Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:3][C:4](Cl)=[C:5]2[C:11]=1[C:10](=[O:12])[C:9]1=[CH:13][S:14][CH:15]=[C:8]1[C:7](=[O:16])[NH:6]2.C(N(CCCC)CCCC)CCC.[H][H]>[Pd].C(O)CC>[CH:2]1[S:3][CH:4]=[C:5]2[C:11]=1[C:10](=[O:12])[C:9]1=[CH:13][S:14][CH:15]=[C:8]1[C:7](=[O:16])[NH:6]2
Reactant: O=c1[nH]c2c(Cl)sc(Cl)c2c(=O)c2cscc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCCN(CCCC)CCCC
Solvent: CCCO
Product: O=c1[nH]c2cscc2c(=O)c2cscc12
Yield: 75.2 %

Procedure:
A mixture of 5.0 g (0.0164 mole) of 1,3-dichloro-4,5-dihydrodithieno[3,4-b:3',4'-e]azepine-5,9-dione, 4 g of 5% strength Pd/C, 6.3 g (0.034 mole) of tributylamine and 300 ml of propanol was stirred in a hydrogen atmosphere at 80° C. When absorption of hydrogen was complete (after 5 hours), the hot mixture was filtered and the filtrate was poured onto ice water. The resulting suspension was acidified with concentrated hydrochloric acid, and the mixture was then stirred for a short time and filtered under suction. The residue from filtration of the crude reaction mixture was washed several times with hot dimethylformamide. The dimethylformamide used for washing was poured onto ice water, and the precipitate formed was filtered off under suction. The solid thus obtained was combined with the solid product obtained from the propanol filtrate. The total solid product was washed with water and then dried at 50° C. in a drying oven under reduced pressure. 2.9 g (75%) of 4,5-dihydrodithieno[3,4-b:3',4'-e]azepine-5,9-dione were obtained in the form of beige crystals of melting point 268°-271° C.
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])(=O)C.[Na+].C1(C)C=CC=CC=1.[CH2:23]=[C:24]1[O:28][C:26](=[O:27])[CH2:25]1>O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:2]=1[NH:1][C:26](=[O:27])[CH2:25][C:24](=[O:28])[CH3:23])#[N:5]
Reactant: C=C1CC(=O)O1
Reactant: N#Cc1cccc(F)c1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)CC(=O)Nc1c(F)cccc1C#N
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a mixture of 2-amino-3-fluorobenzonitrile (41.9 g), sodium acetate (30.3 g) and toluene (200 mL) was added diketene (28.2 mL) over 10 min at 0° C. The reaction mixture was stirred at room temperature for 7 hr. To the reaction mixture were added toluene (150 mL) and diketene (4.7 mL) at room temperature, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether/ethanol to give the title compound (48.64 g).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]1)#[N:13]>>[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[CH2:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)#[N:13]
Reactant: N#CC1CCCCN1
Reactant: BrCCCOc1ccccc1
Product: N#CC1CCCCN1CCCOc1ccccc1

Procedure:
Following the procedure of Preparation 9, the title compound is prepared from 3-phenoxypropyl bromide and 2-cyanopiperidine [Chem. Ber. 92, 1608-1613 (1959), Helv. Chim. Acta 46(4), 1190-1206 (1963)].
Reaction SMILES: N[C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([N:15]1[C:19]([NH2:20])=[N:18][N:17]=[N:16]1)[CH2:13][CH3:14]>>[Cl:11][C:10]1[CH:2]=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([NH:20][C:19]1[N:15]([CH2:12][CH2:13][CH3:14])[N:16]=[N:17][N:18]=1)=[O:6]
Reactant: CCCn1nnnc1N
Reactant: Nc1c(Cl)cccc1C(=O)O
Product: CCCn1nnnc1NC(=O)c1cccc(Cl)c1
Yield: 65 %

Procedure:
Employing 0.25 g (1.5 mmol) of 2-amino-3-chlorobenzoic acid and 0.19 g (1.5 mmol) of 1-propyl-1H-tetrazol-5-amine in the procedure described above and elution with CH2Cl2/MeOH/Et3N (9.4:0.3:0.3) gave the product in 65% yield.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]#[N:13])[CH:8]=[CH:9][CH:10]=1.Br[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Br>CN1C(=O)CCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2([C:12]#[N:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:8]=[CH:9][CH:10]=1
Reactant: BrCCOCCBr
Reactant: COc1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1cccc(C2(C#N)CCOCC2)c1
Temperature: 0 °C
Yield: 93.5 %

Procedure:
A mixture of NaH (3.2 g, 79 mmol) in 50 mL NMP stirred at 0° C., was treated dropwise with a mixture of 2-(3-methoxyphenyl)acetonitrile (3.9 g, 26 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (6.1 g, 26 mmol) in 20 mL. The mixture was allowed to warm to room temperature and stirred for 15 hours, M+1=218. The mixture was then carefully quenched with 100 mL H2O and the pH was adjusted to 5. The mixture was extracted with ether (3×100 mL). The combined organic layers were washed with H2O (3×50 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 10-20% EtOAc/hexane to give 5.28 g of the crude product 5.28 g as a pale yellow oil. MS (m/z)=218 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:9])[CH:5]=[C:6]([NH:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[F:10])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: NCc1ccccc1F
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(NCc2ccccc2F)n1

Procedure:
53 g (323 mmol) of 2-amino-4,6-dichloropyrimidine, 40.4 g (323 mmol) of 2-fluorobenzylamine and 33.4 g (330 mmol) of triethylamine are dissolved in 800 ml of ethanol and the reaction mixture is heated under reflux for 20 hours. After 400 ml of ethanol have been distilled off, the residue is diluted with 500 ml of water, and the precipitated product is filtered off with suction and recrystallised from 1 l of toluene. In this manner 2-amino-4-chloro-6-(2-fluorobenzylamino)-pyrimidine having a melting point of 130°-133° is obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([N:21]2[CH2:24][CH:23]([NH:25][S:26]([C:29]3[CH:34]=[C:33](F)[CH:32]=[C:31]([F:36])[CH:30]=3)(=[O:28])=[O:27])[CH2:22]2)[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1>CS(C)=O.ClCCl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:21]2[CH2:22][CH:23]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:32]=[C:31]([F:36])[CH:30]=3)(=[O:27])=[O:28])[CH2:24]2)=[CH:11][CH:12]=1
Reactant: C1CCNC1
Reactant: O=S(=O)(NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=S(=O)(NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(N2CCCC2)c1
Temperature: 90 °C

Procedure:
0.104 cm3 of pyrrolidine is added, at room temperature, to 0.24 g of N-{-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}-(3,5-difluorophenyl)sulfonamide in solution in 6 cm3 of dimethyl sulfoxide and then the mixture is heated for 18 hours at 90° C. The reaction mixture is diluted with 30 cm3 of dichloromethane and washed with three times 30 cm3 of distilled water. The organic phased is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by flash chromatography on silica gel, eluting with dichloromethane. 50 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3-fluoro-5-pyrrolidin-1-ylphenyl)sulfonamide are thus obtained in the form of a white powder [1H NMR spectrum (600 MHz, CDCl3 with addition of a few drops of CD3COOD d4, δ in ppm): 2.04 (mt: 4H); from 3.20 to 3.35 (mt: 6H); 3.60 (t, J=8.5 Hz: 2H); 4.14 (mt: 1H); 4.57 (s: 1H); 6.31 (broad d, J=11.5 Hz: 1H); 6.70 (broad d, J=8.5 Hz: 1H); 6.72 (broad s: 1H); from 7.20 to 7.35 (mt: 8H)].
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[C:11](O)(=[O:13])C.C1N2CN3CN(C2)CN1C3>O>[CH3:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([CH:11]=[O:13])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Cc1ccc2cc[nH]c2n1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: Cc1ccc2c(C=O)c[nH]c2n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
6-Methyl-1H-pyrrolo[2,3-b]pyridine (0.066 g, 0.50 mmol) was successively added with acetic acid (0.2 mL), water (0.4 mL), and hexamethylenetetramine (0.098 g, 0.70 mmol), and then the mixture was stirred overnight at 120° C. in a sealed tube. The reaction mixture was added with water, and then the precipitated solid was collected by filtration to obtain 6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.054 g, 67%).
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][NH:5][C:6]2[N:7]([N:19]=[CH:20][C:21]=2[C:22]#[N:23])[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)[CH3:2].[Cl:24][CH2:25][C:26](Cl)=[O:27]>>[Cl:24][CH2:25][C:26]([N:5]1[CH2:4][C:3]([CH2:1][CH3:2])=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:7]2[N:19]=[CH:20][C:21]([C:22]#[N:23])=[C:6]12)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: CCC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2NC1
Product: CCC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CCl)C1

Procedure:
The reactants were prepared as follows. Using the method of Example 2, 4,5-dihydro-6-ethyl-7 -[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile was reacted with chloroacetyl chloride to give 4-(chloroacetyl)-4,5-dihydro-6-ethyl-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile, m.p. 150°-152° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1.Br[C:13]1[C:14](=[O:21])[N:15]([CH3:20])[N:16]=[C:17]([Cl:19])[CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>>[Cl:19][C:17]1[CH:18]=[C:13]([NH:1][C:2]2[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=2)[C:14](=[O:21])[N:15]([CH3:20])[N:16]=1
Reactant: COC(=O)c1cc(N)nn1C
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1cc(Nc2cc(Cl)nn(C)c2=O)nn1C
Temperature: 100 °C

Procedure:
In a 3-neck RBF was placed 119a (500 mg, 3.2 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (725 mg, 3.2 mmol), cesium carbonate (2.3 g, 7.0 mmol), and Xantphos (160 mg, 8.5 mol %). The flask was evacuated and filled with nitrogen 3×. Dioxane (20 ml) was added and the mixture degassed for 25 min with bubbling nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (150 mg, 5 mol %) was then added and the reaction heated to 100° C. for 6 hrs. The reaction was cooled and diluted with EtOAc (125 mL) and saturated aqueous NaHCO3 (50 mL), the layers were separated and extracted EtOAc (2×100 mL). The organics were washed with brine 3×, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography: ISCO 40 g silica, EtOAc/hexanes, to give 119b.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]([C@@H:36]([CH3:39])[CH2:37][OH:38])[CH3:35])[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].N[C@H:44](C)[CH2:45]O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]([C@@H:36]5[CH2:39][CH2:45][CH2:44][C@H:37]5[OH:38])[CH3:35])[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)[C@@H](C)CO)c4)cc23)CC1
Reactant: C[C@@H](N)CO
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)[C@@H]5CCC[C@H]5O)c4)cc23)CC1
Yield: 21.8 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate (salt), substituting (1R,2R)-2-aminocyclopentanol (1.20 mmol) for (2R)-2-amino-1-propanol to afford 9.6 mg of the title compound (21.8%)
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])#[N:2].[Br:19]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:19][C:12]1[CH:13]=[C:3]([C:1]#[N:2])[C:4]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(C#N)c(NCC(C)C)c1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(NCC(C)C)c(C#N)cc1Br
Temperature: 45 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of ethyl 4-cyano-3-[(2-methylpropylamino)]benzoate (393 mg, 1.60 mmol) in DMF (10 mL) was added N-bromsuccinimide (284 mg, 1.60 mmol). The mixture was stirred overnight at 45° C. then cooled to room temperature and diluted with water then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (10% ethyl acetate in hexanes) to give ethyl 2-bromo-4-cyano-5-[(2-methylpropyl)amino]benzoate (374 mg, 72.0%) as a yellow solid. MS (EI) for C14H17BrN2O2: 324 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=O)[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]=2[N:7]=1.[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1.P(Cl)(Cl)(Cl)=O.CO/N=C1/C2C(C)=NC(N)=NC=2C[C@@H](C2C=CC(F)=CC=2C2C(F)=NC=CC=2)C/1>C(#N)C>[N:22]1([C:11]2[C:5]3[C:4]([CH3:21])=[N:3][C:2]([NH2:1])=[N:7][C:6]=3[CH2:8][C@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[N:10]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1
Reactant: Cc1nc(N)nc2c1C(=O)N[C@@H](c1ccc(F)cc1Br)C2
Reactant: c1ccc2[nH]nnc2c1
Agent: CO/N=C1\C[C@H](c2ccc(F)cc2-c2cccnc2F)Cc2nc(N)nc(C)c21
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(N)nc2c1C(n1nnc3ccccc31)=N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 75 °C

Procedure:
In a 2-neck round-bottomed flask, under a blanket of nitrogen was added (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (106a, 1.00 g, 2.85 mmol), 1H-benzo[d][1,2,3]triazole (106b, 0.678 g, 5.70 mmol) and anhydrous acetonitrile (14 mL). Phosphoryl trichloride (0.796 mL, 8.54 mmol) was added slowly to the mixture and the reaction was heated in 75° C. oil bath for 18 hours. By LC/MS about 7-10% of compound 1 remained unreacted. The reaction mixture was concentrated, then diluted with 80 mL of ethyl acetate and the resulting mixture was added slowly to 40 mL of saturated sodium bicarbonate. The layers were partitioned. The aqueous layer was washed one more time with 40 mL of ethyl acetate. The organic layers combined, washed with brine, dried over sodium sulfate, and concentrated to a yellow-light brown solid, 1.72 g, contained about 0.37 g of excess benzotriazole. The crude material was taken on to the next step without purification. MS (ES) [M+H] calc'd for C20H15BrFN7, 452; found, 452.3-454.3. 1H NMR (400 MHz, CHLOROFORM-d) δ 1.96 (s, 3H), 2.74 (dd, J=16.42, 14.91 Hz, 1H), 3.13 (dd, J=16.55, 4.17 Hz, 1H), 5.20 (dd, J=14.91, 4.04 Hz, 1H), 5.69 (s, 2H), 7.03-7.12 (m, 1H), 7.38 (dd, J=8.21, 2.65 Hz, 1H), 7.47-7.52 (m, 1H), 7.56-7.63 (m, 1H), 7.74 (dd, J=8.84, 6.06 Hz, 1H), 8.16 (d, J=9.35 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[CH:6][CH:7]=1.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O.CC1(C)N([O])C(C)(C)CCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C:11](=[O:13])[CH2:10][N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1c1cccc(F)c1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@@H]1c1cccc(F)c1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of (2R,4R)-tert-butyl 2-(3-fluorophenyl)-4-hydroxypyrrolidine-1-carboxylate (I-4A) (1.4 g, 5.0 mmol) and trichloroisocyanuric acid (1.2 g, 5.0 mmol) in DCM (70 mL) at −10° C. was added 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) (0.08 g, 0.5 mmol). The mixture was stirred at −10° C. for 15 minutes, then to room temperature over 1 hour and subsequently poured into cold aqueous NaHCO3 containing ice while stirring. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and reduced to dryness to yield (R)-tert-butyl 2-(3-fluorophenyl)-4-oxopyrrolidine-1-carboxylate (I-7) as a light yellow oil. 1H NMR (400 MHz, CD3OD) δ 7.40 (q, J=7.6 Hz, 1 H), 7.01 (d, J=7.6 Hz, 1 H), 7.03-6.99 (m, 2 H), 5.34 (bs, 1 H), 4.07-3.91 (m, 2 H), 3.30 (dd, J=18.8, 10.0 Hz, 1 H), 2.50 (dd, J=18.8, 3.2 Hz, 1 H), 1.31 (bs, 9 H). MS m/z 224.1 (M−56)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([NH2:9])=[O:8])=[CH:5][NH:4][N:3]=1.[C:10]([CH:12]=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)#[N:11].C(#N)C.C1CCN2C(=NCCC2)CC1>O>[NH2:1][C:2]1[C:6]([C:7](=[O:8])[NH2:9])=[CH:5][N:4]([C:13]2([CH2:12][C:10]#[N:11])[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]2)[N:3]=1
Reactant: NC(=O)c1c[nH]nc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Solvent: O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(N)n2)CC1
Temperature: 80 °C

Procedure:
3-Amino-1H-pyrazole-4-carboxamide (0.80 g, 6.3 mmol) and tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate (2.1 g, 9.5 mmol) were combined with acetonitrile (31 mL) in a pressure vessel. DBU (1.05 mL, 6.98 mmol) was then added at ambient temperature. The reaction vessel was sealed and the mixture was heated to 80° C. for 16 hours. The reaction mixture was then allowed to cool to ambient temperature before water (150 mL) was added. The aqueous mixture was extracted with EtOAc (2×). The organic layers were then combined and washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was adsorbed on silica gel in vacuo and purified by MPLC on silica gel (using a gradient elution of 75-100% EtOAc/hexanes) to afford the title compound, Intermediate #35-1.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14]C)=[O:12])[C:6]([O:8][CH2:9]C)=[O:7])(=[O:3])[CH3:2].[H-].[Na+].[CH2:18]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[C:31](=[CH2:35])[C:30](=[O:36])[CH2:29]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].CCOCC>C1COCC1.O>[CH3:14][O:13][C:11](=[O:12])[C:5]([NH:4][C:1](=[O:3])[CH3:2])([CH2:35][CH:31]1[C:32]2[C:28](=[CH:27][C:26]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:34][CH:33]=2)[CH2:29][C:30]1=[O:36])[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: C=C1C(=O)Cc2cc(CCCCCCCC)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCc1ccc2c(c1)CC(=O)C2CC(NC(C)=O)(C(=O)OC)C(=O)OC

Procedure:
Diethyl acetamidomalonate (4.55 g, 21.0 mmol) is dissolved in THF (40 mL). Sodium hydride (0.600 g, 25.0 mmol) is added. The reaction is brought to reflux for 2.0 hours. The residue (compound 16) from Example 12, dissolved in THF (40 mL) is added. The reaction is maintained at reflux for an additional 4 hours, cooled, and poured into a separatory funnel containing ether (100 mL) and water (75 mL). The ether layer is separated and the aqueous layer is re-extracted with ether (100 mL). The combined organic layers are dried over MgSO4 and the solvent removed in vacuo. The residue is chromatographed over silica gel yielding 17 (FIG. 7).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:10]([N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14][CH:13]1[C:21](O)=[O:22])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>O.CN(C=O)C>[CH:24]1([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:10](=[O:11])[N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][C@@H:13]2[C:21](=[O:22])[NH:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1c2ncccc2CC1C(=O)O)C1CCCCC1
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
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1c2ncccc2C[C@@H]1C(=O)Nc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 50 mL round-bottomed flask, 1-((S)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (300 mg, 744 μmol, Eq: 1.00) and HATU (339 mg, 892 μmol, Eq: 1.2) were combined with DMF (7 mL) to give a colorless solution. Triethylamine (124 μL, 892 μmol, Eq: 1.2) and aniline (83 mg, 892 μmol, Eq: 1.2) were added and the reaction was stirred at rt overnight. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 5% to 25% EtOAc in hexanes) to give tert-butyl (R)-(1S)-1-cyclohexyl-2-oxo-2-(2-(phenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)ethylcarbamate (eluted first, 160 mg) and tert-butyl (S)-(1S)-1-cyclohexyl-2-oxo-2-(2-(phenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)ethylcarbamate (eluted second, 130 mg), m/z=479 (M+H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Br[CH2:7]/[CH:8]=[CH:9]\[Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14]>C1COCC1>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:7]/[CH:8]=[CH:9]\[Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])[CH3:2]
Reactant: CCNCC
Reactant: CCCC[Sn](/C=C\CBr)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Reaction time: 3 h

Procedure:
Diethylamine (19 mL) was added to a solution of ((Z)-3-bromoprop-1-enyl)-tributyl-stannane (Intermediate 4, 7.52 g) in THF (60 mL) and the mixture was stirred for 3 hours. The reaction mixture was evaporated to dryness and the residue was purified by chromatography on a silica column which had been pre-washed with 20% triethylamine in acetonitrile. The column was eluted with a mixture of ethyl acetate and pentane with a gradient of 0-10% to give N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (4.75 g) as an orange oil.