Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1.[CH3:21]N(C(OC)OC)C.[CH2:29]([O:31][C:32](=[O:35])[CH2:33]Br)[CH3:30].CO>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:33]([C:32]([O:31][CH2:29][CH3:30])=[O:35])=[CH:21][N:20]=2)[CH:19]=1
Reactant: Nc1ccc(N2CCC[C@@H]2c2cc(F)ccc2F)cn1
Reactant: CCOC(=O)CBr
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)c1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cn12
Temperature: 120 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To stirred solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyridin-2-amine (2.7 g, 9.8 mmol) in dry toluene (27 ml, 10 v) was added DMF-DMA (2.45 g, 20.61 mmol) under N2 atm and stirred for 2 h at 120° C. during which complete consumption of Int-12 was observed by TLC, cool it to 10° C. then added Ethylbromoacetate (3.6 g, 21.59 mmol) drop wise and methanol (2 ml) was added under N2 atm then stirred for 16 h at 120° C. Reaction mixture was cooled to room temperature and solvent was removed in vacuo and residue was dissolved in DCM (200 ml), washed with water and brine, dried over anhydrous Na2SO4 and concentrated under vacuum to get crude product. Crude was purified by column chromatography (eluted with 30-40% ethyl acetate/Hexane) to afford pale green solid (2.25 g, 61.8% yield), MS (ESI): m/z 372.1 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.57-8.56 (1H, m), 8.17 (1H, s), 7.51-7.49 (1H, dd), 7.08-7.04 (1H, m), 6.92-6.91 (1H, m), 6.84-6.80 (2H, m), 5.02-5.00 (1H, m), 4.40-4.35 (2H, q), 3.74-3.72 (1H, m), 3.43-3.42 (1H, m), 2.48-2.46 (1H, m), 2.12-2.02 (3H, m), 1.43-1.37 (3H, t) ppm.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[NH:9][C:10]([C:12](=[O:23])[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:22][CH2:21]4)[CH2:16][CH2:15]3)=[N:11][C:7]=2[CH:6]=1)=[O:4].Br[CH2:27][C:28]1[S:29][C:30]([C:33]2[S:34][C:35]([Cl:38])=[CH:36][CH:37]=2)=[N:31][N:32]=1.CC#N.O>C(O)=O>[Cl:38][C:35]1[S:34][C:33]([C:30]2[S:29][C:28]([CH2:27][N:9]3[C:8]4[CH:24]=[CH:25][C:5]([C:3]([OH:2])=[O:4])=[CH:6][C:7]=4[N:11]=[C:10]3[C:12](=[O:23])[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:22][CH2:21]4)[CH2:16][CH2:15]3)=[N:32][N:31]=2)=[CH:37][CH:36]=1.[Cl:38][C:35]1[S:34][C:33]([C:30]2[S:29][C:28]([CH2:27][N:11]3[C:7]4[CH:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:25]=[CH:24][C:8]=4[N:9]=[C:10]3[C:12](=[O:23])[NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:22][CH2:21]4)[CH2:16][CH2:15]3)=[N:32][N:31]=2)=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc2[nH]c(C(=O)NC3CCN(C4CC4)CC3)nc2c1
Reactant: Clc1ccc(-c2nnc(CBr)s2)s1
Solvent: O
Solvent: CC#N
Solvent: O=CO
Product: O=C(O)c1ccc2c(c1)nc(C(=O)NC1CCN(C3CC3)CC1)n2Cc1nnc(-c2ccc(Cl)s2)s1
Product: O=C(O)c1ccc2nc(C(=O)NC3CCN(C4CC4)CC3)n(Cc3nnc(-c4ccc(Cl)s4)s3)c2c1

Procedure:
1-[5-(5-Chloro-thiophen-2-yl)-[1,3,4]thiadiazol-2-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid and 3-[5-(5-Chloro-thiophen-2-yl)-[1,3,4]thiadiazol-2-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-5-carboxylic acid were prepared by a procedure according to example 81 starting from 200 mg (0.58 mmol) 2-(1-Cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid methyl ester and 181.8 mg (0.58 mmol) 2-bromomethyl-5-(5-chloro-thiophen-2-yl)-[1,3,4]thiadiazole. Hydrolysis of the resulting esters and purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave the title compounds as their formiates in form of white amorphous solids. Structural assignment of both isomers was achieved by NOE-spectroscopy.
Reaction SMILES: [F:1][CH:2]([CH2:5][N:6]1[C:11](=[O:12])[CH:10]=[N:9][C:8]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[N:16][C:7]1=2)[CH:3]=O.[NH2:19][CH:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=3[CH:35]=2)[C:22](=[O:36])[CH2:21]1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.ClCCl>[F:1][CH:2]([CH2:3][NH:19][CH:20]1[CH2:21][C:22](=[O:36])[N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=3[CH:35]=2)[CH2:24]1)[CH2:5][N:6]1[C:11](=[O:12])[CH:10]=[N:9][C:8]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[N:16][C:7]1=2
Reactant: COc1ccc2ncc(=O)n(CC(F)C=O)c2n1
Reactant: NC1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CC(F)CNC3CC(=O)N(c4ccc5c(c4)NC(=O)CO5)C3)c2n1
Reaction time: 12 h
Yield: 40.7 %

Procedure:
A crude product of 2-Fluoro-3-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)propanal (323 mg), 6-(4-amino-2-oxopyrrolidin-1-yl)-2H-1,4-benzoxazin-3(4H)-one (Reference Example 6; 227 mg, 0.917 mmol) were mixed in a mixed solution of dichloromethane (30 ml) and N,N-dimethylformamide (3 ml). Acetic acid (0.105 ml, 1.834 mmol) and anhydrous sodium sulfate (450 mg) were added to the solution and the mixture was stirred for 12 hours. Sodium triacetoxyborohydride (389 mg, 1.834 mmol) was added to the reaction solution, the mixture was stirred for 4 hours and then the solvent was removed under reduced pressure. A lower layer solvent of chloroform/methanol/water (7:3:1) was added to the residue and the resultant was alkalized by adding saturated sodium bicarbonate water under cooling on ice. The mixture was extracted with a lower layer solvent of chloroform/methanol/water (7:3:1), the extract was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) and preparative layer chromatography (silica gel, chloroform/methanol=20:1) to yield 180 mg (41%) of the title compound in the form of a light orange solid.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:20].C([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])C.[CH2:28]1[CH2:32][O:31][CH2:30][CH2:29]1>>[CH2:2]([C@@H:25]1[C@@H:24]2[C@@H:26]([NH:23]2)[CH:27]=[C:29]([C:30]([O:31][CH3:32])=[O:20])[CH2:28]1)[CH:1]=[CH2:6].[CH:17]1[CH:16]=[CH:15][C:14]([P:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:19][CH:18]=1
Reactant: CCN(CC)CC
Reactant: C1CCOC1
Reactant: O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CC[C@H]1CC(C(=O)OC)=C[C@@H]2N[C@H]12
Reaction time: 2 h

Procedure:
Triphenylphosphine (1.14 g, 4.35 mmol) was slowly added to a room temperature solution of Example 1K (0.80 g, 2.54 mmol) in THF (30 mL). After stirring for 2 hours, water (3.0 mL) and triethylamine (1.0 mL, 7.19 mmol) were added. The mixture was stirred for 10 hours, and concentrated. The concentrate was chromatographed on silica gel using ethyl acetate to afford the desired product with Ph3P as a contaminant.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][Br:32]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cl)cc1CBr
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
5.61 g of 5-chloro-2-nitrobenzyl alcohol is mixed with 9.1 g of triphenylphosphine in 100 ml of dichloromethane. To this solution 6.1 g of N-bromosuccinimide is added portionwise over 5 minutes (to avoid foaming as the reaction warms to ca. 5° C.). After stirring 30 minutes 10 wt % of both triphenylphosphine (900 mg) and N-bromosuccinimide (600 mg) are added. After an additional 30 minutes stirring the reaction mixture is concentrated to approximately 10 ml, poured on a bed of Celite®, and then rinsed through with 0.1% methanol in dichloromethane. Evaporation of the filtrate provides 2.43 g of 5-chloro-2-nitrobenzyl bromide as a light yellow oil. 1H-NMR (500 MHz, CDC13) δ (ppm) 4.806 (s, 2H), 7.457-7.479 (dd, 1H), 7.589-7.593 (s, 1H), 8.033-8.051 (d, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH2:11]([NH:14][CH2:15][CH:16]=[CH2:17])[CH:12]=[CH2:13].Cl.[NH2:19][OH:20]>N1C=CC=CC=1.C(#N)C>[CH2:11]([N:14]1[CH2:15][CH:16]2[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)([NH:19][O:20][CH2:17]2)[CH2:2]1)[CH:12]=[CH2:13]
Reactant: O=C(CBr)c1ccccc1
Reactant: NO
Reactant: C=CCNCC=C
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: C=CCN1CC2CONC2(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 79.4 %

Procedure:
Alpha-bromoacetophenone (77.5 g, 389.36 mmol) is added to a rapidly stiffing solution of acetonitrile (1 L) at 0° C. To this solution is added in a drop wise fashion, diallylamine (98.40 mL, 798.18 mmol) over 10 min. The mixture is warmed to room temperature and stirred for 96 h. The solvent is removed under reduced pressure and the residue is dissolved in ethanol (778.71 mL). Pyridine (110.20 mL, 1.36 mmol) is added to the solution followed by hydroxylamine hydrochloride (67.64 g, 973.39 mmol). The reaction is heated to 70° C. for 4 h and then stirred overnight at RT. The solvent is removed under reduced pressure and the residue is dissolved in toluene (1 L). The reaction is heated to 120° C. and stirred overnight. The solvent is removed under reduced pressure. The product is purified via silica gel chromatography eluting with 0-100% ethyl acetate/hexanes to give the title compound as a light red oil (71.2 g, 79.4%) that is used without further purification. EI/MS (m/e): 231.0 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].Cl[CH2:19][C:20]1[O:24][N:23]=[C:22]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])[CH:21]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:19][C:20]2[O:24][N:23]=[C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])[CH:21]=2)[N:7]=1)[CH3:4]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)on1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2cc(OCc3nc(-c4ccccc4)oc3C)no2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (318 mg) and 5-chloromethyl-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)isoxazole (457 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethyl]-1H-pyrazol-4-yl]propionate (653 mg, yield: 91%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 82–83° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:19])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O:22][CH:23]=[C:24]([C:30](OCC)=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26])C.CN(C)C=O.O>C(OCC)(=O)C>[O:22]=[C:23]1[N:3]2[CH:4]=[N:5][C:6]3[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:19])[CH2:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:10][C:11]=3[C:2]2=[N:1][CH:30]=[C:24]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CC(C)(C)CC(=O)Nc1ccc2ncnc(N)c2c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2c3cc(NC(=O)CC(C)(C)C)ccc3ncn2c1=O
Temperature: 150 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
A mixture of 4-amino-6-(3,3-dimethylbutyramido)quinazoline (12.2 g), diethyl ethoxymethylenepropandioate (15.3 g) and N,N-dimethylformamide (50 ml) was stirred at 150° C. for 2 hours. The reaction mixture was cooled to ambient temperature. After adding water, the resultant mixture was extracted with chloroform. The chloroform layer was washed twice with water and once with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, to which was added ethyl acetate. Insoluble materials were separated by filtration and dried to give ethyl 4-oxo-10-(3,3-dimethylbutanamido)-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (4.7 g) melting at 253°-254° C. Further, the filtrate was concentrated under reduced pressure to give a residue, which was recrystallized from a mixture of ethyl acetate and hexane to give crystalline diethyl [{6-(3,3-dimethylbutyramido)4-quinazolinylamino}methylene]propanedioate (10.1 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[N:6][C:7]=1[Br:8].C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[Br:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc(N)c(Br)n2)CC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(C2CCNCC2)nc1Br
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl 4-(5-amino-6-bromopyrazin-2-yl)piperidine-1-carboxylate (70 mg, 0.196 mmol) in DCM (4 mL) was added TFA (1 mL, 12.98 mmol). The reaction mixture was stirred at room temperature for 45 min. After toluene was added, the volatile materials were evaporated yielding 3-bromo-5-(piperidin-4-yl)pyrazin-2-amine. The crude product was used directly for the next reaction (99%). LCMS (m/z): 257.0/259.0 (MH+), 0.329 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([O:16][CH3:17])[C:6]([O:14][CH3:15])=[N:7]2.[CH2:18]([S:20](Cl)(=[O:22])=[O:21])[CH3:19].N1C=CC=CC=1.O>O1CCCC1>[CH3:15][O:14][C:6]1[C:5]([O:16][CH3:17])=[N:4][C:3]2[C:8](=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:2]=2[NH:1][S:20]([CH2:18][CH3:19])(=[O:22])=[O:21])[N:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: COc1nc2cc(C)c(C)c(N)c2nc1OC
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1c(C)c(C)cc2nc(OC)c(OC)nc12
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 96.2 %

Procedure:
A mixture of 5-amino-2,3-dimethoxy-6,7-dimethylquinoxaline (from Preparation 2) (50 mg, 0.214 mmol), ethanesulphonyl chloride (138 mg, 1.07 mmol) and pyridine (87 μl, 1.07 mmol) in dry tetrahydrofuran (1 ml) was stirred at 20° C. for 3.5 hours. Additional portions of ethanesulphonyl chloride (138 mg, 1.07 mmol) and pyridine (87 ml, 1.07 mmol) were added and the mixture was stirred for a further 4 days. Water (0.6 ml) was added, and the mixture was stirred for 40 minutes. The mixture was partitioned between ethyl acetate (15 ml) and 2M hydrochloric acid (5 ml). The organic solution was washed with water (5 ml), saturated aqueous sodium bicarbonate (5 ml), dried (MgSO4), and concentrated under reduced pressure to give the title compound (67 mg, 96%) as a straw-coloured solid, m.p. 201°-203° C.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][CH:27]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[C@H:2]([C:20](O)=[O:21])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=1.[CH2:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH:1]([C:23]([O:25][CH2:26][CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[C:39]1=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:24])[C@H:2]([C:20]([NH:47][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:21])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH:5]=1
Reactant: CC(C)(C)OC(=O)n1cc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c2ccccc21
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)NCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
To the mixture of Fmoc-Trp(Boc)-OH (205 mg, 0.39 mmol) and benzylamine (165 μL, 1.51 mmol) in DMF (5 mL) was added TBTU (249 mg, 0.77 mmol) and N,N-diisopropylethylamine (340 μL, 1.95 mmol). The reaction was stirred for 2 hours at room temperature. The solvent was removed in vacuo and the residue was purified by flash column silica gel chromatography (2:1, hexane:ethyl acetate) to yield the Fmoc-Trp(Boc)-NHBn (151 mg, 63%). The solution of Fmoc-Trp(Boc)-NHBn (151 mg, 0.25 mmol) and piperidine (0.5 mL) in DMF (2 mL) was stirred for 1 hour at room temperature. The solvent was removed in vacuo and the crude product was purified by flash column silica gel chromatography (from ethyl acetate to 5% methanol in ethyl acetate) to afford the NH2-Trp(Boc)-NHBn (81 mg, 80%). Compound 16 (23 mg, 0.04 mmol) was dissolved in DMF (2 mL) and NH2-Trp(Boc)-NHBn (72 mg, 0.18 mmol), TBTU (33 mg, 0.10 mmol), and N,N-diisopropylethylamine (37 μL, 0.21 mmol). The mixture was stirred for 4 hours at room temperature before removing the solvent under reduced pressure. The crude product was purified by flash chromatography using ethyl acetate as eluent to afford 17 (24 mg, 63%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[C:11]([CH3:13])[CH:10]=[N:9]2)[N:3]=1.C([Li])CCC.[Br:19]N1C(=O)CCC1=O.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Br:19][C:12]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=2)[N:9]=[CH:10][C:11]=1[CH3:13]
Reactant: Cc1cnn(-c2cccc(C)n2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(-n2ncc(C)c2Br)n1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a cold (−60° C.) solution of 2-methyl-6-(4-methyl-pyrazol-1-yl)-pyridine (0.52 g) (prepared by Reaction Condition 1 in Step i) in 14 mL of anhydrous THF was added 1.33 mL of a 2.5M solution of n-butyllithium (0.21 g) in hexanes. The reaction mixture was stirred at −60° C. for one hour. A 10 mL solution of N-bromosuccinimide (0.59 g) in THF was added and then the final solution was stirred at −60° C. for 2 hours. Saturated ammonium chloride (20 mL) was added and then the reaction mixture was allowed to warm to 24° C. The reaction mixture was diluted with 300 mL of ethyl acetate and then the aqueous phase was separated. The organic phase was washed with additional saturated ammonium chloride (50 mL) and then with brine (50 mL). The organic layer was separated, dried (sodium sulfate), filtered, and then the filtrate was evaporated to give a crude red oil. Purification by flash chromatography (silica gel, 20% ethyl acetate in heptane) provided, after drying, 0.377 g of the title compound as a yellow oil; 1H-NMR (400 MHz; DMSO-de) δ 7.88 (t, 1H), 7.69 (s, 1H), 7.44 (s, 1H), 7.32 (s, 1H), 2.50 (s, 3H), 2.02 (s, 3H); MS (APCI+) m/z 254 (MH+).
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[Li]CCCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([CH:31]=[O:32])[CH2:27][CH2:26]2)=[CH:19][CH:18]=1>C1COCC1.CCCCCC>[CH3:4][O:3][C:2]1[C:1]([O:9][CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:31]([CH:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[CH2:26][CH2:27]1)[OH:32]
Reactant: COc1ccccc1OC
Reactant: O=CC1CCN(CCc2ccc(F)cc2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(C(O)C2CCN(CCc3ccc(F)cc3)CC2)c1OC
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of veratrole (0.93 g, 6.7 mmol) in THF (20 mL) under argon at 0° C. was added n-BuLi (2.7 mL of a 2.5M solution in hexane, 6.75 mmol). After stirring 2.5 h, the solution was cooled to -78° C. and treated with 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxaldehyde (1.30 g, 5.5 mmol) in THF (25 mL) via an addition funnel. The cooling bath was removed and the solution was allowed to stir for 2 hours. Water was added, the layers separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and chromatographed on silica gel, eluting with acetone. The appropriate fractions were combined and evaporated to afford a white solid. The solid was recrystallized from hexane to afford racemic α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol as shiny white needles, m.p. 126°-127° C. Anal. Calcd for C22H28FNO3 : C, 70.75; H, 7.56; N, 3.75. Found: C, 70.87; H, 7.65; N, 3.68.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F:15][CH2:16][CH:17]([N:20]1[CH2:23][CH:22]([NH2:24])[CH2:21]1)[CH2:18][F:19].C(NC(C)C)(C)C>O1CCOCC1>[F:15][CH2:16][CH:17]([N:20]1[CH2:23][CH:22]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:21]1)[CH2:18][F:19]
Reactant: NC1CN(C(CF)CF)C1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CC(C)NC(C)C
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(NC2CN(C(CF)CF)C2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-chloro-3-nitrobenzenesulfonamide (0.225 g) and 1-(1,3-difluoropropan-2-yl)azetidin-3-amine (0.193 g) in dioxane (5 mL) was added diisopropylamine (0.832 mL). The reaction was sonicated and then heated to 100° C. After stirring overnight, the reaction was concentrated and loaded onto silica gel (GraceResolv 12 g) and eluted with a gradient of 0.5% to 3.5% methanol/dichloromethane to give the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]2[O:9][CH2:10][O:11][C:6]2=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].C[O-].[Na+].C(O)(=O)C>CO.O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([NH:2][CH3:1])[C:4]([N+:12]([O-:14])=[O:13])=[CH:5][C:6]=1[OH:11]
Reactant: CNc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CNc1cc(OC)c(O)cc1[N+](=O)[O-]

Procedure:
A solution of 0.1 mol (19.6 g) of 2-methylamino-4,5-methylenedioxy-1-nitrobenzene, prepared according to Example 3, in 80 ml of a 30% strength solution of sodium methylate in methanol is brought for 15 minutes to the refluxing temperature of the methanol. The reaction medium is diluted with 500 ml of water. After the filtrate has been neutralized with acetic acid, the expected product precipitates.