Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.S1C=CN=C1C(O)(C#C)C.[CH3:36][C:37]1[O:41][N:40]=[C:39]([C:42]([OH:46])([C:44]#[CH:45])[CH3:43])[CH:38]=1>>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:45]#[C:44][C:42]([C:39]4[CH:38]=[C:37]([CH3:36])[O:41][N:40]=4)([OH:46])[CH3:43])[CH:10]=3)[C:6]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: C#CC(C)(O)c1cc(C)on1
Reactant: Nc1nccc(-n2nc(C(=O)N3CCOCC3)c3ccc(Br)cc32)n1
Agent: C#CC(C)(O)c1nccs1
Product: Cc1cc(C(C)(O)C#Cc2ccc3c(C(=O)N4CCOCC4)nn(-c4ccnc(N)n4)c3c2)no1

Procedure:
The title compound was prepared by procedure described in Example 61-c, by substituting 1-(2-aminopyrimidin-4-yl)-6-bromo-N,N-dimethylindazole-3-carboxamide with 4-{6-bromo-3-[(morpholin-4-yl)carbonyl]indazol-1-yl}pyrimidin-2-amine and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol with 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol in Step 3: 1H NMR (500 MHz, DMSO) delta 1.86 (3H, s), 2.42 (3H, s), 3.63-3.70 (2H, m), 3.70-3.80 (4H, m), 3.89-3.97 (2H, m), 6.41 (1H, s), 6.58 (1H, s), 7.08 (1H, d, J=5.36 Hz), 7.16 (2H, br. s.), 7.44 (1H, dd, J=8.35, 1.26 Hz), 8.02 (1H, d, J=8.35 Hz), 8.35 (1H, d, J=5.36 Hz), 8.94 (1H, s); LC-MS: m/z=+474.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:20]2[CH:24]=[C:23]([NH2:25])[N:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]([NH:40][C@H:41]([C:43](O)=[O:44])[CH3:42])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].O=P(Cl)(Cl)Cl.Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:20]2[CH:24]=[C:23]([NH:25][C:43](=[O:44])[CH:41]([NH:40][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH3:42])[N:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:21]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)(c2cc(N)n(C(C)(C)C)n2)CC1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(NC(=O)OCc1ccccc1)C(=O)Nc1cc(C2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)nn1C(C)(C)C
Reaction time: 0.42 h

Procedure:
A solution of 0.68 g (1.7 mmol) of 4-(5-amino-1-tert-butyl-1H-pyrazol-3-yl)-4-phenylpiperidine-1-carboxylic acid tert-butyl ester and 0.39 g (1.7 mmol) of carbobenzyloxy-L-alanine in 9.0 mL of dry pyridine was stirred at −10° C. as 0.18 mL (1.9 mmol) of POCl3 was added. After 25 min, the reaction mixture was poured into 1M HCl and extracted with EtOAc. The organic layer washed with sat. aq. NaHCO3, dried over MgSO4 and concentrated. Purification on silica gel using 50:50 EtOAc-hexanes as eluant afforded 4-[5-(2-benzyloxycarbonylamino-propionylamino)-1-tert-butyl-1H-pyrazol-3-yl]-4-phenylpiperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][CH3:11])(=[O:9])[CH2:7][CH3:8].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:8]#[C:7][C:6]([O:10][CH3:11])=[O:9])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCC(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C#CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.57N hexane solution, 6.4 ml) was added dropwise to a solution of methyl propionate (893 μl) in tetrahydrofuran (50 ml) at −78° C. After stirring for 30 minutes, a solution of 1-(tert-butoxycarbonyl)-4-piperidone (2.0 g) in tetrahydrofuran (10 ml) was added, and the mixture was gradually warmed to room temperature and stirred overnight. A saturated aqueous solution (50 ml) of ammonium chloride and ethyl acetate (50 ml) were added to the reaction mixture to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the title compound (1.78 g) as a pale yellow caramel-like substance.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:21].Cl[C:23]1[CH:28]=[CH:27][C:26](CCl)=[CH:25][N:24]=1.[CH3:31]N(C)C=O>>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[CH:7]=[CH:6][C:5]=1[O:21][CH2:31][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CN(C)C=O
Reactant: ClCc1ccc(Cl)nc1
Reactant: Oc1ccc(Oc2cccc(C(F)(F)F)c2)cc1Cl
Agent: [H-]
Agent: [Na+]
Product: FC(F)(F)c1cccc(Oc2ccc(OCc3ccccn3)c(Cl)c2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution 0.07 g of sodium hydride (60% oil dispersion) in 10 ml of N,N-dimethylformamide, there was added dropwise a solution of 0.50 g of 2-chloro-4-(3-trifluoromethylphenoxy)phenol in 3 ml of N,N-dimethylformamide with stirring and ice-cooling. After 30 minutes, a solution of 0.28 g of 2-chloro-5-chloromethylpyridine in 5 ml of N,N-dimethylformamide was added thereto at room temperature, followed by stirring at the same temperature for 10 hours. The reaction mixture was poured into ice-water and extracted twice with 100 ml of ethyl acetate. The extracts were combined together, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 2-chloro-5[[2-chloro-4-(3-trifluoromethylphenoxy)phenoxy]methylpyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[C:4]([CH3:11])[N:3]=1.[N-:12]=[C:13]=[S:14].[NH4+].[F:16][C:17]1[CH:18]=[C:19]([NH2:25])[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:12][C:13]([NH:25][C:19]2[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=[C:17]([F:16])[CH:18]=2)=[S:14])=[O:9])[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: COc1cc(N)cc(F)c1
Reactant: Cc1cc(C(=O)Cl)cc(Cl)n1
Reactant: [N-]=C=S
Agent: [NH4+]
Solvent: CC(C)=O
Product: COc1cc(F)cc(NC(=S)NC(=O)c2cc(C)nc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-6-methyl-4-pyridinecarbonyl chloride (44.087 g, 0.232 mol) in acetone (1 l) was treated with ammonium isothiocyanate (21.192 g, 0.278 mol) and the mixture was stirred for 1 hour at room temperature. Subsequently, a solution of 3-fluoro-5-methoxybenzenamine (36.02 g, 0.255 mol) in acetone (200 ml) was added dropwise and the reaction mixture was stirred for 4 hours at room temperature. The solvent was evaporated in vacuo and the residue was dissolved in CH2Cl2 (1 l). This organic solution was washed (H2O), dried (MgSO4), filtered and the solvent was evaporated in vacuo to yield a brown solid. The brown solid was triturated in acetonitrile (0.8 l), stirred overnight and the solid was filtered off and dried (vacuum oven, 4 hours at 65° C.). Yield: 59.69 g of intermediate D13 (73%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.C([O-])(=[O:24])C.[NH4+].C[CH2:28][O:29][C:30]([CH3:32])=[O:31]>C(Cl)Cl.C[N+]([O-])=O>[CH3:28][O:29][C:30](=[O:31])[C:32]([C:9]1[C:8]2[C:12](=[C:13]([C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)[N:14]=[CH:15][C:7]=2[O:6][CH3:5])[NH:11][CH:10]=1)=[O:24]
Reactant: COc1cnc(-c2cnccn2)c2[nH]ccc12
Reactant: CC(=O)[O-]
Reactant: CCOC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: COC(=O)C(=O)c1c[nH]c2c(-c3cnccn3)ncc(OC)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
To a mixture of AlCl3 (3.09 g, 23.2 mmol) in 20 mL of CH2Cl2-MeNO2 (4:1) was added 4-methoxy-7-pyrazinyl-6-azaindole (0.525 g, 2.32 mmol) as a solid. To the resulting burgundy solution was added methyl oxalyl chloride (0.853 mL, 9.28 mmol) dropwise and then the mixture was stirred at room temperature for 1.5 h. The reaction mixture was then carefully poured into cold 20% aqueous ammonium acetate and EtOAc was added. The resulting emulsion was filtered and the residue was washed with additional EtOAc. The organic phase was separated and the aqueous phase was again extracted with EtOAc. The combined organic phase was dried (MgSO4) and evaporated to give 4-methoxy-7-pyrazinyl-6-azaindol-3-yl-oxoacetic acid methyl ester (0.494 g, 68%) as a brownish solid: LCMS m/e 313 (M+H)+. This material (0.456 g, 1.46 mmol) was taken up in 20 mL of MeOH, 1M K2CO3 (5.84 mL, 5.84 mmol) was added and the mixture was stirred at room temperature for 30 min. The solution was then diluted with water (4 mL) and concentrated in vacuo. The resulting aqueous solution was cooled at 0° C. and acidified to pH 1-2 with 6N HCl. This gave a bright yellow precipitate which was filtered, washed with cold 0.1N HCl and ether and dried in vacuo to give the title compound (0.309 g, 71%) as a yellow solid:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[CH:11](O)=O>>[NH:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=[CH:11]1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: O=CO
Product: N#Cc1ccc2[nH]cnc2c1
Yield: 98 %

Procedure:
A solution of 3,4-diaminobenzonitrile (1 g; 7.51 mmol) in formic acid (40 mL) was heated at reflux for 3 hours then concentrated in vacuo to give a brown oily residue. It was extracted with EtOAc from a saturated aqueous solution of NaHCO3, dried over MgSO4 and evaporated under vacuum to give the title compound as a light pink solid (1.05 g, 98%). 1H NMR (DMSO-d6): δ 12.97 (br s, 1H), 8.48 (s, 1H), 8.16 (d, J=0.8 Hz, 1H), 7.76 (d, J=8.3 Hz, 1H), 7.59 (dd, J=8.3, 1.5 Hz, 1H). LC/MS (Method B): 144.1 (M+H)+.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][C:5]1([CH3:33])[C@H:7](/[CH:8]=[C:9](/[F:13])\[C:10](=[O:12])[OH:11])[C@H:6]1[C:14]([O:16][C@H:17]([C:31]#[N:32])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:15]>C(Cl)Cl.C(O)(=O)C>[CH3:4][C:5]1([CH3:33])[C@H:7](/[CH:8]=[C:9](/[F:13])\[C:10](=[O:11])[O:12][CH3:3])[C@H:6]1[C:14]([O:16][C@H:17]([C:31]#[N:32])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:15]
Reactant: CC1(C)[C@H](/C=C(/F)C(=O)O)[C@H]1C(=O)O[C@H](C#N)c1cccc(Oc2ccccc2)c1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)/C(F)=C\[C@@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A slight excess of diazomethane in methylene chloride solution was added at 5° to 10° C. to a solution of 860 mg of the product of Step A in 2 ml of methylene chloride and the mixture was stirred at 5° C. for 15 minutes and at room temperature for 30 minutes. A few drops of acetic acid were added to the mixture which was then evaporated to dryness to obtain 950 mg of an oil residue. The latter was chromatographed over silica gel and was eluted with an 85-15 hexane-ethyl acetate mixture to obtain 700 mg of (S)α-cyano-3-phenoxy-benzyl (1R, trans) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =-31°±2.5° (c=0.25% in chloroform).
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[CH:31][NH:32]2.[OH2:37]>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][C:31](=[O:37])[NH:32]2
Reactant: O
Reactant: c1ccc(-c2cccc3[nH]ccc23)nc1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2ccccn2)N1
Reaction time: 1 h
Yield: 92 %

Procedure:
Pyridinium tribromide (90% (Aldrich), 15.4 g, 43.2 mmol) was added portion-wise over 10 minutes to a suspension of 4-pyridin-2-yl-1H-indole (2.8 g, 14.4 mmol) in 2-methyl-2-propanol (84 mL), ethanol (56 mL) and acetic acid (28 mL). The mixture was stirred at room temperature for 2 hours after which acetic acid (100 mL) was added. Stirring was continued for one hour and then water (0.5 mL) and zinc dust (9.4 g, 144 mmol) were added. Stirring was continued for another hour. Residual zinc dust was filtered and washed with methanol. The filtrate was concentrated and the syrupy residue was stirred in water(300 mL) overnight. The solid that formed was filtered, washed with water to remove zinc and pyridine salts and dried under high vacuum to give 2.8 g (92%) of 4-pyridin-2-yl-1,3-dihydroindol-2-one was obtained.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12](=[O:18])OC(C)(C)C)=[CH:10][C:5]=2[N:4]([CH3:19])[CH:3]=1.ClC([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=O>Cl>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[O:18])=[CH:10][C:5]=2[N:4]([CH3:19])[CH:3]=1
Reactant: Cn1cc(Br)c2cnc(NC(=O)OC(C)(C)C)cc21
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: Cl
Product: COC(=O)c1ccc(C(=O)Nc2cc3c(cn2)c(Br)cn3C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
In a 125 ml round bottom flask, tert-butyl 3-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamate (3G, 0.6 g, 1.839 mmol) was dissolved in 4N HCl (15 ml) and the mixture was stirred at room temperature for 3 h. After completion, volatiles were evaporated and the mixture was re-dissolved in DMA (10 ml). To this was added methyl 4-(chlorocarbonyl)benzoate (0.44 g, 2.2 mmol) and the mixture was stirred at 50° C. for five hours. The reaction was poured into ice water. The precipitated product was collected and dried to obtain the product methyl 4-(3-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamoyl)benzoate (3 H, 0.6 g, 84%). Small amount of debrominated product was observed.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([NH2:14])[CH:7]=1)[CH3:2].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([N-]C(C)C)(C)C.[Li+].[N+:32]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1)([O-:34])=[O:33]>C1(C)C=CC=CC=1.O1CCCC1>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([N:14]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1)[CH2:39][C:38]1[CH:41]=[CH:42][C:35]([N+:32]([O-:34])=[O:33])=[CH:36][CH:37]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(N)c1
Reactant: O=Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)c1ccc(OC)c(N=Cc2ccccc2)c1
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
Thus obtained 3-amino-4-methoxyphenylacetic acid ethyl ester (6.06 g, 29 mmol) was dissolved in toluene (200 mL), added with benzaldehyde (2.94 mL, 29 mmol), and refluxed under heating at 130° C. for 14 hours. The reaction mixture was cooled to room temperature, evaporated under reduced pressure so as to remove the solvent, and the resultant residue was dissolved in tetrahydrofuran (200 mL), and added drop-wisely with a 2 mol/L lithium diisopropylamide solution (heptane/tetrahydrofuran/ethylbenzene solution, 15.9 mL, 32 mmol) while keeping the temperature thereof at −78° C. The mixture was heated to −20° C., stirred for 10 minutes, cooled again to −78° C., and at that temperature added drop-wisely with a tetrahydrofuran solution (80 mL) of 4-nitrobenzyl bromide (6.88 g, 32 mmol). The mixture was then heated to room temperature, and 2-[3-(benzylideneamino)-4-methoxy phenyl]-3-(4-nitrophenyl)propionic acid ethyl ester was produced in the reaction solution. Next as a series of processing, the reaction solution was then treated with a 1 mol/L hydrochloric acid (150 mL), the separated aqueous phase was added with an aqueous saturated sodium hydrogen carbonate solution so as to adjust pH of the solution as high as 7 or above, and extracted with ethyl acetate, which series was repeated three times. The ethyl acetate phase was dried over anhydrous sodium sulfate, evaporated under reduced pressure so as to remove the solvent, and the resultant residue was purified through silica gel column chromatography (hexane:ethyl acetate (v/v)=2:1) to thereby obtain 2-(3-amino-4-methoxyphenyl)-3-(4-nitrophenyl)propionic acid ethyl ester (yield: 5.63 g, yield ratio: 56%) as an orange syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:22][C:23]([C:25]1[S:26][C:27]([S:30](=[O:33])(=[O:32])[NH2:31])=[CH:28][CH:29]=1)=[NH:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:18]4[O:20][N:24]=[C:23]([C:25]5[S:26][C:27]([S:30]([NH2:31])(=[O:33])=[O:32])=[CH:28][CH:29]=5)[N:22]=4)=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Product: Cc1cc(-c2ccc(Cl)cc2)nc2c(-c3nc(-c4ccc(S(N)(=O)=O)s4)no3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.24) (144 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH)) and crystallization (MeOH/dichloromethane) as a light yellow solid (79 mg, 33%). MS (ISP) 473.3 [(M+H)+]; mp 253° C.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].N[C:6]1[C:7]([CH3:12])=N[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].[F:15][B-](F)(F)F.[H+]>>[CH3:12][C:7]1[C:6]([F:15])=[CH:11][CH:10]=[CH:9][N+:1]=1[O-:3]
Reactant: O=N[O-]
Reactant: Cc1ncccc1N
Reactant: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(F)ccc[n+]1[O-]
Reaction time: 2 h

Procedure:
Sodium nitrite (15.3 g) was added to a stirred solution of 3-amino-2-picoline (20 g) in 40% fluoroboric acid (215 ml) at -5° to -10°. The mixture was stirred for 2 hours at -10° followed by a further 2 hours at room temperature, after which time, the solution was basified (NaOH) and extracted with dichloromethane. The extracts were back-washed with water (pH 6 HCl) to remove some unreacted amine and, after drying (K2CO3), m-chloroperbenzoic acid (35.7 g) was added and the mixture allowed to stand for 16 hours. Ammonia gas was passed through the solution and the precipitated benzoate salts filtered off. The filtrate was evaporated to dryness to give 2-methyl-3-fluoropyridine-N-oxide (13.36 g) m.p. softens 55° melts 80°.
Reaction SMILES: [Cl:1][C:2]1([Cl:13])[CH2:4][C:3]1([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[CH3:5].CCC[C@@](O)([C@@H]1[C@@]2(OC)[C@@H:25]3[O:42]C4=C(OC(C)=O)C=CC5=C4[C@:26]43[CH2:27][CH2:28][N:29]([CH3:43])[CH:30](C5)[C@@:21]4(C=C2)C1)C.[ClH:47]>>[Cl:1][C:2]1([Cl:13])[CH2:4][C:3]1([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:25]([C:26]2[CH2:21][CH2:30][N:29]([C:43]3[C:6]([Cl:47])=[CH:7][CH:8]=[CH:9][N:12]=3)[CH2:28][CH:27]=2)=[O:42])=[CH:8][CH:7]=1)[CH3:5]
Reactant: CCC[C@@](C)(O)[C@H]1C[C@@]23C=C[C@]1(OC)[C@@H]1Oc4c(OC(C)=O)ccc5c4[C@@]12CCN(C)C3C5
Reactant: Cl
Reactant: CC1(c2ccc(N)cc2)CC1(Cl)Cl
Product: CC1(c2ccc(NC(=O)C3=CCN(c4ncccc4Cl)CC3)cc2)CC1(Cl)Cl

Procedure:
The title compound was prepared using the procedure described in Example 49D using 4-(2,2-dichloro-1-methyl-cyclopropyl)-phenylamine instead of 4-tert-butylaniline. MS (DCI+) m/z 436 (M+H)+ (70%), m/z 252 (M−183)+ (100%); 1H NMR (300 MHz, DMSO-D6) δ ppm 1.61 (s, 3 H), 1.74 (d, J=7.5 Hz, 1 H), 2.14 (d, J=7.8 Hz, 1 H), 2.56 (m, 2 H), 3.45 (t, J=5.4 Hz, 2 H), 4.01 (q, J=3.0 Hz, 2 H), 6.77 (m, 1 H), 7.00 (dd, J=7.6, 4.6 Hz, 1 H), 7.27 (m, 2 H), 7.67 (m, 2 H), 7.83 (dd, J=7.6, 1.5 Hz, 1 H), 8.22 (dd, J=4.7, 1.7 Hz, 1 H), 9.75 (s, 1 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][CH3:6].Cl[CH2:8][CH2:9][CH2:10][OH:11].[OH-].[Na+]>>[OH:11][CH2:10][CH2:9][CH2:8][N:5]([CH3:6])[CH2:4][CH2:3][CH2:2][OH:1]
Reactant: OCCCCl
Reactant: CNCCCO
Agent: [Na+]
Agent: [OH-]
Product: CN(CCCO)CCCO
Temperature: 25 °C

Procedure:
To this aqueous N-(3-hydroxypropyl)methylamine solution is added a second 249.5 g portion of 3-chloro-1-propanol, and the resulting mixture is heated under reflux at a temperature of approximately 105° C. for a period of about 5 hours, during which time about 195 grams of a 50% aqueous sodium hydroxide solution is added slowly at a rate sufficient to maintain the pH between about 8 and 9. The reaction mixture is cooled to room temperature, filtered, and the filtered aqueous solution is extracted with three 500 ml-portions of n-butanol. The butanol extracts are combined, evaporated to a small volume in vacuo, and the residual slurry is triturated with 300 ml of ethyl ether. The resulting ethereal slurry is filtered, thereby removing insoluble inorganic solid material, and the latter is washed with 100 ml of ethyl ether. The ether solution and washings are combined, the ether is evaporated therefrom in vacuo, and the residual oil is distilled in vacuo to give about 123 grams of N,N-bis(3-hydroxypropyl)methylamine; b.p. 110° C. at 150 microns pressure.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[S:9][C@@H:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:7]([C:17](=[O:30])[CH2:18][NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=2)=[O:21])[C@H:6]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])=[O:4].[OH-].[Na+].CO>O1CCCC1>[C:13]([O:12][C:10]([C@H:8]1[N:7]([C:17](=[O:30])[CH2:18][NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=2)=[O:21])[C@@H:6]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[C@H:5]([C:3]([OH:4])=[O:2])[S:9]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)[C@H]1S[C@@H](C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C)c2)[C@H]1c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NCC(=O)N2[C@H](C(=O)OC(C)(C)C)S[C@@H](C(=O)O)[C@@H]2c2ccccc2F)c1
Yield: 70.4 %

Procedure:
The process is performed in a similar manner to that described in Example 3, but starting with 0.35 g of tert-butyl (2S,4S,5S)-5-methoxycarbonyl-3-{2-[3-(3-methylphenyl)ureido]acetyl}-4-(2-fluorophenyl)-2-thiazolidinecarboxylate dissolved in 10 ml of tetrahydrofuran and 6.6 ml of aqueous 0.1N sodium hydroxide solution. 0.24 g of (2S,4S,5R)-2-tert-butoxycarbonyl-3-{2-[3-(3-methylphenyl)ureido]acetyl}-4-(2-fluorophenyl)-5-thiazolidinecarboxylic acid is thus obtained in the form of a white solid melting at 148° C., [α]D25 =-17°±1° (c=0.504; MeOH); 1H NMR (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 373 K, 5 in ppm): 1.51 (s, 9H: CH3 of the tert-butyl); 2.25 (s, 3H: ArCH3); 3.76 and 4.04 (broad d and d respectively, J=18 Hz, 1H each: COCH2N); 4.18 (d, J=3.5 Hz, 1H: H at C5 of the ring); 5.70 (s, 1H: H at C2 of the ring); 5.97 (d, J=3.5 Hz, 1H: H at C4 of the ring); 6.73 (broad d, J=7.5 Hz, 1H: aromatic H (H ortho to the CH3)); 7.06 (t, J=7.5 Hz, 1H: aromatic H (H meta to the CH3)); 7.10 to 7.50 (mt, 5H: aromatic H); 8.00 (mt, 1H: aromatic H at 6 (H meta to the F)).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([C:8]1[CH:13]=[CH:12][C:11](Cl)=[C:10](Cl)[CH:9]=1)[CH2:5][CH:6]=[O:7].COC(=O)CC1C=CC([F:27])=CC=1.COC(OC)CBr.Cl>>[CH3:1][O:2][C:3](=[O:16])[CH:4]([C:8]1[CH:13]=[CH:12][C:11]([F:27])=[CH:10][CH:9]=1)[CH2:5][CH:6]=[O:7]
Reactant: COC(=O)C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)Cc1ccc(F)cc1
Agent: COC(CBr)OC
Agent: Cl
Product: COC(=O)C(CC=O)c1ccc(F)cc1

Procedure:
In analogy to the procedure described for the synthesis of 2-(3,4-Dichloro-phenyl)-4-oxo-butyric acid methyl ester (example 2, step 1) the title compounds was prepared from 4-fluoro-phenyl-acetic acid methyl ester (commercially available), and bromoacetaldehyde dimethylacetal and subsequent treatment with HCl aq. MS (m/e): 209.3 (MH−).