Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH:14]=1)[C:9]([OH:11])=O.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[CH:20]1([NH:23][C:9](=[O:11])[C:8]2[CH:12]=[C:13]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH:14]=[C:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=2)[CH2:22][CH2:21]1
Reactant: COCCCc1cc(CCCOC)cc(C(=O)O)c1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCCCc1cc(CCCOC)cc(C(=O)NC2CC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3,5-bis(3-methoxypropyl)benzoic acid (1 eq.) from the previous step in DCM (0.1 M) was added cyclopropanamine (1.3 eq.), o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (aka. HATU, 1.5 eq.), and triethylamine (3 eq.). After stirring at rt for 18 h, the reaction was diluted with EtOAc. The organic extract was washed with 10% aqueous HCl solution, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 50%→>70% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: C(N1CC(=C([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][Br:34])[CH:24]=2)S(C)(=O)=O)C1)(C1C=CC=CC=1)C1C=CC=CC=1.BrCCCCBr.C(=O)([O-])[O-].[K+].[K+].[CH:47]([N:60]1[CH2:63][C:62](=[C:64](C2C=CC=C(O)C=2)[S:65]([CH3:68])(=[O:67])=[O:66])[CH2:61]1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CC(CC)=O>[CH:47]([N:60]1[CH2:61][C:62](=[CH:64][S:65]([CH2:68][C:27]2[CH:28]=[CH:23][CH:24]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][Br:34])[CH:26]=2)(=[O:67])=[O:66])[CH2:63]1)([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1cccc(O)c1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1cccc(OCCCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: BrCCCCBr
Product: O=S(=O)(C=C1CN(C(c2ccccc2)c2ccccc2)C1)Cc1cccc(OCCCCBr)c1

Procedure:
1-Benzhydryl-3-{[3-(4-bromobutoxy)phenyl]-methanesulfonylmethylene}azetidine may be prepared in the following manner: 0.586 cm3 of 1,4-dibromobutane and 255 mg of potassium carbonate are successively added at a temperature close to 20° C., under an inert atmosphere of argon, to a solution of 500 mg of 1-benzhydryl-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine in 10 cm3 of methylethyl ketone. The reaction mixture is heated at the reflux temperature of the solvent, under an inert atomosphere of argon, for 7 hours and then left at a temperature close to 20° C. for about 4 days. The reaction mixtue is filtered on sintered glass covered with celite. The solid residue is rinsed with ethyl acetate and then the filtrate is concentrated to dryness under reduced pressure (10 kPa) at a temperature close to 40° C. The brown oil obtained is purified by chromatography at atmospheric pressure on 40 g of silica (0.063-0.200 mm) contained in a column 3 cm in diameter, eluting with a methanol-dichloromethane mixture (0.5-99.5 by volume). The fractions (10 cm3) containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40° C. for 2 hours, 408.4 mg of 1-benzhydryl-3-{[3-(4-bromobutoxy)phenyl]methanesulfonylmethylene}azetidine are thus obtained in the form of a brown foam.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:21]([CH:18]([N:13]1[C:12]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH2:19][CH3:20])[CH3:22]
Reactant: OB(O)c1ccccc1
Reactant: CCC(CC)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCC(CC)n1nc2c(c1-c1ccccc1)CCNCC2
Yield: 42.9 %

Procedure:
The title compound (40 mg) was prepared as in Example 177, Steps C and D, using 150 mg of 2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 183, Step A) and 120 mg of phenylboronic acid. MS (ESI): exact mass calculated for C18H25N3, 283.20; found, m/z 284.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.48-7.38 (m, 3H), 7.24-7.19 (m, 2H), 3.77-3.70 (m, 1H), 3.36-3.31 (m, 2H), 3.24-3.19 (m, 2H), 3.14-3.09 (m, 2H), 2.71-2.65 (m, 2H), 1.85-1.75 (m, 2H), 1.68-1.58 (m, 2H), 0.61 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)=[C:4]([C:18]#[N:19])[CH:3]=1.O1CCCC1.[CH3:25][NH:26][CH3:27].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[N:26]([CH3:27])[CH3:25])=[C:4]([C:18]#[N:19])[CH:3]=1
Reactant: CNC
Reactant: N#Cc1cc(Cl)ccc1NC(=O)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)Nc1ccc(Cl)cc1C#N
Reaction time: 8 h

Procedure:
(Step 2) To a solution of phenyl (4-chloro-2-cyanophenyl)carbamate obtained in Step 1 (3.0 g) in tetrahydrofuran (30 ml) was added 2N dimethylamine tetrahydrofuran solution at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into saturated sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4→2:3) to give 3-(4-chloro-2-cyanophenyl)-1,1-dimethylurea (2.33 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15]2[N:21]([CH3:34])[C:22](=[O:33])[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=4[Cl:32])=[CH:24][C:14]3=2)[N:8]([CH2:35][CH3:36])[N:7]=1)=O)C.[BH4-].[Na+].C(Cl)Cl.CO>C(O)C>[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[C:23]1[C:22](=[O:33])[N:21]([CH3:34])[C:15]2[N:16]([CH3:20])[C:17]3[C:13]([C:14]=2[CH:24]=1)=[CH:12][C:11]([C:9]1[N:8]([CH2:35][CH3:36])[N:7]=[C:6]([CH2:4][OH:3])[CH:10]=1)=[CH:19][CH:18]=3
Reactant: CCOC(=O)c1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n(CC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CCn1nc(CO)cc1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C

Procedure:
450 mg (0.86 mmol) of compound from Example 59, 5-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-1-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester, are dissolved in 10 ml of absolute ethanol and 42 mg (1.12 mmol) of NaBH4 are added. The mixture is refluxed overnight. The reaction medium is allowed to return to ambient temperature, CH2Cl2 and MeOH are added, and the product is adsorbed onto silica. Purification is carried out on a silica column, elution being carried our with EtOAc, and then with a 95/05 EtOAc/MeOH mixture. The oil obtained is triturated in ether.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C(=O)=O.CC(C)=O.[CH3:15][C@H:16]([NH:20][C:21](=[O:27])OC(C)(C)C)[C:17](=[O:19])[CH3:18].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[OH:19][C@:17]1([CH3:18])[C@H:16]([CH3:15])[NH:20][C:21](=[O:27])[CH2:1]1
Reactant: CC(C)NC(C)C
Reactant: CC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]1NC(=O)C[C@]1(C)O
Reaction time: 0.33 h
Yield: 48.9 %

Procedure:
A solution of diisopropylamine (3.44 g) in tetrahydrofuran (50 mL) was ice-cooled under a nitrogen atmosphere and 1.6 mol/L n-butyllithium-hexane solution (20.8 mL) was added. The mixture was stirred at the same temperature for 20 min, and the reaction solution was cooled with dry ice/acetone. Ethyl acetate (3.28 mL) was added to the reaction solution, and the mixture was stirred at the same temperature for 30 min. A solution of tert-butyl [(1S)-1-methyl-2-oxopropyl]carbamate (4.48 g) in tetrahydrofuran (10 mL) was added. The mixture was stirred at the same temperature for 5 hr, saturated aqueous ammonium chloride solution (100 mL) was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→30%), the obtained oil was dissolved in 4 mol/L hydrogen chloride-ethyl acetate solution (50 mL), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (150 mL), and diisopropylethylamine (11.5 mL) was added. The reaction solution was refluxed under heating for 4 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol/ethyl acetate=0→10%), and the obtained solid was recrystallized from isopropanol/hexane to give the title compound as colorless crystals (yield: 1.51 g, 55%).
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[N:4]=[CH:3][CH:2]=1.[C:12]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][CH:2]=[N:1]2
Reactant: Oc1cccc2nccnc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc2nccnc12
Temperature: 50 °C

Procedure:
To quinoxalin-5-ol (0.43 g) dissolved in DMF (6 ml) was added K2CO3 (2.5 eq.) and KI (0.2 eq.). To this mixture was then added dropwise iodomethane (1.2 eq.). The resulting mixture then heated to 50° C. overnight. The reaction mixture was subsequently partitioned between satd. NaHCO3 and EtOAc, the EtOAc layer backwashed with water and brine, dried over Na2SO4, and concentrated to dryness under vacuum. The crude material was then purified by SGC (MeOH:DCM) affording 5-methoxyquinoxaline. MS (ESI+) for m/z 160 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([C:14]1[CH:15]=[C:16]([OH:21])[C:17](=[CH:19][CH:20]=1)[OH:18])([CH3:13])([CH3:12])[CH3:11]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:18][C:17]2[CH:19]=[CH:20][C:14]([C:10]([CH3:13])([CH3:11])[CH3:12])=[CH:15][C:16]=2[O:21][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(C)c1ccc(O)c(O)c1
Product: CC(C)(C)c1ccc(Oc2ccc(C#N)cc2)c(Oc2ccc(C#N)cc2)c1
Yield: 96.1 %

Procedure:
The compound 4-fluorobenzonitrile was reacted with 4-tert-butylcatechol according to the procedure of Example 1. The product was recrystallized from methanol/water (3:1) to give a 96.1% yield of the title compound with the formula: ##STR12##
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[O:15][N:14]=[C:13]([C:16]3([C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=5)=[CH:22][CH:21]=4)[CH2:19][CH2:18][CH2:17]3)[N:12]=2)[CH:8]=[N:7]1)C.C1COCC1.O.[OH-].[Li+].Cl>O.CO>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:23]2[CH:24]=[CH:25][C:20]([C:16]3([C:13]4[N:12]=[C:11]([C:9]5[CH:8]=[N:7][N:6]([CH2:5][C:4]([OH:33])=[O:3])[CH:10]=5)[O:15][N:14]=4)[CH2:19][CH2:18][CH2:17]3)=[CH:21][CH:22]=2)=[CH:27][N:28]=1
Reactant: CCOC(=O)Cn1cc(-c2nc(C3(c4ccc(-c5cnc(N)nc5)cc4)CCC3)no2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ncc(-c2ccc(C3(c4noc(-c5cnn(CC(=O)O)c5)n4)CCC3)cc2)cn1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
R102 (784 mg, 1.76 mmol) is treated with THF (7.0 mL), methanol (1.5 mL), water (3.0 mL), and lithium hydroxide monohydrate (222 mg, 5.28 mmol) and the resulting mixture is stirred at 40° C. for 1.5 hours. The mixture is then treated with 1N hydrochloric acid (5.28 mL, 5.28 mmol) and concentrated in vacuo to afford R103 (960 mg).
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][C:22]([CH2:24][C:25](O)=[O:26])=[O:23])=[CH:18][CH:19]=2)[C:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:28])[CH2:13][C:12]1([CH3:36])[CH3:35])(=[O:10])[CH3:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][C:22]([CH2:24][C:25]([O:7][CH2:1][C:2]3[O:6][CH:5]=[CH:4][CH:3]=3)=[O:26])=[O:23])=[CH:18][CH:19]=2)[C:14]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([CH3:28])[CH2:13][C:12]1([CH3:36])[CH3:35])(=[O:10])[CH3:9]
Reactant: OCc1ccco1
Reactant: CC(=O)N1c2ccc(NC(=O)CC(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)CC(=O)OCc3ccco3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Condensation of furfuryl alcohol (17 μl) and 1-acetyl-6-(hydroxycarbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (15 mg) under the agency of HATU (29 mg) and N,N-diisopropylethylamine (33 l) in tetrahydrofuran (2 ml) was performed according to the method described in example 11.
Reaction SMILES: I[CH2:2][CH3:3].[NH:4]1[CH2:8][CH2:7][C@H:6]([CH2:9][C:10]#[N:11])[CH2:5]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:2]([N:4]1[CH2:8][CH2:7][C@H:6]([CH2:9][C:10]#[N:11])[CH2:5]1)[CH3:3]
Reactant: N#CC[C@H]1CCNC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CC[C@H](CC#N)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
Iodoethane (6.46 g) was added in portions to a cooled mixture of 2-((R)-pyrrolidin-3-yl)acetonitrile (Intermediate 210, 4.6 g) and potassium carbonate (8.6 g) in acetonitrile (30 mL) at 0° C. The mixture was stirred for 3 hours at 0° C. then concentrated under vacuum. The residue was partitioned between water and DCM. The organic layer was washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 2-((R)-1-ethylpyrrolidin-3-yl)acetonitrile (2.1 g) as a colourless liquid which was used without further characterisation.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]1.CN1C(=O)CCC1>O>[N+:16]([C:3]1[CH:4]=[C:5]([S:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[S:6][C:2]=1[N:19]1[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]1)([O-:18])=[O:17]
Reactant: O=C(O)C1CCNCC1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)N2CCCCC2)sc1Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)C1CCN(c2sc(S(=O)(=O)N3CCCCC3)cc2[N+](=O)[O-])CC1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
The mixture of 310 mg of 1-(5-chloro-4-nitrothiophene-2-sulfonyl)piperidine, 250 mg of piperidine-4-carboxylic acid and 3 ml of NMP is stirred at 85° C. for 1 h, cooled, diluted with 15 ml of water and stirred. The precipitate is filtered off with suction, washed with water and recrystallized from isopropanol/water (4:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[CH:5]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2ccc(OC)cc2)c1
Yield: 99.3 %

Procedure:
To a solution of methyl-3-hydroxybenzoate (5.0 g, 32.8 mmol) in acetone (30 mL) was added potassium carbonate (6.82 g, 49.2 mmol) and p-methoxybenzyl chloride (4.5 mL, 32.8 mmol). The contents are heated under reflux for forty eight hours, concentrated under pressure and partitioned between ethyl acetate (100 mL) and water (100 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to yield the title compound (8.87 g, 99%). 1H NMR (CDCl3): □ 7.8 (m, 2H), 7.4 (m, 3H), 7.15 (m, 1H), 6.9 (d, 2H), 5.1 (s, 2H), 3.9 (s, 3H), 3.8 (s, 3H).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:3](=[O:24])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])=[N:6][CH:5]=2)[CH2:27][CH2:26]1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Reactant: NC1CC1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 82 %

Procedure:
As described for example 272, 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (97.6 mg, 0.3 mmol) was converted, using cyclopropylamine instead of 4-aminotetrahydropyran, to the title compound (86 mg, 82%) which was obtained as a white solid. MS: m/e=365.4 [M+H]+.
Reaction SMILES: COC1C=CC(O)=CC=1.C[O:11][C:12]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=1[CH:14]=[O:15]>>[OH:11][C:12]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: COc1ccc(OC)c(C=O)c1
Agent: COc1ccc(O)cc1
Product: COc1ccc(O)c(C=O)c1
Yield: 82 %

Procedure:
The oil from Example 1 was distilled at 10 mm through a 6-inch Vigreaux column. A light yellow fraction boiling at 124-129° C. was collected. The liquid chromatograph area percentage was 95% and the liquid chromatographic weight percentage was 90%. The overall assay yield based on the starting 4-methoxyphenol was 70%. The distilled oil was then converted to 2,5-dimethoxybenzaldehyde via the procedure in Comparative Example 1 (a). An 82% yield of light yellow crystals having a liquid chromatograph weight percent assay of 99.3% was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH2:2][C:3]2[O:4][C:5](=[O:9])[O:6][C:7]=2[CH3:8])=[CH:14][CH:13]=1
Reactant: Cc1oc(=O)oc1CCl
Reactant: COc1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(SCc2oc(=O)oc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
In 40 ml of dichloromethane was dissolved 2.0 g of 4-chloromethyl-5-methyl-1,3-dioxol-2-one, and 1.9 g of 4-methoxybenzenethiol was added. Then, 1.4 g of triethylamine was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate. The insoluble materials were separated by filtration, and the solvent was evaporated under reduced pressure. The residue was subjected to medium-pressure silica gel column chromatography as in Example 1. The eluate was evaporated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 2.3 g of the captioned compound as pale yellow crystals.
Reaction SMILES: O.[NH2:2][C@@H:3]1[CH2:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][C@@H:5]([OH:12])[C@H:4]1[OH:13].[CH2:14](O)[CH3:15].S(Cl)([Cl:19])=O.S(OCC)(OCC)=O>C(OCC)(=O)C>[ClH:19].[CH2:14]([O:10][C:9]([C:7]1[CH2:8][C@@H:3]([NH2:2])[C@H:4]([OH:13])[C@H:5]([OH:12])[CH:6]=1)=[O:11])[CH3:15]
Reactant: N[C@@H]1CC(C(=O)O)=C[C@@H](O)[C@H]1O
Reactant: CCO
Reactant: O=S(Cl)Cl
Agent: CCOS(=O)OCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C[C@@H](O)[C@@H](O)[C@H](N)C1
Product: Cl
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
In a 50 ml round bottom flask equipped with a reflux condenser, a magnetic stirrer and an inert gas supply, 1.91 g (10.0 mmol) (3R,4S,5R)-5-amino-3,4-dihydroxy-cyclohex-1-enecarboxylic acid mono hydrate was suspended with 19 ml ethanol and cooled to 0-5° C., treated slowly (3 min) with 0.80 ml (11.0 mmol) thionyl chloride, then 1.28 ml (10.0 mmol) diethyl sulfite was added, the mixture was heated to reflux for 3 hours (a gas mixture was evolved), the black reaction mixture was cooled to 20-25° C., to the black suspension, 19 ml ethyl acetate was added dropwise in the course of 30 min, then the mixture was cooled to 0-5° C. and stirred for 1 hour at 0-5° C. The black suspension was filtered, the filter cake was washed portion wise with a mixture of 6.5 ml ethanol and 6.5 ml ethylacetate. The light grey crystals were dried at 40° C./10 mbar/1 h, to obtain 1.57 g (3R,4S,5R)-5-amino-3,4-dihydroxy-cyclohex-1-enecarboxylic acid ethyl ester hydrochloride, as light grey crystals.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]1>O1CCOCC1.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:25]3[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: OC1CCNC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CO
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC(O)C3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 200 mg, 0.604 mmol) and pyrrolidin-3-ol (80 mg, 0.906 mmol) in Dioxane (6 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 5-95% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (52.5 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ: 10.63 (s, 1H), 7.82-8.10 (m, 3H), 7.58 (d, 2H), 7.05 (s, 1H), 6.17 (d, J=2.3 Hz, 1H), 5.17 (s, 1H), 5.10 (d, J=3.3 Hz, 1H), 4.43 (br. s., 1H), 3.87-4.13 (m, 4H), 1.87-2.12 (m, 2H), 1.45 (s, 6H). ESI-MS: m/z 382.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.[CH2:36](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)C1C=CC=CC=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH:35][C:14](=[O:16])[C@@H:9]([N:8]([CH3:36])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)(=[O:25])=[O:26])=[CH:22][CH:23]=1
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(F)cc3)C[C@@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)C[C@@H](C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(F)cc3)C[C@@H]21)N(C)C(=O)OC(C)(C)C

Procedure:
tert-butyl(S)-1-((3aR,4S,6aS)-2-(4-fluorophenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-ylamino)-4-methyl-1-oxopentan-2-yl(methyl)carbamate was prepared by substituting (S)-2-(tert-butoxycarbonyl(methyl)amino)-4-methylpentanoic acid for N-(tert-butoxycarbonyl)-L-leucine and (3aR,4S,6aS)-2-(4-fluorophenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 261 Step A for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.94 (dd, J=8.1, 5.2, 2H), 7.44-7.37 (m, 1H), 7.20 (t, J=8.5, 2H), 4.85-4.77 (m, 1H), 4.12-4.03 (m, 1H), 3.61-3.55 (m, 1H), 3.27-3.21 (m, 1H), 3.13-3.02 (m, 2H), 2.93 (s, 3H), 2.59-2.44 (m, 2H), 1.83 (ddd, J=37.1, 15.2, 5.0, 4H), 1.50 (d, J=0.6, 2H), 1.46 (d, J=0.8, 9H), 1.33-1.22 (m, 1H), 0.89 (t, J=7.2, 6H); MS (ESI+) m/z 512 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[CH:12]1([NH:17][OH:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N+:17]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[O-:18])[CH3:2]
Reactant: ONC1CCCC1
Reactant: CCOc1ccccc1C=O
Product: CCOc1ccccc1C=[N+]([O-])C1CCCC1
Yield: 72.6 %

Procedure:
Using 2-ethoxybenzaldehyde and N-cyclopentylhydroxylamine and following the procedures described herein, the title compound was obtained in 72.6% yield as white crystals, m.p. 87.3° C. (Rf =0.43 on a silica gel plate using hexanes:EtOAc, 2:1, v:v, as an eluant).