Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[C:25]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:26]([C:31]([NH:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[C:36]([Cl:43])[CH:35]=2)=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1.O>ClCCl>[CH:1]1[C:11]2[CH2:10][N:9]([C:38]([C:37]3[CH:41]=[CH:42][C:34]([NH:33][C:31]([C:26]4[C:25]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:32])=[CH:35][C:36]=3[Cl:43])=[O:39])[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1ccccc1N2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Nc3ccccc32)c(Cl)c1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A mixture of 0.196 g of 5,11-dihydro-10H-dibenzo[b,e][1,4]diazepine, 0.155 g of N,N-diisopropylethylamine and 0.444 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride in 12 ml of dichloromethane is stirred at room temperature overnight. The mixture is poured into water and extracted with dichloromethane. The extract is washed with 2N K2CO3, H2O, brine and dried (Na2 SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated to dryness and the residue triturated with ether and the solvent removed. The residue is triturated with dichloromethane to give 0.31 g of solid, m.p. 158° C.-184° C. Anal. Found for C33H24ClN3O2 1/2 H2O; C,73.7; H, 4.6; N,7.5; Cl,6.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([OH:10])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:10][C:6]2[CH:7]=[C:8]([CH3:9])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:11]([O-:13])=[O:12])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc([N+](=O)[O-])c(O)cc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cc([N+](=O)[O-])c(OS(=O)(=O)c2ccc(C)cc2)cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a solution of 4-methoxy-5-methyl-2-nitro phenol (8.0 g) in methylene chloride (80 mL) was added p-toluenesulfonyl chloride (9.15 g) at room temperature under nitrogen atmosphere. The mixture was cooled to 0° C. To this mixture triethylamine (4.86 g) was added and stirred for 2 h. Then the reaction mixture was poured into water (150 mL) and extracted with methylene chloride (150 mL). The organic layer was washed with water (100 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using hexane/ethyl acetate (9:1) to give the title compound (12.0 g).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[OH:9][C:10]1[CH:11]=[CH:12][C:13]2[C:17](=[O:18])[CH2:16][O:15][C:14]=2[CH:19]=1.N1C=CN=C1.CCCCCC>CN(C)C=O.CCOCC>[Si:5]([O:9][C:10]1[CH:11]=[CH:12][C:13]2[C:17](=[O:18])[CH2:16][O:15][C:14]=2[CH:19]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: O=C1COc2cc(O)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCC2=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 81.4 %

Procedure:
t-butyldimethylchlorosilane (3.6 g, 23.88 mmol) was added to a solution of 6-hydroxy-2,3-dihydrobenzo[b]furan-3-one (3.0 g, 19.98 mmol) and imidazole (2.0 g, 29.38 mmol) in N,N-dimethylformamide (DMF) (30 ml) under cooling with ice. The mixture was warmed to room temperature and stirred for 40 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, washed with water, with diluted hydrochloric acid, with saturated aqueous solution of sodium bicarbonate, and then with saturated brine (aqueous solution of sodium chloride), sequentially, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The oily residue obtained was charged to silica gel column chromatography (hexane:ether=3:1) to obtain a yellow waxy product of 6-t-butyldimethylsilyloxy-2,3- dihydrobenzo[b]furan-3-one (4.3 g, 82%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@@H:27]6[NH:31][C@@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:37](OC(=O)C)(=[O:39])[CH3:38].C(N(C(C)C)CC)(C)C.C(Cl)Cl>CCOC(C)=O>[C:37]([N:31]1[C@@H:27]2[CH2:26][CH2:25][C@H:24]1[CH2:23][N:22]([C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[CH:8]=[C:7]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:10]=4[N:11]=3)=[N:17][CH:18]=1)[C:29](=[O:30])[CH2:28]2)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@H]5CC[C@H](CC4=O)N5)cn3)nc2n1C1CCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1[C@@H]2CC[C@H]1CN(c1ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc1)C(=O)C2
Reaction time: 16 h
Yield: 59.1 %

Procedure:
A sample of 7-Cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (50 mg, 0.102 mmol), acetic anhydride (0.020 ml, 0.113 mmol) and diisopropylethylamine (0.014 ml, 0.154 mmol) were combined with 1 ml DCM. The mixture was allowed to stir for 16 hr and then taken up into EtOAc, washed with brine, dried over Na2SO4 filtered and concentrated. The crude product was purified by silica gel chromatography which gave 2-(5-((1S,6R)-9-acetyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (32 mg) 52% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.70 (d, J=8.08 Hz, 1H), 8.82 (s, 1H), 8.33 (dd, J=9.09, 6.06 Hz, 1H), 8.13 (d, J=2.53 Hz, 1H), 7.60 (dd, J=9.09, 2.53 Hz, 1H), 6.63 (s, 1H), 4.76 (t, J=8.84 Hz, 1H), 4.70 (br. s., 0H), 4.55 (m, 0H), 4.43 (s, 0H), 4.34 (br. s., 0H), 4.18 (d, J=14.65 Hz, 0H), 4.06 (d, J=14.15 Hz, 0H), 3.59 (m, 1H), 3.06 (br. s., 6H), 2.98 (d, J=16.17 Hz, 1H), 2.87 (d, J=14.65 Hz, 0H), 2.73 (m, 1H), 2.44 (br. s., 2H), 2.19 (m, 1H), 2.05 (d, J=4.55 Hz, 3H), 1.98 (m, 6H), 1.82 (m, 2H), 1.66 (d, J=5.56 Hz, 3H), 1.23 (br. s., 1H). MS m/z 531.6 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6](=[O:23])[N:7]3[CH2:22][CH2:21][CH2:20][CH:8]3[C:9](=[O:19])[N:10]3C(C4C=CC=CC=4)[O:12][C:3]=1[C:4]=23.[CH2:26](O)[CH3:27]>>[CH2:26]([O:19][CH:9]1[CH:8]2[CH2:20][CH2:21][CH2:22][N:7]2[C:6](=[O:23])[C:5]2[CH:24]=[CH:25][C:2]([CH3:1])=[C:3]([OH:12])[C:4]=2[NH:10]1)[CH3:27]
Reactant: CCO
Reactant: Cc1ccc2c3c1OC(c1ccccc1)N3C(=O)C1CCCN1C2=O
Product: CCOC1Nc2c(ccc(C)c2O)C(=O)N2CCCC12
Temperature: -20 °C
Reaction time: 72 h

Procedure:
350 mg of 6,8,9,10,10a ,11-hexahydro-3-methyl-1-phenyl-1H-oxazolo[ 5,4,3-jk]pyrrolo[2,1-C][1,4]benzodiazepin-6,11-dione was treated in the same manner as in Example 4. The concentrate of the chloroform layer obtained was dissolved in 2 ml of hot ethanol, cooled to -20° C., and allowed to stand at this temperature for 3 days. Thus, 86 mg of 2,3,5,10,11,11 a-hexahydro-11-ethoxy-9-hydroxy-8-methyl-1H-pyrrolo[2,1-C][1,4]benzodiazepin-5-one was obtained in a colorless crystalline form. Recrystallization of the resulting product from ethanol gave a colorless needle-like crystal having a melting point of 155° to 157° C.
Reaction SMILES: O.NN.[Br:4][C:5]1[CH:6]=[C:7]([CH3:32])[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][C:19]([CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:18][N:17]=2)=[N:9][CH:10]=1>CO.[Ni]>[NH2:22][C:21]1[C:16]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]2[C:7]([CH3:32])=[CH:6][C:5]([Br:4])=[CH:10][N:9]=2)=[N:17][CH:18]=[C:19]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:20]=1
Reactant: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2cccnc2)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2cccnc2)cc1N
Reaction time: 0.33 h
Yield: 62.6 %

Procedure:
Hydrazine hydrate (5 ml) in methanol (25 ml) was added with stirring over 20 minutes to a cooled (10° C.) solution of 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-3-nitro-5-(pyrid-3-ylmethyl)pyridine (4.75 g) in methanol (250 ml) containing Raney Nickel (ca. 3 g). The solution was stirred for a further 30 minutes, the catalyst was removed by filtration and the filtrate was concentrated to dryness in vacuo. The residue was chromatographed on silica eluted with 5% v/v methanol in chloroform and then recrystallized from acetonitrile to give the tile compound (2.78 g), m.p. 85°-87° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[N:19][C:20](C)=[C:21]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[CH:22]=3)[S:16][C:12]=2[C:11]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[C:45]1C=C(C2C=C3C(=CC=2)N(C)N=C3)C=NC=1C>>[C:1]([O:5][C@@H:6]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([C:17]3[C:18]([CH3:45])=[N:19][CH:20]=[C:21]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[CH:22]=3)[S:16][C:12]=2[C:11]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ncc(-c2ccc3c(cnn3C)c2)cc1Br
Reactant: Cc1cc2nc(-c3cnc(C)c(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(-c3cc(-c4ccc5c(cnn5C)c4)cnc3C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-methyl-5-(1-methyl-1H-indazol-5-yl)pyridin-3-yl)benzo[d]thiazol-6-yl)acetic acid was prepared in a similar manner as (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(6-methyl-5-(1-methyl-1H-indazol-5-yl)pyridin-3-yl)benzo[d]thiazol-6-yl)acetic acid except using 5-(5-bromo-6-methylpyridin-3-yl)-1-methyl-1H-indazole instead of 5-(5-bromo-2-methylpyridin-3-yl)-1-methyl-1H-indazole. LCMS-ESI+: calc'd for C34H32ClN4O3S: 611.2 (M+H+); Found: 611.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 9.00 (s, 1H), 8.77 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.84 (m, 1H), 7.72 (m, 2H), 7.60 (m, 3H), 5.28 (s, 1H), 4.11 (s, 3H), 3.00 (s, 3H), 2.64 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: C(O[C:4]([C:6]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[O:8][N:7]=1)=[O:5])C.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][NH2:34])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(OCC)(=O)C>CN(C)C=O>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][NH:34][C:4]([C:6]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=3)[O:8][N:7]=2)=[O:5])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1noc(-c2ccc(C#N)cc2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCNC(=O)c2noc(-c3ccc(C#N)cc3)n2)CC1
Temperature: 120 °C

Procedure:
A mixture of 3-ethoxycarbonyl-5-(4-cyanophenyl)-1,2,4-oxadiazole (2.0 g) and 2-(1-tert-butoxycarbonylpiperidin-4-yl)ethylamine in N,N-dimethylformamide (1 ml) was heated at 120° C. for 5 hours. The mixture was dissolved with ethyl acetate, washed with water, brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to afford 3-[{2-(1-tert-butoxycarbonylpiperidin-4-yl)ethyl}carbamoyl]-5-(4-cyanophenyl)-1,2,4-oxadiazole (2.6 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[O:19]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][C:28](OCC)=[O:29])=[CH:20]1.[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:27]([CH2:26][CH2:25][CH2:24][C:21]3[CH:22]=[CH:23][O:19][CH:20]=3)[C:28]2=[O:29])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCCCc1ccoc1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCc2ccoc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(3-furyl)pentanoate (1.5 eq., prepared in Synthetic Example 19) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(3-furyl)propyl]-1,8-naphthyridin-2(1H)-one, mp 185 to 186° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.[Cl:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH2:26]C(Cl)=O)=[CH:23][CH:22]=1.[CH2:32]([N:34]1[C:46]2[CH:45]=[CH:44][C:43]([NH2:47])=[CH:42][C:41]=2[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH3:33]>>[Cl:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]2[C:17]([NH:47][C:43]2[CH:44]=[CH:45][C:46]3[N:34]([CH2:32][CH3:33])[C:35]4[C:40]([C:41]=3[CH:42]=2)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:19])=[O:7])=[CH:23][CH:22]=1
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)COc2ccc(Cl)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, (4-chlorophenoxy)acetyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 100% purity by LC/MS. MS(ESI+): m/z=533.4.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]1)=O)(C)(C)C.[CH:15]1([C:18]([N:20]2[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)=[O:19])[CH2:17][CH2:16]1.CO.C([BH3-])#N.[Na+]>FC(F)(F)C(O)=O>[CH:15]1([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]3[CH3:14])[CH2:22][CH2:21]2)=[O:19])[CH2:16][CH2:17]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C1CCN(C(=O)C2CC2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C[C@H]1CNCCN1C1CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 141.4 %

Procedure:
To a mixture of (S)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (220 mg, 1.1 mmol) and 1-(cyclopropylcarbonyl)piperidin-4-one (150 mg, 0.9 mmol) in methanol (5 mL, 120 mmol) was added slowly trifluoroacetic acid (6.9 μL, 0.09 mmol) followed by sodium cyanoborohydride (56 mg, 0.9 mmol). The reaction mixture was stirred overnight at RT, concentrated by rotary evaporation, washed with 1 N NaOH (20 mL) and extracted with EtOAc (3×15 mL). Combined organic fractions were washed with brine, dried with sodium sulfate, and concentrated by rotary evaporation to afford a white solid (320 mg). A mixture of the white solid in 4 M HCl in 1,4-dioxane (5 mL) was stirred at RT for 30 min and concentrated to provide the di-HCl salt of the title intermediate (180 mg, 62% yield) as a white suspension.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])C)=O)(C)(C)C.[F:17][C:18]([F:38])([F:37])[C:19]1[CH:20]=[C:21]([S:25]([N:28]2[CH2:32][C@H:31]3[C@H:33]([NH2:36])[CH2:34][CH2:35][C@H:30]3[CH2:29]2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1.[CH2:39](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)[C:40]1[CH:45]=CC=C[CH:41]=1>>[CH2:6]([NH:8][C@H:9]([C:14]([NH:36][C@H:33]1[C@H:31]2[C@H:30]([CH2:29][N:28]([S:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:37])[F:38])[CH:20]=3)(=[O:26])=[O:27])[CH2:32]2)[CH2:35][CH2:34]1)=[O:16])[CH2:10][CH2:11][CH3:13])[C:40]([CH3:45])([CH3:41])[CH3:39]
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CCC[C@H](NCC(C)(C)C)C(=O)N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21

Procedure:
The title compound was prepared by substituting (S)-2-(neopentylamino)pentanoic acid from Step A of Example 246 for N-(tert-butoxycarbonyl)-L-leucine and (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 254 for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.37-8.38 (bs, 1H), 8.18 (d, J=7.9 Hz, 1H), 8.09-8.11 (m, 1H), 7.90-7.92 (m, 1H), 7.71 (t, J=7.8 Hz, 1H), 4.20-4.27 (m, 1H), 3.88 (dd, J=9.9, 2.8 Hz, 1H), 3.20 (dd, J=6.6, 3.1 Hz, 1H), 3.16-3.20 (m, 1H), 3.14 (dd, J=9.9, 7.8 Hz, 1H), 2.96 (dd, J=9.6, 7.3 Hz, 1H), 2.46-2.61 (m, 2H), 2.38 (d, J=11.3 Hz, 1H), 2.33 (d, J=11.3 Hz, 1H), 1.92-1.99 (m, 1H), 1.83-1.90 (m, 1H), 1.76-1.83 (m, 1H), 1.66-1.87 (m, 1H), 1.61-1.70 (m, 1H), 1.38-1.58 (m, 3H), 1.26-1.37 (m, 1H), 0.92 (s, 9H), 0.85 (t, J=7.3 Hz, 3H); MS (ESI+) m/z 504 (M+H)+.
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH3:16])=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])=O.Cl.[C:19](=[NH:22])([NH2:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:20][C:19]1[NH:21][C:3]([C:5]2[C:6]([CH3:16])=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=2)[C:10]([O:12][CH3:13])=[O:11])=[C:2]([CH3:17])[N:22]=1
Reactant: COC(=O)c1cc(C(=O)C(C)Br)c(C)cc1C
Reactant: CC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(-c2[nH]c(C)nc2C)c(C)cc1C
Temperature: 80 °C
Reaction time: 15 h
Yield: 57.8 %

Procedure:
Into a round-bottom flask, was placed a solution of methyl 5-(2-bromopropanoyl)-2,4-dimethylbenzoate (compound 1.6, 400 mg, 1.34 mmol) in acetonitrile (30 mL). Acetimidamide hydrochloride (260 mg, 2.75 mmol) and potassium carbonate (550 mg, 3.99 mmol) were added and the resulting mixture was stirred at 80° C. for 15 h. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (50 mL) and washed with brine (2×25 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:1) to ethyl acetate as the eluent to yield the title compound as a yellow oil (0.20 g, 58%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[N:33][CH:34]=2)O1>>[F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:29]3[CH:34]=[N:33][C:32]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[CH:31][CH:30]=3)=[CH:14][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccc(N5CCOCC5)nc4)cc32)c1
Yield: 48 %

Procedure:
1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (50 mg) was reacted with 4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]-morpholine as in General Procedure 4A to give the title compound as an off-white solid (48% yield). M.p. 206-207° C., LCMS: m/z=423.99 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.45-3.53 (m, 6H), 3.60-3.67 (m, 2H), 3.80-3.87 (m, 4H), 4.48 (s, 2H), 4.86 (s, 1H), 6.64 (d, J=8.6 Hz, 1H), 6.66 (s, 1H), 6.89-7.06 (m, 3H), 7.55 (dd, J=8.8 Hz, 2.5 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 8.24 (d, J=2.3 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(#N)C>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCI
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCOc1cccc(C=O)c1
Yield: 848.3 %

Procedure:
A mixture of 1.00 g (0.82 mmol) of 3-hydroxybenzaldehyde, 1.70 g (12.2 mmol) of potassium carbonate and 2.16 g (9.00 mmol) of 1-iodooctane were warmed in acetonitrile at 80° C. for 16 h. The reaction was cooled, filtered and concentrated. The residue was purified using flash chromatography using 20:1 v/v hexane/ethyl acetate to afford 1.63 g of the title compound as a colorless oil: 1H-NMR (500 MHz) δ 0.89 (t, J=6.9, 3H), 1.24-1.39 (m, 8H), 1.42-1.50 (m, 2H), 1.80 (m, 2H), 4.01 (t, J=6.6, 2H), 7.19 (m, 1H), 7.40 (s, 1H), 7.44-7.46 (m, 2H), 9.99 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:7](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5](=[O:19])[C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH2:36][CH:37]([CH2:42][CH3:43])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]C)=[O:33])=[CH:22][CH:21]=1)#[N:2].O1CCCC1.Cl.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.O>[C:1]([C:3]1[C:7](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5](=[O:19])[C:4]=1[C:20]1[CH:21]=[CH:22][C:23]([N:26]([CH2:36][CH:37]([CH2:42][CH3:43])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:24][CH:25]=1)#[N:2]
Reactant: CCCCCCN1C(=O)C(c2ccc(N(CCCCCC(=O)OC)CC(CC)CCCC)cc2)=C(C#N)C1=C(C#N)C#N
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCN1C(=O)C(c2ccc(N(CCCCCC(=O)O)CC(CC)CCCC)cc2)=C(C#N)C1=C(C#N)C#N
Yield: 87.5 %

Procedure:
The prepared methyl 6-((4-(4-cyano-5-(dicyanomethylene)-1-hexyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)phenyl)(2-ethylhexyl)amino)hexanoate (7.5 g, 12.8 mmol) and tetrahydrofuran (50 ml) were loaded into a flask and stirred. Hydrochloric acid (20 ml, 3 N) was added thereto, and the mixture was allowed to react at 65° C. for 24 hours with stirring. The reaction product was transferred into a separate funnel, and was then added with water and dichloromethane, after which the organic layer was isolated therefrom, dehydrated using sodium sulfate, and then distilled under reduced pressure. Subsequently, the obtained material was separated through silica column chromatography, thus obtaining 6.4 g of a dark blue solid.