Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[CH:11]=[C:10]3[O:13][CH2:14][O:15][C:9]3=[CH:8][C:7]=2[CH:6]([CH2:16][CH2:17]Br)[CH2:5]1)(=[O:3])[CH3:2].[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:1]([N:4]1[C:12]2[CH:11]=[C:10]3[O:13][CH2:14][O:15][C:9]3=[CH:8][C:7]=2[CH:6]([CH2:16][CH2:17][N:28]2[CH2:29][CH2:30][CH:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(=O)N1CC(CCBr)c2cc3c(cc21)OCO3
Solvent: Cc1ccccc1
Product: CC(=O)N1CC(CCN2CCC(c3ccccc3)CC2)c2cc3c(cc21)OCO3

Procedure:
A solution of 580 mg. (18.6 mmol) of 5-acetyl-6,7-dihydro-7-(2-bromoethyl)-5H-1,3-dioxolo[4,5-f]indole and 600 mg. (37.2 mmol) of 4-phenylpiperidine in 30 ml. of toluene is heated at reflux temperature for 18 hours. The solvent is removed, and the residue is extracted with diethyl ether (2 × 25 ml.), and the solid is removed by filtration. The filtrate is evaporated to give a residue that crystallizes on trituration with petroleum ether. The material is recrystallized from dilute acetone to give crystals, m.p. 101°-103°C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:13][C:14]1[CH:15]=[C:16]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[C:27](F)[CH:28]=3)[C:23](=[O:32])[N:22]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:21]2=[O:41])[CH:17]=[CH:18][CH:19]=1>>[F:13][C:14]1[CH:15]=[C:16]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[C:27]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:28]=3)[C:23](=[O:32])[N:22]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:21]2=[O:41])[CH:17]=[CH:18][CH:19]=1
Reactant: C1CCNC1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2cccc(F)c2)c(=O)n1OCc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2cccc(F)c2)c(=O)n1OCc1ccccc1
Yield: 51.7 %

Procedure:
Using General Method 4, the reaction of pyrrolidine (0.1 mL, 1.28 mmol), triethylamine (0.18 mL, 1.28 mmol), and 1-(3-fluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example G-1, 0.17 g, 0.43 mmol) provided 0.1 g of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16])([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)=[O:16])([O-:11])=[O:10]
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Product: O=C(Nc1ccc(F)cc1)c1cccc([N+](=O)[O-])c1
Yield: 76.1 %

Procedure:
Using 4-fluoroaniline (1.1 ml, 10.9 mmol) and 3-nitrobenzoic acid (1.76 g, 10.0 mmol), the procedure of Reference Example 16 was repeated to obtain 1.98 g (76.0%) of the title compound in the form of light yellow needle crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>CN(C=O)C>[CH:38]([O:37][C:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)=[O:36])([CH3:40])[CH3:39]
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Reactant: CC(C)OC(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 2.6 mmol of pyridine were added. After the mixture had been stirred at 0° C. for 15 min, 2 mmol of isopropyl chloroformate in 3 ml of DMF were added. The reaction solution was then stirred at RT for a further 2 h. The crude product was purified using chromatographic methods.
Reaction SMILES: [Na].[NH2:2][C:3]1[C:7]([CH3:8])=[CH:6][S:5][C:4]=1C(O)=O.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:19]2Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C(O)(=O)C>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:19]2[NH:2][C:3]1[C:7]([CH3:8])=[CH:6][S:5][CH:4]=1
Reactant: Cc1csc(C(=O)O)c1N
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cnc2c(OC)cccc2c1Nc1cscc1C
Yield: 31.4 %

Procedure:
The sodium salt of 3-amino-4-methylthiophene-2-carboxylic acid (7.2 g, 0.04 mol) and ethyl 8-methoxy-4-chloroquinoline-3-carboxylate (5.39 g, 0.02 mol) in toluene (75 ml), ethanol (55 ml) and glacial acetic acid (10 ml) were stirred at room temperature for five days. The solvents were removed by evaporation at reduced pressure to give a dark-green slurry. 10% aqueous sodium carbonate was added and the insoluble solid filtered off, washed well with water and dried. This material was crystallised from ethyl acetate (with charcoaling) to give the title compound as pale yellow crystals (2.15 g), m.p. 162°-164°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:26]2[N:30]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)[N:29]=[CH:28][CH:27]=2)O1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:26]4[N:30]([C:31]5[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=5)[N:29]=[CH:28][CH:27]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(-n2nccc2B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Fc1ccc(-c2cnc3ccc(Br)cn23)cc1
Product: Cc1ccc(-n2nccc2-c2ccc3ncc(-c4ccc(F)cc4)n3c2)cc1

Procedure:
The title compound, white solid (14 mg, 11%), MS (ISP) m/z=369.5 [(M+H)+], mp 141° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-fluoro-phenyl)-imidazo[1,2-a]pyridine (intermediate E) (0.1 mg, 0.34 mmol) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-p-tolyl-1H-pyrazole (intermediate C) (0.083 g, 0.41 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=1>>[C:38]([C:35]1[CH:34]=[CH:33][C:32]([CH2:31][O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)=[CH:37][CH:36]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: CC(C)(C)c1ccc(COc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-4-tert-butyl-benzene following the procedure of Example 478: MS (ESI) m/z 540.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2.Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:18]([O:17][C:15]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][CH:13]=[CH:14][C:5]=2[O:4][C:3]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:2]=2[NH:1][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:10]1)=[O:16])([CH3:20])([CH3:21])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2Oc2cc(Cl)ccc2N)C1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCNc1ccc(Cl)cc1Oc1cccc2c1CCN(C(=O)OC(C)(C)C)C2
Temperature: 60 °C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
A mixture of 5-(2-amino-5-chlorophenoxy)-2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinoline (2.92 g, 7.8 mmols), ethyl 4-bromobutyrate (2.2 ml, 15.6 mmols), potassium carbonate (1.08 g, 10 mmols) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 3 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[2-[2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yloxy]-4-chlorophenyl]aminobutyrate (2.47 g, 64.8%).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:34])=[C:6]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2/[CH:20]=[CH:21]/[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=O.Cl.[NH2:36]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:1]([C:3]1[NH:4][C:5]([CH3:34])=[C:6]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2/[CH:20]=[CH:21]/[C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:36]
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1/C=C/C(=O)OC(C)(C)C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(C#N)=C(C(=O)OCC)C1c1ccccc1/C=C/C(=O)OC(C)(C)C
Yield: 15.6 %

Procedure:
A solution of the product of Example 2 (2.9 g), hydroxylamine hydrochloride (0.51 g) and sodium acetate (0.76 g) in acetic acid (30 ml) was stirred for 2 h at room temperature, then acetic anhydride (2.2 g) was added to the reaction. The mixture was heated to 95°-100° for 5 h and then extracted with ethyl acetate. The organic phase was washed with 5% sodium hydroxide and brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with cyclohexane/ethyl acetate 7:3 to give the title compound (0.45 g) as a yellow solid. M.p. 146°-147°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1>>[F:11][C:12]([F:21])([F:22])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:18][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:15][CH:14]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Product: O=[N+]([O-])c1cnccc1OCc1ccc(C(F)(F)F)cc1
Yield: 89.5 %

Procedure:
In accordance with the same procedures as in Preparation 2, except for using 4-chloro-3-nitropyridine prepared in Step 1 of Preparation 1 and 4-trifluoromethylbenzyl alcohol, the titled compound was obtained as a yellow solid. (Yield: 89.5%)
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:39]1[S:43][N:42]=[CH:41][N:40]=1)[S:7]([C:10]1[C:37]([F:38])=[CH:36][C:13]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3/[CH:25]=[CH:26]/[CH2:27][NH:28]C(=O)OC(C)(C)C)[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][CH2:27]/[CH:26]=[CH:25]/[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:14]1[C:13]2[CH:36]=[C:37]([F:38])[C:10]([S:7]([NH:6][C:39]3[S:43][N:42]=[CH:41][N:40]=3)(=[O:9])=[O:8])=[CH:11][C:12]=2[O:16][C:15]1=[O:17]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n(Cc4ccccc4/C=C/CNC(=O)OC(C)(C)C)c3cc2F)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC/C=C/c1ccccc1Cn1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)c(F)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The compound of Formula 12-2 thus prepared (125 mg, 0.176 mmol) was placed into a 1 dram vial containing 702 μL of DCM and 176 μL of TFA at ambient temperature (RT). After 20 minutes of stirring at RT, LCMS indicated complete consumption of was placed 125 mg of 12-2. The reaction mixture was concentrated in vacuo, dissolved in MeOH (1 mL), filtered and purified by reverse-phase HPLC (5-60% MeCN in water with 0.1% TFA, C18 column) to give 12-3 (3-{2-[(1E)-3-Aminoprop-1-en-1-yl]benzyl}-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydro-1,3-benzoxazole-6-sulfonamide) as a white solid. 1H NMR δ (ppm)(DMSO-d6): 8.40 (1H, s), 7.95 (2H, br s), 7.77 (1H, d, J=5.32 Hz), 7.50 (1H, d, J=7.71 Hz), 7.35 (1H, t, J=7.54 Hz), 7.28 (1H, t, J=7.56 Hz), 7.21 (3H, t, J=7.71 Hz), 7.09 (2H, d, J=12 Hz), 6.16-6.09 (2H, m), 5.12 (2H, s). HRMS C19H17FN5O4S2 [M+H] calc 462.0701, obs 462.0706.
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=O.[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][NH2:25])[N+:20]([O-:22])=[O:21].C(OC(C)C)(C)C>>[O:19]([CH2:23][CH2:24][NH:25][C:3](=[O:5])[C:2]([CH3:1])([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:6])[N+:20]([O-:22])=[O:21]
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)NCCO[N+](=O)[O-]
Yield: 19.6 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.91 g of 2-methyl-2-(4-chlorophenoxy)propionic acid and 0.60 g of nitroxyethylamine nitrate, 0.21 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[C:9]1([CH3:17])[CH:14]=[CH:13][C:12]([Mg]Br)=[CH:11][CH:10]=1>>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:12]1[CH:13]=[CH:14][C:9]([CH3:17])=[CH:10][CH:11]=1
Reactant: Fc1ccccc1Br
Reactant: Cc1ccc([Mg]Br)cc1
Product: Cc1ccc(-c2ccccc2F)cc1
Yield: 57 %

Procedure:
6.0 g (57% yield) was prepared as an oil by the method of Example 19A from 10 g 2-bromofluorobenzene, 250 mg bis(diphenylphosphinylethane)nickel dichloride and 89 ml 0.73M 4-toluylmagnesium bromide. The product was used without further purification. NMR (CDCl3, 60 MHz): 7.5-6.9 (m, 8H), 2.3 (s, 3H).
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[S:15])[S-:14])=[N:10][CH:11]=1.C([NH+](CC)CC)C>C(#N)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:1]([OH:2])[CH2:3][CH2:4][S:15][C:13]2=[S:14])=[N:10][CH:11]=1
Reactant: S=C([S-])Nc1ccc(Cl)cn1
Reactant: C=CC=O
Agent: CC[NH+](CC)CC
Solvent: CC#N
Product: OC1CCSC(=S)N1c1ccc(Cl)cn1
Reaction time: 1.5 h
Yield: 42.6 %

Procedure:
A solution of acrolein (17.6 g) in anhydrous acetonitrile (45 cc) is added, at a maximum temperature of 5° C., to a suspension of triethylammonium 5-chloropyrid-2-yldithiocarbamate (91.5 g) in anhydrous acetonitrile (450 cc). The reaction is allowed to proceed for 90 minutes at a maximum temperature of 5° C. The crystals which appear are filtered off, washed with ice-cooled acetonitrile (50 cc) and then four times with distilled water (total 480 cc) and dried in air. The product obtained (38.8 g; m.p.=136°-137° C.) is purified by recrystallisation from acetonitrile (240 cc). 3-(5-Chloropyrid-2-yl)-4-hydroxyperhydro-1,3-thiazine-2-thione (33.2 g), which melts at 141° C., is obtained.
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:11]=[C:10]1[NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=O)(C)(C)C>CCOC(C)=O>[ClH:1].[F:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:13]2[C@@H:12]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[NH:11][C:10]([NH:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[N:9]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C(NCc2ccccc2)=N[C@@H](c2ccc(F)cc2)[C@H]1c1ccc(F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc([C@H]2NC(NCc3ccccc3)=N[C@H]2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride is bubbled into a solution of 160 (350 mg, 0.76 mmol) in EtOAc (20 mL) for 0.5 min, and the solution is stirred at RT overnight. The solvent is removed by rotary evaporation, and the residue is triturated with Et2O to give 230 mg of the product 161. 1H NMR (DMSO-d6) δ 9.50-8.40 (m, 3H), 7.55-7.250 (m, 5H), 7.05-6.85 (m, 8H), 5.48 (s, 2H), 4.55 (d, 2H); MS: m/z 364 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([F:11])[CH:3]=1.[N:12]([Si](C)(C)C)=[N+:13]=[N-:14].C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:10])[NH:14][N:13]=[N:12]2)=[C:4]([F:11])[CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: O=C=Nc1ccc(Cl)cc1F
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1[nH]nnn1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
A stirred solution of 17.1 grams (0.10 mole) of 4-chloro-2-fluorophenyl isocyanate and 20.0 grams (0.17 mole) of azidotrimethylsilane was heated under reflux for 16 hours. The reaction mixture was cooled to ambient temperature and 60 ml of toluene and 100 ml of water were added. The mixture was allowed to stand for two hours and the resultant solid collected by filtration. The filter cake was washed with petroleum ether to yield 14.5 grams of 1-(4-chloro-2-fluorophenyl)-1,4-dihydro-5H-tetrazol-5-one; m.p. 185°-187° C. The reaction was repeated several times.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([OH:23])[C:21]=1[OH:22])[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)=[O:6].CC(C1C=C(C=C(C(C)(C)C)C=1O)C(NCC1C=CC([N+]([O-])=O)=CC=1)=O)(C)C>>[OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([OH:23])[C:21]=1[OH:22])[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)=[O:6]
Reactant: O=C(NCCc1ccc([N+](=O)[O-])cc1)c1cc(O)c(O)c(O)c1
Agent: CC(C)(C)c1cc(C(=O)NCc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Product: Nc1ccc(CCNC(=O)c2cc(O)c(O)c(O)c2)cc1
Yield: 89 %

Procedure:
The experimental protocol used is the same as that described for intermediate 2.2, with 3,4,5-trihydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide replacing the 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide. A beige powder is obtained with a yield of 89%. Melting point: 167-169° C.
Reaction SMILES: C([O:8][C:9](=[O:24])/[CH:10]=[CH:11]/[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22][CH3:23])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)C1C=CC=CC=1.C(O)(=O)C>C(OCC)(=O)C.CO.[Pd]>[CH3:23][O:22][C:20]([C:15]12[CH2:18][CH2:19][C:12]([CH2:11][CH2:10][C:9]([OH:24])=[O:8])([CH2:17][CH2:16]1)[CH2:13][CH2:14]2)=[O:21]
Reactant: COC(=O)C12CCC(/C=C/C(=O)OCc3ccccc3)(CC1)CC2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C12CCC(CCC(=O)O)(CC1)CC2
Reaction time: 2 h

Procedure:
Diester 11-2 (0.625 g, 1.90 mmol) was dissolved in a 1:1 mixture of ethyl acetate/methanol (30 mL), placed under nitrogen atmosphere, then treated with 10% Pd/C (500 mg) and 0.1 mL of acetic acid. The reaction was placed under hydrogen atmosphere and stirred vigorously for 2 hr. The resulting solution was filtered through celite and the solvent was removed under reduced pressure. The residue was partitioned between 200 mL of ethyl acetate and 200 mL of 1 N NaOH solution. The aqueous layer was separated and neutralized, then extracted three times with 50 mL of methylene chloride. The combined organic layers were dried over magnesium sulfate and the solvent was removed under reduced pressure to afford 3-[4-(methoxycarbonyl)bicyclo[2.2.2]oct-1-yl]propanoic acid (11-3). 1H NMR (500 MHz, CDCl3): δ 3.62 (3H, s), 2.20 (2H, broad t, J=9 Hz), 1.75 (6H, m), 1.47 (2H, broad t, J=9 Hz), 1.38 (6H, m) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2=[CH:8][NH:9][CH:10]=[C:4]2[C:3]1=[O:11].CN([CH:15]=[O:16])C.O=P(Cl)(Cl)Cl>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2=[C:8]([CH:15]=[O:16])[NH:9][CH:10]=[C:4]2[C:3]1=[O:11]
Reactant: CN1CCc2c[nH]cc2C1=O
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCc2c(c[nH]c2C=O)C1=O
Yield: 33 %

Procedure:
5-Methyl-2,5,6,7-tetrahydro-pyrrolo[3,4-c]pyridin-4-one was formylated under standard Vilsmeier conditions using DMF (3 equiv.) and POCl3 (1.1 equiv.) to give 250 mg (33%) of 5-methyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-])=[O:4].[C:8]([O:11][C@@:12]1([CH2:44][CH3:45])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:43])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:38])([CH3:37])[CH2:33][CH2:34][CH2:35][NH3+:36])=[C:23]2[CH:39]=[CH:40][CH:41]=[CH:42][C:22]2=[N:21][C:20]3=1)(=[O:10])[CH3:9].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N1C=CC=CC=1>ClCCl>[CH3:38][Si:32]([CH3:37])([CH2:33][CH2:34][CH2:35][NH:36][C:3](=[O:4])[C:2]([F:7])([F:6])[F:1])[CH2:31][CH2:30][C:24]1[C:25]2[CH2:26][N:27]3[C:19](=[CH:18][C:17]4[C@@:12]([O:11][C:8](=[O:10])[CH3:9])([CH2:44][CH3:45])[C:13](=[O:43])[O:14][CH2:15][C:16]=4[C:28]3=[O:29])[C:20]=2[N:21]=[C:22]2[CH:42]=[CH:41][CH:40]=[CH:39][C:23]=12
Reactant: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCC[NH3+]
Reactant: O=C([O-])C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of Compound 21 (150 mg) in dichloromethane (2 mL) at 0° C., trifluoromethanesulfonic anhydride (80 μL) and pyridine were added and stirred at room temperature for 2 hours. Solvents were dried under vacuum and the crude residue was finally shaken between chloroform (2×10 mL) and 1 N HCl (5 mL). The collective organic layer was dried, evaporated and purified on a silica gel column using 2% ethanol in dichloromethane to obtain 96% of the required product (140 mg).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]([CH3:25])([CH3:24])[CH:9](OS(C)(=O)=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N+:12]=2[O-:18])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+]>C(O)(C)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]([CH3:24])([CH3:25])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N+:12]=2[O-:18])=[CH:26][CH:27]=1)#[N:2]
Reactant: Cc1cccc(CC(OS(C)(=O)=O)C(C)(C)Oc2ccc(C#N)cc2)[n+]1[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1cccc(C=CC(C)(C)Oc2ccc(C#N)cc2)[n+]1[O-]
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
1.7 g of 2-[3-(4-cyanophenoxy)-2-methanesulphonyloxy-3-methylbutyl]-6-methylpyridine N-oxide were added to a solution of 200 mg of 80% sodium hydride in 25 ml of isopropanol and the mixture was stirred for 30 minutes. The solvent was removed by evaporation and the residue was partitioned between water and dichloromethane. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 10% (v/v) methanol/ethyl acetate for the elution. There were obtained 960 mg of 2-[3-(4-cyanophenoxy)-3-methyl-1butenyl]-6-methylpyridine N-oxide as a colourless gum.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[NH:39]1[CH2:43][CH2:42][C@H:41]([OH:44])[CH2:40]1.CS(C)(=O)=O>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([N:39]3[CH2:43][CH2:42][C@@H:41]([OH:44])[CH2:40]3)[N:13]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: O[C@H]1CCNC1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(N3CC[C@@H](O)C3)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, (S)-pyrrolidin-3-ol was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give (R)-1-[4-((S)-1-methanesulfonyl-piperidin-3-ylamino)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-2-yl]-pyrrolidin-3-ol. MS: (ES+): 459