Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([C:20]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[OH:21])[CH2:16][CH2:15]3)=[CH:9][CH:8]=2)=[N:3]1.ClC1C=C(C=CC=1)C(OO)=[O:47]>C(Cl)Cl>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][N+:14]3([O-:47])[CH2:15][CH2:16][CH:17]([C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=4)([C:32]4[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:37]=4)[OH:21])[CH2:18][CH2:19]3)=[CH:11][CH:12]=2)=[N:3]1
Reactant: Cn1nnc(-c2ccc(CN3CCC(C(O)(c4ccc(C(F)(F)F)cc4)c4ccc(C(F)(F)F)cc4)CC3)cc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1nnc(-c2ccc(C[N+]3([O-])CCC(C(O)(c4ccc(C(F)(F)F)cc4)c4ccc(C(F)(F)F)cc4)CC3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
A solution of 1.1 grams (0.002 mole) of N-[4-(2-methyl-2H-tetrazol-5-yl)phenylmethyl]-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine (Compound 31- prepared in Example 9) in 100 mL of methylene chloride was stirred, and 0.6 gram (excess) of 50-85% 3-chloroperoxybenzoic acid was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about one hour. After this time the reaction mixture was washed with an aqueous 10% solution of sodium hydroxide. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 1.0 gram of N-[4-(2-methyl-2H-tetrazol-5-yl)phenyl-methyl]-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine N-oxide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[N:11][C:4]=2[NH:3]1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]3)=[N:23]2)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH:32]([NH:35][CH2:12][C:10]4[CH:9]=[CH:8][C:5]5[O:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=5[N:11]=4)[CH2:33][CH2:34]3)=[N:23]2)=[CH:18][CH:17]=1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Product: COc1ccc2ncc(SCCN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow solid (48 mg, 44% yield) following Scheme 3 and in analogy to Example 40 using 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (40 mg, 0.22 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70 mg, 0.22 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:7]=1.Br[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNS(=O)(=O)c2ccccc2)c1
Reactant: Clc1cccc(OCCBr)c1
Product: COC(=O)CCc1cccc(CN(CCOc2cccc(Cl)c2)S(=O)(=O)c2ccccc2)c1

Procedure:
Following the procedure described in Step A of Example 2, 3-[3-(benzenesulfonylamino-methyl)-phenyl]-propionic acid methyl ester was alkylated with 1-(2-bromo-ethoxy)-3-chloro-benzene to provide the title compound of Step A. 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, 2H), 7.60-7.49 (m, 3H), 7.22 (d, 1H), 7.13-7.06 (m, 4H), 6.88 (m, 1H), 6.60 (d, 1H), 6.52 (m, 1H), 4.42 (s, 2H), 3.88 (s, 2H), 3.65 (s, 3H), 3.47 (t, 2H), 2.87 (t, 2H), 2.54 (t, 2H).
Reaction SMILES: [C:1]12([C:9](Cl)=[O:10])[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14]1>>[C:20]1([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][C@H:13]([NH:12][C:9]([C:1]34[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]3)[CH2:3][CH2:2]4)=[O:10])[CH2:14]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Reactant: O=C(Cl)C12CCC(CC1)CC2
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C12CCC(CC1)CC2

Procedure:
Bicyclo[2.2.2]octane-1-carbonyl chloride and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)bicyclo[2.2.2]octane-1-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:12]([CH2:22]OS(C)(=O)=O)[CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C>[N:28]([CH2:22][C@@H:12]1[CH2:11][C@@H:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH2:14][N:13]1[C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[N+:29]=[N-:30]
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1COS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CN=[N+]=[N-]
Temperature: 50 °C
Reaction time: 16 h

Procedure:
330.0 mg (0.75 mmol) tert. Butyl (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-methanesulphonyloxymethyl-pyrrolidine-1-carboxylate are dissolved in 20 ml DMF and combined with 146.6 mg (2.3 mmol) sodium azide. The mixture is stirred at 50° C. for 16 hours. Then a further 73 mg (1.12 mmol) sodium azide are added and the mixture is stirred for a further two hours at 50° C. Then it is concentrated i. vac. The residue is combined with water/sat. Saline solution and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20].S(=O)(=O)(O)O.CCOCC>[N+](C1C=CC=CC=1)([O-])=O>[O:14]=[C:3]1[C:2]2[N:1]=[C:19]([C:18]3[CH:22]=[CH:23][CH:24]=[C:16]([F:15])[CH:17]=3)[O:20][C:11]=2[C:10](=[O:13])[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: NC1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: O=C(Cl)c1cccc(F)c1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2oc(-c3cccc(F)c3)nc21
Reaction time: 0.08 h
Yield: 7.1 %

Procedure:
To a solution of 5.00 g (24 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 50 mL of nitrobenzene, 14.6 mL (120 mmol) of 3-fluorobenzoic acid chloride are added; after 5 min of stirring, 0.50 mL of concentrated sulfuric acid is then added with protection from light. After 24 h of reflux and complete cooling, 200 mL of ether are added to the reaction mixture. The precipitate formed is filtered, then redissolved in 200 mL of dichloromethane, to which 100 mL of a glacial sodium hydroxide solution are added. After 6 h of stirring at this temperature, the organic phase is extracted, washed several times with water and dried over calcium chloride. The solid obtained after evaporation of the solvent is purified on a medium-pressure column (support: silica; conditioning heptane; eluant: dichloromethane/heptane, 50/50). The yellow crystals so obtained are uncolored and recrystallized in a dichloromethane/heptane mixture (volume/volume) to produce 0.50 g of 4,9-dihydro-4,9-dioxo-2-(3-fluorophenyl)-naphtho[2,3-d]oxazole in the form of yellow crystals.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:24][S:25][CH2:26][C@H:27]([O:43][C:44](=[O:56])[NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:28][O:29][C:30](=[O:42])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:3](=[O:23])[NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:1][C@@H:2]([CH2:24][S:25][CH2:26][C@H:27]([O:43][C:44](=[O:56])[NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:28][O:29][C:30](=[O:42])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:3](=[O:23])[NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCC(=O)O)OC(=O)NCCCCCCCCCC

Procedure:
A solution of (15R,19R)-tert-butyl 15-amino-19-(decylcarbamoyloxy)-14,22-dioxo-4,7,10,21-tetraoxa-17-thia-13,23-diazatritriacontan-1-oate in 30% TFA in DCM (0.3 M) was stirred at room temperature until complete deprotection of the tert-butyl group (4 hours). The reaction was diluted with DCM and concentrated with a stream of nitrogen then purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-10% MeOH/DCM with 0.5% AcOH to afford (15R,19R)-15-amino-19-(decylcarbamoyloxy)-14,22-dioxo-4,7,10,21-tetraoxa-17-thia-13,23-diazatritriacontan-1-oic acid as a clear oil. 1H NMR (DMSO-d6): δ 12.21 (br s, 1H), 8.22 (t, 1H), 7.23 (m, 2H), 4.92 (m, 1H), 4.18 (dd, 2H), 3.94 (m, 1H), 3.57 (t, 2H), 3.30-3.54 (m, 12H), 3.37 (t, 2H), 2.90-3.08 (m, 4H), 2.60-2.82 (m, 4H), 2.48 (t, 2H), 1.32 (m, 4H), 1.22-1.28 (m, 28H), 0.79 (t, 6H). LRMS [M+H]=765.5.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]#[CH:24]>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.[Cu]I.C(N(CC)CC)C>[CH:16]1([CH2:15][N:8]([C:4]2[CH:3]=[C:2]([C:24]#[C:23][CH2:22][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH:7]=[CH:6][CH:5]=2)[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: O=C(N(CC1CCCCC1)c1cccc(Br)c1)C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC#Cc1cccc(N(CC2CCCCC2)C(=O)C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Triethylamine (45 mL) was added to a mixture of N-(3-bromophenyl)-N-(cyclohexylmethyl)-2,2,2-trifluoroacetamide (3.8 g, 10.4 mmol), tert-butyl prop-2-ynylcarbamate (2.42 g, 15.6 mmol), Pd(Ph3P)4 (0.6 g, 0.52 mmol) and CuI (0.1 g, 0.52 mmol) and flushed for 15 min with argon. The reaction mixture was stirred for 16 h at 90° C. The reaction mixture was cooled, diluted with ethyl acetate and filtered through Celite bed and the filtrate was concentrated under reduced pressure. Purification by column chromatography (100-200 silica mesh 5% to 10% EtOAc—hexane) gave tert-butyl 3-(3-(N-(cyclohexylmethyl)-2,2,2-trifluoroacetamido)phenyl)prop-2-ynylcarbamate as a yellow semi-solid. Yield (2.1 g, 50%); 1H NMR (400 MHz, DMSO-d6) δ 7.49-7.48 (m, 2H), 7.43-7.41 (m, 2H), 3.99 (bs, 2H), 3.58 (bs, 2H), 1.64-1.57 (m, 6H), 1.39 (s, 9H), 1.19-1.12 (m, 3H), 0.95-0.89 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C@@H:15]3[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:18]([C:27]([O:29][CH3:30])=[O:28])[CH2:17][CH2:16]3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:42][C:43]#[N:44]>C1COCC1>[C:43]([CH2:42][C@@:18]1([C:27]([O:29][CH3:30])=[O:28])[CH2:17][CH2:16][C@H:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:10]=2)[N:19]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])#[N:44]
Reactant: COC(=O)[C@@H]1CC[C@H](c2cccc(OCc3ccccc3)c2)N1C(=O)OC(C)(C)C
Reactant: N#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@]1(CC#N)CC[C@H](c2cccc(OCc3ccccc3)c2)N1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-{3-[(phenylmethyl)oxy]phenyl}-1,2-pyrrolidinedicarboxylate (D43, 1.93 g, 4.7 mmol) in dry THF (20 mL) at −78° C. was added LiHMDS (5.2 mL of a 1M solution in THF, 5.2 mmol). The mixture was allowed to warm to −30° C. and stirred for 30 min at this temperature. Then the yellow slurry was cooled to −78° C. and bromoacetonitrile (2.2 mL, 30.9 mmol) was added. The reaction mixture was left under stirring for 1 h and then quenched with a saturated ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, dried (Na2SO4), filtered and evaporated. The crude material was purified by chromatography on silica gel using cyclohexane/ethyl acetate (9:1) affording the title compound (1.15 g, 54%); 1H NMR (400 MHz, CDCl3) δ(ppm): 2/1 mixture of rotamers; 7.31-7.47 (m, 5H); 7.22-7.28 (m, 2H); 7.07-7.12 (m, 1H); 6.85-6.91 (m, 1H); 5.05-5.17 (m, 3H major+3H minor); 4.94 (bs, 1H major); 3.88 (br. s, 3H); 3.79 (br. s, 1H minor); 3.52 (d, 1H major); 3.05-2.28 (m, 1H major+1H minor); 2.62-2.77 (m, 1H); 2.39-2.57 (m, 1H); 2.23-2.33 (m, 1H); 1.92-2.08 (m, 1H); 1.44 (s, 9H minor); 1.14 (s, 9H major).
Reaction SMILES: [C:1]1(=O)[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.Cl>CC(O)=O>[C:4]1(=[O:6])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:1][NH:5]1
Reactant: O=C1NC(=O)c2ccccc21
Agent: Cl
Solvent: CC(=O)O
Product: O=C1NCc2ccccc21
Yield: 52.6 %

Procedure:
To a suspension of phthalimide (14.7 g, 100.0 mmol) in AcOH (150 mL) was added Sn0 (29.7 g, 250.0 mmol) and concentrated HCl (70 mL). The mixture was heated to reflux for two hours. The hot mixture was filtered and concentrated. The residue was taken up in CH2Cl2 and washed four times with 1M HCl, until no more precipitate was observed when saturated NaHCO3 was added to the organic phase. The organic layer was washed once with saturated NaHCO3, dried over MgSO4, filtered and concentrated to provide the title compound as a pale yellow solid (7.00 g, 53%). 1H NMR (300 MHz, CDCl3): δ 8.08 (d of d, 1H), 7.52 (m, 3H), 4.50 (s, 2H).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:19]
Reactant: O=C(NN1CCOCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(NN1CCOCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Yield: 99.4 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-N-(morpholin-4-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 210 (0.255 g, 0.71 mml) in methanol (15 mL) was added 10% Pd/C (0.5 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2S,5R)-6-hydroxy-N-(morpholin-4-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 211 (0.19 g, quantitative yield) as a colorless foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:14])(=[O:13])[N:5]([CH3:15])[C:4]=1[C:16]([OH:18])=O.S(Cl)([Cl:21])=O.CN(C)C=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:14])(=[O:13])[N:5]([CH3:15])[C:4]=1[C:16]([Cl:21])=[O:18]
Reactant: COC1=C(C(=O)O)N(C)S(=O)(=O)c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COC1=C(C(=O)Cl)N(C)S(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 21801.5 %

Procedure:
6.2 gm (23 millimols) of 4-methoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide were suspended in 60 ml of benzene and 8.2 ml (0.11 millimols) of thionyl chloride and 0.5 ml of anhydrous dimethylformamide were added to the suspension. The reaction mixture was refluxed for 6 hours, stirred overnight at room temperature and evaporated in vacuo. The residue was dissolved in a little toluene, and the solution was evaporated, yielding 6.9 gm (100% of theory) of 4-methoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid chloride-1,1-dioxide.
Reaction SMILES: [Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.O[C@H:27]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:28]([O:30]C)=[O:29].BrBr.P([O-])(O)(O)=O.[K+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:20]=[CH:21][C:22]([O:25][C@@H:27]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:28]([OH:30])=[O:29])=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: COC(=O)[C@H](O)Cc1ccccc1
Reactant: Oc1ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1
Agent: BrBr
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(O)[C@H](Cc1ccccc1)Oc1ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1

Procedure:
Prepared from 4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenol (Example 41) and (R)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 97). White solid: [a]D25=+17.94° (10.30 mg/mL CHCl3): NMR (CDCl3); δ8.31 (ddd, J=8, 1, 1 Hz, 1 H), 7.76 (ddd., J=8, 1, 1 Hz, 1 H), 7.60 (ddd, J=8, 8, 1 Hz, 1 H), 7.54 (d, J=8 Hz, 1 H), 7.44-7.29 (m, 6 H), 7.24-7.20 (m, 4 H), 7.19-7.04 (m, 3 H), 6.62 (d, J=8 Hz, 1 H), 5.08 (dd, J=7, 5 Hz, 1 H), 3.44 (d, J=5 Hz, 1 H), 3.43 (d, J=7 Hz, 1 H); MS (FAB+): [M+H], bromine isotope pattern, 553 (11%), 569 (12%); Anal. Calc. for C31H21BrO3S: C, 67.27, H, 3.82, N, 0.00. Found: C, 65.17, H, 3.64, N, 0.04. Analytical HPLC determined that this compound was 98.9% pure [column:novapak, 5 micron (4.6 ×250 mm); isocratic, 7:3 accetonitrile: 0.01 M potassium dihydrogen phosphate, pH =3.5; flow rate =1.0 mL/min].
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[O:22][C:16]3=[CH:17][N:18]=[C:19](Cl)[CH:20]=[C:15]3[CH2:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:23][S:24]([CH2:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:26])=[O:25]>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[O:22][C:16]3=[CH:17][N:18]=[C:19]([C:31]4[CH:30]=[CH:29][C:28]([CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:33][CH:32]=4)[CH:20]=[C:15]3[CH2:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CS(=O)(=O)Cc1ccc(B(O)O)cc1
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(CS(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid isopropyl ester and [4-[(methylsulfonyl)methyl]phenyl]boronic acid following a procedure analogous to that described in Example 28. LC (method 7): tR=1.07 min; Mass spectrum (ESI+): m/z=459 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=2)[N:8]=[C:7]([C:20]([F:23])([F:22])[F:21])[CH:6]=1)([CH3:3])[CH3:2].[Cl:24]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][N:11]=2)[N:8]=[C:7]([C:20]([F:23])([F:21])[F:22])[C:6]=1[Cl:24])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)Oc1cc(C(F)(F)F)nn1-c1ccc(S(C)(=O)=O)cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1c(Cl)c(C(F)(F)F)nn1-c1ccc(S(C)(=O)=O)cn1
Temperature: 25 °C
Reaction time: 60 h
Yield: 11.3 %

Procedure:
2-(5-Isopropoxy-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine (105 mg) and NCS (N-chlorosuccinimide) (200 mg) were dissolved in DMF under nitrogen, and the reaction mixture was stirred at room temperature for 2.5 days. The reaction mixture was then diluted with 2:1 ethyl acetate:benzene solution (100 ml), and washed with 0.5 N sodium hydroxide solution (100 ml), water (100 ml), and brine (100 ml). The organic layer was dried with sodium sulfate, and the solvent was evaporated in vacuo to give the crude product which was purified by recrystallization from 2:1 of isooctane:methylene chloride to afford the title compound (13 mg, 11%, MS: 384.1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:7][C:6]=2[CH:16]=1.[CH:17]1[CH:22]=[CH:21][C:20]([O:23][C:24](OC2C=CC=CC=2)=[N:25][C:26]#[N:27])=[CH:19][CH:18]=1>C(O)(C)C>[C:26](/[N:25]=[C:24](\[O:23][C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1)/[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][N:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)=[N:7][C:6]=2[CH:16]=1)#[N:27]
Reactant: Nc1ccc2oc(CN3CCCC3)nc2c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Product: N#C/N=C(/Nc1ccc2oc(CN3CCCC3)nc2c1)Oc1ccccc1

Procedure:
A solution of 5-amino-2-[(pyrrolidin-1-yl)methyl]benzoxazole (200 mg, 0.92 mmol) and diphenylcyanocarbonimidate (263 mg, 1.10 mmol) in isopropyl alcohol (3.5 mL) was stirred overnight at ambient temperature, the resulting white solid product, (Z)-phenyl N′-cyano-N-(2-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-5-yl)carbamimidate, was filtered and used directly for the next step (290 mg, 87%).
Reaction SMILES: [I:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][NH:14][CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:16]=O.[BH4-].[Na+]>CO.O>[I:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: Cn1c2c(c3cccc(I)c31)CNCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCc2c(c3cccc(I)c3n2C)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
6-Iodo-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (3.85 g, 12.3 mmol) was suspended in methanol (40 mL). Formaldehyde (14 mL of 37%) was added and heated at reflux for 2 h. The reaction was cooled to 0° C. in an ice bath and sodium borohydride (1.7 g, 46 mmol) was added slowly over 15 min and stirred for 2 h at 0–10° C. The reaction was diluted with water (200 mL) and extracted with CH2Cl2 (3×150 mL). The organics were collected, washed with brine (250 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product was purified by silica gel column chromatography (3% MeOH/CH2Cl2) to give 6-iodo-2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.6 g, 15%). 1H NMR (CDCl3 300 MHz) δ 7.59 (d, 1H, J=7.4 Hz), 7.33 (d, 1H, J=7.6 Hz), 6.73 (t, 1H, J=7.7 Hz), 3.98 (s, 3H), 3.62 (s, 2H), 2.83 (s, 4H), 2.55 (s, 3H) ppm.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[S:11][C:10]([C:12](=O)[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1.[CH3:19][NH:20][NH2:21]>O>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][C:7]1[S:11][C:10]([C:12]2[CH2:13][CH2:14][C:15](=[O:17])[N:20]([CH3:19])[N:21]=2)=[CH:9][CH:8]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cc2ncc[nH]2)s1
Reactant: CNN
Solvent: O
Product: CN1N=C(c2ccc(Cc3ncc[nH]3)s2)CCC1=O
Temperature: 90 °C

Procedure:
A mixture of 8.7 g of 4-[5-(1-imidazolylmethyl)-thien-2-yl]-4-oxobutyric acid, 2.9 ml methylhydrazine and 100 ml water was heated at 90° C. for 2 hours. After cooling, the precipitated solid was filtered off, dissolved in chloroform, the chloroform phase washed with dilute caustic soda solution and with water, dried over sodium sulfate and evaporated. The residue was purified by column chromatography (Silica gel//chloroform) and finally recrystallized from ethanol.