Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9]([OH:11])=[O:10].Cl[C:16]1[C:25]2[C:20](=[C:21]([C:26]3[N:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH:38]([CH3:40])[CH3:39])=[C:33]([Cl:41])[CH:32]=4)[O:28][N:27]=3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1>C(Cl)Cl>[Cl:41][C:33]1[CH:32]=[C:31]([C:29]2[O:28][N:27]=[C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:20]=3[CH:19]=[CH:18][N:17]=[C:16]4[N:7]3[CH2:14][CH2:13][CH2:12][C@H:8]3[C:9]([OH:11])=[O:10])[N:30]=2)[CH:36]=[CH:35][C:34]=1[O:37][CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Cl)nccc34)no2)cc1Cl
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(N5CCC[C@H]5C(=O)O)nccc34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
A mixture of sodium hydride (60%; 9.99 mg, 0.250 mmol), dimethyl sulfoxide (DMSO) (2 ml) and proline (36.0 mg, 0.312 mmol) were stirred at room temp under nitrogen for 1 hour. 1-Chloro-5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline (D7; 50 mg, 0.125 mmol) was added and the reaction mixture was heated at 120° C. under nitrogen for 3 hr. The cooled reaction mixture was loaded onto an SCX column. The column was washed with methanol and then eluted using 2M methanolic ammonia. The appropriate fractions were combined and the solvent was removed in vacuo to give an orange oil which was dissolved in DCM and washed with water. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give the title compound as an orange solid (40 mg).
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([CH2:26][C:27]([O:29][CH3:30])=[O:28])#[N:25]>N1CCCCC1.CO>[C:18]1([CH2:17][N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[CH:10]=[CH:11][C:12]([CH:13]=[C:26]([C:24]#[N:25])[C:27]([O:29][CH3:30])=[O:28])=[CH:15][CH:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Reactant: COC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)C(C#N)=Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1

Procedure:
A mixture of 4-(bis(phenylmethyl)amino]benzaldehyde (60.2 g, 0.20 mol), methyl cyanoacetate (21.8 g, 0.22 mol), methanol (300 mL), and piperidine (10 drops) is heated at reflux for 1.5 hours. After cooling, the yellow product is collected by filtration, washed with methanol, and dried in air. The yellow colorant, methyl 3-[4-[bis(phenylmethyl)amino]phenyl]-2-cyano-propenoate, is obtained in a yield of 53.5 g (70.0% of theory).
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]([CH:17]=[O:18])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1)[C:23]#[N:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[C:23]([C:22]1[CH:25]=[C:26]([C:2]2[CH:16]=[C:15]([CH:17]=[O:18])[CH:14]=[CH:13][C:3]=2[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH:27]=[C:20]([F:19])[CH:21]=1)#[N:24]
Reactant: CC1(C)OB(c2cc(F)cc(C#N)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)COc1ccc(C=O)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc(C=O)cc1-c1cc(F)cc(C#N)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
To solution of tert-butyl 2-(2-bromo-4-formylphenoxy)acetate (1) (120 g, 0.38 mol) in dioxane/H2O (4:1, 700 mL) was added 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (20) (158 g in 60% purity, 0.38 mol), Na2CO3 (81 g, 0.76 mol) and Pd(PPh3)4 (22 g, 19 mmol) under N2. The mixture was stirred at 80° C. for 3 h. After cooling to room temperature, the mixture was concentrated in vacuo and purified by column chromatography (PE:EA=10:1 v/v) to give 90 g of t-butyl 2-(2-(3-cyano-5-fluorophenyl)-4-formylphenoxy)acetate (21) (90 g, 67%).
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[CH2:11]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([N:30](CC)CC)C>>[CH2:11]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:30])=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
A solution of 3R-carboxylate-6-nitro-2H-3,4-dihydro-[2-1b]imidazopyran (Example 21, 1 eq.), triethylamine (1 eq.), diphenylphosphoryl azide (1 eq.) in toluene is heated at 80° C. for 4 h, cooled and t-butanol is added. The reaction is warmed to 70° C. for an additional 1 h. Workup in the standard fashion gives the Boc amine. Deprotection of the Boc group (trifluoroacetic acid:dichloromethane, 1:1) and addition of 4-benzyloxybenzoyl chloride and triethylamine gives the 4-benzyloxybenzamide of 3R-amino-6-nitro-2H-3,4-dihydro-[2-1b]imidazopyran.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:22])[CH2:20][NH2:21])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]([CH3:22])[CH2:20][NH:21][C:23](=[O:25])[CH3:24])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CC(=O)Cl
Reactant: CCCOc1ccc(C#Cc2ccc(C(C)CN)cc2)cc1
Solvent: ClCCl
Product: CCCOc1ccc(C#Cc2ccc(C(C)CNC(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 0.12 g (0.41 mmol) 2-[4-(4-propoxy-phenylethynyl)-phenyl]-propylamine (I65) in 5.0 mL DCM are consecutively added 0.14 mL (1.02 mmol) TEA and 34.9 μL (0.49 mmol) acetyl chloride. The reaction mixture is stirred at r.t. for 3 h. The solvent is removed in vacuo and the residue is purified by HPLC (MeOH/H2O/NH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]([C:13]2[C:17]([CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[N:16][O:15][N:14]=2)SC)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:30][OH:31]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:13]2[C:17]([CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[N:16][O:15][N:14]=2)=[N:30][OH:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NO
Reactant: CSC(=Nc1ccc(F)c(Cl)c1)c1nonc1CO[Si](C(C)C)(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)[Si](OCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 75 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
Methyl N-(3-chloro-4-fluorophenyl)-4-[(triisopropylsilyl)oxy]methyl-1,2,5-oxadiazole-3-carbimidothioate (3.0 g, 6.5 mmol) was dissolved in EtOH followed by addition of 4 mL hydroxylamine (99.9% in water solution). The reaction was stirred at 75° C. for 6 hrs and monitored by HPLC. The reaction was concentrated in vacuo to a yellow oil which was dissolved in chloroform and chromatographed on 120 g of silica gel eluting with (1:4), EtOAc/hexane. The product was concentrated to give the desired product as a white solid (2.57 g, 89%); MF═C19H28ClFN4O3Si; LCMS calculated for C19H29ClFN4O3Si(M+H)+: m/z=443.168.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N+:16]([C:19]1[CH:28]=[C:27]2[C:22]([CH2:23][CH2:24][CH2:25][C:26]2=O)=[CH:21][CH:20]=1)([O-:18])=[O:17].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>ClCCl>[N+:16]([C:19]1[CH:20]=[CH:21][CH:22]2[CH:27]([CH:28]=1)[C:26]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:25][CH2:24][CH2:23]2)([O-:18])=[O:17]
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Product: O=[N+]([O-])C1=CC2C(OS(=O)(=O)C(F)(F)F)=CCCC2C=C1
Reaction time: 24 h

Procedure:
9.8 ml of trifluoromethanesulphonic anhydride are poured at 0° C. into a solution of 10 g of 7-nitrotetralone and 11.8 g of 2,6-di-tert-butyl-4-methylpyridine in 365 ml of dichloromethane. After 24 hours at ambient temperature, concentration to dryness and taking up the residue in 200 ml of pentane at reflux for 30 minutes, the precipitate formed is filtered off. The organic phase is washed with a 1N hydrochloric acid solution and then with water, dried over magnesium sulphate and concentrated.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]([O:43][C:44](=[O:52])[NH:45][CH:46]1[CH2:51][CH2:50][CH2:49][NH:48][CH2:47]1)([CH3:42])([CH3:41])[CH3:40].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:39]([O:43][C:44](=[O:52])[NH:45][C@@H:46]1[CH2:51][CH2:50][CH2:49][N:48]([C:22]([C:21]2[N:20]=[C:19]([C:25]([F:28])([F:27])[F:26])[N:16]3[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:29][C:30]4[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=4[F:38])[CH2:14][C:15]=23)=[O:24])[CH2:47]1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 62.6 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.12 g, 0.218 mmol), piperidin-3-yl-carbamic acid tert-butyl ester 11b (0.173 g, 0.545 mmol) and triethylamine (0.275 g, 2.18 mmol) were dissolved in 12 mL of dichloromethane under stirring, and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.138 g, 0.545 mmol) was then added to the mixture. The reaction mixture was reacted at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-(1-{7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carbonyl}-piperidin-3-yl)-carbamic acid tert-butyl ester 11c (0.1 g, yield 63%) as an oil.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][NH:6][C:7]1[N:8]=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:10]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[N:12]=1)C.[Li+].[OH-].Cl>C1COCC1.O>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:9]1[C:10]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[N:12]=[C:7]([NH:6][CH2:5][C:4]([OH:32])=[O:3])[N:8]=1
Reactant: CCOC(=O)CNc1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNc1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Reaction time: 1 h

Procedure:
To a solution of the product of Example 83 (20 mg, 0.43 mmol) in THF (2 mL) was added LiOH (40 mg, 1.67 mmol) dissolved in H2O (1 mL). The reaction mixture was stirred 1 h at 23° and then neutralized with 1 M HCl, extracted with EtOAc (5 mL) and the layers were separated. The organic layer was washed with H2O, satd. aq NaCl, and dried (MgSO4). The solution was filtered and evaporated to give the title compound [4,8-bis-(2-chloro-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-acetic acid. LC MS (m/e)=441 (MH+). Rt=1.85 min
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[C:21]([OH:24])(=[O:23])[CH3:22]>CCCCCC>[CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[C:21]([O-:24])(=[O:23])[CH3:22]
Reactant: CC(=O)O
Agent: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Solvent: CCCCCC
Product: CC(=O)[O-]
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Sertraline base, (the compound of Preparation AA, 200 mg) was dissolved in hexane (1.5 mL) in a 10 mL reaction vial. The solution was heated to 40° C. Glacial acetic acid (41.2 μL) was added to the sertraline base solution. The reaction mixture was allowed to cool to room temperature and then granulate for one hour. The solids were filtered and dried in a vacuum oven at 40° C. for 72 hours. The yield was determined to be 90%. mp 126° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:23][CH2:24][CH2:25][N:26]1[C:30]([CH3:32])([CH3:31])[C:29](=[O:33])[NH:28][C:27]1=[O:34].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:31][C:30]1([CH3:32])[N:26]([CH2:25][CH2:24][NH:23][C:2]2[N:7]=[C:6]([C:8]3[S:9][C:10]([S:13]([C:16]4[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=4)(=[O:15])=[O:14])=[CH:11][CH:12]=3)[CH:5]=[CH:4][N:3]=2)[C:27](=[O:34])[NH:28][C:29]1=[O:33]
Reactant: Cc1ccc(S(=O)(=O)c2ccc(-c3ccnc(Cl)n3)s2)cc1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)c2ccc(-c3ccnc(NCCN4C(=O)NC(=O)C4(C)C)n3)s2)cc1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 50.1 %

Procedure:
A mixture of 2-chloro-4-(5-tosylthiophen-2-yl)pyrimidine (100 mg, 0.23 mmol), 1-(2-aminoethyl)-5,5-dimethylimidazolidine-2,4-dione (33 mg, 0.26 mmol) and triethylamine (28 mg, 0.27 mmol) in toluene (3 mL) was heated at 160° C. for 35 min in a Personal Chemistry microwave reactor. Upon cooling to rt the precipitate was filtered and washed with diethyl ether. The solid was put into 2 mL of methanol and the suspension was stirred for about 15 min and filtered to afford the title compound as pale yellow crystals (56 mg, 50%). MS (M+H)+ 486.
Reaction SMILES: [C:1]([NH:11][CH:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[C:1]([NH:11][CH:12]([C:17]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:28])=[O:29])=[CH:23][CH:22]=1)=[O:19])[CH2:13][CH:14]([CH3:15])[CH3:16])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)Nc1ccc(S(N)(=O)=O)cc1

Procedure:
Observing the procedure of Example I, N-carbobenzyloxy-DL-leucine is reacted with 4-amino-benzenesulfonamide to yield the desired product, 4-(N-carbobenzyloxy-DL-leucylamino)benzene-sulfonamide having a mp. of 167°-8° C.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[F:15])=O)[CH:2]=[CH2:3].Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C>[CH2:1]([O:4][CH2:5][C:6]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[F:15])=[N:17][OH:18])[CH:2]=[CH2:3]
Reactant: NO
Reactant: C=CCOCC(=O)c1cc(Br)ccc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C=CCOCC(=NO)c1cc(Br)ccc1F
Temperature: 70 °C

Procedure:
To a solution of 2-(allyloxy)-1-(5-bromo-2-fluorophenyl)ethanone (118 g, 432.1 mmol) in ethanol (1.7 L) is added hydroxylamine hydrochloride (34.5 g, 496.9 mmol) and sodium ethanoate (40.8 g, 496.9 mmol) at 25° C. The reaction is heated at 70° C. for 1 hr. The reaction is cooled and the solvent is removed under reduced pressure. The residue is washed with water (1 L) and is extracted three times with dichloromethane (3×500 mL). The organic phase is dried over magnesium sulfate, filtered, and the solvent is removed under reduced pressure, to obtain the title compound as a mixture of two possible oximes (120 g, 96%). ES/MS m/e (79Br/81Br) 288, 290 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]1[C:11](=[O:21])[N:12](CC(O)=O)[C:13]([CH3:16])=[CH:14][N:15]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]N>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]1[C:11](=[O:21])[N:12]([NH:12][C:11](=[O:21])[CH2:10][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=2)[C:13]([CH3:16])=[CH:14][N:15]=1
Reactant: NCc1cccc(Cl)c1
Reactant: Cc1cnc(NCCc2ccccn2)c(=O)n1CC(=O)O
Product: Cc1cnc(NCCc2ccccn2)c(=O)n1NC(=O)CCc1cccc(Cl)c1

Procedure:
The title compound was prepared from 3-[2-(2-pyridyl)ethylamino]-6-methyl-1-carboxymethylpyrazinone and 3-chlorobenzylamine using the procedure of EXAMPLE V, Step F, mp 201°-207° C.: MS (FAB) 412 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:20][C@@H:21]1[CH2:26][O:25][CH2:24][CH2:23][NH:22]1>C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][C@H:21]2[CH3:20])[N:3]=[C:4]([NH:9][CH3:10])[N:5]=1
Reactant: C[C@@H]1COCCN1
Reactant: CNc1nc(Cl)cc(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(Cl)cc(N2CCOC[C@H]2C)n1
Temperature: 100 °C
Reaction time: 48 h
Yield: 68.7 %

Procedure:
To a solution of 4,6-dichloro-N-methyl-2-pyrimidinamine (2 g, 11.23 mmol) in ethanol (50 mL) in a 200-mL RBF were added Hunig's base (5.89 mL, 33.7 mmol) and (3R)-3-methylmorpholine (1.546 g, 11.23 mmol). The reaction mixture was stirred at 100° C. in a sealed tube on a stirrer hotplate for 2 days. The reaction was concentrated in vacuo, and the residue was dissolved in EtOAc (200 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4, filtered, then concentrated to afford the title compound (1.873 g) as a white solid. LC-MS (ES) m/z=243 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])(=[O:27])=[O:26])=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)=[O:11])=[CH:7][C:6]=2[CH:36]=1.C(N(CC)C(C)C)(C)C.[C:46](Cl)(=[O:48])[CH3:47]>C(Cl)Cl>[C:46]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[CH:21][C:22]([S:25]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])(=[O:26])=[O:27])=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)=[O:11])=[CH:7][C:6]=2[CH:36]=1)(=[O:48])[CH3:47]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4cc(N)ccc4o3)cc2)cc1)C(=O)O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[(4′-{[(5-amino-1-benzofuran-2-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valine-Wang resin (0.3 g), from Example 7, was suspended in methylene chloride (6 mL). To the suspension was added N,N-diisopropylethylamine (6.0 equiv.) and acetyl chloride (3.0 equiv.). The reaction was allowed to proceed at room temperature for 0. h and the reagent was removed by filtration. The resin was washed with methylene chloride (2×), methanol and methylene chloride (2×) before being treated with a 95% solution of TFA in methylene chloride (5 mL) and agitated at room temperature for 2 h. The solution was collected by filtration and the solvent was removed via vacuum. The crude product was then purified by flash chromatography to give N-{[4′-({[5-(acetylamino)-1-benzofuran-2-yl]carbonyl}amino)-1,1′-biphenyl-4-yl]sulfonyl}-L-valine. LCMS MH+ (m/z) 550. 1H NMR (300 MHz, DMSO-d6): δ 10.50 ppm (s, 1H), 9.92 ppm (s, 1H), 8.00-7.34 ppm (m, 12H), 3.33 ppm (m, 1H), 1.89 ppm (s, 3 H), 1.76 ppm (m, 1H), 0.63 ppm (m, 6H).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21](COCC[Si](C)(C)C)[N:20]=[C:19]2[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:14])=[O:13])(=[O:5])=[O:4].[OH-].[Na+]>C(O)C.C(OC(C)C)(C)C>[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:14])=[O:13])(=[O:5])=[O:4]
Reactant: C[Si](C)(C)CCOCn1nc(CCc2ccccc2)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(CCc3ccccc3)c2c1
Temperature: 20 °C
Yield: 29.9 %

Procedure:
2-Methylsulfonyl-N-(3-phenethyl-1H-indazol-5-yl)benzenesulfonamide can be obtained in the following way: 5.6 ml of an aqueous 5N hydrochloric acid solution are added dropwise to a suspension of 0.56 g of 2-methylsulfonyl-N-[3-phenethyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]benzenesulfonamide in 17 ml of absolute ethanol. The reaction mixture is then refluxed for 30 minutes and then cooled to a temperature in the region of 20° C. 6.8 ml of an aqueous 5N sodium hydroxide solution are then added and the mixture is stirred. The mixture is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and the residue is taken up in a mixture of 35 ml of ethyl acetate and of 50 ml of water. After settling out, the aqueous phase is extracted with 2 times 30 ml of ethyl acetate. The organic extracts are pooled, washed with 2 times 20 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. The residue thus obtained is purified by chromatography under argon pressure (50 kPa) on a column of 75 g of silica (particle size 40-63 μm), eluting with a dichloromethane/methanol (98/2 by volume) mixture. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. The residue thus obtained is repurified by chromatography under argon pressure (50 kPa), on a column of silica (particle size 40-63 μm), eluting with a cyclohexane/ethyl acetate (70/30 by volume) mixture. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. The residue thus obtained is taken up in 15 ml of diisopropyl ether, triturated, filtered and then dried. 130 mg of 2-methylsulfonyl-N-(3-phenethyl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a white solid melting at 192° C. (Cl mass analysis: m/z 456 (M+H)+).