Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:13]=4[C:7]=3[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:28][N:29]([CH3:33])[C:30]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:13]=4[C:7]=3[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1)=[O:31].[CH3:28][N:29]([CH3:33])[C:30]([C:17]1[CH:18]=[CH:19][C:13]2[C:7]3[C:8](=[O:12])[NH:9][C:10]4[C:5]([C:6]=3[O:15][C:14]=2[CH:16]=1)=[CH:4][CH:3]=[C:2]([OH:1])[CH:11]=4)=[O:31]
Reactant: O=c1[nH]c2cc(O)ccc2c2oc3cc(O)ccc3c12
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)Oc1ccc2c(c1)[nH]c(=O)c1c3ccc(O)cc3oc21
Product: CN(C)C(=O)c1ccc2c(c1)oc1c3ccc(O)cc3[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In 1.0 ml of dry N,N-dimethylformamide was dissolved 100 mg of 3,9-dihydroxy-5H-benzofuro[3,2-c]quinolin-6-one. To the solution were added successively 7.8 μl of triethylamine, 40 mg of dimethylcarbamyl chloride and 3 mg of 4-dimethylaminopyridine, and the mixture was stirred for 15 hours at room temperature. The reaction mixture was evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol/ethyl ether=10/1/2 by volume) to obtain 40 mg of 3-(N,N-dimethylcarbamoyloxy)-9-hydroxy-5H-benzofuro[3,2-c]quinolin-6-one and 25 mg of 9-(N,N-dimethylcarbamoyl)-3-hydroxy-5H-benzofuro[3,2-c]quinolin-6-one.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:11])[CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Br:1][C:2]1[S:6][C:5]([C:7]([C:8](=[CH:14][N:15]([CH3:17])[CH3:16])[C:9]#[N:10])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: N#CCC(=O)c1ccc(Br)s1
Product: CN(C)C=C(C#N)C(=O)c1ccc(Br)s1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3-(5-Bromothiophen-2-yl)-3-oxopropanenitrile (4g, 17 mmol) was treated with dimethyl formamide dimethylacetal and the mixture heated to 100° C. After 1 h, the mixture was allowed to cool down to room temperature. The yellow solid that precipitated was collected by suction filtration and washed well with diethyl ether. Yield=4.6 g. MS (M+H)+ 284.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[C:6]1[C:7]2[N:8]([C:16]([CH2:19][CH3:20])=[N:17][N:18]=2)[C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2>CN(C)C=O>[CH:1]([NH:4][C:6]1[C:7]2[N:8]([C:16]([CH2:19][CH3:20])=[N:17][N:18]=2)[C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Solvent: CN(C)C=O
Product: CCc1nnc2c(NC(C)C)nc3ccccc3n12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Isopropylamine (1.77 g., 0.03 mole) was added to a solution of 4-chloro-1-ethyl-[1,2,4]triazolo-[4,3-a]quinoxaline (2.3 g., 0.01 mole), the product of Example 4, in N,N-dimethylformamide (30 ml.). Within 30 minutes, a precipitate formed. The reaction mixture was then stirred overnight at room temperature. The precipitate was separated by filtration and washed with N,N-dimethylformamide. Recrystallization from ethanol then gave 1.6 g. (63% yield) of 4-isopropylamino-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 222°-4° C. Mass spectrum: m/e, 255 (P).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([CH2:12][C:13]1[N:17]([CH:18]2[CH2:20][CH2:19]2)[C:16]2[CH:21]=[C:22]([N:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[C:23]([F:25])=[CH:24][C:15]=2[N:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.O.[O:51]1CCC[CH2:52]1>>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[CH:12]=[C:13]2[N:17]([CH:18]3[CH2:19][CH2:20]3)[C:16]3[CH:21]=[C:22]([N:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]4)[C:23]([F:25])=[CH:24][C:15]=3[N:14]2[C:52]1=[O:51])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)nc(CC(=O)NOCc2ccccc2)n3C2CC2)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)n2c(=O)n(OCc4ccccc4)c(=O)cc2n3C2CC2)CC1
Yield: 5 %

Procedure:
tert-Butyl 4-[2-[[(benzyloxy)carbamoyl]methyl]-1-cyclopropyl-5-fluoro-6-benzimidazolyl]-1-piperazinecarboxylate (779 mg, 1.18 mmol) is dissolved in tetrahydrofuran (15 ml) and treated with N,N'-carbonyldiimidazole (480 mg, 2.96 mmol) and 1,8-diazabicyclo[5.4.0]-undec-7-ene (225 mg, 1.48 mmol). The suspension obtained is poured into water (200 ml) and then extracted with ethyl acetate. The organic phase is washed in succession with water and 10 percent sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated under reduced pressure and the residue is chromatographed on silica gel (eluent: ethyl acetate/n-hexane 8:2). The product is crystallized from ethyl acetate/n-hexane. There are obtained 42 mg (5%) of tert-butyl 4-[2-(benzyloxy)-5-cyclopropyl-8-fluoro-1,2,3,5-tetrahydro-1,3-dioxopyrimido[1,6-a]benzimidazol-7-yl]-1-piperazinecarboxylate.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1C=O.[I-].[CH2:15]([C@H:18]1[CH2:23][CH2:22][C@H:21]([C@H:24]2[CH2:29][CH2:28][C@H:27]([CH2:30][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:26][CH2:25]2)[CH2:20][CH2:19]1)[CH2:16][CH3:17].[CH3:50]C(C)([O-])C.[K+].Cl>C1COCC1.O>[F:13][C:2]([F:1])([F:12])[O:3][C:4]1[CH:5]=[CH:8][C:9]([CH:50]=[CH:30][C@H:27]2[CH2:26][CH2:25][C@H:24]([C@H:21]3[CH2:20][CH2:19][C@H:18]([CH2:15][CH2:16][CH3:17])[CH2:23][CH2:22]3)[CH2:29][CH2:28]2)=[CH:10][CH:11]=1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CC2)CC1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccccc1OC(F)(F)F
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=Cc3ccc(OC(F)(F)F)cc3)CC2)CC1
Temperature: 25 °C

Procedure:
95 g of trifluoromethoxybenzaldehyde in 150 ml of THF are added over the course of 2-3 hours at -10° to -5° to a mixture of 300 g of trans-4-(trans-4-propylcyclohexyl)cyclohexylmethyltriphenylphosphonium iodide, 56 g of potassium tert.-butoxide and 500 ml of THF. The mixture is allowed to warm to room temperature and neutralized using 2N HCl, water is added, and the mixture is extracted with methyl tert.-butyl ether. After work-up of the organic phase and purification by chromatography on silica gel, 1-(4-trifluoromethoxyphenyl)-2-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]ethene is obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([CH2:23][NH:22][CH2:21][CH:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:19]3)[CH2:15][CH2:14]2)=[O:12])=[CH:7][C:6]=1[CH3:30])([CH3:3])[CH3:2].IC.[CH2:33](N(CC)CC)C.C(Cl)[Cl:41]>>[ClH:41].[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:14][CH2:15][C:16]3([CH2:23][N:22]([CH3:33])[CH2:21][CH:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:19]3)[CH2:17][CH2:18]2)=[O:12])=[CH:7][C:6]=1[CH3:30])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: CCN(CC)CC
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CNCC(c2ccccc2)O3)ccc1OC(C)C
Solvent: CI
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(C)CC(c2ccccc2)O3)ccc1OC(C)C
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
To (4-isopropoxy-3-methyl-phenyl)-(8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl)methanone (22 mg, 0.05 mmol) in DCM (0.3 mL) was added iodomethane (15 mg, 7 μL, 0.11 mmol) followed by the addition of triethylamine (15 μL, 0.11 mmol) and the reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated in vacuo, diluted with methanol, filtered and purified by prep LCMS (1-99% ACN/H2O, 5 mM HCl modifier) to give (4-isopropoxy-3-methyl-phenyl)-(10-methyl-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl)methanone hydrochloride salt as a glassy solid (13 mg, 54%). ESI-MS m/z calc. 422.3. Found 423.5 (M+1)+; Retention time: 1.31 minutes (3 min run).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][N:4]=1.[CH3:9][C:10]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[C:13]([CH3:26])[C:11]=1[NH2:12]>>[CH3:9][C:10]1[CH:16]=[C:15]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][N:4]=2)[CH:14]=[C:13]([CH3:26])[C:11]=1[NH2:12]
Reactant: Brc1ccncn1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1N
Agent: Cl
Product: Cc1cc(-c2ccncn2)cc(C)c1N
Temperature: 70 °C
Reaction time: 12 h

Procedure:
The title compound is prepared from 4-bromopyrimidine hydrochloride and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline following a procedure analogous to that described in Step 2 of Intermediate 62. The mixture is stirred for 12 hours at 70° C. LC (method 9): tR=0.74 min; Mass spectrum (ESI+): m/z=200 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8]([O:11][C:12](=[O:14])[CH3:13])(=[O:10])[CH3:9]>>[C:8]([OH:11])(=[O:10])[CH3:9].[C:12]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)(=[O:14])[CH3:13]
Reactant: Nc1ccncc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccncc1
Product: CC(=O)O
Temperature: 100 °C
Yield: 88.3 %

Procedure:
4-Aminopyridine (101.28 g) and acetic anhydride (110 g) were mixed neat and heated at 100° C. for 1/2 h. The solidified reaction mixture was triturated with acetone, filtered off, and washed with ether to afford 186.48 g of title compound as a white solid in two crops.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=1.[C-:26]#[N:27].[K+].[OH-].[NH4+]>C(O)(=O)C>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11]([NH:23][C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:24])([F:25])[F:15])[CH:18]=3)([C:26]#[N:27])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [C-]#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: N#CC1(Nc2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of 378.5 parts of 1-(phenylmethyl)-4-piperidinone and 362.5 parts of 3-(trifluoromethyl)benzenamine in 1500 parts of acetic acid is stirred for 1 hour at room temperature: exothermic reaction (temperature rises to 40° C). After cooling, there are added 262.7 parts of potassium cyanide and the whole is stirred for 4 days at room temperature. The reaction mixture is poured onto a mixture of crushed ice and ammonium hyroxide and the product is extracted with trichloromethane. The extract is washed with a diluted ammonium hydroxide solution, dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and petroleum-ether (2:1 by volume), yielding 1-(phenylmethyl)-4-{[3-(trifluoromethyl)phenyl]amino}-4-piperidinecarbonitrile; mp. 96° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[CH2:12]([C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O)[CH3:13].[CH2:22]=[C:23]([CH3:25])[CH3:24].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][CH:16]([C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[CH2:12][CH3:13])[CH2:22][C:23]2([CH3:25])[CH3:24])=[O:11]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: C=C(C)C
Reactant: CCc1ccccc1C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCc1ccccc1C1CC(C)(C)c2cc(C(=O)OC)ccc2N1
Temperature: 85 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
To a stirred solution of 4-amino-benzoic acid methyl ester (1 g, 6 mmol) and 2-ethyl-benzaldehyde (1.2 g, 8.9 mmol) in acetonitrile (40 mL) were added isobutene (1.7 mL, 24 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (0.55 g, 0.9 mmol). The resulting mixture was stirred at 85° C. for 16 h in sealed tube. The mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL×2) and brine (50 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(2-ethyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1 g, 49%) as a light yellow solid: MS (ESI) M+1=337.0.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[O:14]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:26]([CH2:25][C:24]1[CH:27]=[CH:28][C:21]([O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:22][CH:23]=1)[CH2:11]2
Reactant: COC(=O)c1c(Cl)cccc1CBr
Reactant: NCc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C1c2c(Cl)cccc2CN1Cc1ccc(Oc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
A mixture of 2-bromomethyl-6-chloro-benzoic acid methyl ester (0.132 g, 0.5 mmol), 4-phenoxy benzylamine (0.124 g, 0.7 mmol), and K2CO3 (0.152 g, 1.1 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-chloro-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.06 g, 34%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.24 (s, 2H), 4.76 (s, 2H), 6.98-7.46 (m, 12H). GC-MS: m/z 349 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[N:22]1([CH2:27][C:28](O)=[O:29])[CH:26]=[N:25][N:24]=[N:23]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:28](=[O:29])[CH2:27][N:22]3[CH:26]=[N:25][N:24]=[N:23]3)[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C(O)Cn1cnnn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1cnnn1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 57.4 %

Procedure:
Preparation of example 12 from the title compound of Example 7 (15 mg, 0.054 mmol), tetrazol-1-yl-acetic acid (8 mg, 0.062 mmol), triethylamine (0.030 mL, 0.22 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) in N,N-dimethylformamide (1.0 mL) was carried out analogously to Example 11. Additional tetrazol-1-yl-acetic acid acid (1.0 mg, 0.008 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.0 mg, 0.008 mmol) were added after c.a. 18 hours to drive the reaction to completion. Filtration, concentration and recrystallization afforded the title compound (12 mg, 0.031 mmol) as a yellow powder in 58% yield.
Reaction SMILES: C([O:5][C:6]1C(C(=O)C=C(C)C)=C[S:8][CH:7]=1)(C)(C)C.C1(C)C=CC(S(O)(=O)=[O:24])=CC=1.[C:28]1([CH3:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:34][C:28]1([CH3:29])[C:33]2[CH:6]([O:5][CH:30]=[CH:31][CH:32]=2)[C:7](=[O:24])[S:8]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccccc1
Reactant: CC(C)=CC(=O)c1cscc1OC(C)(C)C
Product: CC1(C)SC(=O)C2OC=CC=C21

Procedure:
A solution of 3-t-butoxy-4-(3-methyl-1-oxo-2-buten-1-yl) thiophene (12.2 g, 51.2 mmol) and p-toluenesulfonic acid (0.5 g) in toluene was heated to reflux for 2 h. The solvent was evaporated in vacuo and the residue was purified by flash chromatography using 25% hexane in dichloromethane as the eluant to give 24 as a waxy tan solid, 5.9 g (63%); mp 42°-45 0C; IR(neat): 2977, 1692 and 1554 cm-1 ; MS: m/z 183 (MH+); 1H NMR(CDCl3): δ 1.44 (s,6H), 2.62 (s, 2H), 6.43 (d, J=3.3 Hz, 1H) and 8.00 (d, J=3.3 Hz, 1H).
Reaction SMILES: [CH:1]1([C@H:4]2[C:8](=O)[CH2:7][CH:6]([CH:10]3[CH2:12][CH2:11]3)[N:5]2[S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:3][CH2:2]1.C[N:27]([CH:29](OC)OC)C.O.[NH2:35]N>>[CH:1]1([CH:4]2[C:8]3[C:7](=[N:35][NH:27][CH:29]=3)[C@H:6]([CH:10]3[CH2:12][CH2:11]3)[N:5]2[S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(OC)N(C)C
Reactant: O=C1CC(C2CC2)N(S(=O)(=O)c2ccc(C(F)(F)F)cc2)[C@H]1C1CC1
Solvent: O
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1C(C2CC2)c2c[nH]nc2[C@@H]1C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.4 %

Procedure:
(2S)-2,5-Dicyclopropyl-1-(4-(trifluoromethyl)phenylsulfonyl)pyrrolidin-3-one (21) (149 mg, 0.399 mmol) and DMF-DMA (0.059 mL, 0.439 mmol) where heated at 60° C. for 1.5 hr under nitrogen. The reaction was concentrated in vacuo and used directly in next step. This material was dissolved in ethanol (1.5 mL) and acetic acid (0.075 mL). Hydrazine hydrate (0.1 mL, 20.0 mmol) was added dropwise and the reaction stirred for 16 hr at rt. The reaction was concentrated in vacuo and the resulting crude product was purified by column chromatography using EtOAc/hexane gradients to yield (6S)-4,6-dicyclopropyl-5-(4-(trifluoromethyl)phenylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (22) (30.7 mg, 19.4% over two steps) as a white solid. 1H-NMR (CDCl3) δ 8.01 (d, 2H, J=8.2 Hz), 7.71 (d, 2H, J=8.2 Hz), 7.19 (s, 1H), 4.59 (d, 1H, J=10.3 Hz), 4.57 (d, 1H, J=10.3 Hz), 1.35 (m, 2H), 0.81 (m, 1H), 0.68-0.44 (m, 5H), (m, 1H), 0.31 (m, 1H), 0.19 (m, 1H); MS (m/z) 398.1 (M+H)+; retention time=7.168, method [7].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:22]=1.[CH3:23][NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[CH3:23][NH:24][S:25]([C:28]1[CH:29]=[CH:30][C:31]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:22]=2)=[CH:32][CH:33]=1)(=[O:26])=[O:27]
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Reactant: CNS(=O)(=O)c1ccc(B(O)O)cc1
Product: CNS(=O)(=O)c1ccc(-c2ccc3oc(C4CCN(C(=O)OC(C)C)CC4)nc3c2)cc1
Yield: 14.2 %

Procedure:
Following the General Procedure-3, the titled compound (35 mg) was prepared from Intermediate 13 (200 mg, 0.54 mmol) and 4-(N-methylsulfamoyl)phenylboronic acid (120 mg, 0.54 mmol) as a white solid. M.P.: 179-181° C. MS (m/z): 458.3 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[C:9]([F:17])[CH:8]=1.[OH-].[Li+].CO>O1CCCC1.O>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[C:9]([F:17])[CH:8]=1
Reactant: COC(=O)c1ccc(C2OCCCO2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2OCCCO2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of EXAMPLE 22A (1.9 g) in tetrahydrofuran (10 mL) and water (5 mL) was added lithium hydroxide (1 g) in water (5 mL). Methanol was added until homogeneous and the solution stirred at ambient temperature for 4 hours. The mixture was concentrated to 5 mL and the residue acidified to pH 2 with 2 N hydrochloric acid. Ethyl acetate and water were added and the organic phase separated, washed with water, dried over magnesium sulfate, filtered and concentrated to give the title compound (1.7 g, 95%). MS (DCI): m/z 227 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][NH2:17])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[F:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][NH:17][C:25](=[O:27])[CH3:26])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2
Reactant: Cn1cc2c3c(c(F)cc2n1)CCC3=CCN
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NCC=C1CCc2c(F)cc3nn(C)cc3c21
Reaction time: 0.25 h
Yield: 89 %

Procedure:
2-(5-Fluoro-2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-ylidene)ethanamine (78.0 mg, 0.337 mmol) was dissolved in tetrahydrofuran (3.4 mL), triethylamine (56.4 μL, 0.404 mmol) and acetic anhydride (35.0 μL, 0.371 mmol) were added under ice-cooling, and the mixture was stirred for 15 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crystals were washed with diisopropyl ether to give the title compound (82.0 mg, yield 89%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16](Cl)=[N:15][CH:14]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[CH3:22].C(OC(=O)C1C=CC(N2CCN(C3C=CC(C(=O)NC4C=CC(C)=C(I)C=4)=CN=3)CC2)=CC=1)C>CCOC(C)=O>[CH2:21]([O:23][C:24](=[O:37])[C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:32][CH2:33][N:34]([C:16]3[CH:17]=[CH:18][C:13]([C:12](=[O:20])[NH:11][C:7]4[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[CH:9][N:8]=4)=[CH:14][N:15]=3)[CH2:35][CH2:36]2)=[CH:29][CH:30]=1)[CH3:22]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)c1ccnc(NC(=O)c2ccc(Cl)nc2)n1
Agent: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4nccc(C(C)(C)C)n4)cn3)CC2)cc1

Procedure:
4-{4-[5-(4-tert-Butyl-pyrimidin-2-ylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester was prepared from N-(4-tert-butyl-pyrimidin-2-yl)-6-chloro-nicotinamide and 4-(piperazin-1-yl)-benzoic acid ethyl ester following a method similar to the one described in the synthesis of 4-{4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester above. The product was isolated after silica gel column with 30-100% EtOAc in hexanes. HRMS m/z calcd for C27H32N6O3 [M+H]+: 489.2609. Found: 489.2609.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][O:15][CH2:16][CH3:17])[N:8]=1.[I:18]I.[BH4-].[Na+].C1[CH2:26][O:25]CC1>COCCOC.O>[Cl:6][C:7]1[N:8]=[C:9]([O:13][CH2:14][O:15][CH2:16][CH3:17])[C:10]([CH2:26][OH:25])=[C:11]([I:18])[CH:12]=1
Reactant: C1CCOC1
Reactant: CCOCOc1cccc(Cl)n1
Reactant: II
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOCOc1nc(Cl)cc(I)c1CO
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
To a solution of 2.5M n-butyllithium (2.2 mL, 5 mmol) in 20 mL of THF at -10° C. was added 0.94 g 2-chloro-6-(ethoxymethoxy)pyridine (5 mmol) dropwise over 2 min. The reaction mixture was stirred for 10 min. at -10° C., then cooled to -23° C. and 0.72% N-formyl-N,N',N'-trimethytethylenediamine) was added. After stirring at -23° C. for 30 min., n-butyllithium (2.5M, 3 mL, 7.5 mmol) was added dropwise and the dark reaction mixture was stirred at -23° C. for 4 hr. The mixture was transferred via a double-tipped meedle to a solution of 1.9 g of iodine (7.5 mmol) in 10 mL of DME and 10 mL of THF at -78° C. After stirring at -78° C. for 30 min., the cooling bath was removed. 0.3 g of solid sodium borohydride (8 mmol) was added to the red mixture. 10 mL of water was added dropwise with vigorous stirring. After 30 min., the mixture was extracted with three 20-mL portions of EtOAc. The combined organic layers were washed with 20 mL of 10 percent sodium thiosulfate solution, water and brine. After drying over sodium carbonate, the solvents were removed under reduced pressure to yield the 1.3 g of crude product, which was purified by radial PLC (10% EtOAc/hexane) to give 0.7 g (40%) of pure product as a white solid, mp 43°-44° C. 1H NMR (300 MHz, CDCl3) δ7.43 (s, 1H), 5.62 (s, 2H), 4.79 (s, 2H), 3.78 (q, 2H, J=7.1 Hz), 2.24 (brd, 1H), 1.26 (t, 3H, J=7.1 Hz). 13C NMR (75 MHz, CDCl3) δ158.9, 147.8, 127.3, 124.7, 113.5, 92.0, 66.0, 63.2, 15.0. Analysis Calculated for C9H11ClNO3 : C, 31.47; H, 3.23; N, 4.08. Found: C, 31.68; H, 3.28; N, 4.13.