Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[OH:12][C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.N>CN1C(=O)CCC1.CO.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:15]3[CH2:16][CH2:17][C@H:13]([OH:12])[CH2:14]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: O[C@H]1CCNC1
Reactant: Fc1ccc2nnc(Cl)n2c1
Agent: N
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CO
Product: O[C@H]1CCN(c2nnc3ccc(F)cn23)C1
Temperature: 160 °C
Yield: 38.8 %

Procedure:
A mixture of Intermediate 24b (300 mg, 1.74 mmol) and (S)-3-hydroxypyrrolidine (600 mg, 9.96 mmol) in NMP (6 mL) was heated in the microwave at 160° C. for 2 h. The reaction mixture was applied to an SCX-2 cartridge (70 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-8% [2M NH3 in MeOH] in DCM, gave the title compound (150 mg, 38%). LCMS (Method 1): Rt 1.45 min, m/z 223 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13](C3C([N+]([O-])=O)=CC=CC=3S([O-])(=O)=O)[CH2:12]2)=[O:10])=[C:4]([C:36](=[O:43])[NH:37][CH:38]([CH:40]2[CH2:42][CH2:41]2)[CH3:39])[CH:3]=1.C(O)(=O)C.[BrH:48].C(OCC)(=O)C.[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([Br:48])[CH2:12]2)=[O:10])=[C:4]([C:36](=[O:43])[NH:37][CH:38]([CH:40]2[CH2:42][CH2:41]2)[CH3:39])[CH:3]=1
Reactant: Br
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(c2c([N+](=O)[O-])cccc2S(=O)(=O)[O-])=NN1c1ncccc1Cl)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Reaction time: 1.5 h

Procedure:
400 mg of 5-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl3-nitrobenzene sulfonate was dissolved in 0.7 mL of acetic acid, and 0.3 mL of a 33 mass % hydrogen bromide acetic acid solution was dropwise added, followed by stirring for about 1.5 hours. After completion of the reaction, ethyl acetate, water and 1.8 mL of 1 N sodium hydroxide were added, followed by stirring and extraction with ethyl acetate. Then, concentration under reduced pressure was carried out to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/2) to obtain 320 mg of the desired product in a paste form.
Reaction SMILES: C([O:4][CH2:5][C:6](Cl)=[O:7])(=O)C.N[C@@H:10]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:11][NH:12][C:13]1[N:18]([CH3:19])[C:17](=[O:20])[C:16]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:15]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[N:14]=1.C([N:43](CC)CC)C>ClCCl>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:16]2[C:17](=[O:20])[N:18]([CH3:19])[C:13]([NH:12][CH2:11][CH2:10][C@H:34]([NH:43][C:6](=[O:7])[CH2:5][OH:4])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:14][C:15]=2[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:26][CH:25]=1
Reactant: CCN(CC)CC
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cn1c(NC[C@@H](N)Cc2ccccc2)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Solvent: ClCCl
Product: Cn1c(NCC[C@H](NC(=O)CO)c2ccccc2)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reaction time: 0.83 h

Procedure:
Acetoxyacetyl chloride (55 μl, 0.51 mmol) was added at ice-bath temperature to a stirring solution of 2-(((S)-2-amino-3-phenylpropyl)-amino)-5-(4-fluoro phenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone (200 mg, 0.466 mmol) and triethylamine (130 μl, 0.93 mmol) in dichloromethane (4 ml). After 50 min, the reaction was quenched by the addition of a drop of methanol followed by evaporation. The resultant material was taken up in a 1:1:1 mixture of methanol/water/triethylamine (3 ml) and left overnight. Evaporation and subsequent column chromatography (3-7% methanol/chloroforme) provided the title compound. MS (m/z): 488.3 (M+H)+; C27H26FN5O3 requir. 487.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@H:23]4[C@H:19]([O:20][C:21]([CH3:25])([CH3:24])[O:22]4)[C@@H:18]([CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.ClCCCl.O=[C:42]1[CH2:45][CH:44]([CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:43]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:23]4[O:22][C:21]([CH3:24])([CH3:25])[O:20][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:28]([CH3:30])[CH3:29])[CH:42]4[CH2:45][CH:44]([CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:43]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CNC(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: CCOC(=O)CCC1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)CCC1CC(N(C[C@H]2C[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C(C)C)C1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A solution of N-(2,4-dimethoxybenzyl)-7-((3aS,4R,6R,6aR)-6-((isopropylamino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (9.50 g, 15.3 mmol) in 1,2-Dichloroethane (75 mL, 950 mmol) was treated with ethyl 3-(3-oxocyclobutyl)propanoate (3.92 g, 23.0 mmol) and Acetic acid (1.0 mL, 18 mmol) dropwise followed by Sodium triacetoxyborohydride (4.58 g, 21.6 mmol) and the mixture was stirred at RT for 6 days. The reaction mixture was diluted with 150 mL CH2Cl2 and washed with 100 mL sat NaHCO3. The aqueous phase was washed with 100 mL CH2Cl2 and the combined organic phase was dried over Na2SO4, filtered and concentrated to yield a light brown viscous glass.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:22]1[CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:20][CH2:19][CH2:18][O:17][C:15]2[CH:14]=[CH:13][C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)=[N:9][S:10][C:11]=3[CH:16]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: C1CNC1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: Brc1ccc(-c2nsc3cc(OCCCN4CCC4)ccc23)cc1

Procedure:
According to the method in example 4, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and azetidine were converted to yield 6-(3-Azetidin-1-yl-propoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole, MS: 404 (MH+, 1Br).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[CH:7][C:2]([N:28]5[C@H:27]([CH3:26])[CH2:31][O:30][C:29]5=[O:32])=[N:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(Br)cn2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(N3C(=O)OC[C@H]3C)cn2)CC1
Yield: 16.9 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (175 mg) described in Preparation Example 243 and (R)-4-methyloxazolidin-2-one (53 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (31 mg) was obtained.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:34])[C:13]2[O:19][C:18]3[C:20]([Cl:30])=[CH:21][C:22]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:23][C:17]=3[CH2:16][S:15](=[O:32])(=[O:31])[C:14]=2[CH:33]=1)=[O:9].N1C=CC=CC=1>ClCCl>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:34])[C:13]2[O:19][C:18]3[C:20]([Cl:30])=[CH:21][C:22]([N:24]4[CH2:25][CH2:26][N:27]([S:1]([CH3:4])(=[O:3])=[O:2])[CH2:28][CH2:29]4)=[CH:23][C:17]=3[CH2:16][S:15](=[O:31])(=[O:32])[C:14]=2[CH:33]=1)=[O:9]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(S(C)(=O)=O)CC3)cc(Cl)c1O2
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
Mesyl chloride (0.16 mL, 2.059 mmol) was added to a solution of 4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester (free base of example 16, 0.3 g, 0.687 mmol) in dichloromethane (20 mL) and stirred at 20° C. for 10 min. To this pyridine (0.3 mL, 4.12 mmol) was added and the reaction mixture was stirred further for 5 h. The reaction mixture was washed using aqueous hydrochloric acid 10% (15 mL), water and then brine solution. Solvent was removed and the crude product obtained was purified by column chromatography (silica gel, 1% methanol in chloroform) to obtain the title compound. Yield: 0.14 g, (38.45%); 1H NMR (DMSO-d6, 300 MHz): δ 2.63 (s, 3H, CH3), 2.90 (s, 3H, CH3), 3.22 (s, 4H, 2CH2); 3.31 (s, 4H, CH2); 3.85 (s, 3H, OCH3); 5.16 (s, 2H, CH2), 7.13 (d, 1H, Ar), 7.18 (s, 1H, Ar), 8.09 (t, 1H, Ar), 8.15 (d, 1H, Ar); MS: m/e (ES+) 515 (M+1); analysis: C21H23ClN2O7S2.H2O requires C, 47.32; H, 4.73; N, 5.26; Cl, 6.65; S, 12.03. found: C, 46.86; H, 4.18; N, 4.96; Cl, 7.11; S, 12.57%.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[N:17][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C:4]([CH2:7][NH:8][C:9](=[O:16])[C:10]2C=CC=NC=2)=[N:5][N:6]=1.NCC1C(=NNC2C=CC=C(F)C=2)C(N)=NN=1.Cl.C(Cl)(=O)C1C=CC=NC=1.[C:53]([O:56]CC)(=[O:55])[CH3:54]>>[NH2:1][C:2]1[C:3](=[N:17][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C:4]([CH2:7][NH:8][C:9]([CH:10]=[CH:54][C:53]([OH:56])=[O:55])=[O:16])=[N:5][N:6]=1
Reactant: NC1=NN=C(CNC(=O)c2cccnc2)C1=NNc1cccc(F)c1
Reactant: CCOC(C)=O
Agent: Cl
Agent: NCC1=NN=C(N)C1=NNc1cccc(F)c1
Agent: O=C(Cl)c1cccnc1
Product: NC1=NN=C(CNC(=O)C=CC(=O)O)C1=NNc1cccc(F)c1
Yield: 41 %

Procedure:
In a similar manner, N-{5-amino-4-[(3-fluorophenyl)hydrazono]4H-pyrazol-3-ylmethyl}nicotinamide was prepared by reacting 5-aminomethyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (60 mg, 0.25 mmole) with nicotinoyl chloride hydrochloride (46.3 mg, 0.26 mmole). The reaction was worked up by the addition of saline and ethyl acetate. The crude material was purified by preparative TLC (CH2Cl2:MeOH=9:1) to yield 36 mg (41%) of the title compound as a yellow powder. MS (m/z, ES+): 340 (M+1, 100%); 1H NMR (ppm, 300 MHz, DMSO-d6) δ 11.80 (br s, 1H), 9.01 (br s, 2H), 8.70 (d, 1H), 8.20 (d, 1H), 7.30-7.70 (m, 4H), 6.85-7.25 (m, 3H), 4.70 (br s, 2H).
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17]>CN(C)C=O.CO.[Cu]>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1
Reactant: Clc1ccccc1Br
Reactant: Cc1ccc(O)cn1
Agent: [Cu]
Agent: [K]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccccc2Cl)cn1

Procedure:
4 g of a potassium salt of 5-hydroxy-2-methylpyridine, 5.2 g of o-bromochlorobenzene and 250 mg of a copper powder were suspended in 10 ml of dimethylformamide, and the mixture was allowed to react in a nitrogen gas stream at 115° C. for 23 hours under stirring. The reaction mixture was diluted with 70 ml of methanol and filtered. The filtrate was dried to a solid, and 120 ml of chloroform was added to the residue. The mixture was washed with 70 ml of an aqueous sodium hydroxide solution at pH of 9. The solvent layer was washed with water, dried with anhydrous sodium sulfate and immediately dried to obtain 2.8 g of oily 5-(o-chlorophenoxy)-2-methylpyridine.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[OH:13].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:30](=[O:37])[CH:31]=[C:32]([CH2:35][OH:36])[O:33][CH:34]=1.O>CN(C=O)C>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[O:13][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:30](=[O:37])[CH:31]=[C:32]([CH2:35][OH:36])[O:33][CH:34]=1
Reactant: Oc1ccnc2ccc(C(F)(F)F)cc12
Reactant: O=c1cc(CO)occ1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(CO)occ1OCCCCCOc1ccnc2ccc(C(F)(F)F)cc12
Reaction time: 0.17 h
Yield: 21 %

Procedure:
6-Trifluoromethyl-quinolin-4-ol (0.23 g, 1.08 mmol) was dissolved in DMF (3 mL). Cs2CO3 (0.35 g, 1.08 mmol) was added at RT and the mixture was stirred for 10 min. A solution of 5-(5-bromo-pentyloxy)-2-hydroxymethyl-pyran-4-one 10 (0.30 g, 1.03 mmol) in DMF (2 mL) was added via syringe. This mixture was stirred at 50° C. for 1 h. Water (10 mL) was added and the mixture extracted with EtOAc (2×50 mL), washed with water (3×50 mL), brine (3×50 mL) dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent (CH2Cl2:MeOH)=90:10. 5-(5-(6-(trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 11 was obtained (93 mg, 21% yield) as a yellow oil.
Reaction SMILES: Cl[C:2]1([CH2:9][CH:10](O)[CH2:11][CH3:12])[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH2:3]1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.[OH-:19].[Na+]>C1(C)C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:9][CH2:10][CH:11]([OH:19])[CH2:12][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:3][CH:4]=1
Reactant: [OH-]
Reactant: c1c[nH]cn1
Reactant: CCC(O)CC1(Cl)C=CC(Cl)=CC1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OC(CCc1ccc(Cl)cc1)Cn1ccnc1

Procedure:
We have surprisingly found that when the starting material 1-chloro-4-chlorophenyl-2-butanol (II) is reacted with the imidazole (III) in a mixture of toluene and aqueous sodium hydroxide solution in the presence of a phase transfer catalyst, the (1-[4-(4-chlorophenyl)-2-hydroxy-n-butyl]-imidazole) (IV) key intermediate is obtained with short reaction time and excellent yield (95%).
Reaction SMILES: [N:1]1([C:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([OH:33])=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>>[OH:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][C:13]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:8]=[C:7]([C:5]([N:1]5[CH2:4][CH2:3][CH2:2]5)=[O:6])[S:15][C:14]=34)=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23]
Reactant: Cc1c(C(=O)NCCCO)c2ccc(O)cc2n1C
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(C(=O)NCCCO)c2ccc(Oc3ccnc4cc(C(=O)N5CCC5)sc34)cc2n1C

Procedure:
This material was prepared by the reaction of 2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid (3-hydroxy-propyl)-amide 63b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ 8.50 (1H, d, J=5.5 Hz), 7.89 (1H, d, J=8.7 Hz), 7.82 (1H, s), 7.40 (1H, s), 7.06, (1H, d, J=6.6 Hz), 6.72 (1H, d, J=5.5 Hz), 4.74–4.65 (2H, m), 4.31–3.68 (5H, m), 3.60–3.55(2H, m), 2.68 (3H, s), 2.54–2.46 (2H, m), 1.95–1.87 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 478. found 478.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][C:11](=[O:14])[N:10]([C@@H:15]([CH2:23][CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:9]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:32](Br)[CH:33]=[CH2:34].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:34]([C@@H:12]1[CH2:13][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:9]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[N:10]([C@@H:15]([CH2:23][CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:11]1=[O:14])[CH:33]=[CH2:32]
Reactant: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 1.45 g (3.14 mmol) of tert-butyl (2S)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxo-1-piperidinyl)butanoate (Example 1, Step F) and allyl bromide (0.326 mL, 3.76 mmol) in 12.5 mL of THF was added dropwise at −78° C. 3.3 mL of a 1 M solution of lithium bis(trimethylsilyl)-amide in THF (3.3 mmol). After being stirred at −78° C. for 3 h, the reaction was quenched with sat. aqueous NH4Cl solution, extracted with ethyl acetate. The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (50 g SiO2, eluent: 5 to 20% EtOAc/hexanes, gradient elution) provided tert-butyl (2S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate as the faster eluting major isomer.
Reaction SMILES: [C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=2)[N:8]([CH2:18][O:19][CH3:20])[C:7]([CH3:21])=[N:6][C:5]=1[CH3:22])([OH:3])=O.Cl.CN(C)CCCN=C=NCC.[CH3:35][O:36][C:37]([C:39]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47][NH2:48])[CH2:41][CH2:40]1)=[O:38]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:17][C:12]1[CH:11]=[C:10]([CH:9]2[N:8]([CH2:18][O:19][CH3:20])[C:7]([CH3:21])=[N:6][C:5]([CH3:22])=[C:4]2[C:1]([NH:48][CH2:47][CH2:46][CH2:45][N:42]2[CH2:41][CH2:40][C:39]([C:37]([O:36][CH3:35])=[O:38])([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:44][CH2:43]2)=[O:3])[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: COC(=O)C1(c2ccccc2)CCN(CCCN)CC1
Reactant: COCN1C(C)=NC(C)=C(C(=O)O)C1c1ccc(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCN1C(C)=NC(C)=C(C(=O)NCCCN2CCC(C(=O)OC)(c3ccccc3)CC2)C1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
A mixture of 5-carboxy-6-(3,4-difluoro-phenyl)-1,6-dihydro-1-methoxymethyl-2,4-dimethylpyrimidine (0.13 g, 0.42 mmol.), 4-dimethylaminopyridine (0.1 g, 0.84 mmol.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.16 g, 0.82 mmol.) and CH2Cl2 (5 mL) was stirred at room temperature for 0.5 hr. After the addition of 3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propylamine (0.17 g, 0.62 mmol.), the mixture was refluxed overnight. To the mixture was added another 25 mL of CH2Cl2 and washed with saturated NH4Cl solution. After removal of the solvent, the residue was flash chramotographed over silica gel (eluent: 80:20 v/v ethyl acetate-methanol) to give the title compound in 32% yield (0.075 g) as a pale yellow solid: mp 53-57° C. Anal. Calcd. for C31H38F2N4O4.0.25CHCl3: C, 62.71; H, 6.44; N, 9.36. Found: C, 62.62; H, 6.79; N, 9.19.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: O=[N+]([O-])c1ccccc1-c1nc2ccccc2o1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccccc1-c1nc2ccccc2o1
Temperature: 70 °C

Procedure:
A mixture of 8 g (0.033 mol) of 2-(2′-nitrophenyl)benzoxazole and 37.58 g (0.167 mol) of SnCl2.2H2O in 200 ml of ethanol was heated at 70° C. until the reaction was completely finished.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([C:31]2[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:38])=[O:30])=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7].[OH-].[Na+]>C(O)C.O.C(OCC)C>[Cl:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([Cl:37])[C:31]=1[C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C@@H:4]([C:3]([OH:39])=[O:2])[NH:5][C:6]([C:8]2([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[S:7])=[CH:23][CH:24]=1)=[O:30]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CS(=O)(=O)CCCCC1(C(=S)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Temperature: 52.5 °C
Reaction time: 22 h
Yield: 70.2 %

Procedure:
To a solution of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (25.86 mmol, 15.87 g) in ethanol (75 mL) was added aqueous 1.0N sodium hydroxide (60 mL) at 50° C. The mixture was heated to 50-55° C. and the resulting clear light brown solution was stirred for 22 h at which time TLC analysis of the mixture indicated the absence of starting material. The mixture was diluted with water and allowed to cool to room temperature and was filtered to remove a small amount of solids. The filtrate was concentrated and the residual aqueous solution was washed with diethyl ether (2×75 mL). The basic aqueous layer was acidified with 3.0N HCl to form a cloudy suspension and was extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were washed with brine (200 mL) then the dried (MgSO4) solution was filtered and evaporated to dryness. The residue was taken up in dichloromethane and diluted with diethyl ether:hexane (1:1) to obtain a solid which was collected by filtration. Trituration of the solid with hot ethyl acetate (˜100 mL) resulted in a suspension that was then diluted with diethyl ether (˜50 mL) and the solid was collected by filtration. The above Trituration was repeated to afford 10.89 g (70%) of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine as a colorless solid. HR MS: Obs. mass, 599.1193. Calcd. mass, 599.1208 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][NH2:15])=[O:13])=[CH:10][CH:9]=2)[CH:2]=1.[N:18]#[C:19][Br:20]>C1COCC1>[BrH:20].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]3[O:13][C:19]([NH2:18])=[N:15][N:14]=3)=[CH:16][CH:17]=2)[CH:2]=1
Reactant: N#CBr
Reactant: NNC(=O)c1ccc(Oc2cccnc2)cc1
Solvent: C1CCOC1
Product: Br
Product: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 81.3 %

Procedure:
4-(pyridine-3-yloxy)benzohydrazide (3.7 g, 16.14 mmol) was dissolved in 100 mL of anhydrous THF and 3.0 M solution of cyanogen bromide (5.38 mL, 16.14 mmol) was added via syringe. Within 5-10 min of stirring an orange precipitate started to form. The reaction mixture was brought to reflux and refluxed for 1 hr. Then it was cooled down to ambient temperature and filtered. The collected orange precipitate was washed with ca. 100 mL of THF, ca. 100 mL of EtOAc, anhydrous Et2O and dried in vacuo to give the title product as an orange solid (4.40 g). Yield 81.4%.