Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:16][N:17]([CH3:27])[C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:25]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([N:17]([CH3:27])[CH3:16])=[CH:19][CH:20]=3)=[O:26])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: CN(C)c1ccc(N=C=O)cc1
Product: CN(C)c1ccc(NC(=O)NC2CCCc3c2[nH]c2ccc(Br)cc32)cc1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-[4-(dimethylamino)phenyl]urea was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 4-dimethylamino phenyl isocyanate in a similar manner as described above to give a tan solid (40% yield). 1H-NMR (DMSO-d6): δ 10.99 (s, 1H), 7.98 (s, 1H), 7.60 (d, 1H), 7.33-7.23 (m, 3H), 7.17 (dd, 1H), 6.71 (d, 2H), 6.44 (d, 1H), 5.00 (m, 1H), 2.84 (s, 6H), 2.67 (m, 2H), 2.04 (m, 1H), 1.94-1.74 (m, 3H); MS m/z 427 (M−1).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]([O:20]CC)=[O:19]>C1COCC1.CO>[Cl:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
Sodium hydroxide (2M, 3 ml) was added to a stirred solution of ethyl N-(3,4-dichlorobenzyl)-5-hydroxyindole-2-carboxylate (0.1 g) in THF (3 ml) and methanol (1.5 ml). The reaction was stirred at ambient temperature for 4 hours. The reaction was concentrated in vacuo and the residue was dissolved in water (5 ml). The solution was acidified by the addition of aqueous hydrochloric acid (2M, 4 ml) precipitating the product as a white solid. The product was filtered, washed with water and dried in vacuo to yield the title compound (82 mg, 89%). NMR: δ 5.77 (s, 2H), 6.81 (dd, 1H), 6.89 (dd, 1H), 6.95 (d, 1H), 7.13 (s, 1H), 7.26 (d, 1H), 7.34 (d, 1H), 7.52 (d, 1H), 9.01 (s, 1H), 12.85 (s, 1H); m/z 334 (M−H+).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: COc1ccc(CO)cc1
Product: COc1ccc(COc2ccnn2-c2cc(C#N)ccn2)cc1
Yield: 14 %

Procedure:
The title compound was prepared in 14% yield from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 4-methoxybenzyl alcohol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 3.81 (3H, s), 5.17 (2H, s), 5.75 (1H, d, J=2.0 Hz), 6.91-6.93 (2H, m), 7.34-7.39 (3H, m), 7.57 (1H, d, J=2.0 Hz), 8.01 (1H, s), 8.69 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H14N4O2, 307. Found, 307.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](=[CH2:15])=[N-].CO>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:15])=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Nitrobenzoic acid (5 g; 29.92 mmol; 1 eq.) is dissolved in toluene (37.5 ml). Timethylsilyl diazomethane in toluene and MeOH (1/1)(45 ml; 2 M; 89.76 mmol; 3 eq.) is added dropwise. The solution is stirred at rt for 2 h. Solvents are removed affording methyl 4-nitrobenzoate as a yellow powder (5.42 g; 100%).
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[C:9]([C:12]1[S:13][C:14]([Br:17])=[CH:15][CH:16]=1)(=[O:11])[CH3:10].Cl>C1COCC1.O>[Br:17][C:14]1[S:13][C:12]([C:9](=[O:11])[CH2:10][C:3]([O:6][CH3:7])=[O:8])=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccc(Br)s1
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1ccc(Br)s1
Yield: 99 %

Procedure:
Sodium hydride (1.95 g of 60% dispersion in oil, 0.045 mol), dimethyl carbonate (50 mL) and THF (40 mL) were added to a flame dried flask equipped with stirrer and dropping funnel. 2-Acetyl-5-bromothiophene (5.0 g, 0.024 mol) in 20 mL THF was added dropwise. The mixture was then heated at reflux for 2 hours, then poured into 250 mL of water, acidified to pH 2.0 with lN HCl and extracted 3×200 mL ether. The organic layers were combined, dried (MgSO4) and stripped to yield 6.4 g (99%) of present title product as an oil; tlc Rf 0.42 (CHCl3).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:33])=[N:31][N:32]=2)=[CH:24][CH:23]=1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[O:29][C:30]([CH3:33])=[N:31][N:32]=4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2ccco2)cc(OC)c1F
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)o4)cc3)o2)cc(OC)c1F

Procedure:
1-(5-(4-Fluoro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone was prepared from 2-(4-fluoro-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc-hexanes) gave the product as a pale yellow solid (0.036 g, 8% yield). MS: m/z 453.2 [M+H]+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]([NH:19][C:20]2[N:25]=[C:24]([N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=[CH:27]3)[CH:23]=[CH:22][N:21]=2)[CH3:18])=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]([NH:19][C:20]2[N:25]=[C:24]([N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=[CH:27]3)[CH:23]=[CH:22][N:21]=2)[CH3:18])=[CH:9]1
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)c1cn(C(=O)OC(C)(C)C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)c1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
To a solution of 2-[1-(1-N-tert-butoxycarbonyl-indol-3-yl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (25 mg, 0.055 mmol) in methylene chloride (0.25 ml) was added TFA (0.25 ml). The reaction mixture was stirred at 0° C. for an hour and room temperature for 30 min. The solvents were concentrated in vacuo. The crude product was purified by preparative thin layer chromatography eluting with 5% 2M NH3 in MeOH/CH2Cl2 to give 6 mg of the title compound. Mass spectrum (ESI) 355.3 (M+1).
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH:4]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][C:17]3[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:20]([CH2:21]Br)=[CH:19][C:18]=3[C:29]([F:32])([F:31])[F:30])[CH:14]=2)[NH:9][CH:8]=1)([CH3:6])[CH3:5]>CN(C)C=O.O>[CH:4]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][C:17]3[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:20]([CH2:21][C:1]#[N:2])=[CH:19][C:18]=3[C:29]([F:32])([F:31])[F:30])[CH:14]=2)[NH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CBr)cc3C(F)(F)F)cc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CC#N)cc3C(F)(F)F)cc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
72.9 mg (1.49 mmol) of sodium cyanide are added at 50° C. to a solution of 0.57 g (1.19 mmol) of benzyl bromide from Example VII in 3.5 ml of dimethylformamide and 0.38 ml of water and the mixture is stirred for 60 minutes at 50° C. Dimethylformamide is subsequently distilled off, the concentrate is diluted with ethyl acetate and water, and the aqueous phase is separated off and extracted again with ethyl acetate. The combined organic phases are washed with sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The purification of the crude product is carried out on silica gel 60 by means of toluene/ethyl acetate (toluene, toluene/ethyl acetate=18:1 and 18:1.5).
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27][CH:28]=[CH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH2:42][CH2:43][C:44]([F:56])([F:55])[C:45]([F:54])([F:53])[C:46]([F:52])([F:51])[C:47]([F:50])([F:49])[F:48])[C:37]([O:39][CH2:40][CH3:41])=[O:38])([CH3:20])[C@@H:18]([O:57]CC3C=CC=CC=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1>CO.O1CCCC1.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C@@H:22]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH2:42][CH2:43][C:44]([F:55])([F:56])[C:45]([F:53])([F:54])[C:46]([F:51])([F:52])[C:47]([F:48])([F:49])[F:50])[C:37]([O:39][CH2:40][CH3:41])=[O:38])([CH3:20])[C@@H:18]([OH:57])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: CCOC(=O)C(CCCCCCC=CCC1=C2c3ccc(OCc4ccccc4)cc3CC[C@H]2[C@@H]2CC[C@H](OCc3ccccc3)[C@@]2(C)C1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C(CCCCCCCCC[C@H]1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2CCc3cc(O)ccc3[C@@H]12)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 23 h
Yield: 71.4 %

Procedure:
Ethyl 11-[3,17β-bis(benzyloxy)estra-1,3,5(10), 9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoate (500 mg, 0.55 mmol) was dissolved in a mixed solvent of methanol (10 ml) and tetrahydrofuran (1 ml), followed by addition of palladium hydroxide/carbon (150 mg) at room temperature. After purging with hydrogen, the reaction mixture was stirred for 23 hours at room temperature and then filtered. The solvent was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 3/1 2/1) to give ethyl 11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoate (287 mg, Yield 71%).
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1.[OH-].[K+]>C(O)C.O>[I:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1
Reactant: CCOC(=O)c1cn(C)nc1I
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cc(C(=O)O)c(I)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.1 %

Procedure:
134 g (0.478 mol) of ethyl 3-iodo-1-methyl-1H-pyrazole-4-carboxylate were initially charged in 850 ml of ethanol, and a solution of 29.5 g (0.526 mol) of KOH in 340 ml of water was added dropwise. After 2 days of stirring at room temperature, the mixture was concentrated, the residue was taken up in water and extracted with ethyl acetate and, after separation, the aqueous phase was adjusted to pH 1 using hydrochloric acid, resulting in the precipitation of a solid. Filtration with suction and 3 hours of drying under reduced pressure at 40° C. gave 88 g (70% of theory) of 3-iodo-1-methyl-1H-pyrazole-4-carboxylic acid [logP (pH 2.3)=0.57]. The aqueous phase was extracted with ethyl acetate and the organic phase was concentrated, which gave another 5.1 g (2.1% of theory) of product.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH2:16]Br)=[C:14]([CH3:15])[C:10]=2[C:9]([C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([O:25][C:26](=[O:28])[CH3:27])=[C:20]([CH3:29])[CH:19]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:1][C:2]1[C:11]2[S:12][C:13]([CH2:16][N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])=[C:14]([CH3:15])[C:10]=2[C:9]([C:18]2[CH:19]=[C:20]([CH3:29])[C:21]([O:25][C:26](=[O:28])[CH3:27])=[C:22]([CH3:24])[CH:23]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: CC(=O)Oc1c(C)cc(-c2c3ccccc3c(Br)c3sc(CBr)c(C)c23)cc1C
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)Cc1sc2c(Br)c3ccccc3c(-c3cc(C)c(OC(C)=O)c(C)c3)c2c1C
Yield: 94.9 %

Procedure:
Acetic acid 4-(9-bromo-2-bromomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenyl ester (1.21 g, 2.27 mmol) was treated with diethylamine (0.71 mL, 6.82 mmol), potassium carbonate (0.94 g, 6.82 mmol), and N,N-dimethylformamide (12.1 mL). After 1 h at room temperature the reaction mixture was poured in water (250 mL), filtered, and rinsed well with water. Air drying gave the title compound as a yellow solid (1.13 g, 94.5%): NMR (DMSO-d6): δ8.19 (d, 1H), 7.66-7.61 (m, 1H), 7.47 (d, 2 H), 7.13 (s, 2H), 3.73 (s, 2H), 2.58-2.52 (q, 4H), 2.40 (s, 3H), 2.16 (s, 6H), 1.61 (s, 3H), 1.02 (t, 6H); MS(EI): [M+], 1 bromine isotope pattern, 523/525; Anal. Calc. for C28H30BrNO2S: C, 64.12; H, 5.77; N, 2.67. Found: C, 63.30, H, 5.67; N, 2.55.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][CH:8]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([O-:3])=[O:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]([C:28](=[O:30])[CH3:29])[CH:8]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCC1Nc2ccccc2-c2c([N+](=O)[O-])cnn21
Product: CCCCCCCCCCCC1N(C(C)=O)c2ccccc2-c2c([N+](=O)[O-])cnn21
Yield: 85 %

Procedure:
1-Nitro-5-undecyl-5,6-dihydropyrazolo[1,5-c]quinazoline is treated with acetic anhydride as described in Example 27 to give 1-nitro-5-undecyl-6-acetyl-5,6-dihydropyrazolo[1,5-c]quinazoline. M.p.: 83°-85° C. Yield: 85%.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=1)[CH3:9])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:11][CH:12]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(F)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H](N)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
To a solution of (S)-tert-butyl-1-(5-fluoropyridin-2-yl)ethylcarbamate (Method 32; 12.8 g, 53.3 mmol) in DCM (100 ml) was added HCl/dioxane solution (107 ml, 4 N, 428 mmol). The reaction was stirred at room temperature for 3 hours. The solvent was removed and 50 ml of saturated sodium bicarbonate was added. The resulting aqueous solution was extracted with ether (6×400 ml), dried over sodium sulfate and concentrated to give the title compound (7.30 g, 98%) as pale yellow oil. 1H NMR (400 MHz) δ 8.44 (d, J=2.8 Hz, 1H), 7.66 (m, 1H), 7.53 (m, 1H), 4.01 (q, J=6.8 Hz, 1H), 1.94 (b, 2H), 1.26 (d, J=6.8 Hz, 3H). MS: Calcd.: 140. Found: [M+1-1]+141.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.F[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][N:11]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 13.1 %

Procedure:
To the solution of 3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (0.30 g) and 4-fluorobenzonitrile (0.12 g) in DMSO (dimethylsurufoxide) was added potassium carbonate (0.27 g), and the mixture was heated with stirring at 120° C. for 6 hours. The mixture was cooled to room temperature and then poured onto water, which was then extracted twice with ethyl acetate. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield 4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]benzonitrile (0.05 g). 1H-NMR (CDCl3) δ: 2.51-2.62 (1H, m), 2.86-2.94 (1H, m), 3.56-3.61 (2H, m), 3.80 (1H, d), 4.12 (1H, d), 6.59 (2H, d), 7.26 (2H, br s), 7.41 (1H, t), 7.52 (2H, d).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][NH2:26])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1>C1COCC1>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][NH:26][C:38]([C:39]4[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=4)=[O:45])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](Cn1ncc2ccc3oc(CN)cc3c21)NC(=O)OCc1ccccc1
Reactant: O=C(Cl)c1cccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ncc2ccc3oc(CNC(=O)c4cccnc4)cc3c21)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a solution of the product from Step B (0.32 g, 0.847 mmol) in THF (20 mL) was added polymer supported di-isopropyl ethyl amine (3.86 mmol/g, 0.44 g, 1.69 mmol, 2 eq); this suspension was cooled (ice bath) and nicotinoyl chloride (0.15 g, 0.847 mmol) was added. The ice bath was removed and mixture was stirred for one hour, additional nicotinoyl chloride (50 mg) was added and the mixture was stirred at room temperature overnight. Triethylamine was added and after stirring for 10 min saturated aqueous sodium bicarbonate (150 mL) was added. This mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were dried (MgSO4) and evaporated to an oil which was purified by chromatography (silica gel, hexane/ethyl acetate gradient) to give a solid (0.16 g, 39%): LC/MS m/z 484 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([NH:18][C:19]2[C:23]3[CH:24]=[C:25]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=[CH:27][C:22]=3[O:21][C:20]=2[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=2)=[O:33])=[O:17])[CH2:12][CH2:11]1)C)=O)(C)(C)C.Cl>O1CCOCC1.C(OCC)C>[ClH:41].[CH3:31][O:30][C:28]([C:25]1[CH:26]=[CH:27][C:22]2[O:21][C:20]([C:32]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=3)=[O:33])=[C:19]([NH:18][C:16]([C@H:13]3[CH2:12][CH2:11][C@H:10]([NH:8][CH3:6])[CH2:15][CH2:14]3)=[O:17])[C:23]=2[CH:24]=1)=[O:29]
Reactant: COC(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N(C)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(C(=O)OC)cc23)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Trans-3-[4-(N-t-butoxycarbonyl-N-methylamino)cyclohexylcarbonylamino]-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (4.60 g) obtained in Example 202 is dissolved in dioxane (20 ml), and thereto is added 4N hydrogen chloride in dioxane (10 ml), and the mixture is stirred at room temperature for 48 hours. The reaction solution is diluted with diethyl ether, and the precipitates are collected by filtration, washed several times with diethyl ether and dried to give the title compound (4.02 g).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]2[CH:17]=[CH:18][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:20][C:5]=2[N:4]=1)[CH3:2].Br[C:31]1[CH:32]=[N:33][CH:34]=[N:35][CH:36]=1.C([O-])(O)=O.[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][OH:16])=[CH:12][CH:13]=2)[C:6]2[CH:17]=[CH:18][C:19]([C:31]3[CH:32]=[N:33][CH:34]=[N:35][CH:36]=3)=[CH:20][C:5]=2[N:4]=1)[CH3:2]
Reactant: Brc1cncnc1
Reactant: CCc1nc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1-c1ccc(CCO)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCc1nc2cc(-c3cncnc3)ccc2n1-c1ccc(CCO)cc1
Temperature: 70 °C
Reaction time: 17 h
Yield: 50.3 %

Procedure:
To a solution of 2-{4-[2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-1-yl]phenyl}ethanol (step 1, 100 mg, 0.26 mmol) and 5-bromopyrimidine (45 mg, 0.28 mmol) in 1,2-dimethoxyethane (3.5 ml) was added sat. NaHCO3 aq. (1.2 ml) and Pd(PPh3)4 (60 mg, 0.05 mmol). This mixture was stirred at 70° C. for 17 h. The reaction mixture was diluted with water and extracted with CH2Cl2 (3×10 ml). The organic layer was dried (MgSO4) and concentrated to give light brown oil. This mixture was purified by SiO2 preparative TLC (CH2Cl2/methanol=10/1) to afford 45 mg (50%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH:29]2[CH2:31][O:30]2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH:29]([OH:30])[CH2:31][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:25][CH:24]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Clc1ccc(OCC2CO2)cc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC(O)COc3ccc(Cl)cc3)CC1)O2

Procedure:
Compound 176 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-[(4-chlorophenoxy)methyl]oxirane and conditions outlined in procedure X. LCMS: 486 [M+H]; Rt=1.06 min.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]2[C:12](=O)[CH2:11]CC2=O)=[O:7])=[CH:4][CH:3]=1.NCC[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:12][CH2:11][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:7])=[CH:15][CH:16]=1
Reactant: O=C1CCC(=O)N1C(=O)c1ccc(Cl)cc1
Reactant: NCCN1CCOCC1
Solvent: C1COCCO1
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
2.4 G. of N-(p-chlorobenzoyl)-succinimide are added to a solution of 1.3 g. of N-(2-aminoethyl)-morpholine in 100 ml. of dioxane and the mixture is stirred overnight at room temperature. The mixture is then evaporated to dryness. 50 Ml. of ice-water are added to the oily residue and the mixture which crystallizes is allowed to stand overnight in a refrigerator. The product is removed by filtration, washed with cold water, dried and recrystallized from isopropanol, and 0.65 g. of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: C([O:8][C:9](=[O:42])[C@@H:10]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH:11][C:12](=[O:33])[C@H:13]([CH2:29][CH2:30][CH2:31][NH2:32])[N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:15]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:13]([C:12]([NH:11][C@@H:10]([C:9]([OH:42])=[O:8])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:29][CH2:30][CH2:31][NH2:32])([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCN)C(=O)N[C@H](CCc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCN)C(=O)N[C@H](CCc1ccccc1)C(=O)O
Yield: 104.7 %

Procedure:
A solution of NaNd-bis-Boc-L-Ornithyl-D-Homophenylalanine Benzyl ester (2.80 g, 4.80 mmol) in methanol (200 mL) was treated with 10% Pd/C catalyst (0:2 g) and stirred in the atmosphere of hydrogen at 25° C. for 3 hr. The catalyst was removed by filtration through Celite pad and the filtrate evaporated to dryness to give the title product (2.48 g).