Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][NH:10][CH2:11][C:12]12[CH2:17][CH:16]1[CH2:15][NH:14][CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:25]1([N:28]2[C:37]3[C:32](=[CH:33][C:34]([F:39])=[C:35](F)[CH:36]=3)[C:31](=[O:40])[C:30]([C:41]([OH:43])=[O:42])=[CH:29]2)[CH2:27][CH2:26]1>C(#N)C>[C:1]([O:5][C:6]([CH2:8][CH2:9][NH:10][CH2:11][C:12]12[CH2:17][CH:16]1[CH2:15][N:14]([C:35]1[CH:36]=[C:37]3[C:32]([C:31](=[O:40])[C:30]([C:41]([OH:43])=[O:42])=[CH:29][N:28]3[CH:25]3[CH2:27][CH2:26]3)=[CH:33][C:34]=1[F:39])[CH2:13]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)CCNCC12CNCC1C2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCNCC12CC1CN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 31 %

Procedure:
A mixture of 1-[N-(tert-butoxycarbonyl)ethylaminomethyl]-3-azabicyclo[3.1.0]hexane (45.3 mg, 0.18 mmol and triethylamine (50 μl, 0.36 mmol) in acetonitrile (5 ml) was treated with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (50.0 mg, 0.18 mmol) and heated to 80° for 18 hours. Filtration of the reaction mixture provided the title product as a white solid (26.8 mg, 0.055 mmol, 31% yield). 1H NMR (CDCl3): 8.67 (s, 1H), 7.90 (d, J=15 Hz, 1H), 6.89 (d, J=7 Hz, 1H), 3.87 (bs, 2H), 3.5 (m, 5H), 3.3 (bs, 2H), 1.6 (m, 1H), 1.49 (s, 9H), 1.33 (m, 2H), 1.14 (m, 5H), 0.83 (m, 1H), 0.68 (m, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:39]([CH3:45])=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:39]([CH3:45])=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(C)n1
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)c(C)n1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (239 mg, 0.75 mmol) and 3-[3-(2,6-dimethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K8) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous brown substance (201 mg).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH:7]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[C:15](#N)[CH3:16]>>[CH:7]1([CH2:6][CH:2]([N:1]2[CH2:16][C:15]3[C:2](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:3]2=[O:4])[C:3]([OH:5])=[O:4])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC(CC1CCCCCCC1)C(=O)O
Reactant: CC#N
Product: O=C(O)C(CC1CCCCCCC1)N1Cc2ccccc2C1=O
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of phthalic dicarboxaldehyde (349 mg; 2.60 mmol) and 2-Amino-3-cyclooctyl-propionic acid (500 mg; 2.51 mmol) in acetonitrile (20 mL) was heated to reflux for 3 h. The mixture was then hot filtered to remove insoluble material and then allowed to cool to room temperature and then further cooled to 0° C. The solid was filtered off, rinsed with cold acetonitrile and air dried to give 480 mg (62%) of 3-Cyclooctyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid as a white solid: EI-HRMS m/e calcd for C19H25NO3 (M+) 315.1834, found 315.1840.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=O)[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C:24]([O:28][C:29](=[O:41])[NH:30][C@H:31]1[CH2:40][CH2:39][C:34]2[N:35]=[C:36]([NH2:38])[S:37][C:33]=2[CH2:32]1)([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>O.CN(C=O)C>[C:24]([O:28][C:29](=[O:41])[NH:30][C@H:31]1[CH2:40][CH2:39][C:34]2[N:35]=[C:36]([NH:38][C:18](=[O:20])[C:17]3[CH:21]=[CH:22][CH:23]=[C:15]([CH2:14][N:12]4[CH:13]=[C:9]([C:6]5[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=5)[CH:10]=[N:11]4)[CH:16]=3)[S:37][C:33]=2[CH2:32]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: N#Cc1ccc(-c2cnn(Cc3cccc(C(=O)O)c3)c2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2nc(N)sc2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCc2nc(NC(=O)c3cccc(Cn4cc(-c5ccc(C#N)cc5)cn4)c3)sc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
Dissolve 3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-benzoic acid (0.25 g, 0.82 mmol) and ((S)-2-amino-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester (0.22 g, 0.82 mmol) and TBTU (0.40 g, 1.24 mmol) and N,N-diisopropylethylamine (0.40 ml, 2.47 mmol) into 1.5 mL dry DMF and stir overnight at room temperature under Ar. Pour the reaction into H2O, giving a precipitate. Filter the solid, wash with H2O, and dry. Extract the filtrate 3 times with EtOAc and washed 4 times with H2O, 3 times with aq. NH4Cl and once with aq.Na2CO3. Dry the organic phase and concentrate to give an oil. Both crops are combined and purified via prep plate chromatography eluting with 3% MeOH/CH2Cl2 to give 0.42 g, 92% yield as a clear hard resin of ((S)-2-{3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-benzoylamino}-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](Br)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[F:25][C:26]([F:31])([F:30])[C@@H:27]([OH:29])[CH3:28]>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:29][C@@H:27]([CH3:28])[C:26]([F:31])([F:30])[F:25])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1
Reactant: C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)c1cnc(O[C@@H](C)C(F)(F)F)c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
5-Bromo-6-(4-chlorophenyl)-2-pyrazinecarboxylic acid methyl ester (CAN 960247-79-4, 2.420 g, 7.39 mmol) was dissolved in dry DMSO (25 mL). Cesium carbonate (4.41 g, 8.13 mmol) and (S)-1,1,1-trifluoropropan-2-ol (927 mg, 8.13 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. The mixture was partitioned between water and ethyl acetate; the organic phase was dried with MgSO4 and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 100 g, 10% to 50% ethyl acetate in heptane) to yield 2.53 g (95%) of the title compound as yellow oil; MS (EI) 361.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[F:31])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: Fc1ccccc1CBr
Product: Cc1nc2c(ccn2Cc2ccccc2F)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-fluorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.42 (m, 1 H), 7.28-7.17 (m, 3 H), 7.15-7.06 (m, 3 H), 6.93 (dd, J=5.1, 8.4 Hz, 1 H), 6.27 (dd, J=3.5, 11.7 Hz, 1 H), 5.67-5.51 (m, 3 H), 4.32-4.25 (m, 2 H), 2.98-2.81 (m, 2 H), 2.76 (s, 3 H), 2.13-2.06 (m, 2 H), 1.02-0.91 (s, 9 H); LC/MS (m/z) ES+=503.51 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.Cl.[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][NH2:30].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[C:5]([C:11]#[N:12])=[C:6]([NH:30][CH2:29][C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:19]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: NCc1ccc2ccccc2n1
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(NCc2ccc3ccccc3n2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, C-quinolin-2-yl-methylamine hydrochloride and DBU in DME. ES-MS m/e (%): 343 (M+H+, 100).
Reaction SMILES: C[O-].[Na+].[N+](C(C)C)([O-])=[O:5].[Br:10][C:11]1[C:12]([CH3:20])=[N:13][C:14]([CH2:18]Br)=[CH:15][C:16]=1[CH3:17]>CO>[Br:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH:18]=[O:5])=[N:13][C:12]=1[CH3:20]
Reactant: Cc1cc(CBr)nc(C)c1Br
Reactant: CC(C)[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C=O)nc(C)c1Br
Reaction time: 0.33 h

Procedure:
Sodium methoxide (1.16 g) was added to a solution of 2-nitropropane (1.96 mL) in methanol (40 mL) at mom temperature, and the mixture was stirred at the same temperature for 20 minutes. 3-bromo-6-(bromomethyl)-2,4-dimethylpyridine (2.00 g) was added to the reaction mixture, and the mixture was stirred at 50° C. for five hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 50%) to give the title compound (565 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](Br)[S:11][CH:12]=2)=[CH:4][CH:3]=1.Br[C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:25]=1)[C:20]([O:22]CC)=[O:21].O1CC[CH2:28][CH2:27]1>[Cl-].[Zn+2].[Cl-].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>[CH2:27]([C:18]1[N:17]=[CH:16][C:15]([C:10]2[S:11][CH:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)=[CH:25][C:19]=1[C:20]([OH:22])=[O:21])[CH3:28]
Reactant: Clc1ccc(-c2csc(Br)n2)cc1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Product: CCc1ncc(-c2nc(-c3ccc(Cl)cc3)cs2)cc1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A solution of compound (41) (0.25 g, 0.91 mmol) in tetrahydrofuran (5 ml) was cooled to −78° C. under an argon atmosphere and 1.6 M n-butyllithium-hexane solution (0.57 ml, 0.91 mmol) was added. After stirring at −78° C. for 30 min., a solution of zinc chloride (0.12 g, 0.91 mmol) in tetrahydrofuran (2 ml) was added to the reaction mixture. The reaction mixture was warmed to room temperature and stirred for 30 min. and ethyl 5-bromonicotinate (0.21 g, 0.91 mmol) and tetrakis(triphenylphosphine)palladium (0.16 g, 0.14 mmol) were added. The mixture was heated to 75° C. and stirred for 2 hrs. After cooling, the reaction mixture was poured into ice water and partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate and the extracts were combined and dried (MgSO4), and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and crystallized from ethyl acetate-n-hexane to give white crystals (0.16 g, 51%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C1COCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 95.1 %

Procedure:
4-Hydroxybenzoic acid methylester (2.29 g, 20 mmol) was dissolved together with pyridine (2.02 mL, 25 mmol) in anhydrous THF (20 mL) and after cooling down to 0° C., methanesulfonyl chloride (2.16 mL, 21 mmol) was added dropwise. After complete addition the ice bath was removed and the mixture was stirred at room temperature for 5 h. The slurry was diluted with DCM and extracted with H2O and aq. HCl (2N). The separated organic layer was finally dried (MgSO4) and evaporated to afford the crude product as an oil (4.38 g, 95%). 1H NMR (400 MHz, CDCl3): δ 8.07-8.09 (d, 2H), 7.32-7.34 (d, 2H), 3.90 (s, 3H), 3.16 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:25][C:26](=[O:28])[CH3:27])=[N:6][C:7]=1[C@@H:8]([NH:18]S(C(C)(C)C)=O)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1.[ClH:29]>CO.O1CCOCC1>[ClH:29].[NH2:18][CH:8]([C:7]1[N:6]=[C:5]([NH:25][C:26](=[O:28])[CH3:27])[CH:4]=[CH:3][C:2]=1[Br:1])[CH2:9][C:10]1[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=1
Reactant: CC(=O)Nc1ccc(Br)c([C@H](Cc2cc(F)cc(F)c2)NS(=O)C(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)Nc1ccc(Br)c(C(N)Cc2cc(F)cc(F)c2)n1

Procedure:
(S)—N-(5-Bromo-6-(2-(3,5-difluorophenyl)-1-(1,1-dimethylethylsulfinamido)ethyl)pyridin-2-yl)acetamide (1E, crude material from last step) was treated with a mixture of 2 ml of 1.25 M HCl in MeOH (methanol)/1 ml of 4 M HCl in dioxane for 1 hour. The solvent was removed in vacuo. The crude material was used without further purification. MS (m/z) 369.9 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([OH:10])=O)[C:4](=[O:11])[CH2:3]1.[NH2:12][CH2:13][C:14]([N:16]1[CH:20]([CH3:21])[C:19](=[O:22])[NH:18][C:17]1([CH3:24])[CH3:23])=[O:15]>>[OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([NH:12][CH2:13][C:14]([N:16]2[CH:20]([CH3:21])[C:19](=[O:22])[NH:18][C:17]2([CH3:23])[CH3:24])=[O:15])=[O:10])[C:4](=[O:11])[CH2:3]1
Reactant: O=C(O)CN1CC(O)CC1=O
Reactant: CC1C(=O)NC(C)(C)N1C(=O)CN
Product: CC1C(=O)NC(C)(C)N1C(=O)CNC(=O)CN1CC(O)CC1=O

Procedure:
The same procedure of Example 11, starting from 4-hydroxy-2-oxo-1-pyrrolidineacetic acid and 1-(2-aminoacetyl)-2,2,5-trimethyl-4-imidazolidinone, gave the title compound as a diastereoisomeric mixture, m.p. 218°-220° C. Mass spectrum (E.I., 70 eV, 1.5 mA), m/z=269 (M.+ --C3H7N).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[CH:3]=1.[CH2:9]([Mg]Cl)[CH2:10][CH2:11][CH3:12].C[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[CH3:22]>CCOCC>[CH2:9]([C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1)[CH2:10][CH2:11][CH3:12].[CH2:9]([C:19]1[CH:18]=[CH:17][CH:16]=[C:21]([CH2:22][CH2:3][CH2:2][CH3:7])[CH:20]=1)[CH2:10][CH2:11][CH3:12]
Reactant: Clc1cccc(Cl)c1
Reactant: CCCC[Mg]Cl
Reactant: Cc1ccccc1C
Solvent: CCOCC
Product: CCCCc1cccc(CCCC)c1
Product: CCCCc1ccccc1
Yield: 23 %

Procedure:
To 2.00 g (13.60 mmole) of m-dichlorobenzene, 0.050 g (0.065 mmoles) of [NitriphosCl]PF6 in 20 mL of ether at -78° C. was added 7.0 mL (14.0 mmoles) of 2M nBuMgCl in ether. The mixture was refluxed for 2 hrs. Then, 0.841 g of o-xylene was added as an internal standard and GC analysis on Column A (70° C. (0 min), 16°/min to 220° C.) yielded 68% of 1-chloro, 3-n-butylbenzene and 23% of 1,3-di-n-butylbenzene which was confirmed by GC/MS.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].C(=O)([O-])[O-:7].[Na+:10].[Na+]>O>[OH2:2].[OH2:7].[P:1]([OH:5])([O-:4])([O-:3])=[O:2].[Na+:10].[Na+:10].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Na+:10].[Na+:10].[Na+:10]
Reactant: O=P(O)(O)O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=P([O-])([O-])O
Product: O=P([O-])([O-])[O-]

Procedure:
Disodium orthophosphate dihydrate was prepared by a conventional rotary process. Phosphoric acid, sodium carbonate and water were reacted together to give a sodium orthophosphate solution having a molar ratio of sodium to phosphorus of 2/1 and a density of 50° C. baume at 100° C. The resulting solution was then evaporated to dryness in a rotary dryer and the dried product then cooled and screened to separate a -20 +100 mesh granular DSP.Duo product.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([S:7]([OH:10])(=[O:9])=[O:8])[CH:4]=[C:3]([NH2:11])[CH:2]=1.[CH2:12]([O:14][C:15](=[O:29])[CH:16]([CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:17](=O)[CH3:18])[CH3:13].[OH-].[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:20]=[C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:11]([C:3]2[CH:2]=[CH:1][CH:6]=[C:5]([S:7]([OH:10])(=[O:8])=[O:9])[CH:4]=2)[C:17]=1[CH3:18])=[O:29])[CH3:13]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: Nc1cccc(S(=O)(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(S(=O)(=O)O)c2)c1C

Procedure:
Metanilic acid (5 mmol, 0.9 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), sodium hydroxide (5 mmol, 0.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The unreacted metanilic acid was precipitated on ice and filtered from the reaction mixture. The filtrate was evaporated to yield an oil, which was purified over silica gel. After standing, the named product solidified as purple crystals (m.p. 94 C.-96° C.).
Reaction SMILES: CS[C:3]1[S:4][C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][C:24]#[N:25])[N:18]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)OCC>C(O)C>[N+:12]([C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:3](=[C:23]([C:19]3[N:18]=[C:17]([C:16]([F:27])([F:15])[F:26])[CH:22]=[CH:21][N:20]=3)[C:24]#[N:25])[S:4][C:5]=2[CH:11]=1)([O-:14])=[O:13]
Reactant: CSc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: N#CCc1nccc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#CC(=C1Nc2ccc([N+](=O)[O-])cc2S1)c1nccc(C(F)(F)F)n1
Temperature: 160 °C
Yield: 95.5 %

Procedure:
To a solution of 2-(methylthio)-6-nitro-1,3-benzothiazole (226 mg, 1.0 mmol) in ethanol (3.5 mL) was added 2-(4-trifluoromethylpyrimidin-2-yl)acetonitrile (187 mg, 1.0 mmol) and potassium carbonate (207 mg, 1.5 mmol). The orange mixture was heated in the microwave at 160° C. for 15 min, then cooled and poured into EA (60 mL). The organic layer was washed twice with 1N hydrochloric acid (25 mL each), brine (25 mL), and water (5 mL), then dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give 2-(6-nitrobenzothiazol-2(3H)-ylidene)-2-(4-trifluoromethylpyrimidin-2-yl)acetonitrile (349 mg, 96% yield) as a yellow solid.
Reaction SMILES: [F:1][C@@H:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][C@@H:12]2O)([CH3:10])[C:8](=[O:23])[CH2:7][CH2:6]3)[CH2:3]1.F[C@@H:25]1C2[C@](C)(C=CC(=O)C=2)C2[C@H]([C@H]3[C@@](CC=2)(C)C(=O)CC3)C1>>[F:1][C@@H:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH:12]=2)([CH3:10])[C:8](=[O:23])[C:7](=[CH2:25])[CH2:6]3)[CH2:3]1
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C(=O)CC[C@@H]12
Product: C=C1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)C1=O

Procedure:
Likewise diflorasone diacetate (6α,9α-difluoro-11β,17α,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17,21-diacetate) can be produced using the process of the present invention. First, 6α-fluoro-11β-hydroxyandrosta-1,4-diene-3,17-dione (U.S. Pat. No. 2,867,630) is dehydrated to 6α-fluoroandrost-1,4,9(11)-triene-3,17-dione by means well known to those skilled in the art, see Steroid Reactions, C. Djerassi, Holden-Day, San Francisco, 1963 p. 238 & 239. The 16-methylene group is then added by the process of U.S. Pat. No. 4,416,821 to produce 6α-fluoro-16-methyleneandrosta-1,4,9(11)-triene-3,17-dione (IB) which is converted to 6α-fluoro-17α-hydroxy-16-methylenepregna-1,4,9(11)-triene-3,20-dione (VI). The 21-hydroxy function of the corticoids is next introduced as described above followed by transformation of the 16-methylene group to a 16β-methyl group also described above to give 6α-fluoro-17α,21-dihydroxy-16β-methylpregna-1,4,9(11)-triene-3,20-dione 21-acetate which is acylated according to the procedure described in U.S. Pat. No. 4,154,748 (Examples 6 and 7) to produce 6α-fluoro-17α,21-dihydroxy-16β-methylpregna-1,4,9(11)-triene-3,20-dione 17,21-diacetate (U.S. Pat. No. 3,980,778, Example 6). 6α-Fluoro-17α,21-dihydroxy-16β-methylpregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate is then converted to diflorasone diacetate by the process of U.S. Pat. No. 3,980,778 (Examples 7 and 8).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH2:13])[S:11][CH:12]=1.[Cl:14][C:15]1[S:16][C:17]([S:21](Cl)(=[O:23])=[O:22])=[CH:18][C:19]=1[Cl:20]>>[Cl:20][C:19]1[CH:18]=[C:17]([S:21]([NH:13][C:10]2[S:11][CH:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:9]=2)(=[O:23])=[O:22])[S:16][C:15]=1[Cl:14]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)s1
Reactant: Nc1nc(-c2ccccc2Cl)cs1
Product: O=S(=O)(Nc1nc(-c2ccccc2Cl)cs1)c1cc(Cl)c(Cl)s1

Procedure:
The title compound was prepared from 4-(2-chlorophenyl)-1,3-thiazol-2-amine (57 mg) and 2,3-dichlorothiophene-5-sulfonyl chloride (68 mg) as described in the synthetic METHOD B to give a white solid (56.6 mg) with purity >90%: MS (pos) m/z 425.3, 427.3; HRMS m/z 423.8737 (calc. of monoisotopic mass for C13 H7 Cl3 N2 O2 S3 gives 423.8735).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([F:13])[CH:7]=1)[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:18]O>>[ClH:12].[NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([F:13])[CH:7]=1)[C:3]([O:5][CH3:18])=[O:4]
Reactant: NC(C(=O)O)c1ccc(Cl)c(F)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)c1ccc(Cl)c(F)c1
Product: Cl
Reaction time: 18 h
Yield: 105 %

Procedure:
To a solution of 2-amino-2-(4-chloro-3-fluorophenyl)acetic acid (5.00 g, 24.56 mmol) in MeOH (30 mL) at 0° C. was added dropwise thionyl chloride (5.37 mL, 73.67 mmol) and the reaction was stirred for 18 h. The reaction mixture was concentrated and the solids were triturated with Et2O to afford 6.580 g (105%) of methyl 2-amino-2-(4-chloro-3-fluorophenyl)acetate hydrochloride (42) which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28]Cl)=[CH:25][C:19]=3[CH2:18][S:17](=[O:32])(=[O:31])[C:16]=2[CH:33]=1)=[O:11]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28][NH:1][CH2:2][C:3]4[S:4][CH:5]=[CH:6][CH:7]=4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:31])(=[O:32])[C:16]=2[CH:33]=1)=[O:11]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reactant: NCc1cccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNCc3cccs3)cc(Cl)c1O2
Temperature: 110 °C

Procedure:
2-Aminomethyl thiophene (0.38 g, 3.363 mmol) and tetrabutylammonium iodide (0.02 g, 0.054 mmol) were added to a suspension of the carboxylic acid of Example 56k (0.4 g, 0.96 mmol) in methanol (5 mL) under nitrogen in a pressure reactor vessel and heated to 110° C. for 4 h. The reaction mixture was concentrated (oily residue), treated with methanolic HCl (15 mL) and refluxed for 3.5 h. It was concentrated, treated with an aqueous sodium bicarbonate solution to pH 8 and extracted with chloroform. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, 0.5% methanol/chloroform) to obtain the title compound. Yield: 0.21 g, (43.5%). 1H NMR (CDCl3): δ 2.68 (s, 3H, CH3), 2.98 (t, 2H, CH2), 3.18 (t, 2H, CH2), 3.9 (s, 3H, CH3), 4.6 (s, 2H, CH2), 4.67 (s, 1H, NH), 5.21 (s, 2H, CH2), 6.50 (s, 1H, Ar), 6.55 (s, 1H, Ar), 6.95 (s, 2H, Ar), 7.2 (m, 1H, Ar), 8.05 (s, 1H, Ar), 8.45 (s, 1H, Ar); MS: m/e (ES+) 505 (M+1).