Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][CH:10]=1)(=O)=O.[CH2:23]([O:25][C:26](=[O:39])[C@@H:27]([O:36][CH2:37][CH3:38])[CH2:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:19]([O:18][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][O:5][C:32]2[CH:31]=[CH:30][C:29]([CH2:28][C@H:27]([O:36][CH2:37][CH3:38])[C:26]([O:25][CH2:23][CH3:24])=[O:39])=[CH:34][CH:33]=2)=[CH:10][CH:11]=1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCOS(C)(=O)=O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H](Cc1ccc(OCCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)OCC
Yield: 75.5 %

Procedure:
3-{4-[(tert-Butoxycarbonyl)amino]phenyl}propyl methanesulfonate (360 mg, 1.093 mmol) and (S)-2-Ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (260 mg, 1.093 mmol) were mixed in acetonitrile (30 ml). Potassium carbonate (anhydrous, 226.6 mg 1.639 mmol) was added. The mixture was heated to reflux overnight and thereafter it was evaporated to dry. Ethyl acetate (20 ml) and water (5 ml) were added into the residue. The two phases were separated and the water phase was extracted with ethyl acetate (10 ml×2). The organic phases were combined and washed with 0.1 M sodium hydroxide aqueous solution, water and brine and dried with magnesium sulfate. The solvent was evaporated in vacuum and an oil mixture was left. Column chromatography of the oil mixture on silica gel using ethyl acetate/heptane (20:80) as eluant gave the desired product (389 mg), yield 75.5%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=2)=[CH:5][CH:4]=1.[CH3:32][S:33]([NH2:36])(=[O:35])=[O:34]>N1C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH:36][S:33]([CH3:32])(=[O:35])=[O:34])=[O:28])=[CH:25][CH:24]=2)=[CH:5][CH:4]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1

Procedure:
A solution of 25.2 g. of 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl chloride hydrochloride and 5.6 g. of methanesulfonamide in 250 ml. of pyridine is stirred under reflux for 2 hours and then concentrated in vacuo. The residue is partitioned between water and diethyl ether; the aqueous layer acidified with 1 N HCl, and the organic layer separated, dried and evaporated. Crystallization of the residual white solid from 60% aqueous acetic acid and then from methylene chloride-hexane affords N-{4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl}methanesulfonamide as a white solid.
Reaction SMILES: [NH:1]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]([O:28]CC1C=CC=CC=1)=[O:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]>C(OCC)(=O)C.CO.[Pd]>[NH:1]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Yield: 80 %

Procedure:
The Boc-Gly-Phe-Leu-OBzl (1.7 g) obtained in Example 19 was dissolved in a mixed solution of ethyl acetate (30 ml) and methanol (30 ml), and added with 5% Pd-C (1.5 g) to perform catalytic reduction. The reaction mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to give the title compound (1.15 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:27]=[CH:26][C:19]2[C:20]([C:23](O)=[O:24])=[CH:21][O:22][C:18]=2[CH:17]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:50][C:51]1[CH:57]=[CH:56][C:54]([NH2:55])=[CH:53][CH:52]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:50][C:51]1[CH:57]=[CH:56][C:54]([NH:55][C:23]([C:20]2[C:19]3[CH:26]=[CH:27][C:16]([O:15][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][CH:7]=4)=[CH:17][C:18]=3[O:22][CH:21]=2)=[O:24])=[CH:53][CH:52]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1cc2nccc(Oc3ccc4c(C(=O)O)coc4c3)c2cc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc4c(C(=O)Nc5ccc(Cl)cc5)coc4c3)c2cc1OC
Reaction time: 48 h
Yield: 12.4 %

Procedure:
6-(6,7-Dimethoxyquinolin-4-yloxy)benzofuran-3-carboxylic acid (31 mg, 0.085 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (41 mg, 0.127 mmol) were added to a reaction tube then dissolved in DMF (0.6 mL). 4-chloroaniline (13 mg, 0.102 mmol) was added to the reaction mixture, followed by N,N-diisopropylethylamine (22 mg, 0.17 mmol) and stirring was continued for 2 days. The mixture was concentrated in vacuo. The remaining orange oil was purified by silica gel chromatography (1% to 2% methanol in dichloromethane) to afford N-(4-chlorophenyl)-6-(6,7-dimethoxyquinolin-4-yloxy)benzofuran-3-carboxamide as a yellow solid (5 mg). MS (ESI, pos. ion) m/z: 475.1 (M+1). Mass calc'd for C26H19ClN2O5: 474.89.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:57][C:58]1[S:59][CH:60]=[CH:61][N:62]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)[C:8]([NH:57][C:58]2[S:59][CH:60]=[CH:61][N:62]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)CC#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CC#Cc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Yield: 19.4 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-propionic acid (150 mg, 0.50 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.21 mL, 1.50 mmol) and 2-aminothiazole (86 mg, 0.86 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 2 h. At this time, the reaction was diluted with methylene chloride (10 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), and a half-saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 methylene chloride/methanol) afforded 3-cyclopentyl-2-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide (37 mg, 19.3%) as a white solid: mp 164-167° C.; EI-HRMS m/e calcd for C22H27N3OS (M+) 381.1874, found 381.1879.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[C:11]([Cl:12])=[CH:10][C:9]([F:13])=[C:8]([C:14]3[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[C:6]=2[CH:7]=1.[CH3:26][SH:27].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:12][C:11]1[C:5]2[O:4][C:3]([CH2:2][S:27][CH3:26])=[CH:7][C:6]=2[C:8]([C:14]2[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=2)=[C:9]([F:13])[CH:10]=1
Reactant: CS
Reactant: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(CBr)cc23)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CSCc1cc2c(-c3ccc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
0.31 g (0.71 mmol) of 3-(2-bromomethyl-7-chloro-5-fluorobenzofuran-4-yl)-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was dissolved in 20 ml of THF, and 0.014 g (0.85 mmol) of a methanethiol 30% methanol solution and 0.12 g (0.85 mmol) of potassium carbonate were added thereto, followed by stirring at room temperature for 8 hours. THF was distilled off under reduced pressure. Then, the obtained residue was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. Then, the obtained crude crystals were washed with n-hexane to obtain 0.28 g (yield: 98%) of the desired product.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])=O.[O:12]=[C:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:22](=[S:24])[NH2:23])[C:16]=2[CH2:15][NH:14]1>>[CH3:11][C:10]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:3]1[N:23]=[C:22]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:16]=2[CH2:15][NH:14][C:13]3=[O:12])[S:24][CH:2]=1
Reactant: Cc1ccncc1C(=O)CBr
Reactant: NC(=S)c1cccc2c1CNC2=O
Product: Cc1ccncc1-c1csc(-c2cccc3c2CNC3=O)n1

Procedure:
By the reaction in the same manner as in Example 25-ii) using 1-oxo-4-isoindolincarbonitrile (310 mg), 1-oxoisoindolin-4-carbothioamide was obtained as pale-green powder. Then, by the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-methylpyridin-3-yl)ethanone hydrobromate (520 mg) and 1-oxoisoindolin-4-carbothioamide, the title compound (51 mg) was obtained as colorless powder crystals.
Reaction SMILES: C(N(CC)CC)C.[H][H].[CH:10](=[C:17]([CH2:21][OH:22])[C:18]([OH:20])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO.[C].[Pd]>[OH:22][CH2:21][CH:17]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:18]([OH:20])=[O:19]
Reactant: O=C(O)C(=Cc1ccccc1)CO
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)C(CO)Cc1ccccc1
Yield: 65.7 %

Procedure:
The product (107.8 g) in Reference Example 3, namely 2-benzylidene-3-hydroxypropionic acid, is dissolved in methanol (500 ml), followed by addition of triethylamine (100 ml; 717 mmol) and 5% palladium-carbon (5.00 g; water content of 52.7%) for catalytic reduction in a hydrogen atmosphere for 50 hours. The reaction solution is filtered through Celite to remove the palladium-carbon. The resulting filtrate is subjected to HPLC analysis, indicating that the filtrate contains the title compound (71.0 g; 394 mmol) (at a yield of 65.7% (on a benzaldehyde basis)). The filtrate is concentrated under reduced pressure, and the resulting residue is dissolved in ethyl acetate (600 ml), followed by addition of water (600 ml) and 37% hydrochloric acid (150 ml) and subsequent agitation, to extract the resulting organic phase. The organic phase is washed with an aqueous mixture solution of water (240 ml) and 37% hydrochloric acid and then with saturated saline (300 ml), and dried over anhydrous sodium sulfate. By filtering off the resulting dried matter, the solution is concentrated under reduced pressure, to give a crude product of the title compound. The crude product is dissolved in ethyl acetate (150 ml) , followed by addition of hexane (450 ml), and the resulting mixture is gradually cooled from 60° C. to 5° C., to precipitate crystal, which is then filtered and dried to recover the title compound (48.45 g at a purity of 96.5%; 295.5 mmol).
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:18]1([N:24]2[C:28]3[CH:29]=[N:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]2[CH:33](O)[CH3:34])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C(Cl)Cl>[N:15]([CH:33]([C:25]1[N:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH3:34])=[N+:16]=[N-:17]
Reactant: CC(O)c1nc2ccncc2n1-c1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(N=[N+]=[N-])c1nc2ccncc2n1-c1ccccc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 165.2 %

Procedure:
Diphenylphosphoryl azide (1.12 g, 4.06 mmol) and then diisopropyl azadicarboxylate (1.37 g, 6.77 mmol) were added to a stirred solution of 1-(3-phenyl-3H-imidazo[4,5-c]pyridin-2-yl)ethanol (0.81 g, 3.39 mmol) and triphenylphosphine (1.78 g, 6.77 mmol) in dioxane (50 mL) at 0° C. under nitrogen. The reaction mixture was stirred at 20° C. for 16 h then diluted with DCM to dissolve all the material. This was loaded onto an Isolute® SCX-2 cartridge and washed with methanol and the product eluted with 2M NH3/MeOH then concentrated in vacuo. The residue was purified by chromatography (SiO2 0-4% (2M ammonia in methanol) in DCM) to give the title compound as a colourless oil (1.48 g, contaminated with triphenylphosphine oxide). LCMS (method H): Rt 1.79 min, [M+H]+ 265.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:56][C:57]([CH3:62])([CH2:60][OH:61])[CH2:58][OH:59]>CN(C=O)C>[OH:59][CH2:58][C:57]([NH:56][C:30]([C:26]1[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=3)[NH:28][C:27]=1[CH3:29])=[O:31])([CH2:60][OH:61])[CH3:62]
Reactant: CC(N)(CO)CO
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NC(C)(CO)CO
Temperature: 25 °C
Reaction time: 192 h

Procedure:
To a mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.19 mmol), HOBt (31 mg, 1.2 eq.), EDAC.HCl (44 mg, 1.2 eq.) and 2-amino-2-methyl-propane-1,3-diol (49 mg, 1.1 eq.) in DMF (2 mL) was added TEA (0.066 mL, 2.5 eq.). After stirring at rt for 8 days, the reaction was concentrated, diluted with DCM and then added solid sodium bicarbonate. After stirring at rt for 15 mins, the resulted suspension was loaded onto a silica gel column to give the titled compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:24][C:23]1[C:18]([N:14]2[CH2:15][CH2:16][CH:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:9])[CH2:12][CH2:13]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Clc1cccnc1Cl
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1cccc(Cl)c1)C1CCN(c2ncccc2Cl)CC1
Yield: 34.4 %

Procedure:
Using the procedure from Example 7A, 4-[(3-chlorophenyl)sulfonyl]piperidine (150 mg, 0.58 mmol) was reacted with 2,3-dichloropyridine (173 mg, 1.16 mmol), DIEA (0.3 ml, 1.74) and 1,4-dioxane (0.2 ml) to afford the title compound (74 mg), a beige solid, in 34% yield.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][NH:9][CH:10](C(O)=O)[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O>Cl.CO>[F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][NH:9][CH2:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1NCCc2c1[nH]c1cc(F)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Fc1ccc2c3c([nH]c2c1)CNCC3
Yield: 79 %

Procedure:
7-fluoro-2,3,4,9-tetrahydro-1H-β-carboline-1-carboxylic acid (5 g, 21.36 mmol) was suspended in 130 ml of 3N HCl in a 500 ml round-bottom flask and refluxed overnight (16 hr) with stirring. Upon cooling, a light brown solid precipitated out, which was collected by filtration and washed with H2O. The salt obtained by filtration above was then dissolved in hot methanol (200 ml) and treated with 3M K2CO3 (5-10 ml) such that the pH is around 9. 100 ml of H2O was added to this mixture, which was then allowed to stir at RT. The methanol was evaporated on a rotary evaporator to give a white aqueous suspension of the desired free base, which was collected by filtration (3.2 g, 79% yield). 1H-NMR (300 MHz, methanol-d4): δ 2.73 (t, 2H), 3.11 (t, 2H), 3.94 (s, 2H), 6.73 (m, 1H), 6.94 (m, 1H), 7.30 (dd, 1H). Retention Time (LC, method: ammonium acetate standard): 1.25 min. MS (M+H+): 191.1.
Reaction SMILES: [CH3:1][CH:2]([CH3:35])[C@H:3]([NH:11][CH2:12][CH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[O:25][C:26]=2[CH3:27])[CH2:15]1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:36](=[O:39])([O-])[O-:37].[Na+].[Na+]>C(Cl)Cl>[CH3:21][O:20][C:16]1[CH:17]=[CH:18][C:19]([O:37][C:36]([N:11]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=4)[O:25][C:26]=3[CH3:27])[CH2:15]2)[C@@H:3]([CH:2]([CH3:35])[CH3:1])[C:4]([O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:5])=[O:39])=[CH:14][CH:15]=1
Reactant: Cc1cccc(-c2nc(CO[C@@H]3CCC[C@H](CCN[C@H](C(=O)OC(C)(C)C)C(C)C)C3)c(C)o2)c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(OC(=O)N(CC[C@H]2CCC[C@@H](OCc3nc(-c4cccc(C)c4)oc3C)C2)[C@H](C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
130 mg of tert-butyl (S)-3-methyl-2-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-yl-methoxy)cyclohexyl]ethylamino}butyrate are dissolved in 1 ml of methylene chloride, 2 ml of a sat. sodium carbonate solution are added and the mixture is cooled to 0° C., an excess of the acid chloride is then added and the mixture is stirred at RT for 1 h. The entire reaction solution is applied to a kieselguhr cartridge and the cartridge is washed with 20 ml of methylene chloride. The solvent is removed under reduced pressure. This gives 0.1 g of tert-butyl (S)-2-((4-methoxyphenoxycarbonyl)-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}amino)-3-methylbutyrate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 2 h
Yield: 94.8 %

Procedure:
1-(Bromomethyl)-4-nitrobenzene (1.08 g, 5.00 mmol) was added to a vigorously stirred mixture of tert-butyl piperazine-1-carboxylate (1.02 g, 5.50 mmol) and sodium carbonate (0.583 g, 5.50 mmol) in DMF (5 mL) at room temperature and the resulting mixture stirred for two hours. Water (25 mL) was added, and the resulting suspension was allowed to stand for five minutes then filtered. The collected solid was washed with water (25 mL) and air-dried to give the title compound (I92) (1.523 g, 95% yield); 1H NMR (400 MHz, CDCl3) δ 8.32-8.10 (m, 2H), 7.51 (d, J=8.8 Hz, 2H), 3.59 (s, 2H), 3.52-3.39 (m, 4H), 2.43-2.34 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 4.58 min, m/z 266.1 [M-tBu+2H]+, 222.1 [M-Boc+2H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:20]([O:26][CH2:27]Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].C(OCC)C>CN(C=O)C>[CH3:12][N:11]([CH:10]=[N:9][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH2:27][O:26][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[N:4]=1)[CH3:13]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CN(C)C=Nc1nc(O)ncc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)C=Nc1nc(OCOC(=O)C(C)(C)C)ncc1F
Yield: 9.3 %

Procedure:
N′-(5-Fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (100 mg, 0.54 mmol), cesium carbonate (196 mg, 0.60 mmol), and chloromethyl pivalate (90 mg, 0.6 mmol) were shaken together in DMF (3 mL) at ambient temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and water, dried over magnesium sulfate, filtered and evaporated to yield a colorless oil which was treated with diethyl ether (3-4 mL) to produce a solid. The solid was removed and the ether solution was placed onto a silica gel column and eluted with ethyl acetate in petroleum ether (0-50% gradient) to isolate 14 mg, 0.05 mmol (9%) of the title compound as a white solid: mp 86-88° C.; 1H NMR (CDCl3) δ 8.73 (s, 1H), 8.06 (d, J=2.6 Hz, 1H), 6.04 (s, 2H), 3.20 (s, 3H), 3.18 (s, 3H), 1.16 (s, 9H); HPLC-MS (ESI) m/z 299 (M+H)+.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5].[CH3:20][Mg]Br>C1COCC1>[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:7]1)(=[O:5])[CH3:20]
Reactant: CON(C)C(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (8.17 g, 30 mmol) was dissolved in THF (100 mL) and cooled to 0° C., methylmagnesium bromide (3.0 M in Et2O, 11 mL, 33 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. After quench with saturated NH4Cl, the reaction mixture was extracted with EtOAc, dried and concentrated. The crude product was column purified with mixture of hexane and EtOAc to give tert-butyl 3-acetylpiperidine-1-carboxylate (4.8 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].C(=O)(O)[O-].[K+].[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>CN(C=O)C>[OH:21][CH2:20][CH:19]1[O:11][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=2[O:8][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Reactant: BrCC1CO1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)OC(CO)CO2
Temperature: 90 °C
Reaction time: 17 h
Yield: 3.5 %

Procedure:
17.6 g 4-nitrocatechol and 11.0 g potassium bicarbonate were stirred in 200 ml DMF at 10° C. 13.99 g epibromohydrin in 10 ml DMF were added dropwise and stirring was continued at 60° C. for another 17 hrs. DMF was evaporated and the residue diluted with 50 ml water and extracted with ethyl acetate. The combined organic phases were washed with caustic soda and water, dried and evaporated. The crude oily product was heated to 90° C. with 200 ml toluene and the supernatant decanted from insoluble parts. After cooling to RT the solution is again decanted from insoluble oils and left at RT for 3 d. A first crop of 0.75 g crystalline title product was obtained. The mother liquor was evaporated and the residue dissolved in 20 dichloromethane at RT. Seeding and chilling to 0° C. yielded another 2.78 g crystalline title product.