Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:28][CH2:27]4)[CH:25]=3)=[C:17]([NH2:20])[CH:18]=2)[N:13]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:12][C@@H:11]1[CH3:35])(=[O:9])[CH3:8].[C:36](OC(=O)C)(=[O:38])[CH3:37]>ClCCl>[C:36]([NH:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[C:21]1[CH:22]=[N:23][N:24]([CH:26]3[CH2:28][CH2:27]3)[CH:25]=1)[N:13]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:12][C@H:11]([CH3:35])[N:10]2[C:7](=[O:9])[CH3:8])(=[O:38])[CH3:37]
Reactant: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pyridine (5.09 μL, 0.063 mmol) was added to a solution of isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.010 g, 0.025 mmol) in dichloromethane (200 μL). Acetic anhydride (3.56 μL, 0.038 mmol) was added, and the reaction stirred at rt for 18 h. The reaction mixture was concentrated and ethyl acetate was added. The solution was washed with 1 N aqueous HCl, and the organic phase was separated and concentrated. The residue was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford isopropyl (S)-6-acetamido-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 440 [M+H]+.
Reaction SMILES: [CH:1]12[C:7]([CH3:9])([CH3:8])[CH:6]1[CH2:5][CH:4]=[C:3]([CH3:10])[CH2:2]2.N(Cl)=[O:12].C(=O)([O-])[O-].[Na+].[Na+].C12C(C)(C)C1CC(=NO)C(C)=C2.S(=O)(O)[O-].[Na+]>C(O)C>[CH:1]12[C:7]([CH3:9])([CH3:8])[CH:6]1[CH2:5][C:4](=[O:12])[C:3]([CH3:10])=[CH:2]2
Reactant: CC1=CCC2C(C1)C2(C)C
Reactant: O=NCl
Agent: CC1=CC2C(CC1=NO)C2(C)C
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Solvent: CCO
Product: CC1=CC2C(CC1=O)C2(C)C

Procedure:
The starting material 2-caren-4-one can be produced from commercially available, optically pure (+)-3-carene. The (+)-3-carene is treated with nitrosyl chloride followed by the addition of powdered sodium carbonate. The resulting 2-caren-4-one oxime is then treated with sodium bisulfite in aqueous ethanol to yield 2-caren-4-one, the desired starting product for the inventive process.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.C(C1OC(C2C=CC=CC=2)C(C2C=CC=CC=2)[N:23]=1)=O>C(O)C.C(O)(=O)C.[Zn]>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1=NC(c2ccccc2)C(c2ccccc2)O1
Reactant: c1ccc(CNc2ccccc2)cc1
Agent: NN
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: NN(Cc1ccccc1)c1ccccc1
Temperature: 10 °C
Yield: 17.8 %

Procedure:
1-benzyl-1-phenylhydrazine was prepared in the same manner as Synthesis Example 1 except for using 208.6 g (1.14 mol) of N-benzylaniline in place of diphenylamine. Said hydrazine was dissolved in a mixture of 1 l of ethanol and 50 ml of acetic acid, and 286 g (1.14 mol) of 2-formyl-4,5-diphenyloxazoline, represented by the formula ##STR9## was added. The resulting mixture was cooled to 10° C., and 250 g (3.82 mol) of zinc metal was added with caution not to raise the temperature over 20° C. After completion of the reaction, the reaction mixture was filtered and the filtrate was poured into water, thus giving a yellow precipitate. Recrystallization of the precipitate from a methyl ethyl ketone-ethanol (1:1) mixture gave 87.5 g of yellow crystals (yield 17.8% based on the amine).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.C(N(CC)CC)C.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.O>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:21]([CH:18]2[CH2:20][CH2:19]2)=[O:22])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: O=C(Cl)C1CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(NC(=O)C2CC2)n[nH]1
Yield: 51.1 %

Procedure:
7 g (0.05 mole) of 3-amino-5-t-butylpyrazole as prepared in Example 1 and 6 g of triethylamine were dissolved in 50 ml of methylene chloride. To this solution was added dropwise 5.7 g of cyclopropanecarboxylic acid chloride dissolved in 50 ml of carbon tetrachloride. The resulting mixture was allowed to stand over night. Thereafter, water was added thereto whereby crystals were precipitated. The crystals were collected by filtration and washed with water and carbon tetrachloride to obtain 5.3 g of 5-t-butyl-3-cyclopropanecarbonylaminopyrazole.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13]C)=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.Cl.C[C@@H]1CSC[C@@H](C)N1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:3]1[C:4]2=[CH:10][CH:9]=[CH:8][C:7]([C:11]([OH:13])=[O:12])=[C:5]2[N:6]=[CH:2]1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Agent: C[C@@H]1CSC[C@@H](C)N1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccc2ocnc12
Temperature: 55 °C
Yield: 25.2 %

Procedure:
A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (360 mg, 1.70 mmol), (3S,5S)/(3R,5R)-3,5-dimethylthiomorpholine hydrochloride (270 mg, 1.62 mmol) and potassium carbonate (672 mg, 4.86 mmol), in DMF (5 mL), was stirred at ambient temperature for 6 h. The reaction was then heated at 55° C. for 2 h before it was diluted with H2O (20 mL) and extracted with EtOAc (2×40 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude methyl ester was retained for future purification. The remaining aqueous phase was then acidified to pH 5 by addition of 1 N HCl and extracted with CH2Cl2 (2×40 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford crude (3S,5S)/(3R,5R)-3,5-dimethylthiomorpholino)benzoxazole-4-carboxylic acid (70 mg, 15%) which was directly elaborated without purification.
Reaction SMILES: [NH3:1].[Cl:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])[CH3:4]>O1CCCC1>[Cl:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:1])(=[O:13])=[O:12])[CH3:4]
Reactant: N
Reactant: CC(Cl)c1ccccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: CC(Cl)c1ccccc1S(N)(=O)=O

Procedure:
A solution of ammonia (1.2 ml) in tetrahydrofuran (100 ml) at -70° was contacted rapidly with a solution of 2-(1-chloroethyl)benzenesulfonyl chloride (4.32 g, 18.1 mmol) in tetrahydrofuran (50 ml). The stirred mixture was allowed to warm to 0° and volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate and washed with a small volume of water and brine. The dried (MgSO4) solution was evaporated to give 4.7 g of off white solid which was recrystallized from chloroform to give 3.13 g, m.p. 121°-122°. 1H nmr δ(CD3)2COTMS 8.25-7.30 (m), 6.93 (brds), 6.25 (q, J=7 Hz), 3.17 (s), 1.98 (d, J=7 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:20]=[C:19](S(C)(=O)=O)[N:18]=1.[CH3:37][NH:38][CH3:39]>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:20]=[C:19]([N:38]([CH3:39])[CH3:37])[N:18]=1
Reactant: CNC
Reactant: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)nc(S(C)(=O)=O)n2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)nc(N(C)C)n2)cc1
Temperature: 90 °C

Procedure:
A glass microwave reaction vessel was charged with 5-bromo-3-(6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (204 mg, 0.356 mmol) and dimethylamine solution in water (0.4 mL, 3.02 mmol) in NMP (1 ml). The reaction was stirred and heated in a oil bath at 90° C. for 10 min. The mixture was diluted with water. The resulting white ppt was collected by filtration, washed with water, then MeOH, and dried to give the crude product. MS (ESI, pos. ion) m/z: 538/540 (1:1) (M+1).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH:15]1[CH3:19])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>ClCCl>[CH3:27][S:28]([O:18][CH:16]1[CH2:17][N:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:15]1[CH3:19])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC1C(O)CN1C(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CC1C(OS(C)(=O)=O)CN1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
A 500-mL round-bottom flask was charged with 1-benzhydryl-2-methylazetidin-3-ol (15.0 g, 59.2 mmol), dichloromethane (30 mL), and N,N-diisopropylamine (21 mL, 160 mmol), and the solution was cooled to 0° C. A solution of methanesulfonyl chloride (6.2 mL, 77 mmol) in dichloromethane (10 mL) was added, and the resulting solution stirred overnight at room temperature. The reaction mixture was poured into 200 mL of water, and the aqueous phase was separated and extracted with dichloromethane (2×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 20:1, dichloromethane-ethyl acetate). The product was further purified by re-crystallization from hexane to afford 1-benzhydryl-2-methylazetidin-3-yl methanesulfonate (5.6 g, 29%) as a white solid. MS (ESI, pos. ion) m/z 332 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH2:6].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.[O:34]=[C:35]1[NH:39][CH:38]([CH2:40][CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]1>ClCCl.CN(C)C1C=CN=CC=1>[O:43]=[C:42]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:11])[CH2:7][CH2:8][S:9][CH3:10])[CH2:41][CH2:40][CH:38]1[CH2:37][CH2:36][C:35](=[O:34])[NH:39]1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C(O)CCC1CCC(=O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)CCC1CCC(=O)N1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 5.0 g (0.025 mol) L-methionine methyl ester hydrochloride is dissolved in 30 ml of dichloromethane. The solution is cooled to 0° C. and 4.42 ml (0.028 mol) of triethylamine is added dropwise over a ten minute period. The mixture is stirred 15 minutes, filtered, and a mixture of the following is added in a single addition: 6.32 g (0.03 mol) of dicyclohexylcarbodiimide; 200 mg (0.0016 mol) of 4-dimethylaminopyridine; 3.85 g (0.025 mol) of 5-oxo-2-pyrrolidinepropanoic acid. The reaction is allowed to warm to room temperature and stirred for 24 hours. The solids are removed by filtration and are washed with 15 ml of 0° C. dichloromethane. The filtrate is concentrated at reduced pressure to an oil. The oil is chromatographed over silica gel using 19:1 dichloromethanemethanol for elution. Concentration at reduced pressure followed by heating at 0.1 mm pressure and 60° C. yields crystalline analytically pure N-[1-oxo- 3-(5-oxo-2-pyrrolidinyl)propyl]-L-methionine, methyl ester with a melting point of 98°-100° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[H-].[Na+].F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[C:16]([CH3:22])[CH:15]=1.Cl>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)[O:10][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[C:16]([CH3:22])[CH:15]=1
Reactant: COc1cc(O)cc(F)c1
Reactant: Cc1cc(F)ccc1C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cc(F)cc(Oc2ccc(C=O)c(C)c2)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 31.8 %

Procedure:
A 0° C. solution of 3-fluoro-5-methoxy-phenol (2.40 g, 16.9 mmol) in dry DMF (20 mL) is treated with a 60% suspension of NaH (0.74 g, 18.5 mmol) and then stirred for 15 minutes under N2. A solution of 4-fluoro-2-methyl-benzaldehyde (2.33 g, 16.9 mmol) in DMF (10 mL) is added dropwise, and the mixture is warmed to 60° C. for 4 hours. The mixture is cooled and acidified with 1 N HCl. The mixture is then diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 6/1 hexanes/ethyl acetate to afford 1.40 g (32%) of the title compound. Rf=0.41 (2/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C15H13O3F 260, found 261 (M+1, 100%).
Reaction SMILES: C([O:8][C:9](=[O:33])[CH2:10][N:11]1[C:16](=[O:17])[C:15]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:28]([CH3:30])[CH3:29])[CH:22]=2)=[N:14][C:13]([Cl:31])=[C:12]1[CH3:32])C1C=CC=CC=1.Cl>C(O)C.[Pd]>[ClH:31].[Cl:31][C:13]1[N:14]=[C:15]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:28]([CH3:30])[CH3:29])[CH:22]=2)[C:16](=[O:17])[N:11]([CH2:10][C:9]([OH:33])=[O:8])[C:12]=1[CH3:32]
Reactant: Cc1c(Cl)nc(NCCc2cccc(CN(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1c(Cl)nc(NCCc2cccc(CN(C)C)c2)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl-2-[3-chloro-5-(3-[(dimethylamino)methyl]phenethylamino)-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 20) (100 mg, 0.21 mmol) was dissolved in ethanol (10 ml), treated with 10% Pd on carbon catalyst (20 mg), aq HCl (1m, 0.1 ml) and stirred under a hydrogen atmosphere (20 psi, room temperature, 2 hr). The catalyst was removed by filtration, the solvent evaporated to dryness and the residue azeotroped with CH2Cl2 to give the desired product, slightly impure (white solid, 85 mg). 1H NMR (CD3OD) δ 2.30 (s, 3H), 2.80 (s, 6H), 3.00 (t, 2H), 3.60 (t, 2H), 4.20 (s, 2H), 4.70 (s, 2H), 7.30 (m, 2H), 7.40 (m, 2H). LRMS m/z=379.1 (M+1)+.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:11][CH:10]=2)[N:7]=[N:6][C:5]=1[C:21]([OH:23])=O)[CH2:2][CH3:3].C1C=C[C:27]2N(O)N=[N:30][C:28]=2[CH:29]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:28]1([NH:30][C:21]([C:5]2[N:6]=[N:7][N:8]([C:9]3[CH:10]=[CH:11][C:12]([C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:13][CH:14]=3)[C:4]=2[CH2:1][CH2:2][CH3:3])=[O:23])[CH2:29][CH2:27]1
Reactant: CCCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.8 %

Procedure:
5-Propyl-1-{4-[(propylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxylic acid (498 mg, 1.57 mmol) obtained in Example 55b), HOBt (215 mg, 1.57 mmol, 1.0 eq.) and cyclopropylamine (0.146 ml, 2.05 mmol, 1.3 eq.) were dissolved in acetonitrile (4 ml) and DMF (4 ml), WSC (370 mg, 1.89 mmol, 1.2 eq.) was added and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), and washed with 5% aqueous sodium hydrogen carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (2:1, 20 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (542 mg, 1.52 mmol, 97.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.CN(C=O)C.C(Cl)(=O)C(Cl)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:13])[S:10][C:3]=12
Reactant: C1COCCN1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc2nccc(Cl)c2s1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[Lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (100 mg, 455 μmol) was dissolved in CH2Cl2(5 mL) with one drop of DMF and oxalyl chloride (2 mL) was added. The mixture was stirred at RT for one hour then concentrated and dried under high vacuum. Morpholine (60 μl, 683 μmol) was then added to the mixture with N-ethyl-N-isopropylpropan-2-amine (238 μl, 1366 μmol) and the mixture was stirred for 20 hours. The mix was then concentrated and purified using 0 to 100% 90/10/1 CH2Cl2/MeOH/ammonium hydroxide in CH2Cl2 to afford (7-chlorothieno[3,2-b]pyridin-2-yl)(morpholino)methanone.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[NH:4][C:3]1=[O:13].[C:14](=O)([O-])[O-].[K+].[K+].CI>COCCOC.O>[CH3:14][N:4]1[C:5]([C:9]([F:10])([F:12])[F:11])=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[C:3]1=[O:13]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(=O)cc(C(F)(F)F)[nH]c1=O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: COCCOC
Product: Cn1c(C(F)(F)F)cc(=O)n(C)c1=O
Temperature: 25 °C
Yield: 82.8 %

Procedure:
To a suspension of 3-methyl-6-(trifluoromethyl)uracil (20.6 mmol, 4.0 g) and powdered potassium carbonate (41.2 mmol, 5.7 g) in DME (30 mL) was added methyl iodide (82.4 mmol, 5.13 mL). Then, the reaction mixture was refluxed for 4 h at which time the TLC analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). Then, the DME was removed under reduced pressure to afford a white suspension. The solids were collected by filtration and washed with water. After air drying, 3.55 g (83% yield) of 1,3-dimethyl-6-(trifluoromethyl)uracil was obtained as a white solid: mp 85-87° C. EI-HRMS m/e calcd for C7H7F3N2O2 (M+) 208.0459, found 208.0460.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([S:15][C:16]=2[CH:17]=1)=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[CH:11][CH:10]=3)([O-:3])=[O:2].[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>CN(C)C=O>[N+:18]([C:12]1[CH:11]=[CH:10][C:9]2[N:8]([C:21](=[O:23])[CH3:22])[C:7]3[C:16]([S:15][C:14]=2[CH:13]=1)=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)([O-:20])=[O:19]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc2c(c1)Sc1cc([N+](=O)[O-])ccc1N2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccc([N+](=O)[O-])cc2Sc2cc([N+](=O)[O-])ccc21
Temperature: 105 °C
Reaction time: 3 h

Procedure:
To a 3 necked 500 ml round bottom flask fitted with a thermometer and a condenser was added 3,7-dinitro-10H-phenothiazine (MW 289.27 g/mol, 29.00 g, 100 mmol), dimethylformamide (58 ml), acetic anhydride (MW 102.09 g/mol, 102.09 g, 1000 mmol) and triethylamine (MW 101.19 g/mol, 40.88 g, 401 mmol). The mixture was heated to 105° C. and stirred at this temperature for 3 hours. The mixture was cooled to ambient temperature (21° C.) before being cooled to 5° C. whereby it was stirred for 1 hour. The product was isolated by filtration and washed with methanol (3×30 ml) to give a light yellow crystalline solid, which was dried at 50° C. for 15 hours (MW 331.31 g/mol, 26.94 g, 81%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:9]2)=[C:4]([CH:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]2)[CH:3]=1.Cl.[CH3:27][O:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C(C)=CC=CC=1>[CH2:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([N:31]3[CH2:32][CH2:33][CH2:34][C@@H:29]([O:28][CH3:27])[CH2:30]3)=[CH:3][C:4]=2[CH:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]2)[CH2:9][CH2:10]1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN1CCN(c2ccc(Br)cc2C2CCC(C)(C)CC2)CC1
Reactant: CO[C@@H]1CCCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1C
Product: CCCCN1CCN(c2ccc(N3CCC[C@@H](OC)C3)cc2C2CCC(C)(C)CC2)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
A mixture of 1-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]-4-butylpiperazine (37.4 mg, 0.0918 mmol) produced in Example (21c), (R)-3-methoxypiperidine hydrochloride (16.7 mg, 0.110 mmol) produced in Example 49a, tripotassium phosphate (170 mg, 0.801 mmol), palladium(II) acetate (8.2 mg, 0.0365 mmol), tri-t-butylphosphonium tetrafluoroborate (32 mg, 0.110 mmol) and xylene (1.5 mL) was stirred for 4 hours and 30 minutes at an external temperature of 100° C. under a nitrogen atmosphere. The mixture was air-cooled to room temperature and then purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 24 mg of (R)-1-butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypiperidin-1-yl)phenyl]piperazine as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[CH3:23][O-:24].[Na+].Cl.S(=O)(=O)(O)O>CO.O>[CH3:23][O:24][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: C[O-]
Reactant: COC(=O)c1ccc(-c2ccc(OCCCCBr)cc2)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCCCCOc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of methyl 4-[4-(4-bromobutoxy)phenyl]benzoate (1.40 g) in methanol (14 ml) was treated with 28% sodium methoxide in methanol (14 ml) and the solution was reluxed for 5 hours. After cooling to room temperature, the reaction mixture was poured into cold 1N-hydrochloric acid (110 ml) and the resulting precipitate was collected by filtration, washed thoroughly with water and dried to give a white solid. To a mixture of this solid in methanol (20 ml) was added concentrated sulfuric acid (0.5 ml) and refluxed for 4 hours. After cooling to room temperature, the reaction mixture was poured into cold water and the resulting precipitate was collected by filtration, washed thoroughly with water and dried to give methyl 4-[4-(4-methoxybutoxy)phenyl]benzoate (1.16 g) as a white solid.