Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].O[CH:42]([C@@H:68]1[CH2:72][C@H:71]([SH:73])[CH2:70][N:69]1[C:74]([O:76][CH2:77][C:78]1[CH:83]=[CH:82][C:81]([N+:84]([O-:86])=[O:85])=[CH:80][CH:79]=1)=[O:75])[CH2:43][C:44]([N:46]1[CH2:50][CH2:49][C@H:48]([NH:51][C:52](=[NH:67])[CH2:53][C:54]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([N+:64]([O-:66])=[O:65])=[CH:60][CH:59]=2)=[O:55])[CH2:47]1)=[O:45]>>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:73][C@@H:71]3[CH2:70][N:69]([C:74]([O:76][CH2:77][C:78]4[CH:83]=[CH:82][C:81]([N+:84]([O-:86])=[O:85])=[CH:80][CH:79]=4)=[O:75])[C@@H:68]([CH2:42][CH2:43][C:44]([N:46]4[CH2:50][CH2:49][C@H:48]([NH:51][C:52](=[NH:67])[CH2:53][C:54]([O:56][CH2:57][C:58]5[CH:59]=[CH:60][C:61]([N+:64]([O-:66])=[O:65])=[CH:62][CH:63]=5)=[O:55])[CH2:47]4)=[O:45])[CH2:72]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: N=C(CC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCN(C(=O)CC(O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@H](CCC(=O)N4CC[C@H](NC(=N)CC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 73.3 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (563.2 mg) and (2S,4S)-2-[1-hydroxy-2-[(3S)-3-(4-nitrobenzyloxycarbonylacetimidoylamino)pyrrolidin-1-ylcarbonyl]ethyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (594.3 mg), reaction and purification were carried out in a similar manner to that described in Example 40-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[(3S)-3-(4-nitrobenzyloxycarbonylacetimidoylamino)pyrrolidin-1-ylcarbonyl]ethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (653.2 mg) was obtained as an amorphous substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:10]=2[N:11]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][CH:15]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:13]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][N:9]([S:18]([C:14]3[CH:13]=[C:12]([CH3:22])[CH:17]=[CH:16][CH:15]=3)(=[O:20])=[O:19])[C:10]=2[N:11]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Brc1ccc2c(n1)NCCO2
Solvent: c1ccncc1
Product: Cc1cccc(S(=O)(=O)N2CCOc3ccc(Br)nc32)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-Bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (1.0 g, 4.65 mmol) and m-tolylsulfonyl chloride were dissolved in pyridine (10 mL). The resulting mixture was stirred at 80° C. for one hour. An additional portion of m-tolylsulfonyl chloride (0.98 g, 5.12 mmol) was added and the reaction mixture was stirred at 80° C. for 16 hours. Next, excess solvent was removed under vacuum, and the resulting oil was triturated with water to obtain a tan solid, which was collected by vacuum filtration and washed with water and diethyl ether to give 6-bromo-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine. Yield 1.3 g (76%). LCMS (ESI): calc. C14H13BrN2O3S=368, 370; obs. M+H=369, 371.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:10][CH:9]=2)=[CH:5][CH:4]=1.[Cl:26]Cl.CO.C(Cl)(Cl)Cl>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[ClH:2].[Cl:1][CH:9]1[C:8]([Cl:26])([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:25][CH:24]=2)[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH2:10]1
Reactant: ClCl
Reactant: Fc1ccc(OCCN2CC=C(Cc3ccc(Cl)cc3)CC2)cc1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(OCCN2CCC(Cl)(Cc3ccc(Cl)cc3)C(Cl)C2)cc1
Yield: 49 %

Procedure:
To a stirred solution of 4-(4-chlorobenzyl)-1-(2-(4-fluorophenoxy)ethyl)-1,2,5,6-tetrahydropyridine hydrochloride (70 mg, 136 μmol) in CHCl3 (10 mL) a dilute solution of Cl2 in CCl4 was added in portions. After each addition the reaction was checked by TLC (1% MeOH/CHCl3). Cl2 addition was continued until all the starting material was converted to the much higher Rf product spot. The reaction mixture was washed with dilute NH4OH and the organic portion was filtered (cotton). Solvent removal gave a yellow oil. The oil was purified on silica gel with CHCl3 elution to give the free base of the title compound as a pale yellow oil (37 mg, 49%). The free base was converted to hydrochloride as a pale beige powder (40 mg): mp 78-83° C. (foams), 1H NMR (CDCl3) 1.98 (d, J=15 Hz, 1H), 2.95-4.00 (m, 9H), 4.10-4.20 (m, 1H), 4.38-4.75 (m, 2H), 6.79-7.02 (m, 2H), 7.27-7.37 (m, 2H), 12.48 (bs, 1H); HRMS calcd for C20H21Cl3FNO 415.0673, found 415.0664.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[O:28])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])[CH3:9])(C)(C)C.Cl>C(Cl)(Cl)Cl>[Br:18][C:15]1[CH:16]=[CH:17][C:12]2[NH:11][C:10](=[O:28])[CH:8]([CH3:9])[N:7]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:13]=2[CH:14]=1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Br)cc1C(=O)c1ccccc1F
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC1N=C(c2ccccc2F)c2cc(Br)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
To a stirred solution of the benzophenone 116 (30 g, 64.4 mmol) in CHCl3 (300 mL) at rt, hydrogen chloride gas was added slowly. After 20 min, the addition was stopped and the solution was allowed to stir overnight at rt. The reaction mixture was washed with a saturated solution of sodium bicarbonate solution (2×70 mL) and water (2×70 mL). The organic layer was concentrated under reduced pressure. The residual oil was dissolved in methanol-water (1:1, 300 mL) and the pH was adjusted to 8.5 by the addition of aq sodium hydroxide (1 N). The reaction mixture was allowed to stir for 10 h at rt. The solution was then concentrated under reduced pressure and water (100 mL) was added. The solution was extracted with CH2Cl2 (3×50 mL), the organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude solid 11 was purified by recrystallization from methanol/water to provided 117 (17.8 g, 80%). mp 183-185° C.; IR (KBr, cm−1) 2928, 1694, 1611, 1479, 1450, 1377, 1315; 1H NMR (CDCl3) δ 9.50 (bs, 1H), 7.62-7.65 (m, 2H), 7.50 (q, J=6.5 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.29 (t, J=7.5 Hz 1H) 7.15 (d, J=8.6 Hz, 1H), 7.11 (t, J=8.9 Hz, 1H), 3.84 (q, J=6.5 Hz, 1H), 1.82 (d, J=6.5 Hz, 3H); MS (EI) m/e (relative intensity) 348 (M++1, 23), 347 (M+, 38), 346 (24), 345 (36), 329 (19), 327 (20), 307 (40), 306 (41), 305(100), 304 (37), 303 (63); [α]26D=168.8 (c 0.73, EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:16]O>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2)o1
Temperature: 50 °C
Yield: 72 %

Procedure:
To a solution of 5-(4-chlorophenyl)-2-furoic acid (5.0 g, 22 mmol) in MeOH (50 mL) was added conc. H2SO4 (4 drops) and the resulting solution heated to 50° C. for 4 days. The reaction was cooloed and concentrated in vacuo. The residue was taken up in EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (2×20 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash cjromatography (hexane/EtOAc 19:1) to give 3.8 g (72%) of a cream powder; MS m/z 254 (M++18, 100).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH:7]([N:19]([CH3:36])[C:20](=[O:35])[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:18])[CH:10]=1)C.[OH-].[Li+]>O1CCCC1.CO.O>[CH3:36][N:19]([CH:7]([CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:18])[CH:10]=1)[CH2:6][CH2:5][C:4]([OH:37])=[O:3])[C:20](=[O:35])[C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:22]=1
Reactant: CCOC(=O)CCC(Cc1cn(C)c2ccccc12)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)Cc1cn(C)c2ccccc12

Procedure:
A solution of 15 g of 4-[N-methyl-N-(3,5-bistrifluoromethyl-benzoyl)-amino]-5(1-methyl-indol-3-yl)-pentanoic acid ethyl ester and 1.78 g of lithium hydroxide in 102.5 ml of tetrahydrofuran/methanol/water =2/2/1 is stirred at room temperature for 3 hours and then concentrated by evaporation. The residue is dissolved in 150 ml of water, extracted with ether, acidified to pH=2 with 0.1N hydrochloric acid and extracted three times with ether. The combined organic phases originating from the extraction of the acidic aqueous phase are washed with water and saturated NaCl solution, dried (magnesium sulfate) and concentrated by evaporation. In this way the title compound is obtained in the form of a yellow foam. Rf value=0.10 (ethyl acetate/hexane 1:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH2:16][N:15]([C:30](Cl)=[O:31])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:33]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34]1>>[NH2:38][CH:35]1[CH2:36][CH2:37][N:33]([C:30]([N:15]2[CH2:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[CH2:18][CH:13]([C:11]3[O:10][N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[N:12]=3)[CH2:14]2)=[O:31])[CH2:34]1
Reactant: NC1CCNC1
Reactant: O=C(Cl)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1
Product: NC1CCN(C(=O)N2CC(c3ccc(OC(F)(F)F)cc3)CC(c3nc(-c4cccc(F)c4)no3)C2)C1

Procedure:
100 mg (0.21 mmol) of the compound from Example 179A and 34 mg (0.21 mmol) of pyrrolidine-3-amine were reacted according to the General Method 5. Yield: 32 mg (28% of theory)
Reaction SMILES: [CH3:1]N(C)S(C1C=C2C(C=CN2)=C(Br)C=1)(=O)=O.[CH3:17][C:18]1[C:23]([N+:24]([O-])=O)=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[CH:20][C:19]=1[N+:31]([O-])=O>>[F:28][C:27]([F:30])([F:29])[C:21]1[CH:22]=[C:23]2[C:18]([CH:17]=[CH:1][NH:24]2)=[C:19]([NH2:31])[CH:20]=1
Reactant: CN(C)S(=O)(=O)c1cc(Br)c2cc[nH]c2c1
Reactant: Cc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Product: Nc1cc(C(F)(F)F)cc2[nH]ccc12

Procedure:
Prepared according to the method used in the preparation of 4-bromo-1H-indole-6-sulfonic acid dimethylamide using 2-methyl-1,3-dinitro-5-trifluoromethyl-benzene in place of 3-bromo-4,N,N-trimethyl-5-nitro-benzenesulfonamide. The title compound was obtained as a white solid (10.7 g, 99%).
Reaction SMILES: [O:1]=[C:2]([CH3:13])[CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]2[C:41]3[C:36](=[C:37]([CH3:54])[CH:38]=[C:39]([S:42]([C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][NH:52][CH3:53])[CH:46]=4)(=[O:44])=[O:43])[CH:40]=3)[N:35]=[CH:34][C:33]=2[C:55]([NH2:57])=[O:56])[CH:28]=[CH:29][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]2[C:41]3[C:36](=[C:37]([CH3:54])[CH:38]=[C:39]([S:42]([C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][N:52]([C:7]([C:6]5[CH:10]=[CH:11][CH:12]=[C:4]([CH2:3][C:2](=[O:1])[CH3:13])[CH:5]=5)=[O:9])[CH3:53])[CH:46]=4)(=[O:43])=[O:44])[CH:40]=3)[N:35]=[CH:34][C:33]=2[C:55]([NH2:57])=[O:56])[CH:28]=[CH:29][CH:30]=1
Reactant: CNCc1cccc(S(=O)(=O)c2cc(C)c3ncc(C(N)=O)c(Nc4cccc(OC)c4)c3c2)c1
Reactant: CC(=O)Cc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(CN(C)C(=O)c5cccc(CC(C)=O)c5)c4)cc23)c1
Reaction time: 0.08 h
Yield: 88 %

Procedure:
3-(2-Oxopropyl)benzoic acid (33 mg, 0.185 mmol) and DIEA (0.097 mL, 0.555 mmol) were added to a stirring solution of Intermediate 136 (100 mg, 0.204 mmol) in DMF (2 mL) at rt. The reaction mixture was stirred for 5 min and HATU (78 mg, 0.204 mmol) was added. The resulting solution was stirred for 3 h then poured into H2O (50 mL). The precipitate was filtered, washed with H2O (30 mL), and dried to give the title compound (106 mg) as a yellow solid. ES/MS calcd for C36H35N4O6S+ 651.2. Found m/z=651.4 (M+H)+.
Reaction SMILES: C([NH+](CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH2:20][Cl:21])=[N:18][C:17]([C:22]([O-])=[O:23])=[N:16]2)=[C:11]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH:10]=1.O1CCCC1.C(Cl)(=O)OCC.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH2:20][Cl:21])=[N:18][C:17]([C:22]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[O:23])=[N:16]2)=[C:11]([C:25](=[O:34])[C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH:10]=1
Reactant: COc1ccc(C(=O)c2cc(Cl)ccc2-n2nc(C(=O)[O-])nc2CCl)cc1
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Agent: CC[NH+](CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)c2cc(Cl)ccc2-n2nc(C(=O)N3CCOCC3)nc2CCl)cc1
Reaction time: 0.08 h

Procedure:
To a stirred suspension of 5.07 parts of 1-[4-chloro-2-(4-methoxybenzoyl)phenyl]-5-chloromethyl-1H-1,2,4-triazole-3-carboxylic acid triethylammonium salt in 60 volume parts of dry tetrahydrofuran, 1.0 volume part of ethyl chlorocarbonate is added under cooling with ice-salt. After 5 minutes a solution of 2.6 volume parts of morpholine in 3 volume parts of dry tetrahydrofuran is added to the mixture. After stirring for an additional 5 minutes the reaction mixture is diluted with water and concentrated under reduced pressure. The concentrate is extracted with ethyl acetate and the ethyl acetate layer is washed with water. After evaporation of the solvent the residue is treated with ethanol-ether to yield 1-[4-chloro-2-(4-methoxybenzoyl)phenyl]-5-chloromethyl-3-morpholinocarbonyl-1H-1,2,4-triazole as crystals. Recrystallization from aqueous ethanol gives colorless prisms melting at 180°-181°C. The crystals are hemihydrate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:13](=[O:14])[C:12](=[C:15]3[S:19][CH:18]=[CH:17][S:16]3)[C:11](=[O:20])[CH:10](C(OC)=O)[CH2:9]2)[CH:2]=1.[OH-].[Na+].O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:9][CH2:10][C:11](=[O:20])[C:12](=[C:15]3[S:16][CH:17]=[CH:18][S:19]3)[C:13]2=[O:14])[CH:2]=1
Reactant: COC(=O)C1CN(Cc2cccnc2)C(=O)C(=C2SC=CS2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1CCN(Cc2cccnc2)C(=O)C1=C1SC=CS1
Yield: 55.6 %

Procedure:
Methyl 1-(3-pyridylmethyl)-5-(1,3-dithiol-2-ylidene)-4,6-dioxopiperidine-3-carboxylate (244 mg) obtained in Example 27 is dissolved in methanol (15 ml), and thereto is added a 10% sodium hydroxide solution (2 ml). The mixture is refluxed for 2 hours. The mixture is poured into water, and extracted with chloroform. The extract is washed with water, dried and then distilled to remove the solvent. The residue is recrystallized from a mixture of ethyl acetate and and n-hexane to give 1-(3-pyridylmethyl)-3-(1,3-dithiol-2-ylidene)-2,4-dioxopiperidine (114 mg, 66.1%) as yellow plates, m.p. 131.5°-133° C.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=3)[N:15]=[CH:14][C:13]2=[O:23])[CH2:6][CH2:5]1.[O:24]1[C:28]2=[CH:29][N:30]=[C:31]([CH:33]=O)[CH:32]=[C:27]2[CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CO.C(Cl)(Cl)Cl.C(N(CC)CC)C>[ClH:1].[ClH:1].[O:24]1[C:28]2=[CH:29][N:30]=[C:31]([CH2:33][NH:3][CH:4]3[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=5)[N:15]=[CH:14][C:13]4=[O:23])[CH2:8][CH2:9]3)[CH:32]=[C:27]2[CH2:26][CH2:25]1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reactant: O=Cc1cc2c(cn1)OCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1cnc2ccc(F)cc2n1CCN1CCC(NCc2cc3c(cn2)OCC3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.4 %

Procedure:
A solution of 1-[2-(4-amino-1-piperidinyl)ethyl]-7-fluoro-2(1H)-quinoxalinone dihydrochloride (60 mg; 0.166 mmol) and 2,3-dihydrofuro[2,3-c]pyridine-5-carbaldehyde (30 mg, 0.20 mmol) in MeOH (3 ml), chloroform (3 ml) and triethylamine (0.06 ml) was heated under reflux with 3A molecular sieves overnight. It was cooled and sodium triacetoxyborohydride (0.11 g; 0.52 mmol) was added, and the mixture was stirred at rt overnight. Aqueous sodium bicarbonate solution was added to basify and the aqueous phase was extracted several times with 10% MeOH-DCM. The organic fractions were dried and evaporated. Chromatography on silica gel, eluting with 0-20% MeOH-DCM gave the free base of the title compound (50 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].[Cl:19][CH2:20][C:21](Cl)=[O:22].C(N(CC)CC)C.O>ClCCl>[Cl:19][CH2:20][C:21]([N:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:9][C:2]=1[Cl:1])[CH3:5])=[O:22]
Reactant: CNc1ccc(OCOCC[Si](C)(C)C)cc1Cl
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CCl)c1ccc(OCOCC[Si](C)(C)C)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-N-methyl-4-{[2-(trimethylsilyl)ethoxy]methoxy}aniline (1.00 g) in dichloromethane (20.0 mL) were added chloroacetyl chloride (0.415 mL) and triethylamine (0.872 mL) under ice-cooling, followed by stirring for 1 hour under ice-cooling. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2-chloro-N-(2-chloro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-N-methylacetamide (1.08 g).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[NH:5][C:4]2[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[S:22][C:3]1=2.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCCC1>[N:26]1[CH:27]=[CH:28][C:23]([C:21]2[S:22][C:3]3[C:2](=[O:1])[NH:7][C:6]4([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]4)[NH:5][C:4]=3[CH:20]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)c1sc(-c3ccncc3)cc1N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1NC2(CCNCC2)Nc2cc(-c3ccncc3)sc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A mixture of tert-butyl 4′-oxo-6′-(pyridin-4-yl)-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-thieno[3,2-d]pyrimidine]-1-carboxylate (0.154 g, 0.385 mmol) and trifluoroacetic acid (3.0 mL) was stirred for 1 h at room temperature. The mixture was poured into sat. aqueous sodium hydrogen carbonate (100 mL), ethyl acetate (70 mL) and tetrahydrofuran (30 mL). After shaking well, the yellow precipitate was collected by filtration. This solid was suspended in ethyl acetate-dichloromethane (1:2, 10 mL) and the mixture was heated to 60° C. After 10 min, the precipitate was collected by filtration to afford the title compound (0.107 mg, 93%) as a yellow solid:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Sn](C)(C)C.O>CN(C)C=O>[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Reactant: C[Sn](C)(C)c1ccccn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2cccc(-c3ccccn3)c2)cc1
Yield: 34.5 %

Procedure:
Methyl 4-[(3-bromophenyl)methoxy]benzenepropanoate (0.70 g, 2.0 mmol) and 2-pyridyltrimethyltin (0.60 g, 2.4 mmol) were dissolved in N,N-dimethylformamide (15 mL) and, after argon substitution, dichlorobistriphenylphosphinepalladium (II) (0.10 g, 0.070 mmol) was added. The reaction mixture was heated under reflux overnight under an argon atmosphere. The reaction mixture was cooled, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5:1) to give the title compound (0.24 g, yield 35%) as a colorless oil.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH2:16]1[O:18][C@H:17]1[CH2:19][OH:20]>C(Cl)Cl.CCOCC>[C:1]([Si:5]([CH3:7])([CH3:6])[O:20][CH2:19][C@H:17]1[CH2:16][O:18]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OC[C@H]1CO1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CO1
Temperature: 23 °C
Reaction time: 17 h
Yield: 79.3 %

Procedure:
tert-Butyl-chloro-dimethylsilane (12.9 g, 85.5 mmol) followed by Et3N (19 mL, 136 mmol) was added to a 0° C. solution of (S)-(+)-glycidol (5.0 g, 67 mmol) in CH2Cl2 (200 mL). The solution was allowed to warm to 23° C. with stirring over 17 h. The resulting pink solution was diluted with Et2O (800 mL) and stirred an additional 30 min. The Et2O layer was washed with saturated aqueous NaHCO3 (200 mL), H2O (2×100 mL), brine (100 mL), dried over Na2SO4 and concentrated. Purification by column chromatography (silica, 5-10% Et2O/hexanes) gave (R)-tert-Butyl-dimethyl-oxiranylmethoxy-silane (10.01 g, 79%). TLC (silica, 10% Et2O/hexanes): Rf=0.5. 1H NMR (CDCl3, 400 MHz): 3.85 (dd, J=11.9, 3.2 Hz, 1H), 3.66 (dd, J=11.9, 4.8 Hz, 1H), 3.09 (m, 1H), 2.77 (dd, J=5.0, 4.2 Hz, 1H), 2.64 (dd, J=5.2, 2.7 Hz, 1H), 0.90 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][C@H:51]([C:53]([F:56])([F:55])[F:54])[CH2:52][N:44]2[C:43]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][C@H:51]([C:53]([F:54])([F:56])[F:55])[CH2:52][N:44]2[C:43]1=[O:57])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CCS[C@H]2CC[C@H](C(F)(F)F)CN2C1=O
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Product: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CC[C@H](C(F)(F)F)CN3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)-N6-((4S,8S,10aS)-5-oxo-8-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 70 (8.5 mg, 0.016 mmol) and Intermediate 60 (3.5 mg, 0.013 mmol) to give a white solid (7.6 mg, 74% yield). Anal. Calcd. for C43H51F3N4O5S m/z 792.7. found: 793.6 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.38-7.03 (m, 11H), 7.04-6.82 (m, 3H), 5.12 (t, J=7.3 Hz, 1H), 4.90-4.64 (m, 2H), 4.35 (d, J=14.8 Hz, 1H), 3.98 and 3.82 (2s, 3H), 3.97-3.84 (m, 1H), 3.27 (dd, J=14.8, 6.6 Hz, 6H), 2.95-2.53 (m, 5H), 2.48-2.30 (m, 2H), 2.26-2.14 (m, 1H), 2.04-1.15 (m, 15H).