Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])C.C(=O)([O-])[O-].[K+].[K+].[C:20]1([C:26]2[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[C:26]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:27]=[CH:28][C:29]([CH2:30][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:3][C:4]([OH:6])=[O:5])=[CH:12][CH:11]=2)=[CH:32][CH:33]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: CCC(C(=O)O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 84.4 %

Procedure:
To a solution of ethyl 4-hydroxyphenylacetic acid (3.6 g) in DMF (50 ml) were added potassium carbonate (2.5 g) and 4-phenylbenzyl chloride (4 g) sequentially. After stirring at 60° C. for 6 hr, the reaction mixture was poured onto water and the resulting crystals were suspended in ethyl acetate. The suspension was washed with water and concentrated. The resulting crude crystals were dissolved in THF (100 ml)/ethanol (50 ml) and 2 N sodium hydroxide (20 ml) was added to the solution. The reaction mixture was heated under stirring at 60° C. for 18 hr and concentrated. The residue was acidified with 2 N hydrochloric acid and the resulting crystals were collected by filtration and washed with ethyl ether to obtain the titled compound (5.3 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[OH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:5]([C:11]#[N:12])=[C:6]([O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: OCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCCc2ccccn2)nc(N)nc1-c1ccccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile, 2-(2-hydroxyethyl)pyridine and DBU in DME. ES-MS m/e (%): 319 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:12]2[C:13]2[N:14]=[N:15][N:16](S(C4C=CC(Cl)=CC=4)(=O)=O)[C:17]=2[CH2:18]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:12]2[C:13]2[N:14]=[N:15][NH:16][C:17]=2[CH2:18]3)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1nnn(S(=O)(=O)c3ccc(Cl)cc3)c1C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1nn[nH]c1C2
Temperature: 75 °C
Yield: 55.2 %

Procedure:
To 12,5-bis(4-chloro-benzenesulfonyl)-3,4,5,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene (15 mg, 0.029 mmol) in THF (200 μL) was added H2O (100 μM) followed by 1M NaOH solution in H2O (100 μL). The mixture was heated at 75° C. for 3 hr. The mixture was partitioned between EtOAc/H2O. The organic layer was washed with brine, dried and concentrated. The residue was purified by prep TLC to 12-(4-Chloro-benzenesulfonyl)-3,4,5,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene (5.3 mg, 0.016 mmol, 54% yield). MS (ES) m/e 339.0 (M+H)
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:22]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH:17]=[C:16]2[I:32])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>O1CCOCC1>[I:32][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([C:11]3[S:42][C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][N:10]=3)[CH:14]=2)[N:18]([S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:17]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NNC(=O)c4ccccc4)ccc32)cc1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(-c5ccccc5)s4)ccc32)cc1
Temperature: 110 °C
Yield: 40.2 %

Procedure:
To a suspension of N′-benzoyl-3-iodo-1-tosyl-1H-indole-5-carbohydrazide (1.29 g, 2.31 mmol) in dioxane (24 mL) at RT was added Lawesson's Reagent (1.40 g, 3.46 mmol) (Aldrich). The solution was heated to 110° C. for 3 h. The mixture was concentrated and the residue was purified with flash chromatography (eluting with 0-60% EtOAc in Hex) to give 2-(3-iodo-1-tosyl-1H-indol-5-yl)-5-phenyl-1,3,4-thiadiazole (518 mg, 40%) as a light yellow-orange crystalline solid after washing with Et2O. MS (ESI, pos. ion) m/z: 557.9 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 7.96-8.10 (5H, m), 7.81 (2H, d, J=8.4 Hz), 7.77 (1H, s), 7.48-7.55 (3H, m), 7.28 (2H, d, J=8.2 Hz), 2.37 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]([C:12](=[O:21])[CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[C:10]3[N:22]=[CH:23][CH:24]=[CH:25][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:27]=1.[C:29](OCC)(=[O:32])[NH:30][NH2:31]>>[CH3:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]([C:12](=[O:21])[CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[C:10]3[N:22]=[CH:23][CH:24]=[CH:25][C:9]=3[C:8]3[N:7]([C:29](=[O:32])[NH:30][N:31]=3)[C:6]=2[CH:27]=1
Reactant: CCCN(CCC)CC(=O)N1c2cc(C)c(C)cc2NC(=S)c2cccnc21
Reactant: CCOC(=O)NN
Product: CCCN(CCC)CC(=O)N1c2cc(C)c(C)cc2-n2c(n[nH]c2=O)-c2cccnc21

Procedure:
In the manner given in Example 13, 8,9-dimethyl-6,11-dihydro-11-[(dipropylamino)acetyl]-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-thione is heated to about 200° C. wth ethyl carbazate to give 6,7-dimethyl-2,9-dihydro-9-[(dipropylamino)-acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:26]=[CH:27][C:28]=2[CH3:29])[CH2:11][N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@@H:13]2[CH3:25])[CH:5]=[CH:4][N:3]=1.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH2:40])[CH:34]=[C:35]([F:37])[CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:38][CH2:39][NH:40][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]3[CH3:25])[CH:26]=[CH:27][C:28]=2[CH3:29])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cc1-c1ccnc(Cl)n1
Reactant: NCCc1cc(F)cc(F)c1
Product: Cc1ccc(CN2CCNC[C@@H]2C)cc1-c1ccnc(NCCc2cc(F)cc(F)c2)n1

Procedure:
Intermediate 158 from above was coupled with 2-(3,5-difluorophenyl)ethanamine following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 438. 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.31 ppm) δ 8.4 (d, 1H) 8.0 (d, 1H) 7.7 (d, 1H) 7.5 (d, 1H), 7.4 (d, 1H), 6.9 (d, 2H) 6.7 (t, 1H), 3.9-3.8 (m, 3H) 3.7-3.6 (m, 6H) 3.5-3.4 (m, 2H) 3.0 (t, 2H), 2.5 (s, 3H), 1.7 (d, 3H).
Reaction SMILES: Cl.[N:2]1([C:8]2[N:9]=[CH:10][CH:11]=[C:12]3[CH:16]=[CH:15][S:14][C:13]=23)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.O=[CH:27][CH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:38])[CH3:37])[CH2:31][CH2:30]1>C1COCC1>[S:14]1[C:13]2=[C:8]([N:2]3[CH2:3][CH2:4][N:5]([CH2:27][CH2:28][C@H:29]4[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:38])[CH3:37])[CH2:31][CH2:30]4)[CH2:6][CH2:7]3)[N:9]=[CH:10][CH:11]=[C:12]2[CH:16]=[CH:15]1
Reactant: c1cc2ccsc2c(N2CCNCC2)n1
Reactant: CC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccsc34)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution under Ar of commercially available 7-piperazine-1-yl-thieno[2,3-c]pyridine hydrochloride [CAS-No. 850734-85-9] (150 mg, 0.59 mmol) in THF (14 ml) were added subsequently iPr2NEt (0.1 ml, 0.59 mmol), trans-N-[4-(2-oxo-ethyl)-cyclohexyl]-acetamide [CAS-No. 946599-01-5, WO 2007/093540] (118 mg, 0.64 mmol) and Na(AcO)3BH (373 mg, 1.76 mmol). After stirring 18 h at room temperature the reaction mixture was partitioned between sat. aq. NaHCO3 sol. and EtOAc. The aqueous layer was extracted one more time with EtOAc. The combined organic layers were washed with H2O and brine and dried over MgSO4. After evaporation of the solvent, the crude product was purified by flash chromatography on silica gel (heptane to EtOAc) to yield the title compound as an off-white solid (82 mg, 36%), MS (ISP) m/z=387.2 [(M+H)+].
Reaction SMILES: [C:1]([O:5][P:6]([C:13]([F:43])([F:42])[C:14]1[CH:41]=[CH:40][C:17]([CH2:18][CH:19]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:46][C:47]([F:57])([F:56])[C:48]1[CH:55]=[CH:54][C:51]([CH2:52]Br)=[CH:50][CH:49]=1.CCOCC>CN(C=O)C>[C:9]([O:8][P:6]([C:13]([F:43])([F:42])[C:14]1[CH:41]=[CH:40][C:17]([CH2:18][C:19]([CH2:52][C:51]2[CH:50]=[CH:49][C:48]([C:47]([F:46])([F:56])[F:57])=[CH:55][CH:54]=2)([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:16][CH:15]=1)([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CC(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CC(Cc2ccc(C(F)(F)F)cc2)(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 45.6 %

Procedure:
To a solution of the product from Example 18, Step 1 (94 mg, 0.15 mmol) in DMF (2 mL) at 0° C. was added NaH (5.5 mg, 80% in oil). After 15 min., 4-(trifluoromethyl)benzyl bromide (44 mg, 0.18 mmol) was added. After 2 h at 0° C., the mixture was given a standard aqueous/Et2O work-up, and the residue was purified by flash chromatography (1:10 EtOAc/hexane) to give a syrup (53 mg).
Reaction SMILES: Cl.[C:2]([CH:4]([NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:21][C:22]([C:24]1[N:25]([CH3:33])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[O:14])[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)#[N:3].[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:34]([N:9]1[CH2:10][CH2:11][CH:6]([CH2:5][CH:4]([NH:12][C:13]([C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]2[NH:21][C:22]([C:24]2[N:25]([CH3:33])[C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[O:14])[C:2]#[N:3])[CH2:7][CH2:8]1)(=[O:36])[CH3:35]
Reactant: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)NC(C#N)CC2CCNCC2)cc2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(CC(C#N)NC(=O)[C@@H]2CCCC[C@@H]2NC(=O)c2cc3ccccc3n2C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
To a solution of 1-methyl-1H-indole-2-carboxylic acid {(1S,2R)-2-[(cyano-piperidin-4-ylmethyl-methyl)-carbamoyl]-cyclohexyl}-amide hydrochloride (0.50 g, 1.06 mmol) in 2 mL of DMF, was added 0.5 mL of TEA, acetic anhydride (0.15 mL, 1.59 mmol), and a few crystals of DMAP. The reaction mixture was stirred at ambient temperature for 1 hour, and partitioned between 50 mL of water and 50 mL of ethyl acetate. The separated organic layer was washed with water (2×50 mL), dried with sodium sulfate, filtered, concentrated, and purified by column chromatography (5:95, MeOH/CH2Cl2) to give 165 mg (33%) of 1-methyl-1H-indole-2-carboxylic acid ((1S,2R)-2-{[(1-acetyl-piperidin-4-ylmethyl)-cyano-methyl]-carbamoyl}-cyclohexyl)-amide as a white amorphous solid. MS: 478 (M+H+).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(N(CC)CC)C.[NH2:33][C:34]1[C:35]([CH3:40])=[CH:36][CH:37]=[CH:38][CH:39]=1.C(P(C#N)(CC)=O)C>ClCCl>[CH3:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[NH:33][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:16])=[CH:25][CH:24]=1
Reactant: Cc1ccccc1N
Reactant: O=C(O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Agent: CCP(=O)(C#N)CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Yield: 54.6 %

Procedure:
A mixture of 0.332 g of 4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)benzoic acid, 0.111 g of triethylamine, 0.107 g of o-toluidine, and 0.15 ml of diethylphosphoryl cyanide in 20 ml of dichloromethane is heated on a steam bath overnight. The mixture is washed with water, 1M NaHCO3, 1N HCl, brine and dried (Na2SO4). The dichloromethane solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is crystallized from dichloromethane-hexane to give 0.23 g of white crystals, m.p. 228°-231° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[NH:15][C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][CH:11]=[C:10]([Cl:20])[CH:9]=2)=[O:5].N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[C:32]([NH:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[NH:15][C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][CH:11]=[C:10]([Cl:20])[CH:9]=2)=[O:5])(=[O:34])[CH3:33]
Reactant: CCC(=O)Nc1c(C(=O)c2cc(Cl)ccc2N)[nH]c2cc(Cl)ccc12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Nc1c(C(=O)c2cc(Cl)ccc2NC(C)=O)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a solution of 2-(2-amino-5-chlorobenzoyl)-6-chloro-3-(propionylamino)indole (Example 389, 217 mg, 0.576 mmol) and pyridine (0.12 ml, 1.50 mmol) in dichloromethane (10 ml) was added acetyl chloride (53 μl, 0.749 mmol) at 0° C. After stirring at room temperature for 1 h, the mixture was concentrated and the residue was diluted with ethyl acetate (100 ml). The solution was washed with 2N aqueous HCl (30 ml×2), saturated aqueous sodium bicarbonate (30 ml), and dried (MgSO4). Removal of solvent gave a crystalline residue. Recrystallization from ethyl acetate gave 163 mg (68%) of the title compound. m.p.: 264-266° C. IR (KBr) ν: 3260, 1676, 1655, 1578, 1547, 1508, 1313, 1234, 1205, 1006, 918, 841 cm−1
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]([OH:40])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].[CH3:43][O:44][C:45]([C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1)=[O:46].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=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:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:27]=3)[C:22]([O:40][C:50]3[CH:51]=[CH:52][C:47]([C:45]([O:44][CH3:43])=[O:46])=[CH:48][CH:49]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(Oc3ccc(C(=O)OC)cc3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
(2R,4S)-4-{[3, 5-Bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (170 mg) is dissolved in methylene chloride (3 ml), and thereto are added 4-methoxycarbonylphenylboronic acid (51 mg), copper (II) acetate (52 mg), triethylamine (79 μl) and molecular sieves 4A (170 mg). The mixture is stirred overnight at room temperature. The insoluble materials are removed by filtration and the filtrate is partitioned by adding ethyl acetate and saturated brine. 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; hexane:ethyl acetate=9:1→3:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4-methoxycarbonylphenoxy)-pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (132 mg). MS (m/z): 734 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Cl.CCO>C(O)C.CC(C)=O>[ClH:1].[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]4[CH:16]=[C:15]5[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]5)=[CH:9][CH:8]=4)[CH2:30][CH2:31]3)=[N:24][O:25][C:21]=2[CH:20]=1
Reactant: O=C1CCc2ccc(OCCCCCl)cc2N1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: O=C1CCc2ccc(OCCCCN3CCC(c4noc5cc(F)ccc45)CC3)cc2N1
Yield: 42.2 %

Procedure:
7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone (297 mg, 1 mmol), 4-(6-fluoro-1,2-benzisoxazolyl)-piperidine (242 mg, 1.1 mmol), and anhydrous potassium carbonate powder (414 mg, 3.3 mmol) are added to 10 ml and react at reflux for 24 hours. The reaction solution is evaporated to dryness and dispersed with 20 ml of dichloromethane and 20 ml of water respectively. The organic layer is extracted with water (20 ml×2) and saturated saline (20 ml) successively, dried over anhydrous magnesium sulfate, and evaporated to dryness to obtain a light yellow powder. The powder is dissolved with 5 ml of acetone and stirred in an ice bath. A white solid precipitates and is filtered, washed with small amount of acetone, and dried to obtain 260 mg of a whiter powder. The powder is dissolved in anhydrous ethanol and then thereto is drop-added HCl/EtOH to adjust to pH=2. A white deposit precipitates and is filtered out and recrystallized in anhydrous ethanol to obtain 200 mg of a product, with a yield of 42%.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16]SC2SC3C=CC=C(C)C=3N=2)[N:14]([CH:28]([C:47]([CH3:49])=[CH2:48])[C:29]([O:31][CH2:32][C:33]2[C:38]([Cl:39])=[C:37]([O:40][CH3:41])[C:36]([O:42][CH3:43])=[C:35]([O:44][CH3:45])[C:34]=2[Cl:46])=[O:30])[C:13]1=[O:50])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:51]1([S:57](=S)([O:59]C2SC3C=CC=C(C)C=3N=2)=[O:58])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.O.C1(S([O-])=O)C=CC=CC=1.[Na+]>CC(C)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:57]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)(=[O:59])=[O:58])[N:14]([CH:28]([C:47]([CH3:49])=[CH2:48])[C:29]([O:31][CH2:32][C:33]2[C:34]([Cl:46])=[C:35]([O:44][CH3:45])[C:36]([O:42][CH3:43])=[C:37]([O:40][CH3:41])[C:38]=2[Cl:39])=[O:30])[C:13]1=[O:50])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2sc(OS(=O)(=S)c3ccccc3)nc12
Reactant: C=C(C)C(C(=O)OCc1c(Cl)c(OC)c(OC)c(OC)c1Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2c(C)cccc2s1
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=C(C)C(C(=O)OCc1c(Cl)c(OC)c(OC)c(OC)c1Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
A 1.03 g quantity of 3,4,5-trimethoxy-2,6-dichlorobenzyl 2-[3-phenoxyacetamido-4-(4-methylbenzothiazol-2-yldithio)-2-azetidinon-1-yl]-3-methyl-3-butenoate and 448 mg of 4-methylbenzothiazol-2-yl benzenethiosulfonate were dissolved in 10 ml of acetone. To the solution were added 2 ml of water and then 8 mg of sodium benzenesulfinate. The mixture was stirred at room temperature for 5 hours. The precipitated 4-methylbenzothiazol-2-yl disulfide crystals were filtered and the filtrate was concentrated under reduced pressure. The residue was treated in the same manner as in Example 1, giving 3,4,5-trimethoxy-2,6-dichlorobenzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate in a yield of 86%. The NMR spectrum data of the compound thus obtained were identical with those of the desired compound. Table 2 below indicates the data thereof.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:22][C:23](O)=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:26]([NH:33][CH2:34][CH3:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]([CH2:34][CH3:35])[C:23](=[O:24])[CH2:22][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][N:8]=1)(=[O:12])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccc(C(C)C)cn1
Reactant: CCNCc1ccccc1
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-(2-methoxy-phenyl)-amino]-acetic acid with benzyl-ethyl-amine
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH:21](N1CCOCC1)=[O:22]>O1CCCC1>[O:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:21]=[O:22])=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=CN1CCOCC1
Reactant: Brc1ccc(COc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(COc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 100.6 %

Procedure:
To a tetrahydrofuran solution (50 mL) of 1-bromo-4-phenoxymethyl-benzene (4.69 g, 17.8 mmol) described in Manufacturing Example 86-1-1 was added dropwise n-butyl lithium (16.8 mL, 1.59 M hexane solution, 26.7 mmol) at −78° C. After 40 minutes of stirring at −78° C., N-formylmorpholine (2.25 g, 19.6 mmol) was added to this mixture, which was then stirred for a further 30 minutes at that temperature. This mixture was partitioned into diethyl ether and water. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.8 g). This compound was used in the subsequent reaction without purification.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:21])[NH:6][C:7]([CH2:12][O:13]CC2C=CC=CC=2)=[C:8]([CH2:10][CH3:11])[CH:9]=1)([O-])=O.[H][H]>O1CCCC1.CO.[Pd]>[NH2:1][C:4]1[C:5](=[O:21])[NH:6][C:7]([CH2:12][OH:13])=[C:8]([CH2:10][CH3:11])[CH:9]=1
Reactant: [H][H]
Reactant: CCc1cc([N+](=O)[O-])c(=O)[nH]c1COCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(N)c(=O)[nH]c1CO
Reaction time: 84 h
Yield: 90 %

Procedure:
A solution of 3-nitro-5-ethyl-6-benzyloxymethylpyridin-2(1H)-one (576 mg, 2.0 mmol) in tetrahydrofuran (15 mL) and methanol (15 mL) containing 10% palladium/charcoal (130 mg) was hydrogenated at an atmospheric pressure of hydrogen, monitoring the progress by tlc. Additional catalyst was added in 100 mg portions after day 2 and day 3. After 3-4 days, the catalyst was filtered and the solvents evaporated. The catalyst was vigorously washed with methanol/chloroform and combined solvents evaporated. The residue was triturated with methylene chloride and product collected by filtration to give 136 mg of 90% pure product. This material was used as is.