Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=O)[CH:18]([CH3:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24].[OH-].[Na+].Cl>CCO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[N:23][OH:24])[CH:18]([CH3:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(=NO)c1c(-c2ccc(F)cc2)nn2ccccc12
Temperature: 0 °C
Yield: 68.1 %

Procedure:
To a solution of 2.3 g (8.15 mmol) of 1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one in 32 ml of anhydrous EtOH was added 2.26 g of hydroxylamine hydrochloride, followed by a solution of 1.63 g (8.15 mmol) NaOH in 5 ml water dropwise. The mixture was stirred and refluxed over night. After cooling, the solution was poured into a solution of 4.8 ml 6N HCl in 100 ml ice water with stirring for 30 minutes. The mixture was extracted with ethyl acetate three times. The combined organic phases were washed with brine and dried over MgSO4. After solvent evaporation under vacuum, 4.6 g of crude product was obtained. Purification on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant afforded 1.65 g (67%) of 1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime. Compound 1019.
Reaction SMILES: [CH:1]([C:4]1[C:19]([O:20][C:21]2([CH3:32])[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]2)=[CH:18][C:7]2[N:8]3[C@@H:13]([CH3:14])[C:12](=[O:15])[NH:11][N:10]=[C:9]3[CH2:16][O:17][C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH:1]([C:4]1[C:19]([O:20][C:21]2([CH3:32])[CH2:22][NH:23][CH2:24]2)=[CH:18][C:7]2[N:8]3[C@@H:13]([CH3:14])[C:12](=[O:15])[NH:11][N:10]=[C:9]3[CH2:16][O:17][C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc2c(cc1OC1(C)CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@@H]1C)CO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cc2c(cc1OC1(C)CNC1)N1C(=NNC(=O)[C@@H]1C)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of (S)-tert-butyl 3-((8-isopropyl-1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)oxy)-3-methylazetidine-1-carboxylate (enantiomer 1, SFC (Table 1, Method 24), Rt=8.741 min., 0.095 g, 0.213 mmol) in DCM (3 mL) was added TFA (0.5 mL) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give (S)-8-isopropyl-1-methyl-9-((3-methylazetidin-3-yl)oxy)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]-triazin-2(1H)-one trifluoroacetic acid (Example #121-1, Enantiomer 1, SFC (Table 1, Method 24), Rt=3.745 min, 0.085 g, 97%). LC/MS (Table 1, Method 5) Rt=2.175 min.; MS m/z: 345 [M+H]+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](Cl)=[O:12]>CN(C)C=O>[OH:2][CH2:1][CH2:3][NH:4][C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=1)=[O:12]
Reactant: O=C(Cl)c1ccccn1
Reactant: NCCO
Solvent: CN(C)C=O
Product: O=C(NCCO)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15.4 ml of ethanolamine were placed under argon with 30 ml of dimethylformamide and cooled to 0°-5°. A solution of 11.3 g of picolinic acid chloride in 100 ml of dimethylformamide was added dropwise thereto at 0°-10° and the mixture was stirred at room temperature overnight. The dimethylformamide was distilled off under reduced pressure. The residue was dissolved in methylene chloride and separated from the insoluble constituents, and thereafter chromatographed on silica gel; elution agent: methylene chloride, thereafter methylene chloride/methanol (9:1). N-(2-Hydroxyethyl)pyridine-2-carboxamide was obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][NH:9][C:10]=2[CH:11]=[C:12]([Br:14])[CH:13]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[F:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.CN[C@@H]1CCCC[C@H]1NC>O.[Cu]I.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)[C:10]=2[CH:11]=[C:12]([Br:14])[CH:13]=1)=[O:4]
Reactant: Fc1ccc(I)cc1
Reactant: COC(=O)c1cc(Br)cc2[nH]ccc12
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)cc2c1ccn2-c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 6-bromo-1H-indole-4-carboxylic acid methyl ester (2.00 g, 7.84 mmol), CuI (38.0 mg, 0.20 mmol) and K2CO3 (1.18 g, 8.50 mmol) in a sealed tube is degassed with argon. To the mixture is added 4-fluoroiodobenzene (1.78 g, 8.00 mmol) and trans-N,N′-dimethyl-cyclohexane-1,2-diamine (0.20 g, 1.40 mmol) followed by DMF (25 mL). The reaction mixture is warmed at 120° C. After 3 hours, the reaction is diluted with water and extracted with EtOAc. The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with EtOAc-hexanes (20:80) to afford 6-bromo-1-(4-fluorophenyl)-1H-indole-4-carboxylic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]1[C:60]([C:61](Cl)=[O:62])=[C:59]([CH3:64])[O:58][N:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:61]([C:60]2[C:56]([CH3:55])=[N:57][O:58][C:59]=2[CH3:64])=[O:62])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1noc(C)c1C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C)c1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 3,5-dimethylisoxazole-4-carbonyl chloride as starting materials (43% yield). LCMS for C30H32ClN8O3 (M+H)+: m/z=587.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=2)[N:5]=[CH:4][N:3]=1.ClC1C=CC=CC=1C1C(C(OC)=O)=C(C)NC(COCCO)=C1C(OCC)=O>>[CH3:15][N:11]1[CH:12]=[CH:13][N:14]=[C:10]1[CH2:9][O:8][C:6]1[N:5]=[CH:4][N:3]=[CH:2][CH:7]=1
Reactant: Cn1ccnc1COc1cc(Cl)ncn1
Agent: CCOC(=O)C1=C(COCCO)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Product: Cn1ccnc1COc1ccncn1

Procedure:
4-<2-{[4-(2-Chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}ethoxy>-6-(1-methyl-2-imidazolylmethoxy)pyrimidine was prepared by the method described in Example 13 using 4-chloro-6-(1-methyl-2-imidazolylmethoxy)pyrimidine and 4-(2-chlorophenyl)-3-ethoxycarbonyl-2-(2-hydroxyethoxymethyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine as the starting materials. The product had m.p. 48°-51° C.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:10]=[CH:11][C:12]3[C:18](=[O:19])[C:17]([C:20]([OH:22])=[O:21])=[CH:16][NH:15][C:13]=3[N:14]=2)[CH2:5][CH2:4]1)=[O:2].C(N(CC)CC)C.ClC(OC(C)C)=O.O[N:38]1[C:42](=[O:43])[CH2:41][CH2:40][C:39]1=[O:44]>ClCCl.CN(C)C=O>[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:10]=[CH:11][C:12]3[C:18](=[O:19])[C:17]([C:20]([O:22][N:38]4[C:42](=[O:43])[CH2:41][CH2:40][C:39]4=[O:44])=[O:21])=[CH:16][NH:15][C:13]=3[N:14]=2)[CH2:5][CH2:4]1)=[O:2]
Reactant: O=C1CCC(=O)N1O
Reactant: O=CN1CCN(c2ncc3c(=O)c(C(=O)O)c[nH]c3n2)CC1
Agent: CC(C)OC(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CN1CCN(c2ncc3c(=O)c(C(=O)ON4C(=O)CCC4=O)c[nH]c3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
A suspension of 5,8-dihydro-2-(4-formyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid (273 g) and triethylamine (299 ml) in dried dichloromethane (3500 ml) was stirred well at room temperature for one hour. To the suspension, isopropyl chloroformate (221 g) was added dropwise with cooling at 0°-10° C. and the reaction mixture was stirred for 2 hours. A solution of N-hydroxysuccinimide (207 g) in dimethylformamide (350 ml) was added to the mixture and the resulting mixture was kept at 5°-10° C. for an additional 2 hours. The crystalline product was collected by filtration and washed successively with water (2000 ml) and acetone (2000 ml) to give N-[5,8-dihydro-2-(4-formyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carbonyloxy]succinimide (326 g). m.p. above 300° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([C:16](=O)[NH2:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Agent: B
Solvent: C1CCOC1
Product: NCC1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1 g 3-carbamoyl-pyrrolidine-1-carboxylic acid benzyl ester and 24 mL 1M borane-THF was stirred at room temperature for 24 h, then carefully quenched with 50 mL of 3N HCl. The mixture was concentrated under reduced pressure, then partitioned between 50 mL chloroform and 25 mL saturated aqueous sodium carbonate. Concentration of the combined extracts after drying over magnesium sulfate gave 3-aminomethyl-pyrrolidine-1-carboxylic acid benzyl ester:
Reaction SMILES: [Br-].[C:2]1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.[F:27][C:28]([F:42])([F:41])[C:29]1[CH:40]=[CH:39][C:32]2[CH:33](O)[O:34][CH:35]([CH:36]=[CH2:37])[C:31]=2[CH:30]=1>CCOCC.CCCCCC>[F:27][C:28]([F:42])([F:41])[C:29]1[CH:40]=[CH:39][C:32]([CH:33]=[CH2:2])=[C:31]([CH:35]([OH:34])[CH:36]=[CH2:37])[CH:30]=1
Reactant: C=CC1OC(O)c2ccc(C(F)(F)F)cc21
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C=Cc1ccc(C(F)(F)F)cc1C(O)C=C
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
Triphenylmethylphosphonium bromide (1.71 g, 4.78 mmol) was dissolved in ether (20.00 mL). After cooling to 0° C., a 1.60 M solution of n-butyllithium in hexane (2.72 mL) was added rapidly by syringe and the resulting orange mixture was warmed to room temperature and stirred overnight. The stirring was stopped to allow the solids to settle and then the ylid was transferred via cannula to a solution of 5-(trifluoromethyl)-3-vinyl-1,3-dihydro-2-benzofuran-1-ol (1.00 g, 4.34 mmol) in ether (10.00 mL) while stirring at 0° C. Following the addition, the ice bath was removed and the mixture was heated to reflux overnight. The reaction was allowed to cool and then the solids filtered off and washed with a small amount of ether. Most of the solvents were evaporated and the crude product was loaded onto silica gel and eluted with hexane/EtOAc (10:1) to give the desired product (0.81 g, 82%), LC-MS [M+1]=229.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[CH3:24][NH2:25].[I-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:25][CH3:24])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: CN
Agent: [I-]
Agent: [Na+]
Product: CNCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 1, 8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine was reacted with methylamine in the presence of sodium iodide to give 8-chloro-1-[(methylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin of melting point 152°-156° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[NH:9])=[N:6][CH:7]=1.C([O:13][C:14](=O)[CH2:15][C:16]([CH3:18])=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[C:14]([OH:13])[CH:15]=[C:16]([CH3:18])[N:9]=2)=[N:6][CH:7]=1
Reactant: N=C(N)c1ccc(N)cn1
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(O)nc(-c2ccc(N)cn2)n1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a solution of compound of example 12 (0.4 g, 2.9 mmol) in water (10 mL) and ethanol (5 mL) was added ethylacetoacetate (0.611 g, 4.7 mmol) and sodium carbonate (0.561 g, 5.29 mmol) and mixture was stirred at room temperature for about 25 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate (3×30 mL). Ethyl acetate layer was dried over anhydrous sodium sulfate and was concentrated to obtain a crude product, which was purified by column chromatography (silica gel, 6% methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:33])[NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[CH:30]=[CH:29][C:28](C=O)=[CH:27][CH:26]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:46]([O:51][CH3:52])([O:49][CH3:50])OC>CO>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:33])[NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[CH:26]=[CH:27][C:28]([CH:46]([O:49][CH3:50])[O:51][CH3:52])=[CH:29][CH:30]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(OC)OC
Reactant: O=Cc1ccc(-c2ccccc2CNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(OC)c1ccc(-c2ccccc2CNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Yield: 93.1 %

Procedure:
To a vigorously stirred mixture of methanol (250 mL) containing aldehyde (S29) (17.0 g, 39.3 mmol) and p-toluenesulfonic acid monohydrate (0.75 g, 3.9 mmol) was added trimethyl orthoformate (17 mL, 160 mmol). After 1.5 h of moderate heating (flask equipped with short path to drive reaction forward), the reaction was quenched with a 1:1 mixture of saturated sodium bicarbonate and water (150 mL) and diluted with CH2Cl2 (200 mL). The aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give a pale yellow solid (17.5 g, 36.6 mmol, 93%) which was used without further purification. 1H NMR (400 MHz, d6-DMSO): δ 7.88 (d, 2H, J=7.7 Hz), 7.79 (t, 1H, J=5.9 Hz), 7.68 (d, 2H, J=7.3 Hz), 7.43-7.30 (m, 11H), 7.19 (d, 1H, J=7.0 Hz), 5.40 (s, 1H), 4.29 (d, 2H, J=7.0 Hz), 4.20 (t, 1H, J=7.0 Hz), 4.11 (d, 2H, J=5.9 Hz), 3.25 (s, 6H). FAB/MS: 502 (M+Na+).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[F:17][C:18]([F:31])([F:30])[C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[CH:21][CH:20]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:30])([F:31])[F:17])=[CH:24][CH:23]=2)=[N:12]1
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2ccc(C(F)(F)F)cc2)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:25](=[CH:26][CH:27]=1)[CH2:24][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8](COCC[Si](C)(C)C)[C:7]1=[O:23])[CH2:5]2.FC(F)(F)C(OC(=O)C(F)(F)F)=O.NC1C=CC=CC=1.FC(F)(F)C(NC1C=CC=CC=1)=O.[N+:61]([O-])([OH:63])=[O:62].FC(F)(F)C(O)=O.C(N)CN>C(Cl)Cl.O>[NH2:1][C:2]1[CH:3]=[C:4]2[C:25](=[CH:26][C:27]=1[N+:61]([O-:63])=[O:62])[CH2:24][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:23])[CH2:5]2
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@@]2(Cc3ccc(N)cc3C2)c2cccnc21
Reactant: O=[N+]([O-])O
Agent: O=C(Nc1ccccc1)C(F)(F)F
Solvent: NCCN
Solvent: O
Solvent: ClCCl
Product: Nc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of (R)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (28.7 g, 75.2 mmol, described in Intermediate 3) in CH2Cl2 (100 mL) was added trifluoroacetic anhydride (106 mL, 752 mmol). The mixture was stirred for 10 min, after which time the aniline had been converted to the corresponding trifluoroacetanilide. The resulting mixture was cooled in an ice-salt bath and 15.8 M nitric acid (5.0 mL, 79 mmol) was added dropwise over 15 min, keeping the reaction temperature at 10-12° C. After the addition, the reaction mixture was stirred for 30 min, then H2O (12 mL) was carefully added, followed by trifluoroacetic acid (100 mL) and CH2Cl2 (100 mL). The mixture was allowed to warm to ambient temperature and stirring was continued for 2 h, followed by concentration to dryness in vacuo. The residue was dissolved in MeOH (200 mL) and the solution was adjusted to pH 10 by addition of 10 N NaOH. Ethylene diamine (5 mL, 75 mmol) was added and the mixture was stirred at ambient temperature for 18 h, then diluted with H2O (200 mL). The resulting solid was isolated by filtration, washed with H2O, and dried in vacuo to give the title compound. MS: m/z=297 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:21][C@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[C:18](I)[CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:5])C.[ClH:22]>C(#N)C>[Cl:22][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([N:12]2[C:11]3[C@@H:10]4[CH2:21][C@@H:9]4[CH2:8][C:7]=3[C:6]([C:4]([OH:3])=[O:5])=[N:13]2)[CH:19]=1
Reactant: Cl
Reactant: CCOC(=O)c1nn(-c2cc(I)ccn2)c2c1C[C@H]1C[C@@H]21
Solvent: CC#N
Product: O=C(O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of (1aR,5aR)-2-(4-iodo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (1.0 g, 2.53 mmol) in acetonitrile (30 mL) was added concentrated HCl solution (2 mL). The reaction was stirred at 80° C. for 20 h. After removal of acetonitrile, the aqueous residue was diluted with water and a NaHCO3 solution was added to adjust the pH to 2-3. The resulting mixture was extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was dissolved in a mixture of THF/MeOH/H2O (20/20/10) and added LiOH (61 mg). The reaction was stirred overnight and concentrated. The aqueous residue was diluted with water and an HCl solution was added to adjust the pH to 2-3. The resulting solid was filtered, washed with water and dried to give the title compound (610 mg). LCMS m/z=276.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 0.40 (dd, J=7.7, 4.5 Hz, 1H), 1.25 (td, J=7.9, 4.6 Hz, 1H), 2.25-2.30 (m, 1H), 2.71-2.75 (m, 1H), 2.76 (d, J=16.8 Hz, 1H), 2.87 (dd, J=16.4, 6.4 Hz, 1H), 7.55 (dd, J=5.4, 1.9 Hz, 1H), 7.90 (d, J=1.8 Hz, 1H), 8.52 (d, J=5.4 Hz, 1H), 12.98 (s, 1H).
Reaction SMILES: C([Si](C(C)C)(C(C)C)[O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[N:18]2[CH:19]=[C:20]([O:23][C@H:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C@@H:27]([NH2:34])[CH2:26][CH2:25]3)[CH:21]=[CH:22][C:17]2=[N:16][N:15]=1)(C)C.CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C[O:53][C:54](=O)[NH:55][C:56]1[N:57]([C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[CH:67][CH:66]=2)[N:58]=[C:59]([C:61]([CH3:64])([CH3:63])[CH3:62])[CH:60]=1>O1CCOCC1>[C:61]([C:59]1[CH:60]=[C:56]([NH:55][C:54]([NH:34][C@@H:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:24]([O:23][C:20]3[CH:21]=[CH:22][C:17]4[N:18]([C:14]([C@@H:10]5[CH2:11][CH2:12][CH2:13][N:9]5[CH2:8][CH2:7][CH2:6][OH:5])=[N:15][N:16]=4)[CH:19]=3)[CH2:25][CH2:26]2)=[O:53])[N:57]([C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[CH:67][CH:66]=2)[N:58]=1)([CH3:64])([CH3:62])[CH3:63]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)[Si](OCCCN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCCN5CCCO)n4c3)c3ccccc32)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of Intermediate 84g (140 mg, 0.25 mmol) in 1,4-dioxane (3.00 mL) was added DIPEA (86.0 μL, 0.50 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 100 mg, 0.25 mmol). The reaction was heated to 60° C. overnight then further (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (50.0 mg, 0.12 mmol) was added and heating at 60° C. continued overnight. The reaction was cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (70.0 mg, 34%). LCMS (Method 1): Rt 3.46, m/z 820.4 [MH+].
Reaction SMILES: [OH:1][C@@H:2]([CH2:13][CH:14]1[CH2:17][CH2:16][CH2:15]1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.CC1C=CC=C(C)N=1.[Si:41]([O:48][CH2:49][C@@H:50]1[C@@H:54]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:53][NH:52][CH2:51]1)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42].CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:1][C@@H:2]([CH2:13][CH:14]1[CH2:17][CH2:16][CH2:15]1)[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4].[Si:41]([O:48][CH2:49][C@@H:50]1[C@@H:54]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:53][N:52]([C@H:2]([CH2:13][CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH2:51]1)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Agent: O=C(OCc1ccccc1)[C@@H](O)CC1CCC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN([C@H](CC2CCC2)C(=O)OCc2ccccc2)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of 1.84 g (7.8 mmol) of 2-(S)-hydroxy-3-(cyclobutyl)propionic acid, benzyl ester (Hydroxy Ester 2) in 30 mL of CH2Cl2 at −5° C. was treated with 1.40 mL (8.4 mmol) of trifluoromethanesulfonic anhydride maintaining the internal temperature at less than 0° C. The resulting mixture was stirred cold for 2 min, then treated with 1.10 mL (9.6 mmol) of 2,6-lutidene, maintaining the internal temperature at less than 0° C. The resulting mixture was stirred cold for 30 min, then treated with a solution of 2.65 g (9.5 mmol) of 3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidine (Pyrroldine 1) in 10 mL of CH2Cl2 and 3.00 mL (31.2 mmol) of DIEA. The resulting mixture was warmed to rt and stirred for 20 h. The reaction was quenched with 50 mL of sat'd NaHCO3 and the quenched mixture was extracted with 200 mL of ether. The ether extract was dried over MgSO4 and concentrated. Flash chromtography on 150 g of silica gel using 20:1 v/v hexanes/ether as the eluant afforded 3.23 g (81 % based on Hydroxy Ester 2) of the title compound: 1H NMR (300 MHz) δ-0.25 (s, 3H), −0.21 (s, 3H), 0.84 (s, 9H), 1.57-2.07 (8H), 2.29-2.39 (2H), 2.66-2.77 (m, 2H), 2.93 (q, J=7.8, 1H), 3.06 (t, J=8.4, 1H), 3.19 (t, J=8.4, 1H), 3.26 (dd, J=2.1, 6.3, 1H), 3.45-3.60 (m, 2H), 5.15 (s, 2H), 7.17-7.38 (1OH).