Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C=O)C>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][O:21][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
N6-benzoyl-2′-deoxyadenosine (20.95 g ) was dissolved in 200 ml of DMF. Imidazole (15.7 g) was dissolved to the resultant solution by addition. Then, 20.8 g of tert-butyldimethylsilyl chloride was added. DMF (100 ml) was further added and the solution was stirred at room temperature. After 8 hours, extraction using chloroform was carried out and the organic layer was washed by a saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate. After concentration of the extract, the target compound was purified by column chromatography (methanol/chloroform) to obtain 16.1 g of the titled compound (yield; 61%).
Reaction SMILES: [H-].[Na+].C1COCC1.[CH3:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[NH:11][N:10]=1.[CH3:21][Si:22]([CH2:25][CH2:26][O:27][CH2:28]Cl)([CH3:24])[CH3:23]>CCOC(C)=O.O>[CH3:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[N:11]([CH2:28][O:27][CH2:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[N:10]=1
Reactant: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nn(COCC[Si](C)(C)C)c2cc([N+](=O)[O-])ccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A flask was charged with NaH (60% dispersion in mineral oil, 0.325 g, 13.6 mmol) and THF (40 mL). The mixture was cooled to about 0° C. followed by the addition of 3-methyl-6-nitro-1H-indazole (2.00 g, 11.3 mmol, ArkPharm). The mixture was stirred for about 30 min followed by the addition of SEMCl (2.26 g, 13.6 mmol). The mixture was warmed to rt and stirred for about 12 h. Water (5 mL) and EtOAc (70 mL) were added and the layers were separated. The organic layer was concentrated under reduced pressure to give 3-methyl-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (3.2 g, 91%): LC/MS (Table 2, Method f) Rt=2.18 min; MS m/z: 308 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15]O)[CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[NH:17]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=[N:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][N:17]3[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=[N:18]3)[CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: COCCN1CCCc2ccc(CO)cc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnn(Cc2ccc3c(c2)N(CCOC)CCC3)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(1-(2-Methoxyethyl)-1,2,3,4-tetrahydroquinolin-7-yl)methanol (357 mg, 0.807 mmol) and ethyl 1H-pyrazole-4-carboxylate (113 mg, 0.807 mmol) were dissolved in THF (5 ml). Triphenylphosphine (317 mg, 1.210 mmol) was added, and, after cooling to 0° C., a 40% solution of DEAD in Toluene (0.479 ml, 1.210 mmol) was added dropwise. The reaction mixture was stirred for 2 hr at 0° C., then overnight at 20° C. The reaction mixture was diluted with AcOEt and washed with 1N HCl, and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by preparative-HPLC (Waters SunFire Prep C18 OBD 5 μm 19*50, Flow 20 mL/min, ACN: 2 min at 5%, then to 100% within 17.5 min, RT 11.80 min) to give the title compound. HPLC (Method A) Rt=2.001 min; MS (Method A) [M]+=343.9
Reaction SMILES: N1([C:6](N2C=CN=C2)=[O:7])C=CN=C1.[CH:13]1([CH2:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:34]3=[N:35][CH:36]=[N:37][C:38]([O:39][CH:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)=[C:33]3[CH:32]=[N:31]2)=[CH:26][CH:25]=1)(=[O:23])=[O:22].C(N(CC)CC)C>CS(C)=O>[CH:13]1([CH2:18][O:19][C:6]([N:43]2[CH2:44][CH2:45][CH:40]([O:39][C:38]3[N:37]=[CH:36][N:35]=[C:34]4[N:30]([C:27]5[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[CH:25][CH:26]=5)[N:31]=[CH:32][C:33]=34)[CH2:41][CH2:42]2)=[O:7])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCC1CCCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCN(C(=O)OCC5CCCC5)CC4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
Di-imidazol-1-yl-methanone (0.51 mmol, 83 mg), and cyclopentyl-methanol (0.51 mmol, 51 mg) were dissolved in DMSO (1 mL) and stirred for 30 minutes at room temperature. Then, 1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (0.17 mmol, 70 mg) and triethylamine (0.51 mmol, 72 μL) were added and heated in a microwave at 120° C. for 6 minutes. The progress of the reaction was monitored by LCMS. The reaction mixture was quenched with water and the product was extracted with ethylacetate. Removal of organic solvents in vacuo and purification by HPLC provided Compound A120 as a white solid (30 mg, 29%). Exact mass calculated for C24H29N5O5S 499.58, found 500.4 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[C:15]2[C:26]2[CH:31]=[CH:30][N:29]=[C:28](F)[CH:27]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][NH2:34]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[C:15]2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:34][CH3:33])[CH:27]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2ccn(C3CCN(Cc4ccccc4)CC3)c2-c2ccnc(F)c2)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1cc(-c2c(-c3ccc(F)cc3)ccn2C2CCN(Cc3ccccc3)CC2)ccn1
Temperature: 150 °C
Reaction time: 28 h
Yield: 60 %

Procedure:
A mixture of a solution of 1.50 g (3.49 mmol) of 1-(1-benzylpiperidin-4-yl)-3-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)-1H-pyrrole [prepared as described in step 72(i) above] in 30 ml of tetrahydrofuran and 50 ml (100 mmol) of a 2M solution of methylamine in tetrahydrofuran was stirred at 150° C. in an autoclave for 28 hours. At the end of this time, the solvent was distilled off from the reaction mixture under reduced pressure. Ethyl acetate and water were added to the residue, and the organic layer was separated, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column using a 20:1 by volume mixture of dichloromethane and methanol as the eluant to give 1.83 g (yield 60%) of the title compound as a pale brown amorphous solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9]C)=O)=[O:4].[CH2:13]([CH2:15][NH2:16])[OH:14].C(N(CC)C(C)C)(C)C>O1CCCC1>[OH:14][CH2:13][CH2:15][N:16]1[CH2:2][C:3](=[O:4])[NH:5][C:6]([CH3:12])([CH3:11])[C:7]1=[O:9]
Reactant: COC(=O)C(C)(C)NC(=O)CCl
Reactant: NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)NC(=O)CN(CCO)C1=O
Temperature: 155 °C
Yield: 42.3 %

Procedure:
A solution of methyl 2-(2-chloroacetamido)-2-methylpropanoate (2.5 g, 13 mmol), ethanolamine (1.3 g, 21.3 mmol), and N,N-diisopropylethylamine (4.0 mL, 23 mmol) in 250 mL of anhydrous tetrahydrofuran was heated at reflux temperature for 24 hours. The mixture was concentrated to a residue in vacuo and dissolved in ethanol (approximately 300 mL). The mixture was heated in a sealed tube at 155° C. for 24 hours then concentrated to a crude residue and purified by column chromatography (5 to 12% methanol in dichloromethane) to give the title compound as a white solid (1.03 g, 5.5 mmol, 42%). 1H NMR (DMSO-d6, 400 MHz) δ 1.30 (s, 6H), 3.32-3.35 (t, J=5.7, 2H), 3.48-3.53 (q, J=5.7, 2H) 4.02 (s, 2H), 4.75-4.77 (t, J=5.4 Hz, 1H). LRMS (ESI/APCI) m/z 187 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[CH:34]=1)=[O:32])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[CH:34]=1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C#N)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N4CCOCC4)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-cyano-5-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (Example J12) (318 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (400 mg, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8](Br)[CH:9]=1)=[O:4].[CH3:14][C:15]1[O:16][CH:17]=[CH:18][C:19]=1[SH:20]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([S:20][C:19]2[CH:18]=[CH:17][O:16][C:15]=2[CH3:14])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Br)c([N+](=O)[O-])s1
Reactant: Cc1occc1S
Solvent: C1CCOC1
Product: COC(=O)c1cc(Sc2ccoc2C)c([N+](=O)[O-])s1

Procedure:
4-Bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 532 mg, 2 mmol), 2-methyl-furan-3-thiol (600 mg, 5.26 mmol), and DMAP-polystyrene resin (2 g, 2.86 mmol) were stirred in THF (10 mL) for 12 h at rt. The resin was filtered and washed with several portions of DCM (100 mL total volume). The filtrate was concentrated in vacuo and the yellow residue (480 mg, 80%) was used without further purification. 1H-NMR (CDCl3): δ 7.46 (d, 1H, J=1.9 Hz), 7.05 (s, 1H), 6.43 (d, 1H, J=1.9 Hz), 3.90 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=O)[CH:8]=[CH:9][CH:10]=1.Cl.[NH2:30][OH:31].C([O-])(O)=O.[Na+]>>[OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=[N:30][OH:31])[CH:8]=[CH:9][CH:10]=1
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2cccc(C#CCO)c2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2cccc(C#CCO)c2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 3-[3-(3-hydroxy-prop-1-ynyl)-phenyl]-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3:1) as a white foam, MS (ESI+): m/z=385.1 ([M+H]+).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]1([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:46]1(=[O:52])[NH:50][C:49](=[O:51])[CH:48]=[CH:47]1>>[C:34]1([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N:50]2[C:46](=[O:52])[CH:47]=[CH:48][C:49]2=[O:51])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: OCCCCCc1ccccc1
Reactant: O=C1C=CC(=O)N1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1C=CC(=O)N1CCCCCc1ccccc1

Procedure:
Reagents: Ph3P (0.65 g, 2.5 mmol), DIAD (0.5 ml, 2.5 mmol), 5-phenyl-1-pentanol (0.63 ml, 3.75 mmol) and maleimide (0.24 g, 2.5 mmol).
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Br[CH2:18][CH2:19][C:20]1[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=1[CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>C(O)C.C1(C)C=CC=CC=1>[CH2:28]([O:27][P:23]([CH2:22][C:21]1[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=1[CH2:19][CH2:18][C:6]([NH:5][C:2](=[O:4])[CH3:3])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O:24][CH2:25][CH3:26])=[O:30])[CH3:29]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCOP(=O)(Cc1ccccc1CCBr)OCC
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCc1ccccc1CP(=O)(OCC)OCC)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Yield: 34 %

Procedure:
To 1.03 g (44.8 mmol) of sodium in 50 mL of dry ethanol was added 9.72 g (44.8 mmol) of solid diethyl acetamidomalonate portionwise. This solution was stirred at reflux under nitrogen for 2 h. After cooling to room temperature the solvent was removed under reduced pressure yielding a tan solid. This solid was dried under vacuum about 2 h. The sodium salt of diethyl acetamidomalonate was then suspended in 50 mL of dry toluene and 15.0 g (44.8 mmol) of diethyl 2-(2-bromoethyl)benzylphosphonate in 25 mL of toluene was added dropwise. This solution was stirred at reflux under nitrogen for 36 h. After cooling the solution to room temperature the solid precipitate was removed by filtration and washed with 20 mL of toluene. The combined toluene solutions were concentrated under reduced pressure to yield a viscous oil. This oil was chromatographed on a column of silica gel with ethyl acetate as eluant. The combined fractions were concentrated under pressure to give 7.2 g (34%) of the product as a clear viscous oil. IR(neat): 1745, 1676 (C=O) cm-1. 1H NMR(CDCl3) δ 1.0-6 (m, 12H); 1.8-3.2 (complex m, 9H); 3.7-4.6 (m, 8H); 6.8-7.4 (m, 5). Anal. Calcd. for C22H34NO8P0.5H2O: C, 54.99; H, 7.34; N, 2.92. Found: C, 54.75; H, 7.37; N, 2.97.
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Cl[CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(C)CC(=O)C>[CH2:1]1[CH:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][N:2]1[CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNCC21
Reactant: CCOC(=O)COCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)COCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Yield: 84.2 %

Procedure:
2.5 g of 1,2,3,4,10,14b-hexahydrodibenzo[c,f]-pyrazino[1,2-a]azepine, 2.4 g of ethyl 2-chloroethoxyacetate (prepared as described in Preparation 1 or 2), 3.82 g of sodium carbonate and 0.14 g of sodium iodide were added to 80 ml of 4-methyl-2-pentanone, and the mixture was heated under reflux for 18 hours. At the end of this time, it was filtered, and the solvent was removed from the filtrate by distillation under reduced pressure. The residue was subjected to column chromatography through silica gel, and 3.2 g (yield 84%) of the title compound were obtained as a light brown oil from the fractions eluted with ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Cl:9][C:10]1[CH:23]=[CH:22][C:13]([CH:14]=[C:15]([C:19]([O-:21])=O)[C:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.[CH2:24](O)[CH3:25]>Cl.N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:14]2[CH:15]([C:16]([O:18][CH2:24][CH3:25])=[O:17])[C:19](=[O:21])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2)=[CH:22][CH:23]=1
Reactant: Nc1ccccc1S
Reactant: CCO
Reactant: O=C([O-])C(=Cc1ccc(Cl)cc1)C(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1C(=O)Nc2ccccc2SC1c1ccc(Cl)cc1

Procedure:
A mixture of 32 g of o-aminothiophenol, 70.7 g of p-chlorobenzalmalonate and 1.4 g of pyridine hydrochloride was heated at about 180° C. until no further ethanol was distilled out (for about 4 hours). After allowing the reaction mixture to cool, a mixture of benzene-petroleum ether was added to the reaction mixture which was then thoroughly stirred and filtered. The resulting filter cake was recrystallized from chloroform-petroleum ether to obtain 54.5 g of 2-(p-chlorophenyl)-2,3-dihydro-3-ethoxycarbonyl-1,5-benzothiazepin-4(5H)-one as colorless needles having a melting point of 206° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][C:13]3([CH3:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([CH3:36])=[CH:27][C:28](=[O:35])[N:29]2[CH2:32][CH:33]=O)=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][C:13]3([CH3:19])[CH2:14][CH2:15][N:16]([CH2:33][CH2:32][N:29]4[C:30]5[C:25](=[CH:24][CH:23]=[C:22]([O:21][CH3:20])[CH:31]=5)[C:26]([CH3:36])=[CH:27][C:28]4=[O:35])[CH2:17][CH2:18]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC1(NCc2ccc3c(c2)OCCO3)CCNCC1
Reactant: COc1ccc2c(C)cc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(C)cc(=O)n(CCN3CCC(C)(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To 2 mL of dichloromethane solution containing 77 mg of N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methylpiperidine-4-amine, 68 mg of (7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde and 17 μL of acetic acid were added and stirred at room temperature for 1 hour. To the reaction mixture, 93 mg of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=5:1] to give 0.13 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-4-methylpiperidin-1-yl)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:9]1[CH:21]=[CH:22][C:23](OCC)=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].B(F)(F)F.CCOCC.CC(C[AlH]CC(C)C)C.CCOC(C)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][Si:14]([C:17]([CH3:19])([CH3:18])[CH3:20])([CH3:16])[CH3:15])[CH:9]1[CH:21]=[CH:22][CH2:23][OH:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=CC1C(O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)C1C=CCO
Temperature: -78 °C
Reaction time: 1 h
Yield: 108.1 %

Procedure:
A solution containing 42 (8.6 g, 22 mmol) in DCM (80 ml) was cooled to −78° C. To this solution was slowly added boron trifluoride etherate (2.8 mL, 22 mmol) followed by the addition of 1M DIBALH in DCM (60 mL). The solution was stirred at −78° C. for 1 h. The reaction mixture was then treated with EtOAc and stirred for 30 min. The reaction mixture was allowed to warm to −5° C. The reaction was quenched by the dropwise addition of 1M HCl. The mixture was diluted with DCM and H2O and the layers were separated. The aqueous layer was extracted with DCM. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to afford 8.5 g of 43 as a light yellow oil which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ5.70 (m, 1H), 5.59-5.55 (m, 1H), 4.16-4.13 (m, 2H), 4.05 (m, 2H), 3.72-3.35 (m, 4H), 1.95-1.88 (m, 2H), 1.77-1.67 (m, 2H), 1.48-1.44 (m, 9H), 0.88 (s, 9H), 0.08-0.03 (m, 6H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](#[N:14])[CH2:11][C:12]#[N:13].C(N(CC)CC)C.[CH3:22][N:23]1[C:27](=[O:28])[CH2:26][C:25]([CH3:29])=[N:24]1>C(O)C>[NH2:13][C:12]1[O:28][C:27]2[N:23]([CH3:22])[N:24]=[C:25]([CH3:29])[C:26]=2[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:11]=1[C:10]#[N:14]
Reactant: N#CCC#N
Reactant: CC1=NN(C)C(=O)C1
Reactant: O=Cc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nn(C)c2c1C(c1ccc(F)cc1)C(C#N)=C(N)O2
Reaction time: 0.02 h
Yield: 40.8 %

Procedure:
A mixture of 4-fluorobenzaldehyde (300 μL, 2.87 mmol, 1.0 equ.), malononitrile (190 mg, 2.87 mmol, 1.0 equ.) and triethylamine (400 mL, 2.87 mmol, 1.0 equ.) in ethanol (8.0 mL) was stirred for 1 min, followed by the addition of 1,3-dimethyl-1H-pyrazol-5(4H)-one (322 mg, 2.87 mmol, 1 equ.). The reaction mixture was concentrated after 24 h and washed with ethanol and hexanes, and re-crystallized from ethanol to give 6-amino-4-(4-fluorophenyl)-1,3-dimethyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (335 mg, 41%, 1.17 mmol) as a white solid. 1H-NMR (400 MHz) DMSO: 7.23-7.20 (m, 2H), 7.16-7.12 (m, 2H), 7.07 (s, 2H), 4.61 (s, 1H), 3.60 (s, 3H), 1.67 (s, 3H), 13C-NMR (100 MHz) DMSO: 162.7, 159.9, 144.6, 142.9, 140.7, 129.9, 120.6, 115.6, 115.4, 96.3, 59.6, 56.4, 36.7, 33.8, 12.8; LC/MS-MS: 285.1→219.1 m/z; GS1 and GS2 at 30, DP=61, CE=27, CXP=14, tR=3.80 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]([C:10]1[S:11][C:12]([S:34][CH3:35])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH3:32])=[CH:26][C:25]=3[NH2:33])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[Br:37][CH2:38][C:39](Br)=[O:40].CCN(CC)CC.CCOC(C)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]([C:10]1[S:11][C:12]([S:34][CH3:35])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:25]([NH:33][C:39](=[O:40])[CH2:38][Br:37])=[CH:26][C:27]([O:31][CH3:32])=[CH:28][C:29]=3[CH3:30])[CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH:14]=1)=[NH:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(N)c1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(NC(=O)CBr)c1
Yield: 68.7 %

Procedure:
Following the procedure described for Example 234, step a, reaction of {[4-(6′-amino-4′-methoxy-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (204 mg, 0.37 mmol, as prepared in Example 198, step e), bromoacetyl bromide (39 μL, 0.45 mmol), and Et3N (77 μL, 0.56 mmol) in DCM (5 mL) afforded 170 mg (69%) of the title compound as a yellow foamy solid after chromatography (PTLC, 50% EtOAc in hexanes, 4×1000μ SiO2 plate). 1H-NMR (CDCl3; 400 MHz): δ 8.02–8.05 (m, 1H), 7.91 (s, 1H), 7.87 (t, 1H, J=1.6 Hz), 7.73 (br s, 1H), 7.63–7.67 (m, 2H), 7.45–7.49 (m, 1H), 6.69 (d, 1H, J=2.1 Hz), 3.85 (s, 3H), 3.69 and 3.74 (AB quartet, 2H, J=14.1 Hz), 2.59 (s, 3H), 2.00 (s, 3H), 1.52 (s, 9H). ESI-MS (m/z): Calcd. for C27H30BrN3O6S3: 668.0 (M+H); found: 669.6, 667.6, 570.0, 568.0 (M−Boc).