Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:14][OH:15]>C(O)C>[F:1][C:2]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4](=[N:14][OH:15])[NH2:5]
Reactant: CS(=O)(=O)c1ccc(C#N)c(F)c1
Reactant: NO
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(N)=NO)c(F)c1
Temperature: 90 °C

Procedure:
To a stirred solution of the product from Step E (0.29 g, 0.144 mmol) in ethanol (15 mL) was added hydroxylamine (50% in water, 3.0 mL). The reaction was heated at 90° C. for 3 h. The reaction was then concentrated to give the desired product.
Reaction SMILES: [C:1]1([CH2:7][S:8]([CH2:10][C:11]2[S:15][C:14]([NH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C@H:25]4[CH2:30][CH2:29][C@H:28]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[O:18])=[N:13][N:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[C:1]1([CH2:7][S:8]([CH2:10][C:11]2[S:15][C:14]([NH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C@H:25]4[CH2:30][CH2:29][C@H:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:27][CH2:26]4)=[CH:23][CH:24]=3)=[O:18])=[N:13][N:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(CS(=O)Cc4ccccc4)s3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(CS(=O)Cc4ccccc4)s3)cc2)CC1
Reaction time: 1 h

Procedure:
0.072 g of tert-butyl trans-{4-[4-(5-phenylmethanesulfinylmethyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]cyclohexyl}acetate (0.13 mmol, 1 eq.) is placed in 2 mL of dichloromethane with stirring. 1 mL of TFA (13.46 mmol, 104 eq.) is added. After 1 hour, the reaction medium is evaporated and the residue is triturated in ethanol to give 0.055 g of trans-{4-[4-(5-phenylmethanesulfinylmethyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]cyclohexyl}acetic acid.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][C:16](=[O:35])[N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:19][CH2:18]1)(C)(C)C>C(Cl)Cl>[NH2:14][CH2:15][C:16]([N:17]1[CH2:18][CH2:19][N:20]([C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:31])[F:32])[CH2:21][CH2:22]1)=[O:35]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 126.5 %

Procedure:
TFA (13 mL) was added drop wise to {2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-carbamic acid tert-butyl ester (2.6 g, 6.27 mmol) in DCM (15 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. Concentrating the mixture afforded a crude product, which was recrystallized from hexane to afford 2.5 g (93% yield) of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone as TFA salt.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16]I.[Na+].[Cl-]>CN(C)C=O.O>[Cl:13][CH2:14][CH2:15][CH2:16][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: ClCCCI
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(OCCCCl)c1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-nitrophenol (15.00 g, 108.0 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (3.42 g of an 80% dispersion in mineral oil, 114.0 mmol) in DMF (40 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. The mixture was cooled to 0-5° C., and 1-chloro-3-iodopropane (26.37 g, 127.0 mmol) was added drop-wise over 5 min. The resulting dark-brown mixture was stirred at ambient temperature for 2 h. Water (25 mL) was added, followed by saturated NaCl solution (25 mL), and the mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 19.75 g (85.1%) of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH2:17][F:18])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[C:20]([C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1)#[N:21]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:15])([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28](=[O:29])[C:25]3[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:27][N:26]=3)[CH:3]=[CH:4][C:5]=2[F:19])([CH2:17][F:18])[N:9]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: NC1=N[C@](CF)(c2cc(N)ccc2F)C(F)(F)CO1
Product: N#Cc1ccc(C(=O)Nc2ccc(F)c([C@@]3(CF)N=C(N)OCC3(F)F)c2)nc1
Yield: 74 %

Procedure:
In a manner analogous to that described in Example 1, the condensation of (S)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-fluoromethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate F8.1) and 5-cyanopicolinic acid yielded the title compound (35 mg, 74% yield) as a light yellow foam. MS (ISP): m/z=408.4 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC(S(O[CH2:21][C@@H:22]([OH:32])[CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=O)=O)=CC=1.C([Li])CCC>C1COCC1.CCOC(C)=O>[OH:32][C@@H:22]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:21][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[N:9]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)COCc2ccccc2)cc1
Reactant: N#CCc1ccccc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CC(C[C@@H](O)COCc1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
Phenylacetonitrile (4.59 g, 39.2 mmol) and (2S)-2-hydroxy-3-[(phenylmethyl)oxy]propyl 4-methylbenzenesulfonate (13.20 g, 39.2 mmol, 1 eq) were dissolved in 50 mL THF, cooled to −78° C., and treated with 2.5M butyllithium in hexanes (35 mL, 86.3 mmol, 2.2 eq) added dropwise over 30 min. The reaction mixture was stirred 4 h at −78° C., allowed to warm to ambient temperature and stirred an additional 16 h. The reaction mixture was diluted with EtOAc, washed successively with water and brine, dried over MgSO4, filtered and concentrated to give the diastereomeric product as an orange oil in quantitative yield which was carried on without purification. ES-LCMS m/z 304.33 (M+Na).
Reaction SMILES: CN1CCN(C2C=CC3C(C=2)=CC=C2C=3OC(C(NC3C=CC([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=CC=3)=O)=CC2=O)CC1.N1(C([C:46]2[CH:51]=[CH:50][C:49]([NH:52][C:53]([C:55]3[O:56][C:57]4[C:62]([C:63](=[O:65])[CH:64]=3)=[CH:61][CH:60]=[CH:59][C:58]=4[N:66]3[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]3)=[O:54])=[CH:48][CH:47]=2)=O)CCOCC1>>[N:30]1([C:51]2[CH:50]=[C:49]([NH:52][C:53]([C:55]3[O:56][C:57]4[C:62]([C:63](=[O:65])[CH:64]=3)=[CH:61][CH:60]=[CH:59][C:58]=4[N:66]3[CH2:67][CH2:68][N:69]([CH3:72])[CH2:70][CH2:71]3)=[O:54])[CH:48]=[CH:47][CH:46]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: CN1CCN(c2ccc3c(ccc4c(=O)cc(C(=O)Nc5ccc(N6CCOCC6)cc5)oc43)c2)CC1
Reactant: CN1CCN(c2cccc3c(=O)cc(C(=O)Nc4ccc(C(=O)N5CCOCC5)cc4)oc23)CC1
Product: CN1CCN(c2cccc3c(=O)cc(C(=O)Nc4cccc(N5CCOCC5)c4)oc23)CC1

Procedure:
This compound was prepared from 8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) and 3-morpholin-4-yl-phenylamine (Reference Example 18) as prepared in Example 12, yielding a yellow solid. (120 mg=86%), LCMS-m/z=449.5.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]2[N:11]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:9]=1[CH2:24][CH2:25]Cl>CN(C)C=O>[C:17]([C:16]1[CH:15]=[N:14][N:13]2[C:8]3[N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:25][CH2:24][C:9]=3[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:11][C:12]=12)#[N:18]
Reactant: CCOC(=O)c1nc2c(C#N)cnn2c(Cl)c1CCCl
Reactant: NC1CCCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2c(C#N)cnn2c2c1CCN2C1CCCC1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
While stirring at room temperature, 15.0 ml of cyclopentylamine were added at once to a solution of 10.0 g (31.93 mmol) of ethyl 7-chloro-6-(2-chloroethyl)-3-cyanopyrazolo[1,5-a]pyrimidine-5-carboxylate in 80 ml of anhydrous dimethylformamide. The resultant mixture was then stirred for 5 hours at the same temperature. The reaction mixture was then poured into ice water, and solids deposited were collected by filtration, washed with water and air-dried to give 10.02 g (yield: 96.4%) of the intended product.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([O:6][C:7]([C@:9]1([NH2:31])[C@H:14]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:13][C@@H:12]2[C@H:10]1[C@@:11]2([F:30])[C:25]([O:27]CC)=[O:26])=[O:8])[CH3:5].Cl>O1CCCC1.O>[CH3:5][CH2:4][O:6][C:7]([C@:9]1([NH2:31])[C@H:14]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:13][C@@H:12]2[C@H:10]1[C@@:11]2([F:30])[C:25]([OH:27])=[O:26])=[O:8]
Reactant: CCOC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1SCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1SCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
17 mg of lithium hydroxide monohydrate was added to 150 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in a mixture of 3.5 mL tetrahydrofuran and 1.7 mL of water, and the mixture was stirred for 30 minutes at ice-cooling. The mixture was acidified to pH 2 with 1N hydrochloric acid, diluted with 30 mL of water, and then stirred for 30 minutes at ice-cooling. This diluted solution was purified by ion exchange resin (AG 50W-X8 Resin (H form), eluent: water, a 30% aqueous solution of tetrahydrofuran and a 10% aqueous solution of pyridine), thereby yielding 73 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-ethyl ester.
Reaction SMILES: CN(C)S([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[C:8]([Br:15])[CH:7]=1)(=O)=O.BrC1C=C([F:24])C=C([N+]([O-])=O)C=1C>>[Br:15][C:8]1[CH:7]=[C:6]([F:24])[CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2
Reactant: CN(C)S(=O)(=O)c1cc(Br)c2cc[nH]c2c1
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Product: Fc1cc(Br)c2cc[nH]c2c1

Procedure:
Prepared according to the method used in the preparation of 4-bromo-1H-indole-6-sulfonic acid dimethylamide using 1-bromo-5-fluoro-2-methyl-3-nitro-benzene in place of 3-bromo-4-N,N-trimethyl-5-nitro-benzenesulfonamide. The title compound was obtained as a white solid (6.06 g, 33%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[NH:15][C:14]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:13]2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([N:15]1[C:14]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([Br:9])[CH:11]=2)[C:16]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCCCc1cc2cc(Br)ccc2c(=O)[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCc1cc2cc(Br)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
Benzyl bromide (152 mg, 0.887 mmol, 1.50 equiv.) was added to a stirred mixture of methyl 5-(6-bromo-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (200 mg, 0.591 mmol) and Cs2CO3 (289 mg, 0.887 mmol, 1.50 equiv.) in DMF (1 mL) and the mixture was stirred at room temperature overnight. Upon completion, the reaction mixture was diluted with water, extracted with EtOAc (2×5 mL), washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel, eluting with 0-20% EtOAc/hexanes to give 147 mg of methyl 5-(2-benzyl-6-bromo-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate as a pink solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:22])=[C:5]2[CH2:23][N:24]=[C:25]=[O:26].[CH:27]([NH2:30])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][CH:13]=1)/[C:6]([CH3:22])=[C:5]2[CH2:23][NH:24][C:25]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:26]
Reactant: CC1=C(CN=C=O)c2cc(F)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Reactant: CC(C)N
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC1=C(CNC(=O)NC(C)C)c2cc(F)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 750 %

Procedure:
To a solution of the isocyanate from Step 1 in toluene was added 1.2 equivalent of isopropylamine. The reaction mixture was kept under reflux for 1 h. After having been cooled to room temperature, the mixture was diluted with n-hexane to form a yellow precipitate, which was filtered off, and was recrystallized from CH2Cl2, to give the title compound as a yellow solid (750%), mp: 217° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.[OH-].[K+]>C(Cl)(Cl)Cl>[CH3:11][C:10]1([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[C:2]1=[CH2:1]
Reactant: CC1=Nc2ccccc2C1(C)C
Reactant: COc1ccc(CBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=C1N(Cc2ccc(OC)cc2)c2ccccc2C1(C)C
Temperature: 80 °C
Yield: 81.2 %

Procedure:
To a solution of 4.0 g of 2,3,3-trimethylindolenine in 25 ml of chloroform was added 5.6 g of p-methoxybenzyl bromide and the mixture was heated in an autoclave at 80° C. for 21 hours. The resulting precipitate was recovered by filtration to give 8.5 g of 1-(4-methoxybenzyl)-2,3,3-trimethylindolenium as white crystals. To these crystals was added 85 ml of 10N aqueous potassium hydroxide solution in a nitrogen atmosphere and the mixture was heated at 50° C. for 3 hours. The reaction mixture was then extracted with ether and the extract was dried over magnesium sulfate and concentrated under reduced pressure to give 5.7 g of 3,3-dimethyl-1-(4-methoxybenzyl)-2-methyleneindoline (Yield 80.6%).
Reaction SMILES: [C:1](=[O:34])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C@H:3]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:15][C:6]2[C:7]3[CH:8]=[N:9][NH:10][C:11]=3[C:12]([Cl:14])=[CH:13][C:5]=2[CH2:4]1.[NH:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH2:47][CH2:46][C:45]3[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=3[NH:43][C:42]2=[O:52])[CH2:37][CH2:36]1>ClCCl>[O:52]=[C:42]1[NH:43][C:44]2[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=2[CH2:46][CH2:47][N:41]1[CH:38]1[CH2:39][CH2:40][N:35]([C:1]([O:2][C@H:3]2[C:17](=[O:18])[N:16]([CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:15][C:6]3[C:7]4[CH:8]=[N:9][NH:10][C:11]=4[C:12]([Cl:14])=[CH:13][C:5]=3[CH2:4]2)=[O:34])[CH2:36][CH2:37]1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Solvent: ClCCl
Product: O=C(O[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reaction time: 2 h
Yield: 40 %

Procedure:
(R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino [3,4-e]indazol-7-yl 4-nitrophenyl carbonate (60 mg, 0.120 mmol) in dichloromethane (15 mL) was added 3-(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one (32.5 mg, 0.132 mmol). The reaction mixture was stirred for 2 h. LC-MS analysis suggested formation of product (Rf=2.473, 605.22 (M+H)). The reaction mixture was washed with aqueous NaHCO3 followed by 1.0 M HCl. THe crude product was purified by flash chromatography using 5% MeOH in dichloromethane to give (R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino [3,4-e]indazol-7-yl 4-(2-oxo-4,5-dihydro-1H-benzo[d][1,3]diazepin-3 (2H)-yl)piperidine-1-carboxylate (29.00 mg, 0.048 mmol, 40% yield). 1H NMR (500 MHz, CD3OD): in δ 8.30 (s, 1H), 7.32 (s, 1H), 7.09 (m, 3H), 6.93-6.87 (m, 3H), 6.09-6.05 (m, 1H), 5.50 (s, 2H), 5.44 (m, 1H), 4.68-4.54 (m, 1H), 4.39-4.35 (m, 2H), 4.32-4.19 (m, 1H), 4.16-4.05 (m, 3H), 3.55-3.50 (m, 3H), 3.12-2.92 (m, 2H), 1.87-1.74 (m, 4H); MS (ESI) 605 (M+H); Rf=2.47.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CC(O)C>[CH:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][N:10]2[C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CC(C)c1ccc2c(c1)NCC2
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4ccc(C(C)C)cc43)c2cc1OC
Yield: 43 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 43% yield from 6-isopropyl-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 128°-129° C.; LC-MS: 350 (MH+); anal. RP18-HPLC RT: 5.51 min.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.[CH3:20][NH:21][CH2:22][CH2:23][CH3:24].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:10]=[C:6]([C:7]([N:21]([CH3:20])[CH2:22][CH2:23][CH3:24])=[O:9])[CH:5]=1
Reactant: CCCNC
Reactant: COC(=O)c1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
5-(2-Oxo-pyrrolidin-1-yl)-isophthalic acid monomethyl ester (D63) (1.0 g, 3.8 mmol) was dissolved in DMF (7 ml) and treated with N-methyl propylamine (0.42 g, 5.7 mmol), HOBt (0.62 g, 4.56 mmol) and EDC (1.02 g, 5.32 mmol) and the resulting solution was stirred overnight at room temperature. It was then evaporated to dryness and the residue was partitioned between EtOAc and dil.HCl. The organic phase was separated, washed with dil.HCl (×2), dil.NaHCO3 (×3) and brine (×1). It was dried (MgSO4) and evaporated to leave the crude product which was purified by silica chromatography eluting with DCM/MeOH to afford the pure title compound (D64) (0.40 g, 33%).
Reaction SMILES: C([N:11]1[CH2:18][CH2:17][CH2:16][CH:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.[CH2:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CN(C)C=O.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH2:19]([O:15][C:13]([CH:12]1[CH2:16][CH2:17][CH2:18][NH:11]1)=[O:14])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Reactant: CCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCOC(=O)C1CCCN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 24.9 g. (0.01 mol.) of N-carbobenzoxy-DL-proline and 11.22 g. (0.11 mol.) of n-hexanol in 200 ml. of dry dimethylformamide and 7.9 g. pyridine at room temperature is added 20.6 g. (0.01 mol.) of N,N'-dicyclohexylcarbodiimide. After stirring this mixture at room temperature for 16 hours, the precipitated N,N'-dicyclohexylurea is filtered off, the filtrate is diluted with a large volume of saturated aqueous sodium chloride, and this is thoroughly extracted with chloroform. The combined extracts are dried and concentrated in vacuo to give an oil comprising 1-(benzyloxy)carbonyl)]-2-[(hexyloxy)carbonyl]pyrrolidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1>[Pd]>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:10]2[NH:11][C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=2)=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Agent: [Pd]
Product: Nc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Reaction time: 4 h

Procedure:
A mixture containing 4-(4-fluorophenyl)-2-(4-nitrophenyl)-5-(4-pyridyl)-1H-imidazole (2.0 g. 5.6 mmol) [See Ex. 26 above] and 10% palladium on activated carbon (0.4 g) was stirred under an atmosphere of H2 for 4 h, then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography, eluting with a solvent gradient of 1-10% MeOH/CHCl3. The title compound was obtained as a light orange solid (0.50 g, 27%): 1H NMR (DMSO-d6): d 8.40 (d, 2H); 7.73 (d, 2H); 7.57 (m, 2H); 7.35 (m, 4H); 6.62 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:21]([C:23]1[CH:24]([CH3:33])[CH:25]=[C:26]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:27]=1)=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:21][C:23]4[NH:27][C:26]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:25][C:24]=4[CH3:33])[C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1C=C(CCC(=O)O)N=C1C=O
Reactant: CN1C(=O)Cc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(CCC(=O)O)[nH]c1C=C1C(=O)N(C)c2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 80 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
4-(3-Chloro-4-fluoro-phenylamino)-7-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (100 mg, 0.34 mmol) was condensed with 3-(5-formyl-4-methyl-4H-pyrrol-2-yl)-propionic acid (62 mg, 0.41 mmol) and piperidine (2 drops) in ethanol (3 mL) stirred at 80° C. for 2 hours to give 31 mg (20%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.14 (br s, 1H, NH), 9.14 (s, 1H), 8.34 (s, 1H), 7.69 (m, 1H), 7.30-7.40 (m, 3H), 6.08 (s, 1H), 3.32 (s, 3H, CH3), 2.89 (m, 2H, CH2), 2.53 (m, 2H, CH2), 2.16 (s, 3H, CH3).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[NH2:8].Cl.[N:12]([O-])=O.[Na+]>O>[CH3:9][N:4]1[C:3](=[O:10])[C:2]2[N:1]=[N:12][NH:8][C:7]=2[CH:6]=[N:5]1
Reactant: O=N[O-]
Reactant: Cn1ncc(N)c(N)c1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cn1ncc2[nH]nnc2c1=O
Reaction time: 1 h

Procedure:
In water (10 ml) was dissolved 4,5-diamino-2-methyl-3(2H)-pyridazinone (280 mg) followed by addition of concentrated hydrochloric acid (0.5 ml) with ice-cooling. Then, sodium nitrite (290 mg)/water (5 ml) was added dropwise at a temperature not exceeding 10° C. and the mixture was stirred at that temperature for 1 hour and then at 100° C. for 1 hour. This reaction mixture was allowed to stand in the refrigerator for 16 hours and the resulting precipitate was collected by filtration, rinsed with water, and dried. White powder, 262 mg. 1H-NMR (DMSO-d6) δ: 3.76(3H,s), 8.71(1H,s).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[O:15])([CH3:3])[CH3:2].[Br:16]Br.S([O-])([O-])(=O)=O.[Na+].[Na+]>[Fe]>[CH:1]([C:4]1[CH:9]=[C:8]([Br:16])[CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[N:13]=[C:14]=[O:15])([CH3:2])[CH3:3]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: BrBr
Agent: [Fe]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CC(C)c1cc(Br)cc(C(C)C)c1N=C=O
Temperature: 120 °C

Procedure:
0.5 g of anhydrous iron-III chloride is added to 203 g of 2,6-diisopropyl-phenyl isocyanate and 162 g of bromine are added dropwise at 20° C. The mixture is then slowly warmed to 120° C. until the evolution of gas has ceased. 3.0 g of anhydrous sodium sulfate are then added and the mixture is fractionated in vacuo.