylpyridine was mixed with 7.86 g (0.061 mol) of phenylboronic acid, 1.8 g (0.0016 mol) of Pd(Ph3)4, 19.1 g (0.13 mol) of K2CO3 50 mL of DME and 50 mL of water. The reaction mixture was refluxed for 20 hours and separated on silica gel column. MS confirmed the desired product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[C:31]([F:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:34]([NH2:42])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[F:32][C:31]1[C:26]([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[CH2:19][N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[S:15]([CH3:18])(=[O:17])=[O:16])=[N:27][C:28]([NH:42][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3nc(Cl)ncc3F)c2)S(C)(=O)=O)CC1
Reactant: NCCc1ccccc1
Product: CS(=O)(=O)N(Cc1cccc(-c2nc(NCCc3ccccc3)ncc2F)c1)C1CCNCC1

Procedure:
Intermediate 77 was coupled with phenethylamine following procedure Q. The resulting product was deprotected following procedure R. LC-MS showed the product had the expected M+H+ of 484. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.25 (d, 1H), 8.17 (s, 1H), 7.98 (d, 1H), 7.49 (m, 2H), 7.26 (m, 5H), 4.55 (s, 2H), 3.89 (m, 1H), 3.62 (t, 2H), 3.33 (m, 2H), 3.03 (s, 3H), 2.98 (m, 2H), 2.90 (t, 2H), 1.89 (m, 4H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[CH:15]2)[CH2:9]1)C1C=CC=CC=1.[Cl:32]C(OC(Cl)C)=O.C(O)C.CCOCC>ClCCCl>[ClH:32].[C:26]1([S:23]([C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]([CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[CH:15]=2)(=[O:24])=[O:25])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: O=S(=O)(c1ccccc1)c1cn(C2CCCN(Cc3ccccc3)C2)c2ccccc12
Solvent: CCOCC
Solvent: CCO
Solvent: ClCCCl
Product: Cl
Product: O=S(=O)(c1ccccc1)c1cn(C2CCCNC2)c2ccccc12
Yield: 85 %

Procedure:
A solution of 1-(1-benzylpiperidin-3-yl)-3-(phenylsulfonyl)-1H-indole (431 mg, 1.00 mmol) in dry 1,2-dichloroethane is treated with 1-chloroethyl chloroformate (0.27 mL, 2.50 mmol), heated at reflux temperature for 2.5 h, cooled and concentrated in vacuo (reconcentrated twice from CH2Cl2). The resulting residue is heated at reflux temperature in methanol for 3 h, cooled and concentrated in vacuo to give an oil. The oil is reconcentrated from ethanol and then from ether to give a tan solid. The solid is triturated with ethanol and filtered. The filtercake is dried under vacuum to afford the title product as an off-white solid, 322 mg (85% yield), mp 254–256° C., identified by HNMR and mass spectral analyses.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17]C)=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH3:19]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH2:19])=[O:17])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: N
Reactant: COC(=O)Cc1ccc(N2CCN(C)CC2)cc1
Product: CN1CCN(c2ccc(CC(N)=O)cc2)CC1
Yield: 57 %

Procedure:
Methyl 2-(4-(4-methylpiperazin-1-yl)phenyl)acetate (0.45 g, 1.81 mmol) in methanolic ammonia (15 ml) was heated at 100° C. in a pressure bomb overnight. Excess MeOH was concentrated under reduced pressure to give the crude compound. This was washed with n-pentane and dried in vacuo to afford 0.24 g (57%) of 2-(4-(4-methylpiperazin-1-yl)phenyl)acetamide as a brown color solid.
Reaction SMILES: C[O:2][C:3]1[CH:18]=[CH:17][C:6]2[O:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11](=[O:12])[C:5]=2[CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:18]=[CH:17][C:6]2[O:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11](=[O:12])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C1c2ccccc2COc2ccc(O)cc21
Temperature: 180 °C
Yield: 79.7 %

Procedure:
A mixture of 20 g of 2-methoxy-6,11-dihydrodibenz[b,e]oxepin-11-one and 150 g of pyridine hydrochloride is stirred with heating at 180° C for 2 hours. The solution is poured into 2 liter of water with stirring to give 15 g of 2-hydroxy-6,11-dihydrodibenz[b,e]oxepin-11-one. Mass spectrum m/z: 226(M+), melting point: 165°-166° C. (recrystallized from ethanol).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([OH:16])=[S:15])=[O:7].[C:23](=O)([O-])[O-:24].[Na+].[Na+].[BH4-].[Na+].Cl>COCCOC.C(OCC)(=O)C.O>[O:24]1[CH:23]=[CH:5][CH:4]=[C:3]1[C:2]([CH:6]([OH:7])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([OH:16])=[S:15])=[O:1]
Reactant: O=C(CCCCCC(C(O)=S)c1ccccc1)c1ccco1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(c1ccco1)C(O)CCCCCC(C(O)=S)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 3.61 g of 7-(2-furoyl)-2-phenylthioheptanoic acid in 15 ml of DME is added 25 ml of water and 5.45 ml of 1.0 M aqueous sodium carbonate. The resulting solution is treated furing 1 min. with 0.41 g of sodium borohydride in small portions. The mixture is stirred at ambient temperature for 3.5 hours, diluted with ethyl acetate, cooled to 0°, and treated with 4 M hydrochloric acid. The ethyl acetate layer is washed with water and brine, dried over MgSO4, and concentrated to give an oil.
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH3:15])=O)(C)(C)C.C(OC(NC1C=CN=CC=1)=O)(C)(C)C.C([Li])CCC.CI>O1CCCC1>[NH:8]1[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[CH:15]=[CH:6]1
Reactant: Cc1cnccc1NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)Nc1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: c1cc2[nH]ccc2cn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4-tert-Butoxycarbonylamino-3-methylpyridine A solution of 4-tert-butoxycarbonylaminopyridine (10.0 g, 51.5 mmol) in tetrahydrofuran (150 ml) was cooled to -30° C. and n-butyllithium (45.3 ml, 2.5M in hexane, 113.3 mmol) was added at such a rate as to keep the temperature below -20° C. The mixture was stirred at 0° C. for 3 hours, the slurry cooled to -70° C. and a solution of methyl iodide (8.77 g, 61.8 mmol) in tetrahydrofuran (25 ml) added. The mixture was warmed to 20° C. and stirred for 1 hour. The mixture was quenched with water (100 ml) and extracted with ethyl acetate (2×100 ml). The combined ethyl acetate fractions were washed with saturated brine (100 ml), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (95% methylene chloride/5% methanol) and then swished in hot hexane to afford the title compound as a pale yellow solid; yield: 5.75 g (54%). mp 124°-126° C.; Analysis Found: C, 63.35; H, 7.72; N, 13.44. C11H16N2O2 : requires C, 63.44; H, 7.74; N, 13.45%; 1H NMR (CD2Cl1 /TMS) δ1.52 (9H, s), 2.22 (3H, s), 6.92 (1H, br.s), 7.97 (1H, d, J=5.6 Hz), 8.28 (1H, s), 8.33 (1H, d, J=5.6 Hz).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([CH2:30]P(=O)(OCC)OCC)=[N:27]2)=[CH:22][CH:21]=1.C=O>O1CCCC1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([CH:30]=[CH2:1])=[N:27]2)=[CH:22][CH:21]=1
Reactant: CC(C)NC(C)C
Reactant: CCOP(=O)(Cc1ccc2ccc(Cl)cc2n1)OCC
Agent: C=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1ccc2ccc(Cl)cc2n1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
A stirred solution of diisopropylamine (2.24 ml, 15.97 mmol) in tetrahydrofuran (15.0 ml) at -10° C. under nitrogen was treated dropwise with a 2.5M solution of n-butyllithium in hexane (6.4 ml, 15.97 mmol). After stirring below 0° C. for 30 min the pale yellow solution was cooled to -20° C. and a solution of diethyl 7-chloro-2-quinolylmethylphosphonate (5.0 g, 15.97 mmol) in tetrahydrofuran was added dropwise. The resulting dark green solution was stirred below 0° C. for 1 h, cooled to -10° C. and treated with paraformaldehyde (0.53 g, 17.57 mmol) in portions. Stirred cold for 15 min after which the cooling bath was removed and the mixture was stirred at 25° C. for 90 min. Quenched with brine (300 ml), extracted into ethyl acetate (3×100 ml), the combined organic extracts were washed with brine (3×200 ml), dried (Na2 SO4) and the solvent was removed in vacuo to give a dark brown solid. Column chromatography (ethyl acetate--light petroleum (b.p. 40°-60° C.), 1:19) provided the title compound (1.80 g, 59%) as pale yellow crystals. Crystallised from ethyl acetate and light petroleum (b.p. 40°-60° C.) as cream crystals, m.p. 79.7°-80° C. (Found: C, 69.84; H, 4.15; N; 7.25; Cl, 18.91. C11H8ClN requires C, 69.67; H, 4.25; N, 7.39; Cl, 18.69%); νmax (nujol) /cm-1 1628, 160; δH (270 MHz) 5.67 (1H, dd, 2'-H, 3J2',1' =10.89, 2J2',2" =1.0 Hz); 6.29 (1H, dd, 2"-H, 3J2",1' =17.7, 2J2",2' =0.8 Hz); 7.02 (1H, dd, 1'-H, 3J1',2" =17.5, 3J1',2' =10.9 Hz); 7.42 (1H, dd, 7-H, Jo =8.8, Jm =2.1 Hz); 7.53 (1H, d, 3-H, Jo 8.9 Hz); 7.66 (1H, d, 5-H, Jo =8.9 Hz); 8.03 (1H, d, 4-H, Jo =8.3 Hz); 8.05 (1H, s, 8-H). δC (67.8 MHz) 118.6 (2'-C); 120.5 (3-C); 125.7 (4a-C); 135.3 (7-C); 136.0 (4-C); 137.5 (1'-C); 148.3 (8a-C); 156.9 (2-C). Remaining signals fall in the range 127.1-128.5 ppm; m/z 191.0, 189.0 (33.48, 100, M+), 165.0, 163.0 (21.89, 65.87), 154.0 (5.13), 128.1 (9.14).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19]([O:21]CC)=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:24]=1.[Li+].[OH-].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19]([OH:21])=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:24]=1
Reactant: CCOC(=O)C1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: 80 °C
Reaction time: 2 h
Yield: 105.8 %

Procedure:
A mixture of ethyl 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylate (606 mg, 1.75 mmol) and LiOH (168 mg, 7.00 mmol) in dioxane/H2O (6 mL/5 mL) was stirred at 80° C. for 2 hours. The reaction was monitored using TLC. When the reaction was completed, the mixture was adjusted to pH 4-5 with 1 N HCl aqueous. The mixture was extracted with EtOAc (10 mL*3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under reduce pressure, afforded the desired product of 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylic acid (crude: 590 mg, yield: 99%). 1H-NMR (400 MHz, DMSO-d6) δ 7.74 (d, J=8.6 Hz, 1H), 7.56˜7.43 (m, 2H), 7.37 (s, 1H), 7.34˜7.25 (m, 1H), 7.15 (s, 1H), 7.02˜6.92 (m, 1H). MS (M+H)+: 319.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([CH3:19])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][C:16](Cl)=[O:17]>>[C:8]1([CH3:19])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][C:16]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:17]
Reactant: Cc1ccccc1CCC(=O)Cl
Reactant: Oc1ccccc1
Product: Cc1ccccc1CCC(=O)Oc1ccccc1
Yield: 91.9 %

Procedure:
The procedure as described in Example 4a) was repeated with phenol (48 mmol) and 3-o-tolylpropanoyl chloride (55 mmol). The crude product (12.4 g, 97%) was short path distilled at 127-129° C./0.05 mbar to yield 10.6 g (93%) of product as a colourless, semicrystalline oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:30])[N:13]([CH2:20][CH2:21][C:22](=[O:29])[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C1COCC1.C(Cl)Cl>[C:38]([N:26]1[CH2:25][CH2:24][N:23]([C:22](=[O:29])[CH2:21][CH2:20][N:13]2[C:12](=[O:30])[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:8])[C:14]2=[O:19])[CH2:28][CH2:27]1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Nc1cccc2c1C(=O)N(CCC(=O)N1CCNCC1)C2=O)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCN(C(=O)CCN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
90 mg (0.2 mmol) of 5-chloro-N-{1,3-dioxo-2-[3-oxo-3-(1-piperazinyl)propyl]-2,3-dihydro-1H-isoindol-4-yl}-2-thiophenecarboxamide and 41 mg (0.4 mmol) of triethylamine are dissolved in 10 ml of THF, and 20.6 mg (0.2 mmol) of acetic anhydride are added. The reaction mixture is stirred at room temperature for 5 h, diluted with methylene chloride, washed with water, dried over magnesium sulfate, filtered and concentrated. This gives 81 mg (82% of theory) of the product.