Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:42])[C:10]([NH:12][CH:13]([CH:39]([CH3:41])[CH3:40])[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][C:22]1[C:26]2[CH:27]=[C:28](OS(C(F)(F)F)(=O)=O)[CH:29]=[CH:30][C:25]=2[O:24][CH:23]=1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[N:49]1[CH:54]=[CH:53][CH:52]=[C:51](B(O)O)[CH:50]=1>C1(C)C=CC=CC=1.CCOC(C)=O.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>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:11])[NH:12][CH:13]([C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][C:22]1[C:26]2[CH:27]=[C:28]([C:51]3[CH:50]=[N:49][CH:54]=[CH:53][CH:52]=3)[CH:29]=[CH:30][C:25]=2[O:24][CH:23]=1)=[O:15])[CH:39]([CH3:40])[CH3:41])[CH3:42])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)NC(C(=O)N1CCCC1Cc1coc2ccc(OS(=O)(=O)C(F)(F)F)cc12)C(C)C
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(NC(=O)OC(C)(C)C)C(=O)NC(C(=O)N1CCCC1Cc1coc2ccc(-c3cccnc3)cc12)C(C)C
Temperature: 100 °C
Yield: 72.9 %

Procedure:
A mixture of 35 (0.063 g, 0.10 mmol), K2CO3 (70 mg, 0.50 mmol), 3-pyridineboronic acid (0.015 g, 0.12 mmol), and (Ph3P)4Pd (5 mg, 3 mol %) in anhydrous toluene (5 mL) was heated at 100° C. in a sealed tube for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash silica gel chromatography (EtOAc) to afford 40 mg (72%) of 36 as an oil. 1H NMR (CDCl3, 300 MHz) δ8.94 (d, 1H); 8.59 (d, 1H); 8.01-7.95 (m, 1H); 7.74-7.64 (m, 1H); 7.58-7.37 (m, 4H); 6.94 (d, 1H); 4.61 (t, 1H); 4.50-4.47 (m, 1H); 4.30 (t, 1H0; 4.21 (br, 1H); 3.79-3.71 (m, 1H); 3.66-3.59 (m, 1H); 2.42-3.36 (m, 1H); 2.58-2.50 (m, 1H); 2.13-2.09 (m, 1H); 2.01-1.71 (m, 4H); 1.45 (m, 9H); 1.37 (d, 3H); 1.03-0.94 (m, 6H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11](=O)[NH:12][N:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:17])=O.CN(C)C=O>C(Cl)(Cl)Cl>[Cl:17][C:11]1[N:12]=[N:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ncc(-c2ccc(F)cc2)n[nH]1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2cnc(Cl)nn2)cc1

Procedure:
A suspension of 20 g. of 6-(p-fluorophenyl)-1,2,4-triazin-3(2H)-one in 158 ml. of chloroform is cooled in an ice bath and 178.5 ml. of phosphorus oxychloride is added followed by 1.2 g. of N,N-dimethylformamide. The mixture is refluxed for 4.5 hours and then the excess phosphorus oxychloride is removed in vacuo. The residue is redissolved in chloroform and poured into ice-water. When the ice melts the mixture is filtered. The organic layer of the filtrate is washed with water and saturated sodium bicarbonate solution and then dried giving a brown semi-solid. This semi-solid is taken up in chloroform and filtered through a short silica gel column giving 3-chloro-6-(p-fluorophenyl)-1,2,4-triazine as a tan solid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[CH:12][C:13]([N+:15]([O-])=O)=[CH:14][C:6]1=2.I.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](SC)=[NH:26]>C(O)C.ClCCl.[Pd]>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[CH:12][C:13]([NH:15][C:25]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)=[NH:26])=[CH:14][C:6]1=2
Reactant: CSC(=N)c1cccs1
Reactant: CN(C)CCN1CCSc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: I
Solvent: CCO
Solvent: ClCCl
Product: CN(C)CCN1CCSc2ccc(NC(=N)c3cccs3)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.6 %

Procedure:
A suspension of N,N-dimethyl-2-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanamine (75 mg, 0.281 mmol) and palladium, 10 wt. % on activated carbon (29.9 mg, 0.028 mmol) in ethanol (5 mL) was stirred at room temperature under an atmosphere of hydrogen (balloon pressure) for 90 minutes. During this time, the yellow color of the reaction dissipated. To this mixture was then added methyl thiophene-2-carbimidothioate hydroiodide (160 mg, 0.561 mmol), and the resulting suspension was stirred overnight at room temperature. The mixture was then diluted with dichloromethane and filtered to remove palladium. The organic filtrate was further diluted with water and saturated sodium carbonate (1:1). The organic layer was separated, and the aqueous layer was extracted again with dichloromethane. The combined organics were dried, filtered, concentrated, and then chromatographed in 1:19 (2M NH3 in methanol):ethyl acetate, giving the desired product 27 (61 mg, 62.8%). 1H NMR (DMSO-d6) δ 7.71 (d, J=3.3 Hz, 1H), 7.58 (d, J=5.1 Hz, 1H), 7.10-7.06 (m, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.37 (brs, 2H), 6.17 (s, 1H), 6.08 (d, J=7.8 Hz, 1H), 3.63-3.58 (m, 2H), 3.39-3.32 (m, 2H), 3.01-2.96 (m, 2H), 2.42 (t, J=6.9 Hz, 2H), 2.10 (s, 6H); ESI-MS (m/z, %): 347 (MH+, 100), 276 (74); ESI-HRMS calculated for C17H23N4S2 (MH+), calculated: 347.1358, observed: 347.1349; HPLC purity: 95% by area.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:14][CH2:15][C:16](Cl)=[O:17].Cl>CCOC(C)=O.O>[Cl:14][CH2:15][C:16]([C:5]1[CH:4]=[C:3]([CH3:9])[C:2]([F:1])=[CH:7][C:6]=1[F:8])=[O:17]
Reactant: Cc1ccc(F)cc1F
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)CCl)c(F)cc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of 2,4-difluorotoluene was added 6.3 g (47.3 mmol) of AlCl3, and 3.4 mL (42.6 mmol) of chloroacetyl chloride at 0° C. After the mixture was stirred for 10 min. at 0° C. and then at 45° C. for 30 min. The mixture was allowed to cool to r.t., about 16 mL of conc. HCl, 25 mL of water, and 100 mL of EtOAc were added. The organic layer was separated and washed with brine and sat. NaHCO3 (2×), and dried over Na2SO4. The solution was filtered and concentrated to give 9.0 g of 2-chloro-1-(2,4-difluoro-5-methylphenyl)ethanone as a colorless solid that was used without further purification.
Reaction SMILES: [BrH:1].C(OC([NH:9][CH2:10][C:11]#[C:12][CH2:13][NH:14][C:15](=[NH:18])[CH2:16][F:17])=O)CCC.Br>C(O)(=O)C>[BrH:1].[BrH:1].[NH2:9][CH2:10][C:11]#[C:12][CH2:13][NH:14][C:15](=[NH:18])[CH2:16][F:17]
Reactant: CCCCOC(=O)NCC#CCNC(=N)CF
Agent: Br
Solvent: CC(=O)O
Product: N=C(CF)NCC#CCN
Reaction time: 1 h

Procedure:
1-Butoxycarbonylamino-4-(1-imino-2-fluoroethylamino)but-2-yne hydrobromide (500 mg) was deprotected by dissolving in glacial acetic acid (10 ml), cooling until the solution almost solidified and adding HBr in acetic acid (45% wv, 1.8 ml). The mixture was stirred with cooling for 1 h then at room temperature for 1 h. After this time the mother liquor was decanted off and the sticky residue subjected to an oil pump vacuum to remove residual solvent. The resulting material was triturated with dry diethyl ether (×2), filtered off and washed with more dry diethyl ether. The yellow solid was recrystallised from ethanol/diethyl ether and finally dried in a drying pistol to yield 1-amino-4-(1-imino-2-fluoroethylamino)but-2-yne dihydrobromide, Mpt 174°-176.5° C.(dec.), FAB M.S. M+1+ 144.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[NH:20][C:19](=[O:22])[CH2:18][CH2:17]2>C(=S)=S>[Cl:11][C:12]1[CH:13]=[C:14]([C:3](=[O:4])[CH:2]([Br:1])[CH3:6])[CH:15]=[C:16]2[C:21]=1[NH:20][C:19](=[O:22])[CH2:18][CH2:17]2
Reactant: CC(Br)C(=O)Br
Reactant: O=C1CCc2cccc(Cl)c2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Br)C(=O)c1cc(Cl)c2c(c1)CCC(=O)N2
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To a solution of α-bromopropionyl bromide (60 g) and aluminum chloride (40 g) in carbon disulfide (100 ml) was added 8-chloro-3,4-dihydrocarbostyril (10 g). After refluxing the mixture for 5 hours, carbon disulfide was evaporated and heated at 70° to 80° C. for 5 hours. The reaction mixture was poured into ice water and allowed to stand overnight. The mixture was extracted with chloroform and the chloroform layer was washed with water, dried and treated with activated carbon followed by evaporating chloroform. The residue was washed with diethyl ether and collected by filtration. The residue gave uniform crude crystals upon TLC. The crystals thus obtained were re-crystallized from methanol to give 12 g of 8-chloro-6-α-bromopropionyl-3,4-dihydrocarbostyril.
Reaction SMILES: [F:1][C:2]1([F:17])[C:10](=[O:11])[C:9]2[C:8]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:7]=3[CH:6]=[CH:5][C:4]=2[CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(Cl)Cl.Cl>[CH2:31]([O:30][C:28]([N:14]1[CH2:15][CH2:16][C:7]2=[CH:6][CH:5]=[C:4]3[C:9]([C:10](=[O:11])[C:2]([F:1])([F:17])[CH2:3]3)=[C:8]2[CH2:12][CH2:13]1)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1c2c(ccc3c2CCNCC3)CC1(F)F
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCc2ccc3c(c2CC1)C(=O)C(F)(F)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a stirred solution of the product from step (a) (0.13 g, 0.56 mmol) dissolved in DCM (5 ml) at 0° C. was added DIEA (0.12 ml, 0.67 mmol) and benzyl chloroformate (0.095 ml, 0.67 mmol). The reaction mixture was allowed to stir at RT for 1 hour. The reaction mixture was diluted with 1N HCl and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried (Na2SO4), and solvent evaporated in vacuo to give the crude product which was purified by flash silica-gel chromatography (gradient elution: 0-40% EtOAc in hexanes) to give the sub-title compound as a colorless oil (180 mg). MS: ESI (positive): 372 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)(=[O:5])=[O:4].C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl>[CH3:15][N:2]([CH3:1])[S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[C:12]([Br:23])[CH:13]=1)(=[O:4])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C)S(=O)(=O)CCc1ccc(N)cc1
Solvent: ClCCl
Product: CN(C)S(=O)(=O)CCc1ccc(N)c(Br)c1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 96.2 %

Procedure:
A solution of 737 mg (3.23 mmol) of 2-(4-amino-phenyl)-ethanesulfonic acid dimethylamide (as prepared in the previous step) in CH2Cl2 (20 mL) was cooled to 0° C. and treated with 574 mg (3.23 mmol) of NBS. The ice bath was removed and the mixture stirred at RT for 25 min. The mixture was diluted with CH2Cl2 (40 mL) and washed with saturated aqueous NaHCO3 (2×30 mL). The aqueous layer was extracted with CH2Cl2 (1×30 mL) the combined organic layers were dried (MgSO4) and concentrated in vacuo to afford 955 mg (96%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 7.35 (d, 1H, J=2.0 Hz), 7.04 (dd, 1H, J=8.0, 2.0 Hz), 4.44 (br s, 2H), 3.21-3.14 (m, 2H), 2.96-2.89 (m, 2H), 2.84 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C10H15N2OSBr, 307.0/309.0 (M+H). found 307.0/309.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12]C(C3C=CC=C(OC)C=3O[Si](C(C)C)(C(C)C)C(C)C)[N:10]([C:32]([C:34]3[C:39]([F:40])=[CH:38][C:37]([F:41])=[CH:36][C:35]=3[F:42])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.[CH2:43]([O:45][C:46]([C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54][O:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([CH:62]=O)[C:57]=2[O:64][CH2:65][C:66]#[N:67])[N:49]=1)=[O:47])[CH3:44]>>[CH2:43]([O:45][C:46]([C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54][O:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([CH:62]3[N:10]([C:32](=[O:33])[C:34]4[C:35]([F:42])=[CH:36][C:37]([F:41])=[CH:38][C:39]=4[F:40])[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[S:12]3)[C:57]=2[O:64][CH2:65][C:66]#[N:67])[N:49]=1)=[O:47])[CH3:44]
Reactant: CCOC(=O)c1cccc(COc2cccc(C=O)c2OCC#N)n1
Reactant: COc1cccc(C2SC(c3ccc(F)cc3)=NN2C(=O)c2c(F)cc(F)cc2F)c1O[Si](C(C)C)(C(C)C)C(C)C
Product: CCOC(=O)c1cccc(COc2cccc(C3SC(c4ccc(F)cc4)=NN3C(=O)c3c(F)cc(F)cc3F)c2OCC#N)n1

Procedure:
6-{2-Cyanomethoxy-3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxymethyl}-pyridine-2-carboxylic acid ethyl ester is prepared in a similar manner as described for [5-(4-fluoro-phenyl)-2-(3-methoxy-2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone in example 3 using 6-(2-cyanomethoxy-3-formyl-phenoxymethyl)-pyridine-2-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ 8.1 (d, J=7.9 Hz, 1H), 7.94 (t, J=7.9 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.54-7.58 (m, 3H), 7.05-7.14 (m, 3H), 7.01 (d, J=7.3 Hz, 1H), 6.96 (d, J=8.9 Hz, 1H), 6.76 (t, J=8.5 Hz, 2H), 5.4 (s, 2H), 5.12 (d, J=4.4 Hz, 2H), 4.5 (q, J=7.2 Hz, 2H), 1.45 (t, J=7.3 Hz, 3H); LC/MS (ES+): 651.2 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([O:12][CH:13]([C@@H:15]2[C@@H:18]([CH2:19][CH:20]=[O:21])[NH:17][C:16]2=[O:22])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO.C(O)(=O)C>[OH:21][CH2:20][CH2:19][C@H:18]1[NH:17][C:16](=[O:22])[C@@H:15]1[CH:13]([O:12][C:10]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:24][CH:23]=1)=[O:11])[CH3:14]
Reactant: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CCO
Yield: 62.1 %

Procedure:
(3S,4R)-3-[(1RS)-1-(p-Nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-(2-oxoethyl)azetidine (8 mg) was dissolved in methanol (0.8 ml) and sodium borohydride (2 mg) was added at 0° C. The mixture was then stirred for 30 minutes at the same temperature and acetic acid (3 drops) was added. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, and brine, dried over magnesium sulfate and evaporated. The residue was purified by preparative thin layer chromatography (silica gel) developing with benzene: acetone (1:1) to give (3S,4R)-4-(2-hydroxyethyl)-3-[(1RS)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-2-oxoazetidine (5 mg).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[I:23])[C:16]([O:18][CH3:19])=[O:17]>C(C(C)=O)C.CCCCCCC>[CH2:2]([O:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[I:23])[C:16]([O:18][CH3:19])=[O:17])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCI
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCCCCCC
Product: CCCCOc1cc(C(=O)OC)ccc1I
Yield: 97.3 %

Procedure:
6.15 mL (54 mmol) of iodobutane and then 14.9 g (108 mmol) of potassium carbonate are added to 10 g (36 mmol) of methyl 3-hydroxy-4-iodobenzoate in 100 mL of methyl ethyl ketone. The reaction mixture is heated at reflux for 1 hour 30 minutes. The reaction medium is filtered off and the filtrate is evaporated to dryness. The solid obtained is taken up in heptane, filtered and dried. 11.7 g (97%) of methyl 3-butoxy-4-iodobenzoate are obtained in the form of off-white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>CCO.CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(N2CCOCC2)cc1Cl
Yield: 38 %

Procedure:
A solution of 4-(3-chloro-4-nitrophenyl)morpholine (Preparation 112, 450 mg, 1.854 mmol) in EtOH/EtOAc (1:1, 30 mL) was passed through a 10% Pd/C cartridge using an H-cube (atmospheric H2, room temperature, 1 mL/min). The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase column chromatography eluting with 0-20% MeCN in water to afford the title compound (150 mg, 38%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22]Cl)([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>CCOCC>[CH2:24]([N:26]([CH2:27][CH3:28])[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22][N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[CH3:25]
Reactant: CCNCC
Reactant: O=C(c1ccccc1)C(OCCCl)(OCCCl)c1ccccc1
Solvent: CCOCC
Product: CCN(CC)CCOC(OCCN(CC)CC)(C(=O)c1ccccc1)c1ccccc1

Procedure:
20 g (0.057 mole) of benzil-di-(2-chloroethyl)ketal are stirred with 150 g (2.05 moles) of diethylamine for 24 hours at 140° C. in a pressure autoclave. After cooling, the reaction mixture is taken up in ether and extracted with water. The ether layer is dried over Na2SO4 and concentrated. The residual oil is dried in a high vacuum.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C@@H:5]([CH2:15][OH:16])[O:4][CH2:3]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:16][CH2:15][C@H:5]1[O:4][CH2:3][C@@H:2]([CH3:1])[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:6]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CO[C@H](CO)CN1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CO[C@H](COS(C)(=O)=O)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 118.3 %

Procedure:
To a solution of [(2S,5R)-5-methyl-4-(phenylmethyl)-2-morpholinyl]methanol (5 g, 22.59 mmol) and triethylamine (9.45 mL, 67.8 mmol) in CH2Cl2 (50 mL) stirred under nitrogen at 0° C. was added a solution of methanesulfonyl chloride (4.37 mL, 56.5 mmol) in CH2Cl2 (15 mL) dropwise during 5 minutes. The reaction mixture was stirred at 25° C. for 2.5 hours. Then the reaction mixture was washed with saturated NaHCO3 aqueous solution (2×25 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (8.0 g) as a yellow oil. LC-MS (ES) m/z=300 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[C:9](\[CH2:13][CH2:14][CH3:15])/[C:10]([OH:12])=[O:11])=[C:6]([O:16]C)[C:5]([O:18][CH3:19])=[C:4]([O:20][CH3:21])[C:3]=1[O:22]C>CCOCC>[CH3:21][O:20][C:4]1[C:3](=[O:22])[C:2]([CH3:1])=[C:7](/[CH:8]=[C:9](\[CH2:13][CH2:14][CH3:15])/[C:10]([OH:12])=[O:11])[C:6](=[O:16])[C:5]=1[O:18][CH3:19]
Reactant: CCC/C(=C\c1c(C)c(OC)c(OC)c(OC)c1OC)C(=O)O
Solvent: CCOCC
Product: CCC/C(=C\C1=C(C)C(=O)C(OC)=C(OC)C1=O)C(=O)O

Procedure:
Compound 10d was prepared from 9d (0.029 g, 0.090 mmol) as described above for 10a to give 0.016 g (0.053 mmol, 59%) of the product as a red solid following flash chromatography (1:1 Et2O:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].Cl[C:12]1[CH:13]=[CH:14][C:15]([N+:27]([O-:29])=[O:28])=[C:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=1.[H-].[Na+]>CN(C)C=O>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][C:12]2[CH:13]=[CH:14][C:15]([N+:27]([O-:29])=[O:28])=[C:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:17]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1N
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)cc(C)c1N
Yield: 73.4 %

Procedure:
By using 1.10 g of 4-amino-3,5-dimethylphenol, 2.29 g of t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 0.35 g of sodium hydride (55% by weight) and 30 ml of anhydrous N,N-dimethylformamide, reaction and purification were carried out in a similar manner to that described in Reference Example 6, whereby 2.27 g of the title compound were obtained.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>[Pd].CO>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1ccc2cc3n(c2c1)C=CCc1ccccc1-3
Reaction time: 72 h

Procedure:
10% Palladium on carbon (200 mg, 0.19 mmol) was added to a solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxamide, 6-[(4-acetyl-1-piperazinyl)carbonyl]-13-cyclohexyl-N-[(dimethylamino)sulfonyl]- (79 mg, 0.13 mmol) in MeOH (10 mL) and the reaction mixture was vacuum flushed with nitrogen (3×) and then with hydrogen (3×). The reaction mixture was stirred under a balloon of hydrogen for 3 d, filtered through a pad of celite and concentrated. The residue was purified by preparative HPLC (MeOH/H2O with an NH4OAc buffer) to yield 5H-indolo[2,1-a][2]benzazepine-10-carboxamide, 6-[(4-acetyl-1-piperazinyl)carbonyl]-13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6,7-dihydro- (16 mg, 0.03 mmol, 20%) as a white powder. Mixture of atrope diastereomers: 1HNMR (500 MHz, CD3OD) δ 8.09 (s. 0.3H), 7.99 (s. 0.7H), 7.91 (d, J=8.6 Hz, 0.3H), 7.89 (d, J=8.6 Hz, 0.7H), 7.63 (d, J=7.9 Hz, 0.3H), 7.59 (d, J=7.9 Hz, 0.7H), 7.52-7.28 (m, 4H), 4.64-4.56 (m, 0.7H), 4.50 (dd, J=6.1, 14.0 Hz, 0.3H), 4.14-4.05 (m, 0.3H), 3.94-3.57 (m, 9H), 3.02 (s, 4H), 3.01 (s, 2H), 2.98-2.91 (m, 1H), 2.88-2.68 (m, 2H), 2.19 (s, 2H), 2.11 (s, 1H), 2.16-1.91 (m, 4H), 1.87-1.76 (m, 2H) 1.67-1.22 (m, 4H). LCMS: m/e 618 (M−H)−, ret time 1.59 min, column A, 3 minute gradient.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=O)[NH:12][C:13]4[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:11]1[C:10]2[CH:9]=[N:8][C:7]3[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=3[C:15]=2[N:14]2[N:16]=[C:17]([CH3:19])[CH:18]=[C:13]2[N:12]=1
Reactant: CCn1ncc2c1ncc1c(=O)[nH]c3cc(C)nn3c12
Reactant: O=P(Cl)(Cl)Cl
Product: CCn1ncc2c1ncc1c(Cl)nc3cc(C)nn3c12

Procedure:
161 g of 8-ethyl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one (0.06 mol) are heated with stirring in 1 liter of phosphorus oxychloride at 80° for 48 hours. The mixture is decomposed by pouring onto crushed ice. The 5-chloro-8-ethyl-2-methyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine is filtered off and recrystallized from butyl alcohol, yield 148 g (86%); m.p. 179°-180°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:56][O:57][CH:58]1[CH2:63][CH2:62][N:61]([CH2:64][C:65]2[CH:73]=[CH:72][C:68]([CH2:69][NH:70][CH3:71])=[CH:67][CH:66]=2)[CH2:60][CH2:59]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:70]([CH2:69][C:68]3[CH:67]=[CH:66][C:65]([CH2:64][N:61]4[CH2:62][CH2:63][CH:58]([O:57][CH3:56])[CH2:59][CH2:60]4)=[CH:73][CH:72]=3)[CH3:71])=[O:23])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: CNCc1ccc(CN2CCC(OC)CC2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(OC)CC4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-{[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-methyl}-furan-3-carboxylic acid (35 mg, 0.10 mmol), EDCI (26 mg, 0.13 mmol), HOBt (20 mg, 0.15 mmol), DIPEA (0.04 mL, 0.20 mmol), [4-(4-methoxy-piperidin-1-ylmethyl)-benzyl]-methyl-amine hydrochloride (32 mg, 0.10 mmol) and DCM (10 mL).