Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.N.[CH3:13][C:14](=O)[CH3:15]>>[CH3:13][C:14]1([CH3:15])[CH2:9][C:8](=[O:10])[C:6]2[C:5](=[CH:4][CH:3]=[CH:2][CH:7]=2)[O:11]1
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: CC(C)=O
Agent: N
Product: CC1(C)CC(=O)c2ccccc2O1

Procedure:
The title compound was prepared according to the procedure of Example 1A, substituting 1-(2-hydroxyphenyl)ethanone for 1-(5-fluoro-2-hydroxyphenyl)ethanone and using propan-2-one. MS (DCI/NH3) m/z 194 (M+NH4)+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:15])=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O>[Pd]>[N:10]1([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[C:5]([NH2:15])[CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Nc1cc(N2CCCC2)ncc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1cnc(N2CCCC2)cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
To a 100 mL round bottom flask was added 5-nitro-2-(pyrrolidin-1-yl)pyridin-4-amine (compound 20.1, 800 mg, 3.84 mmol, 1.0 equiv) and Pd on carbon (10 wt % Pd, 400 mg, 0.38 mmol, 0.1 equiv). The system was purged with nitrogen and charged with methanol (19 mL) followed by hydrogen. The mixture was stirred at room temperature under hydrogen for 4 hours then purged with nitrogen. The mixture was filtered though celite and washed extensively with MeOH. The solvents were removed in vacuo to obtain the title compound as a purple solid (641 mg, 94%). m/z (ES+) 179.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 7.27 (s, 1H), 5.62 (s, 1H), 5.14 (br s, 2H), 3.67 (br s, 2H), 3.23-3.13 (m, 4H), 1.91-1.79 (m, 4H).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13](S(C)=O)=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[C:24]([F:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=3[F:30])[C:7]2=[O:31])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:32][CH2:33][C@@H:34]([OH:38])[C@H:35]([OH:37])[CH3:36]>>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:32][CH2:33][CH:34]([OH:38])[CH:35]([OH:37])[CH3:36])=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[C:24]([F:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=3[F:30])[C:7]2=[O:31])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(S(C)=O)nc3N(C3CCCC3)C2=O)c1F
Reactant: C[C@@H](O)[C@H](O)CN
Product: COc1cc(OC)c(F)c(N2Cc3cnc(NCC(O)C(C)O)nc3N(C3CCCC3)C2=O)c1F
Yield: 93.8 %

Procedure:
1-Cyclopentyl-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-(2,3-dihydroxy-butylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as described in Example 7 using 0.49 g (1.08 mmol) of 1-cyclopentyl-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.28 g (2.66 mmol) of (2R,3R)-1-amino-butane-2,3-diol. The crude product was purified using medium-pressure chromatography eluting with 20:1 dichloromethane/methanol to give 0.50 g (94%) of the title compound: mp 195° C.–196° C. (dec). MS (APCI) (m+1)/z 494.2.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH2:5][CH2:4]1)[CH3:2].[Cl:17][S:18](O)(=[O:20])=[O:19]>ClCCCl>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C:10]2[CH:11]=[C:12]([F:16])[CH:13]=[CH:14][C:15]=2[S:18]([Cl:17])(=[O:20])=[O:19])[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCN1CCC(Cc2cccc(F)c2)CC1
Solvent: ClCCCl
Product: CCN1CCC(Cc2cc(F)ccc2S(=O)(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-ethyl-4-(3-fluorobenzyl)piperidine (Intermediate 179, 0.210 g) in DCE (1 mL) was added to chlorosulfonic acid (2 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 2 hours. The resultant mixture was added carefully to ice/water and extracted with DCM. The organic layer was dried (Na2SO4) and filtered and the filtrate was evaporated to dryness to give 2-(1-ethylpiperidin-4-ylmethyl)-4-fluorobenzenesulfonyl chloride (0.290 g) as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.O>CN(C=O)C>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:17][CH:16]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Brc1ccc(CN2CCOCC2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
In DMF (108 ml) was dissolved morpholine (9.0 g). To the mixture were added at room temperature triethylamine (24 ml) and 4-bromobenzyl bromide (21.5 g), and the mixture was stirred at 80° C. for 16 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give 4-(4-bromobenzyl)morpholine (17.2 g).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[C:21]1([C:27]2[NH:31][N:30]=[C:29]([C:32]([OH:34])=O)[CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:69])[C:58]2[CH:63]=[C:62]([F:64])[CH:61]=[CH:60][C:59]=2[C:65]([F:68])([F:67])[F:66])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[F:64][C:62]1[CH:61]=[CH:60][C:59]([C:65]([F:67])([F:66])[F:68])=[C:58]([CH:63]=1)[C:57]([N:54]1[CH2:55][CH2:56][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:32]([C:29]2[CH:28]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:31][N:30]=2)=[O:34])[CH2:52][CH2:53]1)=[O:69]
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)[nH]n1
Temperature: 10 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
HOBt (38 mg, 0.28 mmol) and DIPEA (145 mg, 1.12 mmol) were added to a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid hydrochloride (51 mg, 0.22 mmol) in DMF (1.0 mL). The reaction mass was cooled to 10° C., and EDCI.HCl (54 mg, 0.28 mmol) was added, followed by the addition of 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone (100 mg, 0.22 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then diluted with water and the resulting precipitate was filtered and dried under reduced pressure to afford 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide as a solid in 26.8% yield, LC-MS purity: 96.054%, 1H NMR (DMSO): δ 8.1 (s, 1H), 7.95 (s, 1H), 7.8 (d, 2H), 7.56 (m, 2H), 7.5 (t, 2H), 7.4 (m, 1H), 7.1 (s, 1H) 4.2 (m, 2H), 3.75 (m, 1H), 3.6 (m, 4H), 3.5 (m, 2H), 3.2 (m, 2H), 3.1 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:17](O)=[O:18])=[CH:11][N:12]([CH3:16])[C:13](=[O:15])[CH:14]=2)=[C:4]([F:20])[CH:3]=1.CC[N:23]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:17]([NH2:23])=[O:18])=[CH:11][N:12]([CH3:16])[C:13](=[O:15])[CH:14]=2)=[C:4]([F:20])[CH:3]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cc(C(N)=O)c(Nc2ccc(Br)cc2F)cc1=O
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
A mixture of 4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.069 g, 0.202 mmol), EDCI (0.12 g, 0.61 mmol), and HOBt (0.082 g, 0.61 mmol) in DMF (5 mL) was stirred for 30 minutes. NH4Cl (0.033 g, 0.61 mmol) was added followed by Et3N (0.085 mL, 0.61 mmol). After 1 hour, the reaction mixture was diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4) and concentrated to yield 52 mg (76%) clean desired product as an off-white solid. MS APCI (+) m/z 340, 342 (M+, Br pattern) detected; 1H NMR (400 mHz, DMSO-d6) δ 10.39 (s, 1H), 8.34 (s, 1H), 7.67 (dd, 1H), 7.43 (m, 2H), 3.36 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:14][NH:13][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20](Br)[CH:21]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:12][N:13]([C:20]3[CH:19]=[N:18][CH:17]=[C:16]([Br:15])[CH:21]=3)[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N1CC2(C1)CN(c1cncc(Br)c1)C2

Procedure:
In analogy to the procedure described for the preparation of intermediate A-3 [B], 2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester was reacted with 3,5-dibromopyridine in the presence of Pd2(dba)3, rac-BINAP and sodium tert-butoxide to give the title compound as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:49])[CH2:7][N:8]([C:18](=[O:48])[C@H:19]([CH3:47])[NH:20][C@H:21]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29](C(OCC2C=CC=CC=2)=O)[CH2:28][CH2:27]1)[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(C)(C)C.[BrH:50].C(O)(=O)C.C(OCC)C>C(O)(=O)C>[BrH:50].[BrH:50].[CH2:45]([O:44][C:42]([C@@H:21]([NH:20][C@H:19]([C:18]([N:8]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)[CH2:7][C:6]([OH:49])=[O:5])=[O:48])[CH3:47])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]1)=[O:43])[CH3:46]
Reactant: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@@H](C)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 1 h

Procedure:
In 2 ml of acetic acid is dissolved 0.4 g of N-[N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-N-(indan-2-yl)glycine tert-butyl ester, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by standing at room temperature for 1 hour. 50 ml of ethyl ether is added to the reaction mixture, followed by shaking, and the supernatant layer is removed by decantation. The colorless precipitate is rinsed with ethyl ether and dried under reduced pressure to give 0.3 g of N-[N-[(S)-1-ethoxycarbonyl-5-(4-piperidyl)pentyl]-L-alanyl]-N-(indan-2-yl)glycine dihydrobromide as a colorless powder.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:20][Si](C(C)(C)C)(C)C)=[C:13]([O:18][CH3:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:20])=[C:13]([O:18][CH3:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:1])[CH3:3]
Reactant: COc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CN(C(=O)OC(C)(C)C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc2c(cc1O)CN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C

Procedure:
A 6.0 g portion of 3,4-dihydro-7-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-methoxy-2(1H)isoquinolinecarboxylic acid-1,1-dimethylethyl ester is dissolved in 30 mL tetrahydrofuran and cooled to 0° C. To this is added 22.8 mL of a 1.0M solution of tetrabutylammonium fluoride, while stirring. The reaction mixture is brought to room temperature, and stirred for three hours. The reaction is quenched with 10 mL saturated sodium bicarbonate solution and 10 mL water, followed by the addition of 20 mL diethyl ether. After separating the layers, the aqueous phase is extracted with 2×20 mL diethyl ether. The combined organic layers are washed with 20 mL brine, and dried over magnesium sulfate. Following removal of the solvent, the product is purified by silica gel chromatography (eluting with 2:1 hexane/ethyl acetate) to produce 4.15 g of the desired product as a white solid. mp 80°-83° C. MS(Hi res): m/z Calcd for C15H21NO4 279.1470 Found 279.1469 Calcd for C15H21NO4 : C=64.50, H=7.58, N=5.01 Found C=64.47, H=7.61, N=5.19
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[O:22][CH2:23][CH3:24])/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=1[N+:25]([O-])=O)C1C=CC=CC=1>C(OC(=O)C)C.[Pd]>[NH2:25][C:10]1[CH:11]=[C:12]([CH2:15][CH:16]([O:22][CH2:23][CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: CCOC(=O)/C(=C/c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(O)c(N)c1)OCC
Yield: 13.1 %

Procedure:
Ethyl (2Z)-3-[4-(benzyloxy)-3-nitrophenyl]-2-ethoxyacrylate (0.83 g, 1.57 mmole) was hydrogenated in ethylacetate (10 ml) at atmospheric pressure using Pd/C (5%) as a catalyst. The mixture was filtered through celite and evaporated in vacuo. Purification of the crude product with preparative HPLC (Kromasil C8, 7 μm, 50×250 mm) using actonitrile(0-60%) in ammonium acetate buffer (pH 7) as mobile phase gave 0.052 g (13% yield) of the desired product.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][C:2]1=[O:12].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23](Cl)(=[O:25])=[O:24])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23]([N:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:1][C:2](=[O:12])[CH2:3][CH2:4]2)(=[O:24])=[O:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: O=C1CCNc2ccccc2N1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N2CCC(=O)Nc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (700 mg) in pyridine (10 ml) was added 3,4-dimethoxybenzenesulfonyl chloride (1.07 g) and the mixture was stirred at ambient temperature for 2 hours. The resulting mixture was diluted with ethyl acetate, and then the organic solution was washed successively with 0.5N hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine. Drying, filtering and the removal of solvents afforded a crude product. The crude product was triturated with a mixture of diethyl ether and n-hexane (1:1) to give 5-(3,4-dimethoxybenzenesulfonyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (1.33 g) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[CH2:5][NH:6][C:7]([C:9]1[C:10]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=1)=[O:8].[CH3:29]N(C)C=O.CI.O>[Cl-].[Na+].O.C(Cl)Cl>[Cl:28][C:26]1[CH:25]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:27]=1)[CH2:5][N:6]([CH3:29])[C:7]([C:9]1[C:10]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=1)=[O:8]
Reactant: CSc1ncc(C(=O)NCc2cc(Cl)cc(Cl)c2)c(Oc2ccccc2C)n1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CI
Solvent: O
Product: CSc1ncc(C(=O)N(C)Cc2cc(Cl)cc(Cl)c2)c(Oc2ccccc2C)n1
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 0.6 g (1.8 mmol) 2-methylsulfanyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid 3,5-dichloro-benzylamide in 20 ml N,N-dimethylformamide 0.096 g (2.4 mmol) sodiumhydride (60% dispersion in mineraloil) was added and the mixture stirred for 1 h. After the addition of 0.18 ml (2.9 mmol) methyl iodide at 0°, the reaction mixture was stirred for 3 hrs. at RT. The reaction mixture was distributed between 50 ml H2O, 50 ml brine and 50 ml CH2Cl2. The phases were separated, and the aqueous layer extracted twice with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 19:1) to give 0.5 g (61%) 2-methylsulfanyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid (3,5-dichloro-benzyl)-methyl-amide as a light yellow oil, MS (EI): 447.1 (M+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.Br[CH2:21][C:22]1[CH:30]=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=1.[NH4+].[Cl-]>C1CCCCC1.C1COCC1>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([CH2:21][CH:10]3[CH2:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9]3=[O:14])=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: BrCc1ccc2c(c1)OCO2
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: O=C1C(Cc2ccc3c(c2)OCO3)CCCN1Cc1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
1-Benzyl-piperidin-2-one (4.8 g, 25.4 mmol) in abs. THF (200 ml) is cooled to −70° C.; sec.-BuLi (23.4 ml of a 1.3 M solution in cyclohexane; 30.4 mmol) is added dropwise under an Ar atmosphere and the mixture is stirred at −70° C. for 30 min. A solution of 5-bromomethyl-benzo[1,3]dioxole (see Harrowven et al., Tetrahedron (2001), 57(29), 4447) (8.0 g, 37.2 mmol) in abs. THF (80 ml) is added dropwise, stirring is continued at −70° C. for 3 h, then at rt for 15 h. sat. aq. NH4Cl solution is added, the organic layer is separated, dried over Na2SO4 and evaporated. The oily residue is purified by MPLC (140 g silica gel, eluent cyclohexane, then cyclohexane:AcOEt 7:3) to give 3-benzo[1,3]dioxol-5-ylmethyl-1-benzyl-piperidin-2-one as a yellow oil. Preparative resolution using a Chiralpak AD 5×50 cm/20 μm column (Daicel Chiral Technologies, Inc., Exton USA; a chiral stationary phase); eluent hexane: isopropanol 90:10; flow 80 ml/min; UV detection (210 nM) gives (−)-3-benzo[1,3]dioxol-5-ylmethyl-1-benzyl-piperidin-2-one ([α]Drt=−61.1° (c=0.5, EtOH)).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:32][N:33]([CH3:40])[CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[NH2:41][C:42]1[C:73]([C:74]([F:77])([F:76])[F:75])=[CH:72][C:45]([CH2:46][C@@H:47]([CH2:51][C:52](=[O:71])[N:53]2[CH2:58][CH2:57][CH:56]([N:59]3[CH2:65][CH2:64][C:63]4[CH:66]=[CH:67][CH:68]=[CH:69][C:62]=4[NH:61][C:60]3=[O:70])[CH2:55][CH2:54]2)[C:48](O)=[O:49])=[CH:44][C:43]=1[Cl:78].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:41][C:42]1[C:73]([C:74]([F:76])([F:75])[F:77])=[CH:72][C:45]([CH2:46][C@@H:47]([CH2:51][C:52]([N:53]2[CH2:58][CH2:57][CH:56]([N:59]3[CH2:65][CH2:64][C:63]4[CH:66]=[CH:67][CH:68]=[CH:69][C:62]=4[NH:61][C:60]3=[O:70])[CH2:55][CH2:54]2)=[O:71])[C:48]([N:37]2[CH2:38][CH2:39][CH:34]([N:33]([CH3:40])[CH3:32])[CH2:35][CH2:36]2)=[O:49])=[CH:44][C:43]=1[Cl:78]
Reactant: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: CN(C)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C1CCN(C(=O)[C@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)Cc2cc(Cl)c(N)c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80.3 mg (0.25 mmol) TBTU, 0.21 mL (1.2 mmol) ethyldiisopropylamine and 38.5 mg (0.3 mmol) dimethyl-piperidin-4-yl-amine were added to a solution of 130 mg (0.24 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid in 10 mL DMF and the reaction mixture was stirred overnight at RT. The reaction solution was poured into 80 mL 15% K2CO3 solution, stirred for 10 min at RT, the precipitated substance was suction filtered, washed with 5 mL water and dried in the air over the weekend. Then the product was purified by chromatography using HPLC.
Reaction SMILES: [Li].[CH3:2][C@H:3]([NH:12][CH3:13])[C@H:4](O)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1>N>[CH3:2][C@H:3]([NH:12][CH3:13])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN[C@@H](C)[C@H](O)c1ccccc1
Agent: N
Agent: [Li]
Product: CN[C@@H](C)Cc1ccccc1

Procedure:
In the dissolving metal reduction method of methamphetamine synthesis, the ephedrine or pseudo-ephedrine starting ingredient is obtained, often by extraction from over-the-counter cold medication. Anhydrous ammonia is obtained, typically by theft from agricultural supplies. Lithium metal is obtained from lithium batteries. Lithium metal is dissolved in the liquid, anhydrous ammonia to give a blue colored solution, to which ephedrine is added. The ammonia is allowed to boil off leaving the crude, free-base methamphetamine product, which is typically purified by common practice and converted to the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.CC(C)([O-])C.[K+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][C:25]([NH2:27])=[O:26])[CH:19]=1.[OH-].[Na+]>CS(C)=O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][C:25]([NH2:27])=[O:26])[CH:19]=2)=[C:4]([F:10])[CH:3]=1
Reactant: NC(=O)Cc1cc(Cl)ccn1
Reactant: Nc1cc(F)c(O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: NC(=O)Cc1cc(Oc2cc(F)c(N)cc2F)ccn1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 76.5 %

Procedure:
After dissolving 4-amino-2,5-difluorophenol (4.95 g) in dimethyl sulfoxide (50 ml) under a nitrogen stream, potassium tert-butoxide (4.05 g) was added at room temperature and the mixture was stirred for 25 minutes. After adding 4-chloropyridine-2-carboxyamide (2.70 g) to the mixture, stirring was continued at 80° C. for 2.5 hours. After cooling the reaction mixture to room temperature, a 1N aqueous solution of sodium hydroxide (74.25 ml) was added and stirring was continued for 10 hours. The precipitated solid was collected by filtration and washed with water. The solid was dried with warm air at 100° C. for 24 hours to give the title compound (3.38 g, 74%) as purple powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:31](Cl)(=[O:33])[CH3:32]>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:31](=[O:33])[CH3:32])[CH2:25][C:26]([F:29])([F:28])[F:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCC(F)(F)F)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC(F)(F)F)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: {6-methoxy-2′-[(2,2,2-trifluoro-ethylamino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.