Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@@:12]3([C:20]#[CH:21])[F:19])[C:4]=2[N:5]=[CH:6][N:7]=1.ClC1N=CN=C2C=1[N:25]=CN2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C#C)F>>[NH2:25][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@@:12]3([C:20]#[CH:21])[F:19])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C#C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)ncnc21
Reactant: C#C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(Cl)ncnc21
Product: C#C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21

Procedure:
7l was synthesized from 6g as described for 6a. White lyophilised powder. Molecular Formula C13H13FN4O3. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 3.61 (d, J=5.52 Hz, 1H), 3.63-3.67 (m, 1H), 3.80-3.83 (d, J=12.14 Hz, 1H), 3.86-3.88 (d, J=9.38 Hz, 1H), 4.46-4.54 (dd, J=23.23 Hz and J=9.39 Hz, 1H), 5.30 (brs, 1H), 6.1 (brs, 1H), 6.41-6.47 (d, J=16.47 Hz, 1H), 6.57-6.61 (d, J=16.47 Hz, 1H), 7.04 (s, 2H), 7.37-7.38 (d, J=3.65 Hz, 1H), 8.05 (s, 1H) 19F NMR (DMSO-d6, 235 MHz) δ (ppm) −157.15 (s, 1F) Scan ES+ 293 (M+H)+, UV λmax 275 nm
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:13]N.O.NN.C(O)CO>O>[CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][NH2:13])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1cccc2sc(N)nc12
Agent: Cl
Solvent: OCCO
Solvent: O
Product: Cc1cccc2sc(NN)nc12
Temperature: 140 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
4-Methyl-2-aminobenzothiazole (8.21 g.; 0.05 mole), hydrazine monohydrochloride (1.14 g.; 0.017 mole), 85% hydrazine hydrate (1.96 g.; 0.033 mole), and 41 ml. of ethylene glycol were mixed, and the mixture heated under N2 atmosphere to 140°C. These reaction conditions were continued for 15 hours; the reaction mixture was then permitted to cool slowly to romm temperature and, for convenience only, stored overnight under N2 atmosphere. Water (45 ml.) was added to the reaction mixture in the morning to force crystallization. The reaction mixture was then filtered to separate the desired 4-methyl-2-hydrazinobenzothiazole compound. It was dried in vacuo overnight at 60°C. The yield was 8.00 g., 89% yield, m.p. 143°-51°C. Non-aqueous titration showed the product to be 85.8% pure.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[NH:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:20]1.Cl>CC(C)=O>[C:9]1([CH2:8][N:19]2[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:20]2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: ClCc1cccc2ccccc12
Reactant: CCOC(=O)c1c[nH]cc1C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cn(Cc2cccc3ccccc23)cc1C(=O)OCC
Temperature: 25 °C
Reaction time: 96 h
Yield: 91.6 %

Procedure:
Potassium carbonate (5 g) followed by 1-(chloromethyl)naphthalene (4.60 g) were added to a solution of diethyl 3,4-pyrroledicarboxylate (5.00 g) in acetone (50 ml). The mixture was stirred at room temperature for 4 days, dilute hydrochloric acid (100 ml) was added and the mixture was extracted with ether (2×100 ml). The organic extracts were dried, filtered and evaporated to give the sub-title compound as a solid (7.62 g).
Reaction SMILES: C([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.I[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[BrH:38].C(O)(=O)C>C(OCC)C>[BrH:38].[CH2:25]([C:22]1[CH:23]=[N:24][C:19]([N:18]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:27])[S:12][CH:13]=2)=[N:20][CH:21]=1)[CH3:26]
Reactant: CCCCCCCCCI
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(CC)cn1

Procedure:
A compound obtained using 2-[(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 265-1 and 1-iodononane as starting materials and by an operation similar to that of Example 326 was dissolved in diethyl ether, and reacted with 30% hydrobromic acid-acetic acid to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][C:20]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[C:21]([C:22](O)=[O:23])[C:16]=4[N:15]=[C:14]3[C:31](=[O:42])[NH:32][CH:33]3[CH2:38][CH2:37][N:36]([CH:39]([CH3:41])[CH3:40])[CH2:35][CH2:34]3)[CH:8]=2)=[CH:4][CH:3]=1.[NH:43]1[CH2:46][CH:45]([OH:47])[CH2:44]1>>[CH:39]([N:36]1[CH2:37][CH2:38][CH:33]([NH:32][C:31]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:17]3[CH:18]=[CH:19][C:20]([O:25][CH2:26][C:27]([F:30])([F:28])[F:29])=[C:21]([C:22]([N:43]4[CH2:46][CH:45]([OH:47])[CH2:44]4)=[O:23])[C:16]=3[N:15]=2)=[O:42])[CH2:34][CH2:35]1)([CH3:41])[CH3:40]
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)c(OCC(F)(F)F)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Reactant: OC1CNC1
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)N4CC(O)C4)c(OCC(F)(F)F)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1

Procedure:
1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-4-(3-hydroxy-azetidine-1-carbonyl)-5-(2,2,2-trifluoro-ethoxy)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 50.0 mg (0.08 mmol) 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-5-(2,2,2-trifluoro-ethoxy)-1H-benzoimidazole-4-carboxylic acid and 8.7 mg (0.12 mmol) azetidin-3-ol. The title compound was obtained as its formiate in form of a white amorphous solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[S:13][C:14]([C:16]([N:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[CH3:19])=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:27]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:18]([CH3:19])[C:16]([C:14]1[S:13][C:12]2[C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[CH:27][C:7]=3[O:8][CH2:9][CH2:10][C:11]=2[CH:15]=1)=[O:17]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(CBr)cc1OCC2)c1ccccc1Cl
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2ccc3c(c2)OCCc2cc(C(=O)N(C)c4ccccc4Cl)sc2-3)CC1

Procedure:
8-(Bromomethyl)-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide was reacted with N-methylpiperazine using the procedure of Example 153 for 243 to give 241. MS: (ESI+) 482.0
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH:24]([NH:27][CH2:28][CH2:29][CH2:30][NH2:31])([CH3:26])[CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:31][CH2:30][CH2:29][CH2:28][NH:27][CH:24]([CH3:26])[CH3:25])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: CC(C)NCCCN
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)NCCCNCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4.7 %

Procedure:
A mixture of 2-chloro-5-formyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.244 g, Example 25b), N-isopropyl-1,3-propanediamine (0.211 g), p-toluenesulfonic acid (0.005 g) and toluene (30 ml) were refluxed together under Dean-Stark conditions for 3 h. The mixture was cooled and concentrated under reduced pressure to an oil. This was dissolved in ethanol (30 ml) and cooled to 0° C. under a nitrogen atmosphere. Solid sodium borohydride (0.040 g) was added portionwise and the mixture stirred at room temperature for 30 min, then concentrated under reduced pressure and the residue purified by column chromatography over silica (eluting with 9:1:0.1 dichloromethane/methanol/35% aqueous ammonia) to give the title compound (0.015 g) and a by-product (see Example 27).
Reaction SMILES: O.[OH-].[Li+].[NH2:4][C:5]1[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][C:8]([CH2:9][C@@H:10]([CH2:15][C:16](=[O:35])[N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:29][CH2:28][C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[NH:25][C:24]3=[O:34])[CH2:19][CH2:18]2)[C:11]([O:13]C)=[O:12])=[CH:7][C:6]=1[C:42]([F:45])([F:44])[F:43].Cl>O.C1COCC1>[NH2:4][C:5]1[C:6]([C:42]([F:43])([F:44])[F:45])=[CH:7][C:8]([CH2:9][C@@H:10]([CH2:15][C:16](=[O:35])[N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:29][CH2:28][C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[NH:25][C:24]3=[O:34])[CH2:19][CH2:18]2)[C:11]([OH:13])=[O:12])=[CH:36][C:37]=1[C:38]([F:41])([F:40])[F:39]
Reactant: COC(=O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(C(F)(F)F)c(N)c(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(C(F)(F)F)cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 0.72 g (16.75 mmol) lithium hydroxide hydrate in 30 mL water was added to a solution of 6.7 g (11.16 mmol) methyl (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoate in 50 mL THF at RT and the reaction mixture was stirred for 5 h at RT. The THF was eliminated i. vac., the aqueous solution cooled to 10° C. and adjusted to pH 1 with conc. HCl, during which time the product was precipitated. This was suction filtered and dried at 65° C. The dried substance was combined with 300 mL diisopropylether, stirred overnight, suction filtered, washed with diisopropylether and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[Cl:22][C:23]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][C:23]=3[Cl:22])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2OC(=O)c2ccc([N+](=O)[O-])cc2Cl)cc1
Temperature: 0 °C
Yield: 99.3 %

Procedure:
3.01 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are dissolved in 50 ml of pyridine, and 2.31 g of 2-chloro-4-nitrobenzoyl chloride are added thereto under ice-cooling and stirring. The mixture is stirred at room temperature overnight. The mixture is poured into ice-water and then extracted with ethyl acetate. The extract is washed with 10% hydrochloric acid and water, dried and then evaporated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, chloroform:methanol=100:1). 4.81 g of (-)-cis-2-(4-methoxyphenyl)-3-(2-chloro-4-nitrobenzoyloxy)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as a pale yellow powder. Yield: 99%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([CH2:13][OH:14])[CH2:11][OH:12])=[CH:4][CH:3]=1.[C:15](OC)(=[O:17])[CH3:16]>>[C:15]([O:14][CH2:13][C@@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)(=[O:17])[CH3:16]
Reactant: OCC(CO)CCc1ccc(Br)cc1
Reactant: COC(C)=O
Product: CC(=O)OC[C@@H](CO)CCc1ccc(Br)cc1

Procedure:
To a solution of 4.6 g of 4-(4-bromophenyl)-2-(hydroxymethyl)butanol in 300 ml of methyl acetate was added 33.1 g of the above PPL preparation. The mixture was stirred while the progress of the reaction was monitored by HPLC method A. When the consumption of diol was complete, the mixture was immediately filtered and the filtrate was concentrated to an oil under vacuum. The oil was purified by flash chromatography on 200 g of silica with 3:1 ethyl acetate: hexane to obtain 4.82 g of the desired product as an oil. The 1-naphthyl carbamate derivative of a small portion of the product was prepared and analyzed by HPLC method B to determine that the product was 99% R and 1% S; the R isomer eluted at 9.4 minutes, and the S isomer at 12.6 minutes.
Reaction SMILES: [NH2:1][CH:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([O-:13])=[O:12])=[C:6]([CH2:9]I)[CH2:7][S:8][C@H:3]12.[CH:16]1[C:17]2[N:18]([CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:20][N:21]=1.O>C(#N)C>[NH2:1][CH:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([O-:13])=[O:12])=[C:6]([CH2:9][N+:21]3[CH:20]=[CH:19][N:18]4[CH:22]=[CH:23][CH:24]=[C:17]4[CH:16]=3)[CH2:7][S:8][C@H:3]12
Reactant: c1cc2cnccn2c1
Reactant: NC1C(=O)N2C(C(=O)[O-])=C(CI)CS[C@H]12
Solvent: O
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccn4cccc4c3)CS[C@H]12
Temperature: 0 °C
Yield: 93 %

Procedure:
2.5 g of 7-amino-3-iodomethyl-3-cephem-4-carboxylate was suspended in 30 ml of acetonitrile; and 2 ml bistrimethyl-silylacetamide was added thereto. To the mixture was added 2 g of pyrrolo[1,2-a]pyrazine prepared in Preparation Example 1. The reaction mixture was reacted at 10° C. for 1 hour and then cooled to 0° C. To this solution was added 0.6 ml of water; and the resulting mixture was filtered and then washed with 30 ml of cold acetonitrile to obtain 2.4 g of light yellow title compound (yield: 93%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].[BH4-].[Na+]>CO.C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][OH:15]
Reactant: O=Cc1ccccc1Sc1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccccc1Sc1ccc2ccccc2c1
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To 2-(2-naphthylthio)benzaldehyde (7.24 g; 27.4 mmol from Example 6, step 1) in 70 mL of methanol and 30 mL of THF at 0° C. was added NaBH4 (54.8 mml) portionwise. After 1 h at 0° C., the solution was brought to r.t. and quenched with water. After dilution with EtOAc, the solution was washed with water and brine. The organic phase was dry over Na2SO4, filtered and the crude purified by silica gel chromatography to yield 6.71 g of the title compound.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]=[CH:15][C:16]#[N:17])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.S(=O)(=O)(O)O.[N+:23]([O-])([OH:25])=[O:24]>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]=[CH:15][C:16]#[N:17])(=[O:13])=[O:12])=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)C=CC#N)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: N#CC=CS(=O)(=O)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
3-(4-acetamidobenzenesulfonyl)acrylonitrile, prepared as described in the aforesaid U.S. Pat. No. 3,541,119, is nitrated at about room temperature in a mixture of nitric acid and concentrated sulfuric acid for about two hours, and thereafter drowned in ice water. The 2-cyanovinyl 4-acetamido-3-nitrophenyl sulfone recovered is hydrolyzed in a mixture of dilute hydrochloric acid and ethanol to give 2-cyanovinyl 4-amino-3-nitrophenyl sulfone. 25.3 g (0.1 mol) of this material is carefully dried and is dispersed in 500 ml chloroform and 11.2 g 1,4-diaza-[2.2.2]octane is added thereto. A chloroform solution of difluoromethanesulfonyl chloride in about 10% excess is added to the stirred mixture of the substituted aminoarene and the acid acceptor at 50° C. The mixture is stirred at this temperature for 2 hours and is then maintained at room temperature for 2 days. After treatment with dilute HCl to remove the tertiary amine and unreacted starting material, and evaporation of the solvent, a crude material is obtained which is purified by recrystallization, giving 2-cyanovinyl 4-difluoroacetamido-3-nitrophenyl sulfone: ##SPC7##
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][N:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CC(O)C.O.[OH-].[Na+]>[C:12]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)Cc1ccc(-c2ccccc2)nc1
Temperature: 67.5 °C

Procedure:
2-chloropyridine-5-acetic acid (0.2 gm, 1.21 mmole), phenylboronic acid (0.16 gm, 1.3 mmole) and 50% water wet 10% Palladium carbon (0.08 gm, 0.036 mmole Pd) were added to 10 ml of 5:1 water isopropanol mixture, then Na2CO3 (0.15 gm, 1.4 mmole) dissolved in 3 ml of water was added to the above mixture, the reaction was heated at 65-70° C. overnight, the reaction was cooled to room temperature, diluted with 20 ml of 70:15:1 i-PrOH/H2O/10% NaOH, filtered, the catalyst was washed with 20 ml×3 using the above mixture, the filtrate was dried under vacuum and crude mixture was used without any purification in the next step.
Reaction SMILES: C(O[C@@H:5]1[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[Cl:38]CCl>[Ti](Cl)(Cl)(Cl)Cl>[C:8]([O:7][C@@H:6]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][CH:5]1[Cl:38])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Product: O=C(OC[C@H]1OC(Cl)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (3.02 g, 5.98 mmol) in dry dichloromethane (100 ml) was added via cannula a dichloromethane solution of titanium tetrachloride (1.13 g, 5.98 mmol, 5.98 ml of a 1M solution). The solution was stirred at room temperature for 1. 5 hours under argon, then washed with water (3×100 ml), dried over anhydrous magnesium sulfate and evaporated in vacuo to give the title compounds as a colourless oil (2.9 g, 1 00%). 1H nmr indicated it to be an approximately 1:1 mixture of α:β-anomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:21])[CH2:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.[CH2:22]1N2CN3CN(C2)CN1C3.C(OC(=O)C)(=O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:8](=[O:21])[CH:9]([CH2:10][C:11]13[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]1)[CH2:18]3)[CH2:22]2
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(CCC12CC3CC(CC(C3)C1)C2)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1c2c(Cl)cccc2CC1CC12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Reaction time: 4 h
Yield: 70.9 %

Procedure:
78.7 g (260 mmole) 1-(2-Chloro-phenyl)-3-(1-adamantyl)-propan-1-one, 77.5 g (2.1 eq.) urotropine and 72.6 g (2.7 eq.) of acetic anhydride were placed in a 500 ml roundbottom flask and the mixture was stirred at 80° C. for 4 h. Then 100 ml water and 100 ml 2M NaOH were added and the mixture was extracted two times with 200 ml dichloromethane each. The organic layer was washed two times with 100 ml saturated aqueous ammonium chloride and dried over magnesium sulphate. The solvent amount was reduced in vacuo to a total of 150 ml volume and the solution was added dropwise over a period of 2.5 h to 660 g of hot (70-75° C.) concentrated sulphuric acid. After stirring for an additional 30 min at 75° C. the mixture was allowed to stand overnight at room temperature. The mixture was given to approx. 500 g of ice and extracted three times with 150 ml dichloromethane each. The organic layer was washed twice with 150 ml of a saturated sodium bicarbonate solution and once with 100 ml of a saturated sodium chloride solution. After drying over magnesium sulphate the solvent was removed in vacuo. The product was purified by column chromatography on silica (heptane/dichloromethane 5:1) to yield 58 g (71%) of the desired product as a slightly off-white glassy solid. 1H-NMR (400 MHz, CDCl3): δ=7.39 (t, 1H, aromatic), 7.27 (d, 1H, aromatic), 7.21 (d, 1H, aromatic), 3.37 (dd, 1H, COCH), 2.70 (m, 2H, benzylic), 1.36-1.18 (m, 17H, aliphatic) ppm.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[N:2]([C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])=[C:18]=[O:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)N=C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the methyl 2-amino-2-methylpropanoate hydrochloride(65.5 g) in THF (650 mL) was treated with triethylamine (60 mL), heated to reflux, stirred for 30 minutes, cooled to room temperature, treated dropwise with a solution of triphosgene (43.2 g) in THF (250 mL) over 5 minutes, heated to reflux, stirred for 4 hours, cooled to 15° C., treated with triethylamine (120 mL) over 7 minutes, heated to reflux, stirred for 40 minutes, cooled to room temperature, and filtered. The solid was washed with THF and the filtrate was collected to provide a solution of methyl 2-isocyanato-2-methylpropanoate in THF.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[CH:18][C:17]2=[O:30])[C:8]([NH:10][C:11]2SC=C[N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.NC1[CH:36]=[CH:35][N:34]([CH2:37][C:38]([CH3:41])([OH:40])[CH3:39])N=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1([CH2:6][C@H:7]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[CH:18][C:17]2=[O:30])[C:8]([NH:10][C:11]2[CH:36]=[CH:35][N:34]([CH2:37][C:38]([OH:40])([CH3:41])[CH3:39])[N:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: COc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2nccs2)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.6 %

Procedure:
A solution of (S)-3-cyclopentyl-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (prepared as in Example 26, 150 mg, 0.43 mmol) in dichloromethane (10 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 75 mg, 0.48 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (230 mg, 0.52 mmol) and N,N-diisopropylethylamine (170 mg, 1.30 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (47 mg, 22%) as a white solid: LR-ES-MS m/z calculated for C26H34N4O5 [M]+ 482, observed [M+H]+ 483; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00-1.94 (m, 11H) 1.04 (br. s., 3H) 1.06 (br. s., 3H) 3.81 (s, 3H) 3.89 (s, 2H) 4.13 (d, J=18.4 Hz, 1H) 4.52 (d, J=18.4 Hz, 1H) 4.68 (s, 1H) 4.70 (s, 1H) 4.81 (dd, J=10.4, 4.7 Hz, 1H) 6.44 (d, J=2.2 Hz, 1H) 6.95-7.05 (m, 1H) 7.18-7.24 (m, 1H) 7.25-7.36 (m, 2H) 7.53 (d, J=2.2 Hz, 1H) 10.79 (s, 1H).