Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][C@@H:15]([CH3:19])[NH:14]1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:17]1[CH2:16][C@H:15]([CH3:19])[NH:14][C@H:13]([CH3:12])[CH2:18]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2Cl)C[C@H](C)N1

Procedure:
1.0 g (5.21 mmol) of 3,4-dichloronitrobenzene (Fluke, Buchs, Switzerland), 624 mg (5.47 mmol) cis-2,6-dimethylpiperazine (Aldrich, Buchs, Switzerland) and 580 mg (5.73 mmol) triethylamine in 20 ml of EtOH are heated in a microwave oven at 170° C. for 6 h and 180° C. for 2 h. The reaction mixture is evaporated to dryness and then taken in EtOAc. The organic layers is extracted with 1 M aqueous HCl (5×) and the combined aqueous layers are basified with NaHCO3 and extracted with CH2Cl2 (3×), washed with brine, dried over MgSO4, filtered and evaporated to dryness to give the title compound as a yellow solid. ES-MS: 270 (M+H)+; analytical HPLC: tret=2.72 minutes (Grad 1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[CH3:19][C:20]1[C:21]([CH2:27][OH:28])=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:28][CH2:27][C:21]2[C:20]([CH3:19])=[CH:25][C:24]([CH3:26])=[CH:23][N:22]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: Cc1cnc(CO)c(C)c1
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cnc(COc2nc(N)nc(-c3ccccn3)c2C#N)c(C)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile, 3,5-dimethyl-2-pyridinemethanol and DBU in DME. EI-MS m/e (%): 332 (M+, 100), 303 (34), 120 (31).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]1=[O:16])=O)(C)(C)C.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[C:17]([OH:23])=[O:18].[NH2:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]1=[O:16]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)NC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCC(=O)NC1=O
Reaction time: 4 h

Procedure:
Compound 203 (1.14 g, 5 mmol) was suspended in CH2Cl2 (100 mL). To the mixture was added CF3COOH (10 mL) and this then was stirred at room for 4 h. The solvent was evaporated to give crude 204 (1.25 g): 1H NMR (DMSO-d6) δ 11.42 (s, 1H), 8.70 (br, 2H), 4.31 (dd, J=5.4 Hz, J=13 Hz), 2.88-2.72 (m, 2H), 2.25-2.09 (m, 2H). A mixture of crude 204 (1.25 g) and phthalic anhydride (0.89 g, 6 mmol) and Et3N (1.39 ml, 10 mmol) in THF (150 mL) was refluxed for two days. The reaction mixture was concentrated and the residue was crystallized from ethyl acetate to give thalidomide (201) (0.89 g, 69%) as white crystals; mp 276° C. (lit.276-279° C.). A mixture of thalidomide 201 (258 mg, 1 mmol) and Lawesson's reagent (222 mg, 0.55 mmol) in toluene (50 ml) was stirred at reflux for 12 h; thereafter, solvent was removed under vacuum. The resulting residue was purified by column chromatography using CH2Cl2 as the eluent to afford compound 205 (200 mg, 73%) as a yellow solid: mp 225-226° C.; 1H NMR (DMSO-d6) δ 12.83 (s, 1H, NH), 8.00-7.92 (m, 4H, Ph), 5.32 (dd, J=5.6 Hz, J=12.9 Hz, 1H, H-3′), 3.28-3.25 (m, 2H, H-5′), 2.60-2.54 (m, 1H, H-4′), 2.17-2.10 (m, 1H, H-4′); 13C NMR (DMSO-d6) δ 208.7 (C-6′), 165.3 (C-2′), 165.2 (C-1 & C-3), 133.1 (C-5 & C-6), 129.3 (C-3a, C-7a), 121.7 (C-4 & C-7), 46.9 (C-3′), 38.9 (C-5′), 21.79 (C-4′); MS (CI/CH4) m/z 274 (M+); Anal. (C13H10N2O3S) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]Cl)[C:5]([CH2:10]Cl)=[CH:4][CH:3]=1.[C:12]1([C:18]([NH2:31])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][N:31]([C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:10][C:5]2=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCc1ccc(Cl)nc1CCl
Product: Clc1ccc2c(n1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2

Procedure:
Prepared in analogy to Example A2(b) from 6-chloro-2,3-bis-chloromethyl-pyridine (CAS: 220001-94-5) and triphenylmethylamine. Light yellow foam. MS (m/e): 397.0 ([MH+, 100%).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C:16]2[S:17][C:18]([C:21]#[N:22])=[CH:19][N:20]=2)[CH:9]=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[Cl:14][C:12]1[N:11]=[C:10]([NH:15][C:16]2[S:17][C:18]([C:21]#[N:22])=[CH:19][N:20]=2)[CH:9]=[C:8]([CH2:7][OH:6])[CH:13]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(Cl)nc(Nc2ncc(C#N)s2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cnc(Nc2cc(CO)cc(Cl)n2)s1
Temperature: 25 °C

Procedure:
2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-6-chloro-pyridin-2-ylamino]-thiazole-5-carbonitrile (11-6) was dissolved in 5 mL of THF. HF-pyr (Aldrich), 0.5 mL was added and the reaction was stirred at room temperature. After 1.5 hours the reaction was diluted with water and adjuted to pH 7 by the gradual addition of solid K2CO3. The mixture was extracted 3× with DCM. Large amounts of solid were suspended in the DCM extracts so the extracts were filtered and washed with DCM to afford the desired product, 11-7. 1H NMR (DMSO-d6) δ 12.49 (s, 1H), 8.30 (s, 1H), 7.09 (s, 1H), 7.06 (s, 1H), 5.59 (t, 1H, J=5.8 Hz), 4.55 (d, 2H, J=5.5 Hz).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][CH:11]3[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH2:15][C@H:16]1[O:20][C:19]([NH2:21])=[N:18][CH2:17]1.C1O[C@H]1CCl.[CH:27]1[C:39]2CC3C(CCCC3)[C:31]=2[CH:30]=C[C:28]=1[OH:40].C(OCC)(=O)C#CCC>C(O)C>[CH2:31]([C:39]1[N:18]2[CH2:17][C@@H:16]([CH2:15][O:14][C:2]3[CH:3]=[CH:4][C:5]4[CH:6]5[CH:11]([CH2:10][CH2:9][CH2:8][CH2:7]5)[CH2:12][C:13]=4[CH:1]=3)[O:20][C:19]2=[N:21][C:28](=[O:40])[CH:27]=1)[CH3:30]
Reactant: NC1=NC[C@@H](COc2ccc3c(c2)CC2CCCCC32)O1
Reactant: Oc1ccc2c(c1)CC1CCCCC21
Agent: CCC#CC(=O)OCC
Agent: ClC[C@H]1CO1
Solvent: CCO
Product: CCc1cc(=O)nc2n1C[C@@H](COc1ccc3c(c1)CC1CCCCC31)O2
Temperature: 25 °C

Procedure:
To a solution of (S)-5-(5,6,7,8,8a,9-hexahydro-4bH-fluoren-2-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine (16 mg, 0.055 mmol), prepared in accordance with the procedures in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 5,6,7,8,8a,9-hexahydro-4bH-fluoren-2-ol (prepared by the same procedure as in Step 1 of Example 19), in ethanol (2 mL) was added ethyl 2-pentynoate (4.2 mg, 0.065 mmol). The reaction mixture was heated at reflux for 14 hrs and then cooled to room temperature. The reaction mixture was concentrated and then loaded onto a silica gel column, and eluted with 2-6% methanol/methylene chloride to afford 8 mg of (S)-5-ethyl-2-(5,6,7,8,8a,9-hexahydro-4bH-fluoren-2-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[C:20](B1OC(C)(C)C(C)(C)O1)([CH3:22])=[CH2:21].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][CH:9]1[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]2[S:4][CH:3]=[C:2]([C:20]([CH3:22])=[CH2:21])[C:11]=2[O:10]1
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C=C(C)c1csc2c1OC(C)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Yield: 74 %

Procedure:
A mixed solution of tert-butyl 8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (418 mg) obtained in Example 6, steps 1-6, isopropenylboronic acid pinacol ester (0.293 ml), dichlorobis(triphenylphosphine)palladium (42 mg) and potassium carbonate (498 mg) in DME-water (1:1, 10 mL) was stirred at 85° C. for 1 hr under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 5→12% ethyl acetate/hexane) to give the title compound (274 mg, 74%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:22][NH:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25].C([O-])([O-])=O.[Na+].[Na+].O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:29]3[CH:30]=[CH:31][C:26]([C:24]([NH:23][CH3:22])=[O:25])=[CH:27][CH:28]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1ccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(Br)cc23)cc1
Yield: 121 %

Procedure:
5-Bromo-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (350 mg, 0.73 mmol), 4-(N-methylaminocarbonyl)phenylboronic acid (160 mg, 0.88 mmol) and dichlorobis(triphenylphosphine)palladium (II) (52 mg, 0.073 mmol) were combined in CH3CN (10 ml) and 1 M Na2CO3 (10 ml) and stirred at 60° C. for 5 hrs. Water was added and the mixture was extracted with DCM, combined organic phases were dried and evaporated to yield 428 mg (121%) of the title compound. 1H NMR (CDCl3, 300 MHz): δ 8.50 (d, J=1.3 Hz, 1H), 8.20 (d, J=1.2 Hz, 1H), 8.09 (d, J=5.1 Hz, 2H), 7.94 (s, 1H), 7.87 (d, J=5.1, 2H), 7.61 (d, J=5.0 Hz, 2H), 7.31 (d, J=5.0 Hz, 2H), 6.21 (bd, J=2.5 Hz, 1H), 3.06, (d, J=2.9 Hz, 3H), 2.39 (s, 3H).
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.[CH2:10]([C:12]([CH2:14][CH3:15])=[O:13])[CH3:11].Br[C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1.B(OC)(OC)OC.[Zn]>[CH3:23][C:17]([CH3:24])([C:12]([CH2:14][CH3:15])([OH:13])[CH2:10][CH3:11])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCC(=O)CC
Reactant: CCOC(=O)C(C)(C)Br
Agent: COB(OC)OC
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CCOC(=O)C(C)(C)C(O)(CC)CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 47 %

Procedure:
A suspension of zinc dust (39.2 g, 0.6 mol) in 150 ml of THF and 150 ml of B(OCH3)3 is activated with 1,2 dibromoethane (3.0 ml) and chlorotrimethylsilane (3.0 ml). Diethyl ketone (95.7 ml, 0.9 mol) is added to the activated zinc suspension. Ethyl 2-bromo-2-methylpropanoate (Fuka, Buchs, Schweiz) is added dropwise within 90 min to the mixture. The mixture is stirred at r.t. for 20 h. The reaction is quenched by addition of concentrated aqueous ammonia solution (150 ml) at 0° C. Glycerine (150 ml) and diethyl ether (150 ml) is added and the organic layer is separated. The aqueous layer is extracted twice with diethyl ether. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo. Purfication of the residue by vacuum distillation affords ethyl 2,2-dimethyl-3-ethyl-3-hydroxypentanoate 22 (56.65 g, 47%) as a colourless liquid (b.p. 108-110° C./10 mbar). 13C-NMR (100 MHz, CDCl3): δ=179.2; 76.2; 60.9; 50.3; 28.2; 21.6; 14.1; 8.9
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15].O>ClCCl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[O:8])[CH:9]=[CH:10][C:11]=1[O:12][S:14]([CH3:13])(=[O:16])=[O:15])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1cc(C=O)ccc1O
Solvent: ClCCl
Solvent: O
Product: CCOc1cc(C=O)ccc1OS(C)(=O)=O
Reaction time: 1 h

Procedure:
To a solution of 3-ethoxy-4-hydroxybenzaldehyde (3.0 g, 18.1 mmol, 1.0 equiv) and N,N-dimethylaminopyridine (2.87 g, 23.5 mmol, 1.3 equiv) in dichloromethane (10 mL) under Ar at 0° C. was added methanesulfonyl chloride (1.68 mL, 2.48 g, 21.7 mmol, 1.2 equiv). After the reaction mixture was stirred for 1 h, water (100 mL) was added, the solution extracted with dichloro-methane (3×50 mL) and the combined organic phases dried over MgSO4. Removal of the solvent by evaporation under reduced pressure provided the title compound in quantitative yield (4.8 g). 1H NMR (300 MHz, CDCl3): δ 1.42 (t, J=7.0 Hz, 3H), 3.19 (s, 3H), 4.14 (q, J=7.0 Hz, 2H), 7.41 (s, 2H), 7.45 (s, 1H), 9.89 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.53, 38.94, 64.99, 112.20, 124.38, 125.17, 136.01, 142.92, 151.63, 190.65. MS (ISP): 245.2 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([O:22]CC)=O)[N:16]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[NH2:32][CH:33]1[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]1>C(O)C>[C:40]([O:39][C:37]([N:35]1[CH2:36][CH:33]([NH:32][C:20]([C:17]2[N:16]=[C:15]([C@H:10]([CH2:9][CH2:8][CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:11][C:12]([OH:14])=[O:13])[O:19][N:18]=2)=[O:22])[CH2:34]1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(NC(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)O)n2)C1
Temperature: 80 °C

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(ethoxycarbonyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 4) (480 mg, 1.42 mmol) and triethylamine (1 ml, 7.18 mmol) in ethanol (8 ml) was treated with tert-butyl 3-amino-1-azetidinecarboxylate (Preparation 78) (300 mg, 1.74 mmol) and the resulting mixture was heated at 80° C. under a nitrogen atmosphere for 18 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (99:1) gradually changing to dichloromethane:methanol (90:10) to afford the title compound contaminated with starting amine. The solid was dissolved in ethyl acetate and washed with hydrochloric acid (0.5M) (2×), water and brine, dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure to afford the title compound as a sticky foam.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:36](C)=O.[Na+]>C(Cl)Cl>[CH3:36][N:3]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N[C@H]3CCNC3)ccc21
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CN1CC[C@H](NC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(Cl)cc4s2)n3C)C1
Yield: 88.2 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid ((S)-1-methyl-pyrrolidin-3-yl)amide (35 mg) was prepared by following General Procedure P starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (S)-pyrrolidin-3-ylamide dihydrochloride (45 mg), 37% formaldehyde (500 uL), and Na(OAc)3BH (32 mg) in DCM (500 uL). LC/MS: m/z 440.7.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]([CH3:25])[C:20]([CH3:24])([CH3:23])[CH2:21][OH:22].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:18][N:19]([CH3:25])[C:20]([CH3:24])([CH3:23])[CH2:21][O:22][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1OCCOC1CCCCO1
Reactant: CN(C)C(C)(C)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CN(C)C(C)(C)COc1ncccc1OCCO
Temperature: 50 °C
Reaction time: 48 h
Yield: 79.5 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 2-(dimethylamino)-2-methyl-1-propanol (68 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 79 mg (0.31 mmol, 80%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 255 (M+1)+, calc. 255 (M+1)+.
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:23][C:24]([CH3:53])([CH3:52])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49][CH:50]=[CH2:51])[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27].[CH3:54][C:55]1[CH:56]=[C:57](Br)[CH:58]=[CH:59][C:60]=1[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:53][C:24]([CH3:52])([CH3:23])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49]/[CH:50]=[CH:51]/[C:57]1[CH:58]=[CH:59][C:60]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[C:55]([CH3:54])[CH:56]=1)[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27]
Reactant: Cc1cc(Br)ccc1-c1ccccc1
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(/C=C/C[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c2ccccc2)C(C)(C)C)ccc1-c1ccccc1
Yield: 69 %

Procedure:
A mixture of palladium acetate (52 mg, 0.23 mmol) and tri-(2-methylphenyl)phosphine (141 mg, 0.46 mmol) in anhydrous acetonitrile (10 mL) was sonicated at room temperature for 1 min until a creamy-coloured suspension formed. This suspension was added via Pasteur pipette to a stirred solution of tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)hex-5-enoate (Preparation 2)(861 mg, 2.0 mmol), 3-methyl-4-phenylbromobenzene (M. Gomberg, J. C. Pernert, J. Amer. Chem. Soc., 1926, 48, 1372-84, and see also Preparation 19B)(1.32 gm, 5.34 mmol), and triethylamine (1.28 mL, 9.29 mmol) in anhydrous acetonitrile (15 mL) under nitrogen. The mixture was purged with nitrogen, then heated at reflux for 24 h. The mixture was poured into ethyl acetate (200 mL) and washed with saturated aqueous sodium chloride (2×100 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with dichloromethane:ethyl acetate) to give mainly tert-butyl (3R,5E)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]hex-5-enoate as a colourless foam (1.91 gm, 69%). 1H NMR suggests that two alkene isomers, the (5Z) and (4E) were also present. The mixture of alkenes was taken onto the next step (see b, below).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[CH:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.N1CCCCC1>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][C:10]([OH:12])=[O:11])=[CH:17][CH:16]=1
Reactant: O=C(O)C=CCc1ccccc1
Reactant: COc1ccc(S)cc1
Solvent: C1CCNCC1
Product: COc1ccc(SC(CC(=O)O)Cc2ccccc2)cc1
Temperature: 110 °C
Yield: 81 %

Procedure:
A mixture of 2 g (12.53 mmol) of 4-phenylbut-2-enoic acid, 1.8 mL (14.8 mmol) of 4-methoxybenzenethiol, and 0.4 mL (3.7 mmol) of piperidine is heated at 110° C. in a bomb for 18 hours. The reaction is partitioned between ethyl ether and 1N HCl. The organic layer is dried over anhydrous MgSO4 and concentrated in vacuo. Purification by flash silica gel chromatography affords 3.07 g (82%) of 3-(4-methoxyphenylsulfanyl)-4-phenylbutyric acid as a white crystalline solid.
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[OH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[C:17]([OH:19])=[O:18]>CN1CCN(C)C1=O>[CH:1]1([O:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=2[N+:23]([O-:25])=[O:24])[C:17]([O:19][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrC1CCCC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Product: O=C(OC1CCCC1)c1ccc([N+](=O)[O-])c(OC2CCCC2)c1
Reaction time: 14 h
Yield: 63.9 %

Procedure:
Cyclopentyl bromide (20 g, 134 mmol) is added slowly (over 30 minutes) to a stirred suspension of potassium carbonate (27.6 g, 200 mmol) in N,N'-dimethylimidazolidinone (75 mL) containing 3-hydroxy-4-nitrobenzoic acid (9.15 g, 50 mmol) at 85° C. and then stirring is continued for 14 hours. The mixture is allowed to cool and then filtered. The flitrate is diluted with water (100 mL) then extracted with toluene (2×100 mL). The combined organic extract is dried over magnesium sulfate and then the solvent is removed under reduced pressure to give a brown mobile oil. This oil is subjected by flash chromatography on silica gel (dichloromethane as eluent) and the eluent evaporated under reduced pressure to give cyclopentyl 3-cyclopentyloxy-4-nitrobenzoate (10.2 g, 81.6%) as a yellow solid m.p. 45.5°-46.5° C. [Elemental analysis: C,63.7; H,6.66; N,4.37%; calculated: C,63.93; H,6.63; N, 4.39%].
Reaction SMILES: [K].[CH3:2][CH:3]([CH:5]1[CH2:10][C:9](=[O:11])[CH:8]([C:12]2[C:17]([CH3:18])=[N:16][C:15]([CH3:19])=[C:14]([CH3:20])[N:13]=2)[C:7](=[O:21])[CH2:6]1)[CH3:4].[C:22](Cl)(=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(OCC)(=O)C.CCCCCC>[C:22]([O:21][C:7]1[CH2:6][CH:5]([CH:3]([CH3:2])[CH3:4])[CH2:10][C:9](=[O:11])[C:8]=1[C:12]1[C:17]([CH3:18])=[N:16][C:15]([CH3:19])=[C:14]([CH3:20])[N:13]=1)(=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCC(=O)Cl
Reactant: Cc1nc(C)c(C2C(=O)CC(C(C)C)CC2=O)nc1C
Agent: [K]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC(=O)OC1=C(c2nc(C)c(C)nc2C)C(=O)CC(C(C)C)C1
Temperature: 25 °C

Procedure:
The subject compound was prepared by reaction of 5-(1-methylethyl)-2-(3,5,6-trimethyl-2-pyrazinyl)-1,3-cyclohexanedione potassium salt (Example 8) with hexanoyl chloride employing the general procedure described in Example 3, but allowing the reaction mixture to stir at room temperature over the weekend. Following the reaction, the ether solution of crude product was extracted quickly with ice-cold 0.25N NaOH, dried (MgSO4), filtered and evaporated to give a residue product showing some acid chloride contamination by IR examination. Dry-column chromatography using 1:1 ethyl acetate/hexane gave analytically pure material as shown by the elemental analysis of Table II.