Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][N:47]1[C:51]2=[C:52]3[C:57](=[CH:58][CH:59]=[C:50]2[NH:49][S:48]1(=[O:70])=[O:69])[CH:56]=[CH:55][C:54]([CH2:60][O:61][Si:62]([CH2:67][CH3:68])([CH2:65][CH3:66])[CH2:63][CH3:64])=[CH:53]3.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17][N:49]3[C:50]4=[CH:59][CH:58]=[C:57]5[C:52]([CH:53]=[C:54]([CH2:60][O:61][Si:62]([CH2:67][CH3:68])([CH2:63][CH3:64])[CH2:65][CH3:66])[CH:55]=[CH:56]5)=[C:51]4[N:47]([CH3:46])[S:48]3(=[O:70])=[O:69])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: CC[Si](CC)(CC)OCc1ccc2ccc3c(c2c1)N(C)S(=O)(=O)N3
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3c4ccc5ccc(CO[Si](CC)(CC)CC)cc5c4N(C)S3(=O)=O)[C@H](C)[C@H]12
Reaction time: 0.5 h

Procedure:
A solution of allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-hydroxymethyl-1-methyl-carbapen-2-em-3-carboxylate (365 mg, 1.0 mmol), triphenylphosphine (315 mg, 1.2 mmol), and 1-methyl-8-triethylsilanyloxymethyl-1,3-dihydro-2-thia-1,3-diaza-cyclopenta[α]naphthalene 2,2-dioxide (416 mg, 1.1 mmol) in anhydrous tetrahydrofuran (7 mL) is cooled in an ice-bath and stirred under a nitrogen atmosphere while diisopropyl azodicarboxylate (0.24 mL, 1.2 mmol) is added dropwise over a few minutes. The resulting solution is stirred in the cold for 30 minutes, then diluted with chloroform, washed with 5% aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated under vacuum. The residue is purified by silica gel flash chromatography, eluting with hexane-ethyl acetate, to afford allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-1-methyl-2-(1-methyl-2,2-dioxo-8-triethylsilanyloxymethyl-1,2-dihydro-2-thia-1,3-diaza-cyclopenta[α]naphthalen-3-ylmethyl)-carbapen-2-em-3-carboxylate.
Reaction SMILES: [O:1]=[C:2]([CH3:14])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].S(Cl)([Cl:18])(=O)=O>C(Cl)(Cl)Cl>[Cl:18][CH:3]([C:2](=[O:1])[CH3:14])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: CC(=O)CC(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)C(Cl)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a solution of benzyl 3-oxobutanoate (15 g, 78 mmol) in chloroform (150 mL) at 0° C. was added sulfuryl chloride (6.35 mL, 78 mmol) during a period of 20 min. The ice bath was removed and reaction mixture was allowed to warm to room temperature and stirred for 4 h. The solvent was evaporated and the crude product was diluted with EtOAc (250 mL). The organic layer was washed with H2O (100 mL), separated, dried over MgSO4 and concentrated to give the desired product as a light yellow oil (17.6 g, 99% yield). 1H NMR (CDCl3) δ 2.31 (s, 3H), 4.80 (s, 1H), 5.25 (s, 2H), 7.30-7.42 (m, 5H). LCMS, [M−H]+=225.4.
Reaction SMILES: [C:1]([C:5]1[C:13]2[S:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[C:1]([C:5]1[C:13]2[S:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)c1cccc2c1SCC2(C)C
Solvent: CC(=O)O
Product: CC(C)(C)c1cc([N+](=O)[O-])cc2c1SCC2(C)C

Procedure:
To a solution of 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzothiophene (4.0 g, 18.2 mmol) in glacial acetic acid (30 mL) is added dropwise 70% HNO3 (2.0 mL, 2.8 g, 31.8 mmol). The reaction mixture darkens to a deep green color over the course of the addition. The reaction is monitored by TLC (2% EtOAc/hexanes). Then the reaction mixture is partitioned between Et2O (50 mL) and H2O (2×50 mL). The ethereal layer is washed with saturated aqueous Na2CO3 (50 mL), dried (MgSO4), filtered and evaporated to a red solid. Crystallization from hexane provides the title compound as orange prisms. A second crop yielded slightly less pure material which is combined with the former and used without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[C:10]([F:18])=[C:11]([C:14]([F:17])=[CH:15][CH:16]=1)[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[C:34]3[CH:40]=[CH:39][NH:38][C:35]3=[N:36][CH:37]=2)[CH:27]=1.[OH-].[K+].O>CO>[CH2:19]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:10]([F:18])=[C:11]([CH:12]([C:40]2[C:34]3[C:35](=[N:36][CH:37]=[C:32]([C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)[CH:33]=3)[NH:38][CH:39]=2)[OH:13])[C:14]([F:17])=[CH:15][CH:16]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Reactant: O=Cc1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC(c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F)c1c[nH]c2ncc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-dibenzylamino-2,6-difluoro-benzaldehyde (53, 0.76 g, 2.3 mmol) in methanol (50 mL) were added 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 0.40 g, 2.1 mmol, prepared as described in Example 17) and potassium hydroxide (0.50 g, 8.9 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% methanol in methylene chloride to provide the compound (54, 0.60 g, 50%). MS (ESI) [M+H+]+=533.2.
Reaction SMILES: C([NH:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Br:16])(OC(C)(C)C)=O.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[Br:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][NH2:8]
Reactant: CC(C)(C)OC(=O)NOCCCCCCBr
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NOCCCCCCBr
Reaction time: 1 h

Procedure:
To a stirring solution of N-Boc-O-(6-bromohexyl)hydroxylamine (954 mg, 3.22 mmol) in dichloromethane (16 mL) at 0° C. was added trifluoroacetic acid (8.0 mL). Stirring continued for 1 h at 0° C. (Gilmore, J. M.; Scheck, R. A.; Esser-Kahn, A. P.; Joshi, N. S.; Francis, M. B. Angew. Chem. Int. Ed. 2006, 45, 5307.) The volatile compounds were removed under reduced pressure and the excess acid was removed by azeotroping with toluene (3×20 mL). O-(6-bromohexyl)hydroxylamine trifluoroacetate salt (1b) was obtained as a clear oil (998 mg, quant.), which was carried on without further purification. 1H-NMR (CDCl3, 300 MHz): δ 10.41 (broad s, 3H), 4.05 (broad t, J=6.2 Hz, 2H), 3.4 (t, J=7.0 Hz, 2H), 1.85 (pent, J=6.7 Hz, 2H), 1.68 (broad pent, J=6.3 Hz, 2H), 1.51-1.33 (m, 4H). 13C-NMR (CDCl3, 75 MHz): δ 33.7, 32.6, 27.8, 27.6, 24.2. HRESI-MS calcd for C6H15BrON [M+H]+ 196.0332. found 196.0332.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([CH:14]=O)[N:2]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1>O>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([CH:14]=[CH:17][C:18]([OH:20])=[O:19])[N:2]=1
Reactant: O=Cc1cc2c(cn1)[nH]c1ccccc12
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: O
Product: O=C(O)C=Cc1cc2c(cn1)[nH]c1ccccc12
Yield: 94.7 %

Procedure:
A mixture of 2.0 g of beta-carboline-3-carboxaldehyde, 2.0 g of malonic acid, 40 ml of water-free pyridine and 0.1 ml of piperidine is heated in a steam bath for 4 h. The solvent is evacuated in vacuum and after adding 20 ml of 2-propanol, the precipitate is filtered off. 2.3 g of 3-(3-beta-carbolinyl)-acrylic acid with a m.p. of 240°-260° C. (decomposition) is obtained.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH:18]1[N:22]=[CH:21][NH:20][C:19]=1[CH2:23][CH2:24][NH2:25]>>[C:1]([NH:3][C:4]([NH:25][CH2:24][CH2:23][C:19]1[N:20]=[CH:21][NH:22][CH:18]=1)=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])#[N:2]
Reactant: NCCc1cnc[nH]1
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCc1c[nH]cn1
Reaction time: 3 h

Procedure:
A mixture of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (8.07 g) and histamine base (3.36 g) was heated for 3 hours at 100° and then for 3 hours at 130°-140°. The product was chromatographed on a column of silica gel with ethyl acetate/isopropyl alcohol (5:1) as eluent and crystallised by slow evaporation from isopropyl alcohol. Recrystallisation from water afforded the title compound, m.p. 170°-171°.
Reaction SMILES: FC(F)(F)S([O:6][C@@H:7]1[C@@H:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:11]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:10]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:9][CH2:8]1)(=O)=O.N([O-])=O.[Na+].O>CN(C=O)C>[CH2:14]([O:13][C@H:12]1[C@H:11]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:10]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:9][CH2:8][C@@H:7]1[OH:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(O[C@H]1CO[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O[C@H]1CO[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 10 °C
Reaction time: 14 h

Procedure:
The triflate (12) was dissolved in DMF (36.2 kg, 3.02 kg/kg starting material) and cooled to 10° C. Sodium nitrite (5.9 kg, 3.0 equivalents) was added, the solution exothermed to approximately 30° C., then the reaction mixture was cooled to 15° C. to 25° C. and stirred for 12-16 h. The mixture was cooled to 5° C., and water (152 kg, 4.2 kg/kg DMF) was added at a rate that kept the temperature <15° C. The resulting mixture was agitated at 10° C. for 2 hours. The solids were filtered and washed with water (2×12 kg). The filtered solids were dissolved in ethyl acetate (21.6 kg, 1.8 kg/kg starting material). The solution was washed with brine (15.5 kg), dried with MgSO4 (2.5 kg), filtered, and the filtrate was concentrated to dryness under vacuum at 35° C. Isopropanol (9.5 kg) was added and heated to 75° C. to dissolve the crude product. Heptane (24.6 kg) was added to the solution and the mixture cooled to 15° C. to 25° C. The mixture was further cooled to 0° C. and stirred overnight. The solids were filtered and washed with heptane (2×8.2 kg). The material was dried in a vacuum oven. (3S,4R,5S,6R)-4,5,6-Tris(benzyloxy)tetrahydro-2H-pyran-3-ol (13) was obtained as a yellow solid, 5.3 kg (44%). 1H NMR (300 MHz, CDCl3): δ 7.37 (m, 15H), 4.96 (d, J=11 Hz, 1H), 4.80 (m, 2H), 4.68 (d, J=12 Hz, 1H), 4.61 (m, 2H), 4.53 (d, J=12 Hz, 1H), 3.78 (m, 1H), 3.67 (m, 3H), 3.50 (dd, J=9, 3 Hz, 1H), 2.42 (br s, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([NH2:22])[C:6]1[CH:7]=[C:8]([C:12]2[N:13]([CH3:21])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=[N:10][CH:11]=1)(=[O:4])=[O:3].ClS([N:34]=[C:35]=O)(=O)=O.CN(C=O)C>ClCCl>[CH3:1][S:2]([C:5]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([NH2:22])[C:6]1[CH:7]=[C:8]([C:12]2[N:13]([CH3:21])[C:14]3[C:19]([C:20]=2[C:35]#[N:34])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=[N:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cn1c(-c2cncc(C(N)(C(=O)OC(C)(C)C)S(C)(=O)=O)c2)cc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(-c2cncc(C(N)(C(=O)OC(C)(C)C)S(C)(=O)=O)c2)c(C#N)c2ccccc21
Reaction time: 1 h

Procedure:
To a solution of 2-[5-(methanesulfonyl-(tert-butoxycarbonyl)-amino-methyl)-pyridin-3-yl]-1-methyl-indole (350 mg, 0.842 mmol) in dichloromethane (10 mL) is added chlorosulfonyl isocyanate (0.358 g, 2.53 mmol). The mixture is stirred at ambient temperature for 20 min, whereupon anhydrous DMF (2 mL) is added. After 1 h, the mixture is concentrated to a volume of 3 mL, and filtered. Purification by RP HPLC affords 2-[5-(methanesulfonyl-(tert-butoxycarbonyl)-amino-methyl)-pyridin-3-yl]-1-methyl-3-cyano-indole. MS (ESI) m/z 441.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH2:11])([O-:3])=[O:2].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>CC(O)=O>[N+:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[CH:18][CH:17]=[CH:16]2)[CH:7]=[CH:6][C:5]=1[NH2:11])([O-:3])=[O:2]
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: Nc1ccc(-n2cccc2)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 2-nitro-1,4-phenylenediamine (20 g, 131 mmol), 2,5-dimethoxytetrahydrofuran (18.3 mL, 135 mmol) in HOAc (37 mL) at 95° C. for 3 h according to the general procedure F. Obtained as a red solid (13.5 g).
Reaction SMILES: [CH3:1]C(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CC(C)=O.[Br:18][C@H:19]1[C@@H:24]([OH:25])[CH2:23][C@@H:22]([C:26]([O-:28])=[O:27])[C@H:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Br:35])[CH2:20]1>O>[Br:18][C@H:19]1[C:24](=[O:25])[CH2:23][C@@H:22]([C:26]([O:28][CH3:1])=[O:27])[C@H:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Br:35])[CH2:20]1
Reactant: CC(C)=O
Reactant: O=C([O-])[C@@H]1C[C@H](O)[C@H](Br)C[C@H]1c1ccccc1Br
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)[C@@H]1CC(=O)[C@H](Br)C[C@H]1c1ccccc1Br
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Freshly prepared Jones reagent (2.7 M, 7.0 mL) was added at 0° C. to an acetone (25 mL) solution of (1R,2R,4R,5S)-4-bromo-2-(2-bromophenyl)-5-hydroxycyclohexanecarboxylate (2.50 g, 6.38 mmol) with stirring at room temperature for 40 minutes. The mixture was then diluted with water and extracted with ether (3×). The combined extracts were washed with water, saturated aqueous sodium bicarbonate and brine solutions, and dried (Na2SO4). Concentration in vacuo gave methyl (1R,2R,4R)-4-bromo-2-(2-bromophenyl)-5-oxocyclohexanecarboxylate as a colorless, thick syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH2:14][CH:15]([O:21][CH:22]([CH3:24])[CH3:23])[C:16]([O:18]CC)=[O:17])[CH:11]=[CH:10][N:9]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH2:14][CH:15]([O:21][CH:22]([CH3:24])[CH3:23])[C:16]([OH:18])=[O:17])[CH:11]=[CH:10][N:9]=1
Reactant: CCOC(=O)C(Cc1ccnc(OCCOc2ccc(Cl)cc2Cl)c1)OC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)OC(Cc1ccnc(OCCOc2ccc(Cl)cc2Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.2 %

Procedure:
To a suspension of ethyl 3-{2-[2-(2,4-dichlorophenoxy)ethoxy]-4-pyridyl}-2-isopropoxypropanoate (24 mg) in methanol (2 mL) was added 5N aqueous sodium hydroxide solution (0.4 mL), and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was diluted with water, and adjusted to pH 5 with 5N hydrochloric acid. After extracting with ethyl acetate (×2), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified on a preparative TLC plate to give the title compound as a colorless solid (16 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[S:17][CH3:18])[NH:6][C:5]=2[CH:4]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[S:17][CH3:18])[N:6]([C:19](=[O:21])[CH3:20])[C:5]=2[CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)Nc1cccc(SC)c1S2
Product: COc1ccc2c(c1)N(C(C)=O)c1cccc(SC)c1S2

Procedure:
2-Methoxy-6-methylthio-10-acetylphenothiazine (m.p. 106°-108°C.; 29.6 g.) is prepared by acetylation of 2-methoxy-6-methylthiophenothiazine (m.p. 152°-154°C.; 26.2 g.) by means of acetic anhydride.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: NCC(CC1CC1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1c(F)cccc1Cl
Product: O=C(NCC(CC1CC1)c1ccc(C(F)(F)F)nc1)c1c(F)cccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-6-fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=401.1, tR (minutes, Method G)=2.88. [α]D20=−25.9 (c=0.81 mg/mL,CHCl3)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[C:10]1([C:16]2[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:16]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=[CH:18][C:19]([CH2:20][O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])=[CH:22][CH:23]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: OCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCc1ccccc1OCc1ccc(-c2ccccc2)cc1

Procedure:
A mixture of 2.92 g (23.49 mmol) of 2-hydroxybenzyl alcohol, 5.00 g (24.67 mmol) of 4-phenylbenzyl chloride and 3.41 g (24.67 mmol) of potassium carbonate in 60 ml of acetone was heated at reflux overnight. The precipitate formed was filtered off. The residue was taken up in 1N NaOH, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and the solvent was removed. The product was purified chromatographically (silica gel, cyclohexane/ethyl acetate 10:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:25]([C:24]2[C:23]([Cl:22])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:32])=[O:26])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.5 %

Procedure:
To a solution of 4-amino-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (127.6 mmol, 37.57 g) and 2,6-dichlorobenzoyl chloride (140.6 mmol, 29.45 g) in dichloromethane (350 mL) was added diisopropylethylamine (192 mmol, 33.4 mL) at room temperature. The brown solution was stirred for 15 h at room temperature to afford a white suspension. At this time, TLC analysis of the mixture indicated the absence of starting material. The solids were collected by filtration and were washed with dichloromethane (150 mL) and air dried to obtain 52.75 g (88.4%) of a white solid: mp 192-194° C. 1H NMR (DMSO-d6) (400 MHz) δ 10.68 (s, 1H), 7.47-7.6 (m, 5H), 7.2-7.29 (m, 3H), 4.12-4.17 (m, 1H), 3.62 (s, 3H), 2.79-2.99 (m, 2H), 1.33 (s, 9H), 13C NMR, CDCl3 (100 Mhz) d 172.49, 161.82, 155.37, 136.99, 136.36, 131.28, 131.16, 129.48, 128.19, 119.31, 78.27, 55.3, 51.76, 35.9, 27.77. HR MS: Obs. mass, 466.1069. Calcd. mass, 466.1062).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[C:4]([CH3:34])[N:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:36]/[OH:37])/[CH2:9][C@H:10]([C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[C:4]([CH3:34])[N:3]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccccc2C)cc(C)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccccc2C)=N/O)cc(C)n1

Procedure:
In analogy to example 132, step 6, from 4′-[(R)-3-(2,6-dimethyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white semisolid, MS (ESI−): m/z=463.3 ([M−H]−).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[C:12]([OH:14])=[O:13].[CH3:15]O>>[CH3:15][O:13][C:12]([C@H:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C@H:6]1[NH2:5])=[O:14]
Reactant: CO
Reactant: N[C@@H]1CCCC[C@@H]1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CCCC[C@H]1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Thionyl chloride (4.73 mL, 64.8 mmol) was slowly added to a chilled (ice-water bath) suspension of (1S,2R)-2-aminocyclohexanecarboxylic acid (16.2 mmol) in anhydrous methanol (200 mL). After complete addition, the cold bath was removed and the resulting mixture warmed to room temperature. After 24 h, the reaction mixture was evaporated to dryness under a stream of dry nitrogen. The crude product, (1S,2R)-2-aminocyclohexanecarboxylic acid methyl ester, was obtained as a white solid and used in the next step without purification or characterization.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[N:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:5]=[C:6]([CH2:8]O)[CH:7]=1.[Cl:24]C1N=C(Cl)N=C(Cl)N=1>CS(C)=O.CCOC(C)=O>[Cl:24][CH2:8][C:6]1[CH:5]=[C:4]([C@H:10]2[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[N:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2cc(F)cc(CO)c2)COC1(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](c2cc(F)cc(CCl)c2)COC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 157.1 %

Procedure:
To a solution of (S)-tert-butyl 4-(3-fluoro-5-(hydroxymethyl)phenyl)-2,2-dimethyloxazolidine-3-carboxylate (330 mg, 1.014 mmol) in anhydrous DMSO (2. 028 mL) was added 2,4,6-trichloro-1,3,5-triazine (112 mg, 0.609 mmol) portionwise. The mixture was stirred at room temperature for 30 min. The mixture was diluted with EtOAc, and separated. The organic phase was washed with H2O (5×30 mL), dried over anhydrous Na2SO4, filtered off and concentrated under reduced pressure. The residue was purified with flash chromatography eluting with 0-100% EtOAc/heptane to provide (S)-tert-butyl 4-(3-(chloromethyl)-5-fluorophenyl)-2,2-dimethyloxazolidine-3-carboxylate (329 mg, 94%). LCMS (m/z): 288.1 (MH+-56), 1.12 min.
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=O)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>>[C:25]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])=[O:21])[CH2:12][CH2:11]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCC(F)(F)F
Reactant: O=C(O)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Agent: Cl
Product: O=C(NCC(F)(F)F)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
The procedure of step (d) of Example 1 was repeated using the compound prepared in step (c) of Example 1, except that 2,2,2-trifluoroethylamine hydrochloride was used instead of N-methylbenzylamine. Thus, 3-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-N-(2,2,2-trifluoroethyl)benzamide was prepared.