Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:21]1[N:25]([CH3:26])[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])=[N:23][N:22]=1)([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]([O:18]CC)=[O:17])[N:12]=2)=[CH:7][CH:6]=1)[CH3:3].[OH-].[Na+].O.Cl>C(O)C>[CH3:3][C:2]([C:21]1[N:25]([CH3:26])[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])=[N:23][N:22]=1)([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]([OH:18])=[O:17])[N:12]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CCOC(=O)c1noc(-c2ccc(OC(C)(C)c3nnc(-c4ccccc4C(F)(F)F)n3C)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(-c2nc(C(=O)O)no2)cc1
Reaction time: 0.08 h
Yield: 87.4 %

Procedure:
Ethyl 5-[4-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,2,4-oxadiazole-3-carboxylate (251 mg) was suspended in ethanol (5 ml) and a 1M aqueous sodium hydroxide solution (1 ml) was added thereto, followed by stirring for 5 minutes. Water and 1M hydrochloric acid were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting solid was washed with ethyl acetate to obtain 5-[4-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,2,4-oxadiazole-3-carboxylic acid (207 mg), as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][CH2:22][CH2:23]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:23][CH2:22][Cl:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2OCCCl)CC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A solution of 4-(2-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester Compound 2a (0.67 g, 2.42 mmol), toluene-4-sulfonic acid 2-chloro-ethyl ester Compound 2b (1.13 g, 4.84 mmol), Cs2CO3 (1.60 g, 4.84 mmol) and DMF (20 mL) were heated and stirred at 50° C. overnight (18 hrs). The excess DMF was removed under reduced pressure and the white residue was mixed with AcOEt (100 mL), washed with water and dried over Na2SO4. The filtered dry solution was evaporated and the product was purified via flash chromatography (silica gel, 25% AcOEt/hexane) to provide 4-[2-(2-chloro-ethoxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester Compound 2c (0.78 g, 95%) as a colorless sticky oil. LC-MS (3.943 min.) m/z 362.1 (M+Na+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([C:14]#[C:15][CH:16]([OH:18])[CH3:17])=[CH:4][N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:14]=[C:15]([CH:16]([OH:18])[CH3:17])[N:8]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:6]=2[N:7]=1
Reactant: CCC(CC)Nc1nc(Cl)ncc1C#CC(C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)n1c(C(C)O)cc2cnc(Cl)nc21
Yield: 52.7 %

Procedure:
To a solution of 4-[2-chloro-4-(1-ethyl-propylamino)-pyrimidin-5-yl]-but-3-yn-2-ol (0.23 g, 0.85 mmol) in THF (0.5 mL) is added 1M TBAF (4.3 mL). The reaction mixture is heated at reflux for 16 h, diluted with water, extracted with EtOAc. The extracts are dried over Na2SO4 and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, EtOAc/Hexane 1:3) to provide 0.12 g of 1-[2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-ethanol.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([O:31][C:32]([O:34][CH2:35]I)=[O:33])[CH2:28][CH2:29][CH3:30]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:35][O:34][C:32]([O:31][CH2:27][CH2:28][CH2:29][CH3:30])=[O:33])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CCCCOC(=O)OCI
Agent: [Na+]
Product: CCCCOC(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 100.5 %

Procedure:
In the same manner as in Example 81, 223 mg of the title compound was prepared from 175 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 164 mg of (butan-1-yl)oxycarbonyloxymethyl iodide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[Sn:13](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17].[Cl-].[NH4+]>C1COCC1>[CH2:22]([Sn:13]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:18][CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 2-bromopyridine (XCVI) (10 g, 63 mmol, 1.00 eq) in THF (150 mL) was added n-BuLi (25.3 mL, 63 mmol, 1.00 eq) and the mixture was stirred at −70° C. for 30 min under nitrogen atmosphere. Then n-Bu3SnCl (21.7 g, 67 mmol, 1.06 eq) was added and the mixture was stirred at the same temperature for another 2 h. Saturated ammonium chloride solution (150 mL) was added to the solution and extracted with ethyl acetate (150 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford the crude 2-(tributylstannyl)pyridine (XCVII) (25.9 g, 63 mmol, 100% yield) as a yellow oil. The crude product was used without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.CC1(C)C(C)(C)OB([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)O1>>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:10]=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:35]3[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)cc1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)cc1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.1) (0.22 g, 0.5 mmol) and commercially available 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a brown solid (0.032 g, 14%). MS (ISP) 450.1 [(M+H)+]; mp 270° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[C:11]([NH:14][CH2:15][C:16]([OH:18])=[O:17])(=O)[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C.[Na+].C(=O)([O-])[O-]>C(OC(=O)C)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])/[CH:5]=[C:15]1\[N:14]=[C:11]([CH3:12])[O:18][C:16]\1=[O:17]
Reactant: CC(=O)NCC(=O)O
Reactant: O=Cc1ccc(O)c(F)c1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC1=N/C(=C\c2ccc(O)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 85 %

Procedure:
Commercially available 3-fluoro-4-hydroxybenzaldehyde (14 g, 0.1 mol), N-acetylglycine (14 g, 0.12 mol), sodium carbonate (10.6 g, 0.1 mol) and sodium acetate (16.6 g, 0.2 mol) were mixed at r.t. in 60 mL of acetic anhydride and stirred at moderate heating until full dissolution of carbonate. Then the mixture was refluxed for 2 hours, cooled down to r.t. and diluted with water (200 mL). The precipitate was filtered and used without further purification: 22.34 g. (Yield ˜85%)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[N:5]([CH3:14])[C:4](=[O:15])[CH:3]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>C(#N)C>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:1][C:2]2[C:11]3[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=3[N:5]([CH3:14])[C:4](=[O:15])[CH:3]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cn1cnc2c(c(O)cc(=O)n2C)c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2cc(=O)n(C)c3ncn(C)c(=O)c23)cc1
Temperature: 110 °C

Procedure:
5-hydroxy-3,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (compound 1C, 125 mg, 0.60 mmol, 1 eq), p-toluenesulfonyl chloride (138 mg, 0.72 mmol, 1.2 eq) and triethylamine (126 μl, 0.90 mmol, 1.5 eq) were dissolved in acetonitrile (2 ml). The mixture was heated at reflux (oil bath at 110° C.) for 3 hours to yield 3,8-dimethyl-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzenesulfonate (compound 1D). The product was confirm by LC-MS. Solvent was removed in vacuo and the crude product 3,8-dimethyl-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzenesulfonate used in the following reaction.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([OH:8])[C@@H:6]([OH:9])[CH:5]([OH:10])[O:4][C@@H:3]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[O:21]=[S:22]1(=[O:69])[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH:30][C@:31]23[CH2:65][CH2:64][C@@H:63]([C:66]([CH3:68])=[CH2:67])[C@@H:32]2[C@@H:33]2[C@@:46]([CH3:49])([CH2:47][CH2:48]3)[C@@:45]3([CH3:50])[C@@H:36]([C@:37]4([CH3:62])[C@@H:42]([CH2:43][CH2:44]3)[C:41]([CH3:52])([CH3:51])[C:40]([C:53]3[CH:61]=[CH:60][C:56]([C:57](O)=[O:58])=[CH:55][CH:54]=3)=[CH:39][CH2:38]4)[CH2:35][CH2:34]2)[CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>O1CCOCC1>[O:69]=[S:22]1(=[O:21])[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH:30][C@:31]23[CH2:65][CH2:64][C@@H:63]([C:66]([CH3:68])=[CH2:67])[C@@H:32]2[C@@H:33]2[C@@:46]([CH3:49])([CH2:47][CH2:48]3)[C@@:45]3([CH3:50])[C@@H:36]([C@:37]4([CH3:62])[C@@H:42]([CH2:43][CH2:44]3)[C:41]([CH3:52])([CH3:51])[C:40]([C:53]3[CH:54]=[CH:55][C:56]([C:57]([O:10][C@H:5]5[O:4][C@H:3]([C:11]([O:13][CH2:14][C:15]6[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=6)=[O:12])[C@@H:2]([OH:1])[C@H:7]([OH:8])[C@H:6]5[OH:9])=[O:58])=[CH:60][CH:61]=3)=[CH:39][CH2:38]4)[CH2:35][CH2:34]2)[CH2:24][CH2:23]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(OCc1ccccc1)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O[C@H]7O[C@H](C(=O)OCc8ccccc8)[C@@H](O)[C@H](O)[C@H]7O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
A mixture of (2S,3S,4S,5R)-benzyl 3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylate (61.7 mg, 0.217 mmol), 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (100 mg, 0.145 mmol), HATU (88 mg, 0.232 mmol) and N-methylmorpholine (0.048 mL, 0.434 mmol) in dioxane (3 mL) was stirred overnight at room temperature. The reaction mixture was filtered, the clear solution was purified by prep HPLC with acetonitrile/water/ammonium acetate to provide the desired product as white solid (20 mg, 14%). LCMS: m/e 957.7 (M+H)+, 2.36 min (method 6). 1H NMR (500 MHz, Acetic) δ 8.05 (d, J=8.2 Hz, 2H), 7.58-7.14 (m, 7H), 5.95 (d, J=7.6 Hz, 1H), 5.38 (d, J=4.6 Hz, 1H), 5.26 (s, 2H), 4.84 (s, 1H), 4.74 (s, 1H), 4.30 (d, J=9.5 Hz, 1H), 4.05-3.78 (m, 3H), 3.46 (d, J=11.9 Hz, 1H), 3.38-3.22 (m, 6H), 3.20-3.11 (m, 3H), 3.07 (br. s., 2H), 2.95 (dt, J=10.8, 5.5 Hz, 1H), 2.42-1.01 (m, 22H), 1.77 (s, 3H), 1.30 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.BrN1[C:32](=[O:33])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C[O-].[Na+]>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH2:18][O:33][CH3:32])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: COCc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(F)cc2OC)o1
Temperature: 70 °C
Reaction time: 4 h
Yield: 1.2 %

Procedure:
To a solution of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (1.95 g, 5.56 mmol) in carbon tetrachloride (20 ml) was added N-bromo succinimide (990 mg, 5.56 mmol) and 2,2′-azobis(2-methylpropionitrile) (46 mg, 0.28 mmol) and the reaction mixture was stirred for 4 h at 70° C. Further 2,2′-azobis(2-methylpropionitrile) (46 mg, 0.28 mmol) was added and stirring was continued for another 14 h at 70° C. N-Bromo succinimide (378 mg, 2.12 mmol) was added and the mixture stirred for another 4 h at 90° C. After the reaction mixture was cooled to 0° C. the suspension was filtered off and was washed with dichloromethane (30 mL) and aqueous sodium hydrogencarbonate (1 N). It was extracted with dichloroemthane and dried over sodium sulfate resulting in crude material (1.66 g). A part of this light brown solid (200 mg) was dissolved in tetrahydropyran (2 mL), sodium methoxide (30% in methanol, 0.43 ml, 2.32 mmol) was added and the resulting mixture was stirred for 1 h at ambient temperature. It was diluted with ethyl acetate (20 mL) and washed aqueous ammonium chloride (saturated). The aqueous layers were extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20) afforded the title compound (25 mg, 14%) as a white solid. MS: m/e=382.3 [M+H]+.
Reaction SMILES: [CH:1]([OH:14])([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.[Br:15][CH2:16][CH2:17][CH2:18]O.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH2:18][CH2:17][CH2:16][Br:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: OC(c1ccccc1)c1ccccc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: BrCCCOC(c1ccccc1)c1ccccc1
Yield: 84.5 %

Procedure:
In a reactor fitted with a water trap, a mixture of benzhydrol (5.0 g), 3-bromo-1-propanol (3.8 g), camphor-10-sulfonic acid (1.0 g), and toluene (80 mL) was refluxed for 2 hours. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to provide 7.0 g of the title compound. Yield 85%.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[Br:10]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([NH:3][CH2:1][CH3:2])=[CH:5][CH:6]=1
Reactant: CCNc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CCNc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 103.4 %

Procedure:
To a solution of N-ethylaniline (10.0 g) in DMF (50 ml) was added dropwise at room temperature a solution of N-bromosuccinimide (14.69 g) in DMF (100 ml), and the mixture was stirred at room temperature for 19 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give pale yellow oil of 4-bromo-N-ethylaniline (17.08 g).
Reaction SMILES: C([N:8]1[C:15]2[CH:14]3[CH2:16][CH:13]3[CH2:12][C:11]=2[C:10]([C:17]2[N:18]=[N:19][NH:20][N:21]=2)=[N:9]1)C1C=CC=CC=1.CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[N:21]1[NH:20][N:19]=[N:18][C:17]=1[C:10]1[NH:9][N:8]=[C:15]2[C:11]=1[CH2:12][C@H:13]1[CH2:16][C@H:14]12
Reactant: c1ccc(Cn2nc(-c3nn[nH]n3)c3c2C2CC2C3)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: C1c2c(n[nH]c2-c2nn[nH]n2)[C@@H]2C[C@H]12

Procedure:
Air was bubbled through a stirring solution of 2-benzyl-4-(2H-tetrazol-5-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene (10.4 g, 37.4 mmol) and KOt-Bu (374 mL of a 1M solution in THF, 374 mmol) in DMSO (300 mL) for 20 h at rt. The remaining THF was removed in vacuo and the reaction was acidified to pH=2 by the addition of HCl (3M aq). The mixture was concentrated in vacuo to near dryness. The residue was dissolved in HCl (1N aq., 250 mL) and extracted with EtOAc (5×250 mL). The organics were dried over MgSO4, filtered, and concentrated. The product was purified and converted to the ammonium salt by loading material (as a solution in MeOH) on to a column containing Bondesil SCX SPE resin (˜250 g). The column was flushed with MeOH (200 mL) to remove unbound impurities. The product was eluted using 2N NH3/MeOH (approx. 200 mL). Concentration of the basic eluant yielded the ammonium salt of Compound 4 as a white solid. 1H NMR (400 MHz, MeOD): δ 3.02 (1H, dd, J=16.4, 6.0 Hz), 2.90 (1H, d, J=16.0 Hz), 2.19 (2H, m), 1.17 (1H, m), 0.33 (1H, m). HPLC/MS: Discovery® C18 column (5μ, 50×2.1 mm), 5% v/v CH3CN (containing 1% v/v TFA) in H2O (containing 1% v/v TFA) gradient to 99% v/v CH3CN in H2O, 0.75 mL/min, tr=1.21 min, ESI+=189.0 (M+H). [α]25D+35.7 (c 0.39, MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[F:18].[Al+3].[Cl-].[Cl-].[Cl-].Cl.CCOC(C)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[F:18]
Reactant: COc1ccc(C(=O)c2ccc(Br)c(F)c2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(O)cc1)c1ccc(Br)c(F)c1
Temperature: 25 °C
Yield: 112.1 %

Procedure:
To a stirred solution of (4-bromo-3-fluorophenyl)[4-(methyloxy)phenyl]methanone (185) (3.20 g, 10.4 mmol) in benzene (80 mL) was slowly added AlCl3 (5.91 g, 44.2 moL., 4.3 eq) via a powder addition funnel under a nitrogen atmosphere at room temperature. The stirred reaction mixture was heated at reflux for 3 h under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and then poured onto a mixture of 1 N HCl (150 mL) and ice (300 g). The quenched reaction mixture was transferred to a separatory funnel and EtOAc (200 mL) added. The organic phase was separated and the aqueous phase was extracted with EtOAc. The organic phase washed with brine (200 mL), dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give 3.44 g of a brown solid. Crystallization from toluene yielded 2.68 g (88%) of the title compound 186 as a brown crystalline solid. 1H NMR (400 MHz, DMSO-d6): δ 6.91 (d, J=8.7 Hz, 2 H), 7.43 (d, J=8.2 Hz, 1 H), 7.61 (d, J=8.2 Hz, 1 H), 7.69 (d, J=8.7 Hz, 2 H), 7.89 (t, J=7.1 Hz, 1H), 10.54 (s, 1 H).
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].C(=O)([O-])O.[Na+].[Cl:19][C:20]([Cl:27])([Cl:26])[CH2:21][O:22][C:23](Cl)=[O:24]>O>[Cl:19][C:20]([Cl:27])([Cl:26])[CH2:21][O:22][C:23]([NH:5][C@@H:4]1[C@@H:6]([OH:7])[C@H:8]([OH:9])[C@@H:10]([CH2:12][OH:13])[O:11][CH:3]1[OH:2])=[O:24]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O)OCC(Cl)(Cl)Cl
Reaction time: 11 h

Procedure:
Thirty grams of D-glucosamine hydrochloride was dissolved in 500 ml of water, and 30.0 g of sodium hydrogen carbonate was added thereto, followed by cooling in an ice bath. To the cooled solution was added 27.5 ml of trichloroethoxycarbonyl chloride, and the mixture was stirred under ice-cooling for 2 hours and then at room temperature for 11 hours. The precipitate was collected by filtration, washed successively with water and diethyl ether, and recrystallized from 95% ethanol to obtain 42.3 g of N-trichloroethoxycarbonyl-D-glucosamine (Compound A) having a melting point of 183° to 184° C. (with decomposition).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.[C:16](=O)(O)[O-].[Na+]>CO>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: O=C([O-])O
Reactant: Cc1cc(C(=O)O)ccc1O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(O)c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-hydroxy-3-methylbenzoic acid (Matrix Scientific, 1 g) was dissolved in methanol and cooled in an ice-bath under a nitrogen atmosphere. Thionyl chloride (5 mL) was added slowly. The reaction was stirred at 0° C. for one hour and then warmed to room temperature and stirred for 16 hours. Solid sodium bicarbonate was then added to neutralize the acid and the mixture was evaporated to dryness. The residue was partitioned between ethyl acetate (75 mL and water (100 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to afford 1.0 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[N:7]([CH3:16])[CH2:8][CH:9]([CH2:13][CH2:14]Cl)[CH2:10][C:11]=2[N:12]=1.[NH:18]1[CH2:21][CH2:20][CH2:19]1.[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24]>>[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24].[N:18]1([CH2:14][CH2:13][CH:9]2[CH2:8][N:7]([CH3:16])[C:6](=[O:17])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[N:12][C:11]=3[CH2:10]2)[CH2:21][CH2:20][CH2:19]1
Reactant: CN1CC(CCCl)Cc2nc(Cl)ccc2C1=O
Reactant: C1CNC1
Agent: O=C(O)C(=O)O
Product: CN1CC(CCN2CCC2)Cc2nc(Cl)ccc2C1=O

Procedure:
Following the procedure of Example 21, 2-chloro-8-(2-chloroethyl)-6,7,8,9-tetrahydro-6-methyl-5H-pyrido[3,2-c]azepin-5-one and azetidine are reacted and the free base of the title is isolated and reacted with oxalic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:16][O:17][NH:18][CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:16][O:17][N:18]([CH3:19])[C:10](=[O:12])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:14])[CH3:13]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 17 h
Yield: 79.2 %

Procedure:
2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (6.62 g, 32.6 mmol), O,N-dimethylhydroxylamine hydrochloride (3.50 g, 35.8 mmol), and HATU (14.86 g, 39.1 mmol) were combined in DMF (100 mL). To this solution was added Hunig's Base (17.07 mL, 98 mmol). The reaction was stirred for overnight (17 hours). The reaction was then concentrated under vacuum and the residue was diluted with EtOAc (300 mL) and washed with water (2×80 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography (10-50 percent EtOAc-Hexanes) to afford the desired product as a white solid (6.36 g). LCMS m/z 247.2 (M+H)+, Rt 0.61 min.