Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][C@H:2]1[C@H:6]([OH:19])[CH2:7][NH:8]C(=O)OCC1C=CC=CC=1.[Cl-].[NH4+].CC1C=CC(S(O[C@H]2CO[C@@H]3[C@@H](Br)CO[C@H]23)(=O)=O)=CC=1.N>O.CC(O)C.[Zn].CO>[NH2:8][CH2:7][C@H:6]([C@@H:2]1[CH:3]=[CH:4][CH2:5][O:1]1)[OH:19]
Reactant: O=C(NC[C@@H](O)[C@@H]1C=CCO1)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@@H]3Br)cc1
Agent: N
Agent: [Cl-]
Solvent: CO
Solvent: CC(C)O
Solvent: O
Product: NC[C@@H](O)[C@@H]1C=CCO1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
Alternative preparation of Benzyl(R)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethylcarbamate (18); Zinc and ‘One-pot’ procedure. A solution of ammonium chloride (600 mg, 11.2 mmol) in water (7.5 mL) was added to a solution of bromotosylate (47) (3.0 g, 8.26 mmol) in propan-2-ol (15 mL) under argon. Zinc dust (600 mg, 9.2 mmol) was then added in portions over 4 minutes and the mixture was stirred for 16 hours before filtering the suspension through celite in vacuo. The filter cake was washed with diethyl ether (60 mL). Hydrochloric acid (1M, 60 mL) was added to the filtrate then the organic phase separated. The aqueous layer was extracted with diethyl ether (60 mL) then the combined organic phase was washed with brine (60 mL), then dried (MgSO4), filtered and reduced in vacuo. The residue was dissolved in ammonium hydroxide (18 mL) and a solution of ammonia in propan-2-ol (12 mL, 2.0M, 24 mmol), then divided into two equal portions and heated in sealed tubes at 75° C. for 16 hours. The mixtures were combined using methanol then the solvents were removed in vacuo. The residue was azeotroped with diethyl ether (3×10 mL) to obtain (R)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol which was used without further purification.
Reaction SMILES: [ClH:1].Cl[C:3]1([C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:8])[C:6]([Cl:9])=[CH:5][S:4]1>C(O)(=O)C>[Cl:9][C:6]1[C:7]([OH:8])=[C:3]([C:10]([O:12][CH3:13])=[O:11])[S:4][C:5]=1[Cl:1]
Reactant: COC(=O)C1(Cl)SC=C(Cl)C1=O
Reactant: Cl
Solvent: CC(=O)O
Product: COC(=O)c1sc(Cl)c(Cl)c1O
Reaction time: 48 h

Procedure:
Dry hydrogen chloride gas was bubbled into a solution of crude 2,4-dichloro-2-methoxycarbonylthiophen-3(2H)-one (6.8 g, 30 mmol) in acetic acid (30 ml) until saturated. The mixture was allowed to stand for 2 days, concentrated under reduced pressure and the precipitate filtered and recrystallised from methanol, m.p. 107°-108° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][O:25][CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][O:25][CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C)OCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)OCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-{3-[(2-ethoxy-1-methyl-2-oxoethoxy)methyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 88) (480 mg, 1.06 mmol) in dichloromethane (8 ml) was treated with trifluoroacetic acid (3.5 ml) and stirred at room temperature for 5 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene and dichloromethane. The oil was purified by column chromatography on silica gel eluting with a gradient system of 100:0:0 (dichloromethane:methanol:acetic acid) gradually changing to 95:5:0.5 (dichloromethane:methanol:acetic acid) to afford the title compound as a colourless oil (395 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3Cl)[C:3]=12.CN1C(N)=CC(C2C=CC=CC=2)=N1.[F:38]C1C=C(C#C)C=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:38])[CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: C#Cc1cccc(F)c1
Reactant: Cn1nc(-c2ccccc2Cl)c2c(Cl)c(-c3ccccc3)nnc21
Agent: Cn1nc(-c2ccccc2)cc1N
Product: Cn1nc(-c2ccccc2)c2c(Cl)c(-c3cccc(F)c3)nnc21

Procedure:
Compound 10 was synthesised following similar procedures outlined in Example 1 (Compound 37), starting from Step 2 using 1-methyl-3-phenyl-1H-pyrazol-5-amine instead of 3-(2-chlorophenyl)-1-methyl-1H-pyrazol-5-amine and 3-fluorophenylacetylene instead of phenyl acetylene in Step 4.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[NH:19][C:18]([CH3:20])=[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2].Cl[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:18]([CH3:20])=[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(F)ccc3OCC)ncnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(F)ccc3OCC)ncnc12

Procedure:
Starting from ethyl 4-(2-ethoxy-5-fluorophenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a4) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: Br[C:2]1[C:3]([Cl:23])=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])[S:5][CH:6]=1.Br[C:25]1[S:26][CH:27]=[CH:28][N:29]=1>[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:23][C:3]1[C:2]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[CH:6][S:5][C:4]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22]
Reactant: Brc1nccs1
Reactant: CCC(CC)c1cc(C)nn2c(-c3scc(Br)c3Cl)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Zn]
Product: CCC(CC)c1cc(C)nn2c(-c3scc(-c4nccs4)c3Cl)c(C)nc12
Yield: 47.5 %

Procedure:
Using a procedure analogous to Example 175, 3-(4-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.25 g, 0.61 mmol), Reike® Zn (0.5 g/mL solution in THF, 1.6 mL, 1.21 mmol), 2-bromo-thiazole (0.11 mL, 1.21 mmol), and PdCl2(dppf) (0.022 g, 0.030 mmol) furnish the title compound (0.012 g, 0.29 mmol, 6.8%). 1H-NMR (CDCl3), δ 0.89 (t, J=7.5 Hz, 6H), 1.75-1.94 (m, 4H), 2.52 (s, 6H), 3.27-3.43 (m, 1H), 6.73 (s, 1H), 7.43 (d, J=3.3 Hz, 1H), 7.94 (d, J=3.3 Hz, 1H), 8.30 (s, 1H) ppm. LC/MS (m/z): calcd. for C20H21ClN4S2 (M+H)+: 417.1; found: 417.2.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9](C)[C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:28]2[CH2:33][CH2:32][N:31]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])[CH2:30][CH2:29]2)[CH:13]=[CH:12][N:11]=1.[CH3:40]NC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:37]([S:34]([N:31]1[CH2:32][CH2:33][CH:28]([C:19]2[C:18]3[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=[C:16]([C:14]4[CH:13]=[CH:12][N:11]=[C:10]([NH:9][CH2:8][CH:2]([CH3:3])[CH3:40])[CH:15]=4)[CH:17]=3)[NH:21][CH:20]=2)[CH2:29][CH2:30]1)(=[O:35])=[O:36])[CH3:38]
Reactant: CNC
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccnc(N(C)C)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccnc(NCC(C)C)c4)cc23)CC1
Yield: 20 %

Procedure:
The title compound was prepared according to the general procedure of 5-[2-(dimethylamino)-4-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 2-methyl-1-propanamine (1 mL) for dimethylamine to afford 11.1 mg of the title compound (20%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3].Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][NH:26]2.CCN(C(C)C)C(C)C>C(O)CCC>[N:30]1[C:22]([NH:1][C@H:2]([C:4]2[N:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:7]=3[N:8]=2)[CH3:3])=[C:23]2[C:27]([NH:26][CH:25]=[N:24]2)=[N:28][CH:29]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: C[C@H](N)c1nc2ccc(C#N)cc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(C#N)cc2n1-c1ccccc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 37.6 %

Procedure:
A mixture of 2-((S)-1-aminoethyl)-3-phenyl-3H-benzoimidazole-5-carbonitrile from Example 11 (370 mg, 1.4 mmol), 6-chloro-9H-purine (217 mg, 1.4 mmol) and DIPEA (0.36 mL, 2.1 mmol) in n-butanol (2.8 mL) was stirred in a sealed tube for 6 h at 120° C. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in EtOAc followed by gradient 0-10% 2M NH3/MeOH in DCM) affording 122 as a white solid (200 mg, 37%). LCMS: RT 3.29 min [M+H]+ 381.1. 1H NMR (DMSO, 400 MHz): δ 8.21-7.97 (3H, m), 7.84 (1H, d, J=8.35 Hz), 7.72-7.46 (7H, m), 5.49 (1H, br), 1.59 (3H, d, J=6.87 Hz)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([N:16]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)[CH3:17])[CH2:10]2>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([N:16]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][CH:24]=1)[CH3:17])[CH2:10]2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CN(Cc1ccc(N)cc1)C1Cc2ccc(N)cc2C1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CN(Cc1ccc(NS(C)(=O)=O)cc1)C1Cc2ccc(NS(C)(=O)=O)cc2C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Methanesulphonyl chloride (0.53 ml) was added to 5-amino-2-[N-(4-aminobenzyl)-N-methylamino]indane (1.1 g) in pyridine and the reaction mixture was stirred at room temperature for 17 hours. The solvent was then removed by evaporation in vacuo and the residue taken up in methylene chloride, washed with aqueous sodium bicarbonate, dried (MgSO4) and evaporated in vacuo. The resulting gum was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 2%). The product-containing fractions were combined and evaporated to dryness in vacuo to give a colourless foam. This foam was dissolved in chloroform and the solution was evaporated to dryness in vacuo to give the title compound as a colourless foam, yield 0.2 g.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13].I[CH3:15].O>CN(C=O)C>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH3:15]
Reactant: CI
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)=O)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60 percent in mineral oil, 1.44 g, 36 mmol) in anhydrous DMF (30 mL) was added dropwise a solution of 4-hydroxy-3-methylacetophenone (4.5 g, 30 mmol) in dry DMF (20 mL) at 0° C. over a period of 20 minutes. After addition, the mixture was stirred at 0° C. for 30 minutes and iodomethane (2.2 mL, 36 mmol) was added in one portion. The mixture was then stirred at approximately 25° C. overnight. Water was added (10 mL) and the mixture was extracted with ether three times. The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, and dried under vacuum to give crude product as a colorless oil.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([F:29])=[N:23][C:24]=2Cl)(=O)C.[O:30]([CH2:37][C@H:38]([NH2:40])[CH3:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>O1CCOCC1>[F:29][C:22]1[N:23]=[C:24]([NH:40][C@H:38]([CH3:39])[CH2:37][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[N:26]=[CH:27][N:19]([C:20]=2[N:21]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(F)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C[C@@H](N)COc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@H](COc1ccccc1)Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 28.1 %

Procedure:
9-(2,3,5-Tri- O-acetyl-β-D-ribofuranosyl)-6-chloro-2-fluoro-9H-purine (1.03 g, 2.38 mmol) PCT Publication No. WO 938206, (R)-1-phenoxy-2-propylamine (0.36 g, 2.38 mmol) and triethylamine (0.29 g, 0.28 mmol) in dioxan (20 ml) were stirred at room temperature for 18 h. The reaction mixture was filtered and evaporated to a residue which was purified by flash chromatography. The resultant 2',3',5'-tri- O-acetyl-2-fluoro- N-[(R)-1-phenoxy-2-propyl]adenosine was deprotected using methanolic ammonia to provide the title 2-fluoro- N-[(R)-1-phenoxy-2-propyl]adenosine (0.28 g, 23%)(after column chromatography), mp 148°-150° C.; 1H NMR (DMSO-d6)δ 1.33 (3H, d, -3.59 (1H, m, H-5'a), 3.63-3.71 (1H, m, H-5'b), 3.92-3.99 (2H, m, H-4' and --C--H), 4.10-4.18 (2H, m, H-3' and --C--H), 4.51 (1H, q, H-2'), 4.61 (1H, m, --CH3C H--), 5.06 (1H, t, 5'-OH), 5.22, 5.48 (2H, 2d, 2' and 3'-OH), 5.82 (1H, d, H-1'), 6.89-6.97 (3H, m, Ar--H), 7.25-7.30 (2H, t, Ar--H), 8.39 (1H, s, H-8), 8.49 (1H, d, N--H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:18])[CH2:16][C:15](=O)[O:14][C:12](=[O:13])[CH2:11]1.C.O.C(O)C>C(O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:12](=[O:13])[CH2:11][C:10]([CH3:18])([CH3:9])[CH2:16][C:15]2=[O:14])=[CH:3][CH:4]=1
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: Nc1ccc(O)cc1
Solvent: CCO
Solvent: O
Product: CC1(C)CC(=O)N(c2ccc(O)cc2)C(=O)C1
Temperature: 165 °C
Yield: 50.2 %

Procedure:
A mixture of 4-aminophenol (3.27 g, 30.0 mmol) and 3,3-dimethylglutaric anhydride (4.26 g, 30.0 mmol) was heated in a round bottom flask at 165° C. for 1 h, followed by heating at 180° C. for 7 h. After cooling to room temperature the solid material was dissolved in hot ethanol, activated charcoal was added and the solution was heated at reflux for 1 h. The solid material was removed by hot filtration. The solvent was evaporated and the residue was crystallised from water/ethanol yielding the title compound (3.51 g, 50% yield, pink solid).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([O:20]C)[CH:14]=[C:13]([O:22]C)[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31].Cl.N1C=CC=CC=1>>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([OH:20])[CH:14]=[C:13]([OH:22])[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(F)c3Br)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc(F)c4Br)oc23)[C@@H]1CO

Procedure:
Compound of example 135 (0.45 g, 0.914 mmol) was subjected to demethylation using pyridine hydrochloride (4.5 g, 38.96 mmol) as described in example 17 to obtain the title compound.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([O:26]CC)=O)[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:30][NH2:31]>CO>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([NH:30][NH2:31])=[O:26])[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cccc(OCCN2CCC(Cc3ccccc3)CC2)c1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)Cc1cccc(OCCN2CCC(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
To a solution of 4-benzyl-1-(2-(3-(ethoxycarbonylmethyl)phenoxy)ethyl)piperidine (0.382 g, 1.00 mmol) in 5 mL of MeOH was added 5 mL of hydrazine hydrate. The resulting solution was allowed to stir at rt for 12 hr. The MeOH was evaporated in vacuo and water (10 mL) was added. A colorless solid precipitated. The solid was collected by filtration and dried in vacuo giving the title product (240 mg, 65%): mp 89-91° C.; 1H NMR (CDCl3) 1.31 (m, 2 H), 1.60 (m, 1 H), 1.62 (m, 2 H), 2.04 (t, J=11.7 Hz, 2 H), 2.52 (d, J=6.9 Hz, 2 H), 2.76 (t, J=6.0 Hz, 2 H), 2.95 (d, J=11.4 Hz, 2 H), 3.53 (s, 2 H), 3.83 (bs, 2 H), 4.08 (t, J=6.3 Hz, 2 H), 6.66 (s, 1 H), 6.79 (m, 3 H), 7.12-7.27 (m, 6 H).
Reaction SMILES: C([O:3][C:4](=[O:52])[C@@H:5]([CH:49]([CH3:51])[CH3:50])[C:6](C(OCC)=O)(C(OCCC)=O)[C:7](=[O:37])[C@@H:8]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:16]=1)[CH:11]([CH3:13])[CH3:12])C.[OH-].[Na+]>C(O)C>[C:33]([O:32][C:30]([NH:29][C@@H:8]([CH2:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:16]=1)[CH:11]([CH3:12])[CH3:13])[C:7](=[O:37])[CH2:6][C@@H:5]([CH:49]([CH3:50])[CH3:51])[C:4]([OH:52])=[O:3])=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCCOC(=O)C(C(=O)OCC)(C(=O)[C@H](C[C@H](Cc1ccc(OC)c(OCCCOC)c1)C(C)C)NC(=O)OC(C)(C)C)[C@@H](C(=O)OCC)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)C[C@H](C(=O)O)C(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 10.0 g of (2S,5S,7S)-5-tert-butoxycarbonylamino-3-ethoxycarbonyl-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-8-methyl-4-oxo-3-propoxycarbonyl-nonanoic acid ethyl ester in 20 mL of ethanol is treated with 25 mL of a 37% solution of sodium hydroxide at room temperature. The reaction mixture is stirred for 24 hours at room temperature and the ethanol removed by distillation in vacuum. The residue is extracted twice with 25 mL of dichloromethane. The pH of the aqueous layer is carefully adjusted to 2.5 with 2 N hydrochloric acid at 0° C., the reaction mixture is then stirred for 16 hours and extracted 4 times with 50 mL of dichloromethane. The organic layer is dried and the solvent removed to give the title compound as an oil.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][N:3]=1.[CH3:13][NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([N:14]([CH3:13])[CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:3][O:4][C:5]=2[CH:10]=1
Reactant: CNCCN1CCOCC1
Reactant: COc1ccc2c(Cl)noc2c1
Product: COc1ccc2c(N(C)CCN3CCOCC3)noc2c1
Temperature: 140 °C
Yield: 49.4 %

Procedure:
To a sealed tube was added 3-chloro-6-methoxy-1,2-benzisoxazole (6.0 g) and N-methyl-N-[2-(4-morpholinyl)ethyl]-amine (13.8 g). The reaction was heated to 140° C. over 48 hours and then cooled to room temperature. The residue was partitioned between ethyl acetate (EtOAc) and water, extracted again with EtOAc, and the organic phase was dried over magnesium sulfate (MgSO4) and concentrated in vacuo. Flash column chromatography (silica gel) eluting with 1% methanol/dichloromethane (MeOH/DCM) provided the product (4.7 g), m.p. 43°-44° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][S:7][C:8](=[N:14][NH:15]C(OC)=O)[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:2].[S:21](Cl)(Cl)=O>ClCCl>[CH3:11][C:10]([C:9]1[S:21][N:15]=[N:14][C:8]=1[S:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:20])([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCSC(CC(C)(C)C)=NNC(=O)OC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CCSc1nnsc1C(C)(C)C

Procedure:
A mixture of [1-[(3-ethoxy-3-oxopropyl)thio]-3,3-dimethylbutylidene]hydrazinecarboxylic acid, methyl ester, thionyl chloride and dichloromethane was heated at reflux for 40 hours and then quenched with ice water. The orange product was extracted twice into ether. The extracts were combined, washed with 0.1N sodium hydroxide twice, water twice, saturated sodium chloride twice, dried and concentrated in vacuo. The resulting orange liquid was evaporated onto 70 g of silica gel. The gel was dried and poured onto a column of silica gel packed in petroleum ether. The column was eluted with a gradient of 1-10% ethyl acetate in petroleum ether. The desired fractions were purified on silica gel preparative TLC plates eluting with 3% ethyl acetate in petroleum ether, giving 2.9 g of the desired compound as a light yellow oil. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90 MHz: 1.23 (t, 3H, J=7.0 Hz, CH3); 1.49 (s, 9H, t-butyl); 2.84 (t, 2H, J=7.0 Hz, CH2CO); 3.59 (t, 2H, SCH2); 4.14 (q, 2H, OCH2).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=1)[CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:33]4[CH:34]=[CH:22][CH:23]=[C:24]([CH2:25][N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH:32]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: Brc1cccc(CN2CCOCC2)c1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(CN5CCOCC5)c4)nc23)cc1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(3-morpholin-4-ylmethyl-phenyl)-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50.0 mg, 0.173 mmol) and 4-(3-bromo-benzyl)-morpholine (54.0 mg, 0.211 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d and was isolated as an orange foam (0.021 g, 26%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.5 Hz, 1H), 8.24 (d, J=7.4 Hz, 2H), 8.09 (d, J=7.3 Hz, 2H), 7.66 (d, J=7.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.49 (s, 1H), 7.35-7.29 (m, 1H), 7.05-6.97 (m, 2H), 6.87 (s, 1H), 3.75-3.70 (m, 4H), 3.54 (s, 2H), 3.11 (s, 3H), 2.52-2.45 (m, 4H). MS=464 (MH)+.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.S([Cl:33])(C1C=CC(C)=CC=1)(=O)=O.O>C1COCC1.CCOC(C)=O>[Cl:33][CH:9]1[CH2:10][CH2:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:12]
Reactant: O=C1CCCN1c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1C(Cl)CCN1c1ccccc1
Reaction time: 0.67 h

Procedure:
1-Phenyl-2-pyrrolidinone (1 g, 6.2 mmol) in THF (60 mL, anhydrous) was cooled to −40° C. and LiHMDS (8 mL, 8 mmol, 1 M soln. in THF) was added. The resulting solution was stirred for 40 min. and tosyl chloride (1.78 g, 9.33 mmol) was then added. After warming the solution to RT over a 14 hour period, H2O added to quench reaction. The solution was then concentrated to provide an oil. Next, the oil was redissovled in EtOAc and washed with H2O and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to an oil once again. Purified via flash column chromatography (4:1 hexane/EtOAc) provided 3-chloro-1-phenylpyrrolidin-2-one.