Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.O.NN>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(CCCCN3C(=O)c4ccccc4C3=O)ccnc2c1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc2c(CCCCN)ccnc2c1
Yield: 99.1 %

Procedure:
3.46 g of the product of Stage C were dissolved in 70 ml of hot ethanol and 1.86 ml of hydrazine hydrate were added. The reaction medium was refluxed for 17 hours and the precipitate was eliminated by filtration. The solvent was evaporated and the residue was taken up in 70 ml of dichloromethane. Filtration was carried out and the solvent was evaporated to obtain 2.19 g of the expected product.
Reaction SMILES: Cl.[CH2:2]([C:10]1[NH:11][NH:12][C:13]2[CH:19]=[CH:18][N:17]=[CH:16][C:14]=2[N:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:20](OC(=O)C)(=[O:22])[CH3:21].C([O-])(O)=O.[Na+]>>[CH2:2]([C:10]1[NH:11][N:12]([C:20](=[O:22])[CH3:21])[C:13]2[CH:19]=[CH:18][N:17]=[CH:16][C:14]=2[N:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCC1=Nc2cnccc2NN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCCCCCC1=Nc2cnccc2N(C(C)=O)N1
Yield: 75 %

Procedure:
3-Octyl-1,2-dihydropyrido[3,4-e]-as-triazine hydrochloride is reacted with acetic anhydride as described in Example 1, and the resulting salt is treated with a solution of sodium hydrocarbonate to obtain 3-octyl-1-acetyl-1,2-dihydropyrido[3,4-e]-as-triazine with a yield of 75%. This compound is reacted with an equimolar amount of fumaric acid in ethanol to obtain the hydrogen fumarate melting at 285°-287° C.
Reaction SMILES: [C:1]1([C:7]2[C:8](O)=[N:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:22])=O>CC#N>[Cl:22][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:9]=1
Reactant: Oc1nc(-c2ccccn2)ncc1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Clc1nc(-c2ccccn2)ncc1-c1ccccc1

Procedure:
5-Phenyl-2-pyridin-2-ylpyrimidin-4-ol (4-1; 206 mg, 0.826 mmol) was stirred in 4 ml of anhydrous MeCN. Phosphorous oxychloride (0.077 ml, 0.83 mmol) was added and the resulting mixture was heated to reflux. After 1 h the reaction was cooled and concentrated in vacuo and quenched with half-saturated aqueous NaHCO3. The mixture was extracted 3× with DCM. The combined organic phases was dried over Na2SO4, filtered and concentrated to provide 4-chloro-5-phenyl-2-pyridin-2-ylpyrimidine (4-2). 1H NMR (CDCl3): δ 8.88 (s, 1H), 8.84 (s, 1H), 8.57 (d, J=8.0 Hz, 1H), 7.90 (dt, J=1.5, 7.6 Hz, 1H), 7.53 (m, 5H), 7.46 (dd, J=4.9, 7.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](/[CH:21]=[C:22]2\[O:23][C:24]3[C:31]([CH2:32][N:33]4[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]4)=[C:30]([OH:46])[CH:29]=[CH:28][C:25]=3[C:26]\2=[O:27])=[CH:13]1)(=[O:11])=[O:10].FC(F)(F)C(O)=O>C(Cl)Cl>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](/[CH:21]=[C:22]2\[O:23][C:24]3[C:31]([CH2:32][N:33]4[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]4)=[C:30]([OH:46])[CH:29]=[CH:28][C:25]=3[C:26]\2=[O:27])=[CH:13]1)(=[O:10])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(=O)(=O)c4ccc(Cl)cc4Cl)c4ccccc24)C3=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: O=C1/C(=C/c2cn(S(=O)(=O)c3ccc(Cl)cc3Cl)c3ccccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 157.6 %

Procedure:
A solution of tert-butyl (Z)-4-[(2-{[1-(2,4-dichlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.139 g, 0.203 mmol) in methylene chloride (6 mL) was added with trifluoroacetic acid (6 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, then a solution of the resulting residue in methanol (8 mL) was added with a 5% solution of hydrogen chloride in methanol (2 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the resulting solid was suspended in acetonitrile and thereby washed to obtain (Z)-2-{[1-(2,4-dichlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.0701 g, 52%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:22])=[C:5]([CH2:18][C:19]([OH:21])=[O:20])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[CH2:8][C:9]([OH:11])=[O:10].[N+]([O-])(O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:22][C:4]1[C:5]([CH2:18][C:19]([OH:21])=[O:20])=[C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[C:2]([CH3:1])[N:3]=1
Reactant: CC1=C(CC(=O)O)C(c2ccccc2)C(CC(=O)O)=C(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: Cc1nc(C)c(CC(=O)O)c(-c2ccccc2)c1CC(=O)O
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
90.3 g (0.3 mol) of 1,4-dihydro-2,6-dimethyl-4-phenyl-3,5-bis(carboxymethyl)pyridine were added in portions at from 92° to 98° C. to a solution of 375 g of 98% strength nitric acid in 1580 ml of water in the course of 30 minutes. After a further 30 minutes at 95°-98° C., the mixture was cooled to +5° C. and brought to pH 9 with solid potassium carbonate. The mixture was extracted three times with methylene chloride, the combined extracts were concentrated under reduced pressure and the residue was crystallized at 0° C. using 1:1 diethyl ether/pentane (50 ml). 58.8 g (65.5% of theory) of 2,6-dimethyl-4-phenyl-3,5-bis(carboxymethyl)pyridine were obtained as white crystals of m.p. 137°-138° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH:18]1([N:13]2[C:12]([C:33]3[CH:34]=[CH:35][C:30]([CH3:29])=[CH:31][CH:32]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Cc1ccc(-c2c3c(nn2C2CC2)CCNCC3)cc1
Yield: 105.8 %

Procedure:
The title compound (133 mg) was prepared according to Example 281 using 200 mg of 2-cyclopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 281, Step C) and 90 mg of 4-methylphenylboronic acid. MS (ESI): exact mass calculated for C17H21N3, 267.17; found, m/z 268.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.42-7.34 (m, 4H), 4.68-4.65 (m, 2H), 3.80-3.30 (m, 6H), 2.97 (br s, 2H), 2.44 (s, 3H), 0.94-0.91 (m, 4H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[NH2:27][C:28]1[C:29](=[O:40])[NH:30][C:31](=[O:39])[N:32]([CH2:35][CH2:36][CH2:37][CH3:38])[C:33]=1[NH2:34]>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([NH:27][C:28]2[C:29](=[O:40])[NH:30][C:31](=[O:39])[N:32]([CH2:35][CH2:36][CH2:37][CH3:38])[C:33]=2[NH2:34])=[O:14])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: CCCCn1c(N)c(N)c(=O)[nH]c1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCn1c(N)c(NC(=O)Cc2ccc(NC(C)=O)cc2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.9 %

Procedure:
A solution of (4-acetylamino-phenyl)-acetic acid (348 mg, 1.65 mmol) in N,N-dimethylformamide (2.5 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (316 mg, 1.80 mmol). The resulting mixture was stirred at 25° C. for 20 min. At this time, the reaction was treated with 5,6-diamino-1-butyl-1H-pyrimidine-2,4-dione (300 mg, 1.5 mmol) followed by 4-dimethylaminopyridine (37 mg, 0.3 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (5.0 mL) and was brought to pH=5 with a 1N aqueous hydrochloric acid solution. The resulting solid was collected by filtration, washed with water, and dried in vacuo to afford 2-(4-acetylamino-phenyl)-N-(6-amino-1-butyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-acetamide (330 mg, 59%) as a light tan solid: LR-MS for C18H23N5O4 (M+H)+ at m/z=374
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10].Cl.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([CH:25]([NH:27][C:28](=[O:34])[CH:29]([NH2:33])[CH:30]([CH3:32])[CH3:31])[CH3:26])=[CH:22][C:21]=2[CH:35]=1.O>ClCCl>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([CH:25]([NH:27][C:28](=[O:34])[C@H:29]([CH:30]([CH3:31])[CH3:32])[NH:33][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH3:26])=[CH:22][C:21]=2[CH:35]=1
Reactant: CC(C)OC(=O)Cl
Reactant: CC(NC(=O)C(N)C(C)C)c1cc2cc(Cl)ccc2o1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CC(C)OC(=O)N[C@H](C(=O)NC(C)c1cc2cc(Cl)ccc2o1)C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 47.1 %

Procedure:
0.54 g of N-methylmorpholine, and subsequently 0.7 g of isopropyl chloroformate were added to a solution containing 1.57 g of N-[1-(5-chloro-2-benzofuranyl)ethyl]-2-amino-3-methylbutanamide hydrochloride dissolved in 40 ml of dichloromethane at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the dichloromethane layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue, which was a crude crystal, was purified by column chromatography on silica gel, thus obtaining 0.85 g of the desired product in the form of a white powder.
Reaction SMILES: Br[CH:2]([CH2:14][CH3:15])[C:3]([NH:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[O:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.[C:21](OCC)(=O)C>>[CH2:14]([C@H:2]1[C@@H:21]2[C:20](=[O:16])[C@H:19]([CH:18]=[CH:17]2)[N:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=[O:4])[CH3:15]
Reactant: c1ccoc1
Reactant: CCOC(C)=O
Reactant: CCC(Br)C(=O)NOCc1ccccc1
Product: CC[C@@H]1C(=O)N(OCc2ccccc2)[C@H]2C=C[C@H]1C2=O
Yield: 86 %

Procedure:
Prepared in 86% yield (40.6 mg, 0.157 mmol) from the reaction of 2-bromo-N-(phenylmethoxy)butanamide (50.0 mg, 0.183 mmol) with furan via general procedure B. Rf=0.3 (3:1, hexanes:EtOAc); Rf 0.50 (3:1, hexanes:ethyl acetate); 1H-NMR (500 MHz, CDCl3): δ 7.45-7.42 (m, 2H), 7.41-7.32 (m, 3H), 6.51 (dd, J=6.0, 1 Hz, 1H), 6.38 (dd, J=6.0, 1.8 Hz, 1H), 5.25 (d, J=1.2 Hz, 1H), 4.99 (d, J=11.0 Hz, 1H), 4.95 (dd, J=5.1, 1.8 Hz, 1H), 4.87 (d, J=11.0 Hz, 1H), 2.99 (dt, J=10.1, 5.1 Hz, 1H), 2.07-1.96 (dqd, J=15.4, 7.5 5.3, 7.5, 15.4 Hz, 1H), 1.24-1.14 (m, 1H), and 1.03 (t, J=7.5 Hz, 3H). 13C-NMR (126 MHz, CDCl3): δ 172.1, 135.8, 133.6, 129.7, 128.8, 128.6, 91.4, 91.4, 81.3, 78.0, 51.8, 19.5, and 12.3; IR (film) 3250 (br), 3032, 2966, 2929, 2877, 1696, 1497, 1455, 1371, 1209, 1104, 1055, 1033 cm-1; HR-ESIMS calculated for C15H17NNaO3 (M+Na)+282.1101; observed 282.1083.
Reaction SMILES: [Li][CH3:2].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[CH2:14][CH:15]=[O:16].O>CCOCC.Cl[Ti](Cl)(Cl)Cl>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[CH2:14][CH:15]([OH:16])[CH3:2]
Reactant: [Li]C
Reactant: COc1cc([N+](=O)[O-])ccc1CC=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: COc1cc([N+](=O)[O-])ccc1CC(C)O
Temperature: -10 °C
Yield: 83.8 %

Procedure:
To a stirred −78° C. solution of TiCl4 (1.0 M in CH2Cl2, 1.43 mL, 1.43 mmol) in anhydrous Et2O (7 mL) was added MeLi (1.6 M in Et2O, 0.9 mL, 1.43 mmol) dropwise over a period of 20 min. The reaction mixture was allowed to slowly warm to −30° C. at which point a solution of 2-(2-methoxy-4-nitrophenyl)acetaldehyde (275 mg, 1.43 mmol) (prepared as described in PCT WO 2000/73288 A1) in anhydrous Et2O (0.750 mL) was added dropwise and allowed slowly warm to −10° C. The reaction mixture was poured into cold water and extracted with Et2O (3×50 mL). The combined ether extracts were washed with water (1×100 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure to afford 0.253 g (85%) of the title compound as an orange solid. 1H NMR (500 MHz, CDCl3) δ 1.25 (d, J=6.0 Hz, 3 H), 1.62 (br. s., 1 H), 2.81 (dd, J=13.2, 7.7 Hz, 1 H), 2.89-2.94 (m, 1 H), 3.93 (s, 3 H), 4.06-4.15 (m, 1 H), 7.32 (d, J=8.2 Hz, 1 H), 7.72 (d, J=2.2 Hz, 1 H), 7.82 (dd, J=8.2, 2.2 Hz, 1 H); HPLC (Method #1): 2.68 min retention time, (89%); LCMS (ES): m/z 194 [M−H2O+H]+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1COCC1.[C-:20]#[N:21].[K+].OS([O-])=O.[Na+]>C(Cl)Cl.O>[C:20]([C:10]1([OH:14])[CH2:11][CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)#[N:21]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)(C#N)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a solution of N-Boc-3-piperidone (5.00 g, 25.1 mmol) and THF (15 mL) was added KCN (2.34 g, 37.6 mmol) and H2O (15 mL) and the resulting solution was cooled to 0° C. To the resulting homogeneous orange solution was added a solution of NaHSO3 (1.25 g, 37.6 mmol) and H2O (15 mL). The resulting solution was stirred at 0° C. for 1 hour. The solution was twice extracted DCM and the combined extracts were dried by Na2SO4, filtered and evaporated to afford title compound 5.7 g as white solid. MS (m/z): 127 (M+H-Boc)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14]I)[C:6]=2[CH:17]=1.[CH2:18]([CH:23]1[CH2:29][CH:28]2[NH:30][CH:25]([CH2:26][CH2:27]2)[CH2:24]1)[CH2:19][CH2:20][CH2:21][CH3:22]>CCCCCCC.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14][N:30]3[CH:25]4[CH2:26][CH2:27][CH:28]3[CH2:29][CH:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:24]4)[C:6]=2[CH:17]=1
Reactant: CCCCCC1CC2CCC(C1)N2
Reactant: C[C@H](CI)CN1C(=O)COc2ccc(F)cc21
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(F)cc21
Yield: 58 %

Procedure:
The compound (S)-6-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF04)_(0.208 g, 0.6 mmol) and 3-Pentyl-8-azabicyclo[3.2.1]octane (0.10 g, 0.56 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF27) (0.16 g, 58%). 1H NMR (CDCl3) δ 7.13 (dd, J=2.8 Hz, J=10.0 Hz, 1H), 6.90 (dd, J=5.2 Hz, J=8.8 Hz, 1H), 6.68-6.63 (m, 1H), 4.57 (q, J=14.8 Hz, J=40.0 Hz, 1H), 4.11-3.94 (m, 2H), 3.14-3.04 (m, 2H), 2.30 (dd, J=4.0 Hz, J=12.8 Hz, 1H), 2.20-2.09 (m, 2H), 2.06-2.00 (m, 1H), 1.95-1.82 (m, 3H), 1.71-1.52 (m, 3H), 1.40-1.34 (m, 2H), 1.32-1.19 (m, 8H), 0.89-0.85 (m, 6H); 13C NMR (CDCl3) δ 164.9, 158.5 (d, J=239.4 Hz), 141.6 (d, J=2.6 Hz), 130.0 (d, J=10.8 Hz), 117.5 (d, J=9.3 Hz), 109.4 (d, J=23.4 Hz), 103.8 (d, J=28.9 Hz), 67.8, 61.0, 59.0, 58.2, 45.5, 38.4, 36.6, 36.5, 32.8, 31.8, 28.4, 28.4, 28.2, 27.2, 22.8, 7.0, 14.2.
Reaction SMILES: [CH3:1][C:2]1([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[Br:19]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1([CH2:12][C:13]2[CH:18]=[N:17][CH:16]=[N:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:19])[CH:9]=2)[NH:4][C:3]1=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(Cc2cncnc2)C(=O)Nc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(Cc2cncnc2)C(=O)Nc2ccc(Br)cc21

Procedure:
3-Methyl-3-(pyrimidin-5-ylmethyl)-1,3-dihydro-2H-indol-2-one (900 mg, 3.76 mmol) and N-bromosuccinimide (669 mg, 3.76 mmol) in N,N-dimethylformamide (20 mL) were stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC on Chiralpak AS, eluting with 25% isopropyl alcohol/CO2, to afford the enantiomers of 3-methyl-3-(pyrimidin-5-ylmethyl)-5-bromo-1,3-dihydro-2H-indol-2-one. Enantiomer A was isolated as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][CH2:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[C:36]([F:44])[CH:35]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:41][O:40][C:38](=[O:39])[C:37]1[CH:42]=[CH:43][C:34]([CH2:33][NH:32][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[CH:35][C:36]=1[F:44]
Reactant: COC(=O)c1ccc(CN)cc1F
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1F
Yield: 98 %

Procedure:
In a manner similar to the method described in Example 379, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (66.1 mg, 0.141 mmol) and methyl 4-(aminomethyl)-2-fluorobenzoate (51.0 mg, 0.278 mmol in N,N-dimethyl formamide (5 mL) were reacted with DIPEA (111 mg, 0.857 mmol), HOBt (37.6 mg, 0.277 mmol) and HBTU (104.9 mg, 0.275 mmol) at room temperature to give rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid methyl ester (88.5 mg, 98%). HRMS (ES+) m/z Calcd C32H30Cl2F3N3O3+H [(M+H):632.1689. Found: 632.1692.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8](C)[O:7][C:6](=[O:11])[CH:5]=1)=[N+]=[N-].[H][H].[CH2:14](O)C>[Pd]>[NH2:1][C:4]1([CH3:14])[CH:9]=[CH:8][O:7][C:6](=[O:11])[CH2:5]1
Reactant: [H][H]
Reactant: CCO
Reactant: Cc1cc(N=[N+]=[N-])cc(=O)o1
Agent: [Pd]
Product: CC1(N)C=COC(=O)C1
Yield: 100 %

Procedure:
To a 0.310 g (2.05 mmol) of 38 and 0.031 g of 10% Pd/C in 10 mL of ethanol was maintained under 1 atm (a ballonn) of hydrogen gas for 1 hour. The reaction mixture was then filtered through Celite, and ethanol of the filtrate was removed through rotary evaporation to give 0.260 g of 39 (100% yield). 1H NMR δ 5.56 (s, 1H, C3H), 5.12 (s, 1H, C5 H), 4.45 (s, 2H, NH2), 2.20 (s, Me); 13C NMR δ 163.6 (s, C2), 161.3 (s), 98.6 (d, C5), 80.4 (d, C3), 19.5 (q, Me).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]N1C(=O)CCC1=O.[C:28]([N:38]([CH2:42][CH2:43][OH:44])[CH2:39][CH2:40]O)([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].N1C(C)=CC=CC=1C.O([Si:61]([CH:68]([CH3:70])[CH3:69])([CH:65]([CH3:67])[CH3:66])[CH:62]([CH3:64])[CH3:63])S(C(F)(F)F)(=O)=O>C(Cl)Cl.O>[CH2:31]([O:30][C:28](=[O:29])[N:38]([CH2:39][CH2:40][Br:20])[CH2:42][CH2:43][O:44][Si:61]([CH:68]([CH3:70])[CH3:69])([CH:65]([CH3:67])[CH3:66])[CH:62]([CH3:64])[CH3:63])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=C(OCc1ccccc1)N(CCO)CCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)[Si](OCCN(CCBr)C(=O)OCc1ccccc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.9 %

Procedure:
Triphenylphosphine (1.15 g, 4.39 mmol) and N-bromosuccinimide (0.79 g, 4.39 mmol) were added to a 0° C. solution of N-Cbz-diethanolamine (1 g, 4.18 mmol) in 40 ml of methylene chloride. The reaction was stirred at room temperature for 4 hours and then cooled to 0° C. 2,6-Lutidine (0.97 ml, 8.36 mmol) was added, followed by the dropwise addition of triisopropylsilyl triflate (1.35 ml, 5 mmol). The reaction was stirred at room temperature for 12 h, diluted with water, and concentrated under vacuum and the residue was extracted with ethyl acetate (2×50 ml). The organic layer was washed with 0.5 M HCl, saturated sodium bicarbonate, brine and dried over sodium sulfate. Evaporation of the solvent followed by chromatography (SiO2 Biotage 40 M, 3%-5% ethyl acetate/hexanes) gave (2-bromo-ethyl)-(2-triisopropylsilanyloxy-ethyl)-carbamic acid benzyl ester (400 mg) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:59])[C:10]2[C:5](=[CH:6][C:7]([CH2:11][O:12][CH:13]3[CH:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[O:37][CH3:38])=[CH:21][CH:20]=4)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]3)=[CH:8][CH:9]=2)[N:4]([CH2:46][CH2:47][O:48][Si](C(C)C)(C(C)C)C(C)C)[CH2:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[OH:48][CH2:47][CH2:46][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH2:11][O:12][CH:13]3[CH:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[O:37][CH3:38])=[CH:21][CH:20]=4)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]3)[CH:6]=2)[C:2]([CH3:59])([CH3:1])[CH2:3]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCO[Si](C(C)C)(C(C)C)C(C)C)CC3(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCO)CC3(C)C)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The solution of 0.595 g of tert-butyl 3-[3,3-dimethyl-1-(2-triisopropylsilanyloxyethyl)-2,3-dihydro-1H-indol-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 8.0 ml of tetrahydrofuran is admixed with tetrabutylammonium fluoride solution (1M in tetrahydrofuran) and stirred at 60° C. over 1 hour. The reaction mixture is cooled, admixed with water (15 ml) and extracted with tert-butyl methyl ether (2×15 ml). The organic phases are washed successively with water (15 ml) and brine (15 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.13 (1:1 EtOAc-heptane); Rt=5.72.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1C(OC(C)(C)C)=O)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([NH:9][C:10]([C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNC(=O)[C@H]1CCCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCNC(=O)[C@H]1CCCCN1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
(R)-(+)-1-(tert-Butoxycarbonyl)-2-piperidinecarboxylic acid n-octyl amide (8) (1.00 g; 2.94 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added and the solution is stirred for 7 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3 times, 50 mL each). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (23) as a solid. ISMS: MH+ 240.8