Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH2:43])[CH:38]=[CH:39][C:40]=1[F:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH:43][C:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[N:28]=2)=[O:30])[CH:38]=[CH:39][C:40]=1[F:41]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Reactant: NCc1ccc(F)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(Br)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.4 %

Procedure:
A mixture of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (900 mg, 1.989 mmol), 1-(3-bromo-4-fluorophenyl)methanamine (406 mg, 1.989 mmol), HBTU (905 mg, 2.387 mmol) and Et3N (1.386 mL, 9.94 mmol) in DCM was stirred at room temperature overnight. The reaction did not go to completion overnight. An additional equivalent of each reagent was added and the reaction stirred over the weekend. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give the crude residue. It was then purified using flash chromatography eluting with 0 to 100% ethyl acetate in hexane (product came out at 100% ethyl acetate in hexane). However, this product batch was not pure. It was purified with a Gilson HPLC. Product crashed out from the HPLC solution. The solid was filtered to obtain N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (120 mg) as a solid. The mother liquor was purified with a Gilson HPLC to obtain another batch of N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (160 mg). LC-MS m/z 638.4 (M+H)+, 0.89 min (ret time).
Reaction SMILES: [N:1]([CH:4]([C:8]1[N:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10](=[O:18])[C:11]2[C:16]([CH3:17])=[N:15][S:14][C:12]=2[N:13]=1)[CH:5]([CH3:7])[CH3:6])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH:4]([C:8]1[N:9]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:10](=[O:18])[C:11]2[C:16]([CH3:17])=[N:15][S:14][C:12]=2[N:13]=1)[CH:5]([CH3:7])[CH3:6]
Reactant: Cc1nsc2nc(C(N=[N+]=[N-])C(C)C)n(Cc3ccccc3)c(=O)c12
Agent: [Pd]
Solvent: CO
Product: Cc1nsc2nc(C(N)C(C)C)n(Cc3ccccc3)c(=O)c12
Temperature: 25 °C

Procedure:
To a solution of 6-(1-azido-2-methyl-propyl)-5-benzyl-3-methyl-5H-isothiazolo[5,4-d]pyramidin-4-one (method 29) (0.5 g, 1.41 mmol) in methanol (20 mL) was added 5% Pd/C (20% by wt.) and the resulting mixture was stirred at r.t. in an atmosphere of H2 and the progress of the reaction was monitored by MS. After the disappearance of the starting material the reaction mixture was filtered through celite and washed with EtOAc. Concentration of the filtrate provided 6-(1-amino-2-methyl-propyl)-5-benzyl-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one as a thick oil. The product was used as such in the next reaction with out further purification. m/z 349 (MH+).
Reaction SMILES: CC1C=CC(S(O[CH:12]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([N+:24]([O-:26])=[O:25])[CH:15]=2)[CH3:13])(=O)=O)=CC=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(C(C)C)CC)(C)C>C1COCC1>[N+:24]([C:16]1[CH:15]=[C:14]([CH:12]([N:37]2[CH2:36][CH2:35][N:34]([C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH2:39][CH2:38]2)[CH3:13])[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=1)([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OC(C)c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 77.1 %

Procedure:
Stir the mixture of 1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl 4-methylbenzenesulfonate (350 mg, 0.90 mmol), 1-piperazinecarboxylic acid tert-butyl ester (335 mg, 1.8 mmol) and diisopropylethylamine (232 mg, 1.8 mmol) in THF (10 mL) for 12 hrs at 80° C. Concentrate the reaction mixture to obtain the crude product, purify by flash chromatography (silica gel, EtOAc:PE=1:10) to afford the title compound (280 mg, 77.1%). MS: (M+1): 404.2.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:26]=[CH:25][S:24][CH:23]=2)=[CH:16][C:4]=1[O:5][CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([OH:9])=O)#[N:2].C(=O)=O.[CH:30]([C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1)([CH3:32])[CH3:31].[H-].[Na+]>ClCCl.CN(C)C=O>[C:1]([C:3]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:26]=[CH:25][S:24][CH:23]=2)=[CH:16][C:4]=1[O:5][CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([NH:42][S:39]([C:36]1[CH:37]=[CH:38][C:33]([CH:30]([CH3:32])[CH3:31])=[CH:34][CH:35]=1)(=[O:40])=[O:41])=[O:9])#[N:2]
Reactant: CC(C)c1ccc(S(N)(=O)=O)cc1
Reactant: N#Cc1ccc(OCc2ccsc2)cc1OC(C(=O)O)c1ccccc1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1ccc(S(=O)(=O)NC(=O)C(Oc2cc(OCc3ccsc3)ccc2C#N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 2 (0.73 g) in dry dichloromethane (50 ml) was treated with N,N' carbonyidilmidazole (0.36 g) and stirred at 25° C. for 2 hours, when evolution of carbon dioxide was complete. A solution of 4-isopropylbenzenesulphonamide (0.60 g) in dry dimethylformamide (20 ml) was treated with sodium hydride (0.13 g, 60% dispersion in mineral oil) and stirred at 25° C. for 2 hours. This solution was then treated dropwise with the solution of acylimidazole prepared above and stirring was continued at 25° C. for 8 hours. The reaction mixture was evaporated, the residue diluted with water (50 ml) and extracted twice with ethyl acetate. The extracts were washed with water, dried and evaporated to give an orange oil which was purified by flash chromatography on silica eluting with ether. Fractions homogenous in the required product were combined and evaporated. The residual pale yellow solid (0.35 g) was recrystallized from a mixture of ethyl acetate and pentane affording the title compound (0.20 g) as colourless crystals, m.p. 187-189° C. [Elemental analysis:- C,63.7; H,4.79; N,5.12%. Calculated:- C,63.7; H,5.17; N,5.17%].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:15]=[CH:14][N:13]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=4)[N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]3)=[CH:45][CH:44]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][N:13]1[CH:14]=[CH:15][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:43]4[CH:44]=[CH:45][C:46]([N:49]5[CH2:50][CH2:51][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:53][CH2:54]5)=[CH:47][CH:48]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=3)(=[O:27])=[O:26])[CH:9]=2)=[N:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(Cc4cc(F)cc(F)c4)n3)c3cc(Br)cnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(Cc4cc(F)cc(F)c4)n3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 28.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3,5-difluorobenzyl)-1H-pyrazol-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (intermediate 63) (150 mg, 0.276 mmol) was coupled with 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (intermediate 40) (139 mg, 0.359 mmol) using sodium carbonate (82 mg, 0.78 mmol) and Pd(PPh3)4 (10 mg, 0.013 mmol) in DME/water (10/1 ml). This afforded 58 mg (28.7% yield) after purification by column (Silica gel 60/120) using 20% ethyl acetate in hexane as eluent. MS: m/z=725.4 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].N1C=CC=CC=1.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(Cl)Cl>[S:35]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])([C:32]1[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=1)(=[O:37])=[O:36]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCCCCCCCCCCCCCCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 16 h
Yield: 84.9 %

Procedure:
In 50 ml of methylene chloride, methyl 18-hydroxyoctadecanoate (4.5 g, 14.3 mmoles) was dissolved. To the obtained solution was added pyridine (4.53 g, 57.2 mmoles), and then was gradually added p-toluenesulfonyl chloride (5.46 g, 28.6 mmoles) with ice-cooling over a period of 1 hour. Thereafter, reaction was carried out for 16 hours in a refrigerator. The reaction mixture was washed with a 10% aqueous hydrochloric acid solution, water, saturated aqueous sodium hydrogen carbonate solution, water and aqueous sodium chloride solution in this order, dried, and then concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (eluent: benzene) to give methyl 18-tosyloxyoctadecanoate (5.69 g, 85%) having the following properties.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]1)[NH:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]1)[N:12]=[C:11]2[N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNCC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(Cc4ccccc4)cc3c(=O)[nH]2)c1
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2cc(Cl)c(Cc3ccccc3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI): predicted mass calcd. for C23H22ClN5O2, 435.9
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[C:10]([CH3:18])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([OH:24])[CH2:20][CH2:21][C:22]#[CH:23]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:23]#[C:22][CH2:21][CH2:20][CH2:19][OH:24])=[CH:14][CH:15]=2)[C:10]([CH3:18])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCCO
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2ccc(Br)cc12
Product: Cc1cn(C(=O)OC(C)(C)C)c2ccc(C#CCCCO)cc12

Procedure:
In analogy to example 7.2, 5-Bromo-3-methyl-indole-1-carboxylic acid tert-butyl ester and 4-pentynol were converted to yield 5-(5-Hydroxy-pent-1-ynyl)-3-methyl-indole-1-carboxylic acid tert-butyl ester as brown gum, MS: 313 (M).
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([C:7]1[C:8]([CH2:13][P+](C)(C)C)=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6])C.CC(C)([O-])C.[K+].[CH2:24]([N:31]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@H:32]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[F:42])[CH:33]=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CCOCC>[CH3:2][O:4][C:5](=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][C:8]=1/[CH:13]=[CH:33]/[C@H:32]([N:31]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[F:42]
Reactant: O=C[C@@H](Cc1ccccc1F)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCOC(=O)c1cccnc1C[P+](C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)c1cccnc1/C=C/[C@@H](Cc1ccccc1F)N(Cc1ccccc1)Cc1ccccc1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
To a suspension of (3-ethoxycarbonyl-pyridin-2-ylmethyl)-trimethyl-phosphonium bromide (0.9 g, 2.6 mmol) in 50 mL of ether is added potassium tert-butoxide (0.32 g, 2.9 mmol) and the reaction is heated at reflux for 30 minutes. The reaction is then cooled to −78° C., a solution of (R)-2-dibenzylamino-3-(2-fluoro-phenyl)-propionaldehyde (1.8 g, 3.5 mmol) in 10 mL of ether is added, and the reaction is allowed to stir at room temperature for 16 hours. The reaction is then concentrated under reduced pressure and purification of the resultant residue by silica gel flash column chromatography gives the title compound.
Reaction SMILES: CC1(CN2C=C([N+]([O-])=O)N=C2)CO1.C(OC(N1CCNCC1)=O)(C)(C)C.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]([OH:53])([CH3:52])[CH2:42][N:43]2[CH:47]=[C:46]([N+:48]([O-:50])=[O:49])[N:45]=[C:44]2Br)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].[H-].[Na+]>CC(O)C.CN(C=O)C.O>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2([CH3:52])[O:53][C:44]3=[N:45][C:46]([N+:48]([O-:50])=[O:49])=[CH:47][N:43]3[CH2:42]2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(O)(CN1CCN(C(=O)OC(C)(C)C)CC1)Cn1cc([N+](=O)[O-])nc1Br
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC1(Cn2cnc([N+](=O)[O-])c2)CO1
Agent: [H-]
Solvent: O
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 50.1 %

Procedure:
A solution of 1-(2-methyl-oxiranylmethyl)-4-nitro-1H-imidazole (1.5 g, 5.72 mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.1 g, 5.72 mmol) is dissolved in IPA and heated to 60° C. for 24 h. The solution is concentrated and partitioned between water and ethyl acetate. The organic layer is dried over sodium sulfate and concentrated. The resulting solution of 4-[3-(2-bromo-4-nitro-imidazol-1-yl)-2-hydroxy-2-methyl-propyl]-piperazine-1-carboxylic acid tert-butyl ester (1.1 g, 2.46 mmol) in DMF (15 ml) was treated with sodium hydride (148 mg, 3.69 mmol) and stirred for 3 h at 60° C. The mixture was diluted with water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated. The residue is purified by silica gel chromatography to give 4-(2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (453 mg, 50%) of as a light yellow oil. ESI MS m/z 367 (M+Na+); 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 4.30 (d, J=10 Hz, 1H), 3.92 (d, J=10 Hz, 1H), 3.45-3.02 (m, 4H), 2.86 (d, J=14.8 Hz, 1H), 2.70-2.39 (m, 4H), 2.55 (d, J=14.8, 1H), 1.58 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH:3]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:4]([N:6]1[CH2:10][C@@H:9]2[C@@H:11]([NH:14]C(=O)OC(C)(C)C)[CH2:12][CH2:13][C@@H:8]2[CH2:7]1)=[O:5].[ClH:29].O1CCOCC1>CCOCC>[ClH:29].[NH2:14][C@@H:11]1[C@@H:9]2[C@@H:8]([CH2:7][N:6]([C:4](=[O:5])[CH:3]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:2]([CH3:28])[CH3:1])[CH2:10]2)[CH2:13][CH2:12]1
Reactant: CC(C)C(C(=O)N1C[C@H]2CC[C@H](NC(=O)OC(C)(C)C)[C@H]2C1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)C(C(=O)N1C[C@H]2CC[C@H](N)[C@H]2C1)c1ccccc1
Reaction time: 2 h

Procedure:
tert-Butyl(3aR,4S,6aS)-2-(3-methyl-2-phenylbutanoyl)octahydrocyclopenta[c]pyrrol-4-ylcarbamate (39 mg, 0.101 mmol) from Step C was combined with 4 M HCl in dioxane (5 mL, 20.00 mmol) in ether (5 mL). After about 2 hours, the solvent was removed in vacuo to give 1-((3aR,4S,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-methyl-2-phenylbutan-1-one hydrochloric acid salt which was used in the next step without additional purification: MS (ESI+) m/z 287 (M+H)+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CCCCCC.[CH3:12][O:13][C:14]1[N:19]=CC(C=O)=[CH:16][N:15]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[CH3:12][O:13][C:14]1[N:15]=[CH:16][C:2]([CH:3]=[CH2:4])=[CH:1][N:19]=1
Reactant: COc1ncc(C=O)cn1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: C=Cc1cnc(OC)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (24.8 g, 69.4 mmol) in THF (150 mL) at −78° C. under an atmosphere of nitrogen was added 2.5 M of n-butyllithium in hexane (28 mL, 70 mmol) during a period of 12 mins. The reaction was warmed to room temperature to yield a deep red ylide solution. To the ylide solution, cooled in ice, was introduced 2-methoxypyrimidine-5-carbaldehyde (8 g, 65.6 mmol) in THF (50 mL). The reaction was allowed to reach room temperature and stirred for 3 hours. The result suspension was heated to 60° C. over 30 minutes and then heated at 60° C. for 1 hour. After cooling, the reaction mixture was diluted with water (400 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography (EtOAc/hexane 0-30%) to yield title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1>C(O)(=O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([N+:1]([O-:4])=[O:2])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(F)cc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(F)ccc1O
Reaction time: 2 h

Procedure:
To a mechanically stirred solution of 400 ml concentrated nitric acid, at 0° C., was added dropwise a solution of 4-fluorophenol (204 g, 1.8 mole) in acetic acid (200 ml) over 2 hours. Stirring was continued for another 2 hours at 5° C. The reaction mixture was poured onto ice, and the resulting yellow solids were collected and washed with water. The solids were recrystallized from methanol-water (5:1) to afford 198 g of the title compound. The NMR spectrum showed absorption at 7.17 (dd, 1H, J=9, 5 Hz), 7.44-7.52 (m, 1H) and 7.80 (dd, 1H, J=8, 3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[O:28]1[CH2:33][CH2:32][CH2:31][CH:30]=[C:29]1[C:34]1[N:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:40][C:37]2[CH:36]=[N:35][C:34]([C:29]3[O:28][CH2:33][CH2:32][CH2:31][CH:30]=3)=[CH:39][N:38]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1cnc(C2=CCCCO2)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C3=CCCCO3)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 40 mg, 0.12 mmol) in methylene chloride (2 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (70 μL, 1.40 mmol) and N,N-dimethylformamide (1 drop). The reaction mixture was stirred at 0° C. for 30 min, concentrated in vacuo, and azeotroped with methylene chloride (2 mL) three times. The resulting oil was dissolved in tetrahydrofuran (1 mL) at 25° C. and then treated dropwise with a solution of 5-(5,6-dihydro-4H-pyran-2-yl)-pyrazin-2-ylamine (24 mg, 0.13 mmol) and 2,6-lutidine (17 μL, 0.15 mmol) in tetrahydrofuran (1.5 mL) via an addition funnel. The resulting cloudy solution was then stirred overnight at 25° C. for 16 h. After this time, the reaction was diluted with water (10 mL) and then extracted with methylene chloride (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 4/1 to 7/3 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(5,6-dihydro-4H-pyran-2-yl)-pyrazin-2-yl]-propionamide (25 mg, 42%) as a white foam: (ES)+-HRMS m/e calcd for C24H28ClN3O4S (M+H)+ 490.1562, found 490.1562.
Reaction SMILES: [S].Cl[C:3]1[CH:12]=[CH:11][C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][C:4]=1[N+:13]([O-])=O.[C:16](=[S:18])=[S:17].COS(OC)(=O)=O>O>[C:8]([NH:7][C:6]1[CH:11]=[CH:12][C:3]2[S:17][C:16]([SH:18])=[N:13][C:4]=2[CH:5]=1)(=[O:10])[CH3:9]
Reactant: S=C=S
Reactant: CC(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [S]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CC(=O)Nc1ccc2sc(S)nc2c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
A mixture of Na2S.9H2O (65 g, 0.28 mol), sulfur (25 g, 0.78 mol) and water (150 mL) were heated with stirring at 90° C. for 10 min, and then poured into a flask charged with the above 4′-chloro-3′-nitroacetanilide (21.5 g, 0.10 mol). The resulting mixture was heated at 80° C. for 10 min, and then CS2 (12 mL, 0.2 mol) was added dropwise while maintaining a gentle reflux. The resulting mixture was heated at 90° C. for 7 h. The solids were collected by filtration, washed with water and dilute HCl solution. The solids were taken up in water, and the solution was made alkaline with solid NaOH. The solution was filtered, and the filtrate was acidified with conc HCl. The precipitates were collected by filtration, washed with water, and dried under high vacuum. The crude product was suspended in cold water (200 mL) and solid Na2CO3 was added to obtain pH 13. Dimethylsulfate was added to the above milky solution, and the resulting mixture was stirred at ambient temperature for 3 h. The solids were collected by filtration, washed with water, and dried under high vacuum to yield the title compound (12.4 g, 55%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]([CH2:14][CH3:15])[NH:12][C:11](=[O:16])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][C@@H:9]1[CH2:10][C:11](=[O:16])[N:12]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=2)[C@H:13]1[CH2:14][CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: CC[C@@H]1NC(=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using (4R,5S)-4-(tert-butyldimethylsilyloxy)-5-ethylpyrrolidin-2-one (320 mg), 4-bromo-2-chlorobenzonitrile (325 mg), cesium carbonate (643 mg), tris(dibenzylideneacetone)dipalladium(0) (60 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (152 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 366 mg, 73%).