Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:15]([N:18]1[CH2:24][CH:23]3[CH2:25][CH2:26][CH:20]([CH2:21][CH2:22]3)[CH2:19]1)(=[O:17])=[O:16])=[CH:10]2)(=O)C.O.C(=O)(O)[O-].[Na+]>C1COCC1>[OH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:15]([N:18]1[CH2:24][CH:23]3[CH2:25][CH2:26][CH:20]([CH2:21][CH2:22]3)[CH2:19]1)(=[O:17])=[O:16])=[CH:10]2
Reactant: CC(=O)Oc1cccc2cc(S(=O)(=O)N3CC4CCC(CC4)C3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc2c(O)cccc2c1)N1CC2CCC(CC2)C1
Reaction time: 8 h

Procedure:
The title compound was prepared from 3-(5-Acetoxy-2-naphthylsulfonyl)-3-azabicyclo[3.2.2]nonane, by dissolving the acetoxy compound in 3 ml THF and then adding 2 ml water and 2 ml saturated sodium bicarbonate solution. After stirring overnight, the solvent was evaporated and the product extracted with chloroform. After drying over magnesium sulfate, the solvent was evaporated to give an orange oil. This was purified by chromatotron using 3/1 hexane/ethyl acetate which gave a yellow solid (32 mg, 48% yield): 1H NMR (CDCl3): 8.33 (d, J=8.8, 1 H, H3), 8.25 (d, J=1.6, 1 H, H1), 7.70 (d, J=8.8, 1 H, H4), 7.49 (d, J=8.3, 1 H, H6), 7.40 (t, J=7.8, 1 H, H7), 7.02 (d, J=7.4, 1 H, H8), 6.68 (br s, 1 H, OH), 3.30 (d, J=4.2, 4 H, N(CH2R)2), 2.08 (s, 2 H, N(CH2CHR)2),1.72-1.58 (in, 8 H, alkyl H's).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH2:1]([O:8][CH2:9][C:10]1[N:14]([CH3:26])[C:13]([CH:15]([CH3:17])[CH3:16])=[C:12]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[N:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(COCc2ccccc2)[nH]c1Sc1cccc(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)c1c(Sc2cccc(Cl)c2)nc(COCc2ccccc2)n1C
Temperature: 25 °C
Reaction time: 7 h
Yield: 2.7 %

Procedure:
In 218 g of dry dimethylformamide was dissolved 21.8 g (58.5 mmol)of 2-benzyloxymethyl-5-(3-chlorophenylthio)-4-isopropyl-iH-imidazole (16e), followed by addition of 12.2 g (88.3 mmol)of anhydrous potassium carbonate and 11.6 g (81.7 mmol)of methyl iodide, the mixture was stirred at room temperature for 7 hours. To the reaction mixture was added ice-water, and the mixture was extracted with diethyl ether. The extract was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate:methylene chloride=1:8). From the first eluted fraction, 620 mg (yield 3%)of 2-benzyloxymethyl-4-(3-chlorophenylthio)-5-isopropyl-1-methyl-1H-imidazole (17ab') was obtained as oil. From the latter eluted fraction, 17.6 g (yield 78%)of 2-benzyloxymethyl-5-(3-chlorophenylthio)-4-isopropyl-1-methyl-1H-imidazole (17ab)was obtained as oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].O.[CH:15]([C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)([CH3:17])[CH3:16]>C1COCC1>[CH:15]([C:18]1[CH:19]=[C:20]([NH:24][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH:21]=[CH:22][CH:23]=1)([CH3:17])[CH3:16]
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: CC(C)c1cccc(N)c1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-3-nitro-benzoyl chloride (2.00 g, 0.010 mol) in THF (30 mL), in a water bath-cooled 100 mL round bottom flask, was added 3-isopropyl-phenylamine (1.35 g, 0.010 mol) dropwise. The reaction was allowed to stir at room temperature for 1 hour before being concentrated. The mixture was taken up in EtOAc and washed with NaHCO3 (aq., conc.) and then brine. The solution was dried over MgSO4, filtered, and concentrated to yield the title compound as an orange oil that solidifies upon standing. MS m/z 299=[M+H]+. Calc'd for C17H18N2O3: 298.34.
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6]2.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:31]([CH3:30])(=[O:33])=[O:32])[CH:20]=[CH:21][CH:22]=2)[CH:3]2[CH:7]1[CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4]2
Reactant: CC1(c2cccc(N)c2)C2CN(CCCc3ccccc3)CC21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCCc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of 3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 8, 28 mg, 0.09 mmol) in dichloromethane (2 ml), at 0° C. under nitrogen was added pyridine (20 μl, 0.24 mmol) and then methanesulfonylchloride (25 μl, 37 mg, 0.32 mmol) over 5 minutes. The mixture was allowed to warm to room temperature and was then stirred for 2 hours. The mixture was concentrated in vacuo and the residue was purified by silica (5 g) column chromatography eluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil (18 mg, 52%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=2)[CH:6]=1.C([O-])=O.[Na+].C(O)=O>CO.[Pd]>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=1
Reactant: Cc1cn(-c2cccc([N+](=O)[O-])c2)cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Product: Cc1cn(-c2cccc(N)c2)cn1
Reaction time: 18 h
Yield: 82.8 %

Procedure:
A mixture of 14.6 g of 4-methyl-1-(3-nitrophenyl)-1H-imidazole, 766 mg of palladium black, 19.6 g of sodium formate, 12.8 ml of formic acid in 300 ml of methyl alcohol is stirred for 18 hours under a hydrogen atmosphere. The mixture is filtered through diatomaceous earth and the filtrate evaporated to a residue. The residue is partitioned between saturated potassium bicarbonate and chloroform. The organic layer is dried and evaporated to a residue which is dissolved in a minimum of chloroform and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated to a residue which is stirred with ether and the resulting solid filtered and air dried to give 10.3 g of the desired product as a solid, m.p. 117°-119° C.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Br:21])[CH:19]=2)[N:14]=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:12]1=[O:26])=[O:7])(=O)C.[Li+].[OH-].Cl>O1CCCC1.CO>[Br:21][C:18]1[CH:19]=[C:20]2[C:15]([N:14]=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:12](=[O:26])[N:11]2[CH2:10][CH2:9][NH:8][C:6](=[O:7])[CH2:5][OH:4])=[CH:16][CH:17]=1
Reactant: CC(=O)OCC(=O)NCCn1c(=O)c(C(C)(C)C)nc2ccc(Br)cc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1nc2ccc(Br)cc2n(CCNC(=O)CO)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(2-(7-Bromo-3-tert-butyl-2-oxoquinoxalin-1(2H)-yl)ethylamino)-2-oxoethyl acetate was dissolved in 4 mL of 1:1 tetrahydrofuran/methanol, and 0.99 mL of aq. 1N LiOH was added. After 30 minutes of stirring at room temperature the reaction was complete. Hydrochloric acid was used to adjust the pH to 6, and the solution was extracted with ethyl acetate 3 times, the combined organic layers washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to provide 197 mg of N-(2-(7-bromo-3-tert-butyl-2-oxoquinoxalin-1(2H)-yl)ethyl)-2-hydroxyacetamide. The product was pure by TLC and was used in the next step (Suzuki coupling) without purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][NH:11]2)=[CH:2]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(Cl)Cl.CN(C=O)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([N:11]2[CH2:12][CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]2[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: c1ccc2c(c1)CCNC2c1c[nH]c2ccccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CCc2ccccc2C1c1c[nH]c2ccccc12
Reaction time: 48 h

Procedure:
To a solution of 1-(1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline (16.3 mg, 66 μmol) in CH2Cl2 (0.5 mL) at RT was added 1-fluoro-4-isocyanatobenzene (10 μL, 66 μmol). The reaction was stirred 48 h, the suspension dissolved in DMF and purified by HPLC to give N-(4-fluorophenyl)-1-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide as a white solid. MS (ESI pos. ion) m/z: 386 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1C2C=CC=C(O[P+](N3CCCC3)(N3CCCC3)N3CCCC3)C=2N=N1.[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH:51][C:52](=[O:65])[C:53]1[CH:58]=[CH:57][C:56]([CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)=[CH:55][CH:54]=1>CN(C=O)C>[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH:51][C:52](=[O:65])[C:53]1[CH:58]=[CH:57][C:56]([CH:59]2[CH2:64][CH2:63][N:62]([C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=3)[CH2:61][CH2:60]2)=[CH:55][CH:54]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cc(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)c2nn[nH]c2c1
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(C2CCN(C(=O)c3ccc(Br)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
To a solution of 4-bromobenzoic acid (1.0 g, 3.3 mmol) in DMF (5 ml) was added benzotriazolyloxytripyrollidinophosphonium hexafluorophosphate (99 mg, 0.19 mmol) and the mixture stirred at ambient temperature for 30 minutes. N-(2-aminophenyl)-4-piperidin-4-ylbenzamide (Example 5, 50 mg, 0.17 mmol) was added and the mixture stirred for a further 24 hours. The resulting solution was absorbed onto an SCX-2 column, washed with methanol (2 column volumes) and eluted with a 2M solution of ammonia in methanol (2 column volumes) to afford the product. This was purified by flash chromatography (eluting with 0-20% methanol/dichloromethane) to afford the title compound as a colourless solid (29 mg, 18%); NMR Spectrum: (DMSO-d6) 1.70 (m, 4H), 2.60 (m, 1H), 2.91 (m, 2H), 3.31 (m, 2H), 4.89 (s, 2H), 6.60 (t, 1H), 6.78 (d, 1H), 6.97 (t, 1H), 7.16 (d, 1H), 7.43 (d, 4H), 7.67 (d, 2H), 7.93 (d, 2H), 9.60 (s, 1H); Mass Spectrum: M+H+ 478.
Reaction SMILES: [H-].[Na+].[C:3]1([N:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:30]4[C:26](=[N:27][NH:28][N:29]=4)[C:25]([C:31]4[CH:36]=[CH:35][C:34]([N:37]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[CH:33][CH:32]=4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:51]1[CH:52]=[CH:53][C:54]([C:57]#[N:58])=[N:55][CH:56]=1>CN(C)C=O>[C:10]1([N:9]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:30]4[C:26](=[N:27][N:28]([C:51]5[CH:56]=[N:55][C:54]([C:57]#[N:58])=[CH:53][CH:52]=5)[N:29]=4)[C:25]([C:31]4[CH:36]=[CH:35][C:34]([N:37]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)=[CH:33][CH:32]=4)=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)c4n[nH]nc34)cc2)cc1
Reactant: N#Cc1ccc(F)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2nc3c(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)c3n2)cn1
Temperature: 80 °C

Procedure:
Sodium hydride (60%, 120 mg, 3 mmol) was added to a solution of Intermediate P (1.21 g, 2.0 mmol) and 5-fluoro-2-pyridinecarbonitrile (0.61 g, 5.0 mmol) in anhydrous dimethylformamide (20 mL), stirred under argon, and the obtained mixture was heated at 80° C. for 16 hours. The reaction mixture was poured into ice/water (200 mL), and extracted with dichloromethane (200 mL). The extract was dried over sodium sulfate, and the solvent was evaporated. The residue was diluted with chlorobenzene (50 mL), and the volatiles were removed under high vacuum. The crude product was purified by chromatography (dichloromethane/hexane 2:1) to give 4,7-bis(4-(N,N-diphenylamino)phenyl)-2-(6-cyanopyridin-3-yl)-2H-benzo[d][1,2,3]triazole, dark-red crystals, 1.20 g (85%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[S:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[NH:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([CH3:29])=[CH:23]3)[CH:11]=1>>[CH3:29][C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([NH:19][C:16]1[CH:15]=[CH:14][N:13]=[C:12]3[CH:11]=[C:10]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[S:18][C:17]=13)=[CH:28][CH:27]=2
Reactant: Cc1cc2cc(Nc3ccnc4cc(Br)sc34)ccc2[nH]1
Reactant: OB(O)c1cccs1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cccs5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-thiophene-boronic acid and (2-bromothieno[3,2-b]pyridin-7-yl)-(2-methyl-1H-indol-5-yl)-amine by the procedure analogous to example 2 above. 1H NMR (400 MHz, CD3OD) δ8.01 (d, 1H), 7.39 (d, 1H), 7.36 (s, 1H), 7.30 (s, 1H), 7.26 (d, 1H), 7.01 (dd, 1H), 6.94 (dd, 1H), 6.53 (d, 1H), 6.09 (s, 1H), 2.39 (s, 3H); RP18-HPLC RT: 5.78 minutes; API MS: 362 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](Cl)=[O:12])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>COCCOC.CCOC(C)=O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc2nccnc2c1
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=Cc1ccc2nccnc2c1
Reaction time: 5 h
Yield: 73 %

Procedure:
In a 1 l 3-neck flask under argon was placed Quinoxaline-6-carbonyl chloride in 600 ml of DME. To this solution was added lithium tri-tert-butoxyaluminohydride (1 eq.) at −78° C. over 1.5 h. The reaction was kept at that temperature for 5 h. Then ice was added, and the reaction was diluted with AcOEt and filtrated over celite. The two layers were separated and the organic phase was washed with NaHCO3 sat. Quinoxaline-6-carbaldehyde was obtained upon evaporating the solvent in 73% yield as yellowish solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@H:7]([NH2:20])[CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])([CH3:4])([CH3:3])[CH3:2].C[Si](C#N)(C)C.[CH3:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([CH3:37])[C:30]=1[S:38](Cl)(=[O:40])=[O:39].Cl>C(#N)C.C(OCC)(=O)C>[CH3:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([CH3:37])[C:30]=1[S:38]([NH:20][C@H:7]([CH2:8][N:9]1[C:10](=[O:19])[C:11]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]2[C:13]1=[O:14])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])(=[O:39])=[O:40]
Reactant: CC(C)(C)OC(=O)[C@H](N)CN1C(=O)c2ccccc2C1=O
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: C[Si](C)(C)C#N
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N[C@H](CN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a stirred solution of tert-butyl-2(R)-amino-3-phthalimido-propionate (5.7 g, 19.63 mmol) in dry acetonitrile (60 ml) was added trimethylsilylcyanide (8.6 ml, 68.7 mmol). After 5 minutes 2,6-dimethyl-4-methoxybenzenesulfonyl chloride (4.84 g, 20.6 mmol) was added in one portion. The material was stirred at ambient temperature for 1 hour and then ethyl acetate (80 ml) was added and the mixture was transferred to a seperatory funnel. The organic phase was partioned with aqueous hydrochloric acid (1.5%, 100 ml), collected and washed with an equal volume of brine. The aqueous phases were back extracted with ethyl acetate (2×80 ml) and the organic phases combined, dried (magnesium sulfate), filtered and condensed. The residue was chromatographed (flash silica gel, 30% ethyl acetate-hexanes) to provide tert-butyl 2(R)-(2,6-dimethyl-4-methoxybenzene sulfonylamino)-3-phthalimido-propionate as white semi-solid (6.9 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=1.[CH:36]1([O:41][C:42](=[O:49])[C@H:43]([CH2:45][CH:46]([CH3:48])[CH3:47])[NH2:44])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:44][C@@H:43]([CH2:45][CH:46]([CH3:47])[CH3:48])[C:42]([O:41][CH:36]3[CH2:37][CH2:38][CH2:39][CH2:40]3)=[O:49])=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Reactant: Cc1cc(C(=O)c2ccc(=O)n(-c3c(F)cc(OCCCOS(C)(=O)=O)cc3F)c2N)ccc1F
Product: Cc1cc(C(=O)c2ccc(=O)n(-c3c(F)cc(OCCCN[C@@H](CC(C)C)C(=O)OC4CCCC4)cc3F)c2N)ccc1F

Procedure:
From Intermediate 4D and L-leucine cyclopentyl ester (Intermediate 8), LCMS purity 100%, m/z 614 [M+H]+, 1H NMR (400 MHz, d6-DMSO), δ: 0.90 (6H, m), 1.60-1.70 (10H, m), 1.90 (2H, m), 2.15 (2H, m), 2.30 (3H, s), 3.00-3.20 (2H, m), 4.10 (1H, s), 4.20 (2H, m), 5.25 (1H, m), 5.70 (1H, d), 7.05 (1H, d), 7.25 (1H, m), 7.40 (1H, m), 7.50 (1H, m), 7.60 (1H, d).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].I[CH3:24]>>[CH3:24][N:15]([C@@H:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11]1)[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: CI
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
tert-Butyl (R)-[1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate was alkylated with iodomethane by method F. This resulted in the product with the molecular weight of 321.38 (C16H23N3O4); MS (ESI): 322 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][C:15]=3[CH3:29])[N:10]=2)[CH:5]=[N:6][C:7]=1Cl.[CH3:30][CH:31]([OH:33])[CH3:32].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][C:15]=3[CH3:29])[N:10]=2)[CH:5]=[N:6][C:7]=1[O:33][CH:31]([CH3:32])[CH3:30]
Reactant: CC(C)O
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1noc(-c2cnc(Cl)c(Cl)c2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1noc(-c2cnc(OC(C)C)c(Cl)c2)n1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
To a solution of 138 mg (0.32 mmol) of tert-butyl 3-(4-(5-(5,6-dichloropyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)propanoate and 36.5 μL (0.48 mmol) of 2-propanol in 10 mL of THF was added 477 μL (0.48 mmol) of sodium bis(trimethylsilyl)amide (1.0 M in THF). The mixture was refluxed overnight, cooled to rt and concentrated. Chromatography on a Biotage 40S cartridge using 1:19 v/v EtOAc/hexanes as the eluant gave 106 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.43 (s, 9H), 1.44 (d, J=6.2, 6H), 2.58 (t, J=7.8, 2H), 2.65 (s, 3H), 2.95 (t, J=7.7, 2H), 5.49 (m, 1H), 7.17-7.18 (m, 2H), 8.00 (d, J=8.4, 1H), 8.38 (d, J=2.0, 1H), 8.86 (d, J=2.3, 1H).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[CH:11][C:10]1=[O:22])[CH2:5][CH:6]([F:8])[F:7].O1CCCC1.O.[OH-].[Li+]>O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:12]1[CH2:13][N:9]([CH:4]([CH2:5][CH:6]([F:8])[F:7])[C:3]([OH:23])=[O:2])[C:10](=[O:22])[CH:11]=1
Reactant: COC(=O)C(CC(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(CC(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
A mixture of 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4-difluoro-butyric acid methyl ester (790 mg, 2.28 mmol) in a 1:1 solution of tetrahydrofuran:water (20 mL) was treated with lithium hydroxide monohydrate (230 mg, 4.56 mmol). The mixture was stirred for 2 h at 25° C. After such time, the mixture was concentrated in vacuo to remove the tetrahydrofuran and then diluted with water, and the pH adjusted to pH=5 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4-difluoro-butyric acid (571 mg, 75%) as a cream colored solid: HR-ES-MS m/z calculated for C14H12NO4ClF2 [M+H]+ 332.0496, observed 332.0496.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@@:4]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])([CH:7]([CH3:9])[CH3:8])[CH2:3]1.[OH:28][C:29]1([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[N:47]=[CH:46][CH:45]=[CH:44][N:43]=3)=[CH:38][N:37]=2)[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:7]([C@:4]1([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:5][CH2:6][C@@H:2]([NH:1][CH:32]2[CH2:31][CH2:30][C:29]([C:36]3[CH:41]=[CH:40][C:39]([C:42]4[N:43]=[CH:44][CH:45]=[CH:46][N:47]=4)=[CH:38][N:37]=3)([OH:28])[CH2:34][CH2:33]2)[CH2:3]1)([CH3:8])[CH3:9]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N)C1
Reactant: O=C1CCC(O)(c2ccc(-c3ncccn3)cn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](NC2CCC(O)(c3ccc(-c4ncccn4)cn3)CC2)C1

Procedure:
To a solution of ((1S,3R)-3-amino-1-isopropylcyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone (50 mg, 0.13 mmol) in DCM (2 mL) was added 4-hydroxy-4-(5-(pyrimidin-2-yl)pyridin-2-yl)cyclohexanone (1.5 equiv) and sodium triacetoxyborohydride (1.5 equiv). The mixture was stirred until complete, portioned and the aqueous phase extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate. Chromatography gave the title compound as a white powder after lypholization. MS calculated for C32H42F3N7O2: (M+H) 638; found 638.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:15].Cl[CH:17]([CH:20]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2)[CH3:21])[CH:18]=O.C(N(CC)CC)C>C(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:17]([CH:20]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)[CH3:21])=[CH:18][N:14]=3)[N:13]=2)=[CH:4][C:3]=1[F:15]
Reactant: CC(c1ccc2ncccc2c1)C(Cl)C=O
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(c1ccc2ncccc2c1)c1cnc2ncc(-c3ccc(Br)c(F)c3)nn12
Temperature: 110 °C
Yield: 60 %

Procedure:
A mixture of 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (100.0 mg, 0.3716 mmol, prepared as described for Example 7, Steps 1-5) and 2-chloro-3-quinolin-6-ylbutanal (0.10 g, 0.44 mmol, prepared as described for Example 122, Steps 1-4) in isopropyl alcohol (3 mL) was heated at 110° C. for 48 h. The mixture was adjusted to pH 9 by adding triethylamine. The volatiles were removed under reduced pressure and the residue was purified by chromatography on silica gel with MeOH in methylene chloride (0-8%) to afford the desired product (0.10 g, 60%). LCMS: (M+H)=448/450.0.