Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:34]1[N:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][N:35]=1)[C:9]1[CH:10]=[C:11]([C:16]2[S:20][C:19]([C:21]3([O:32][CH3:33])[CH2:26][CH2:25][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:18][CH:17]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[CH3:33][O:32][C:21]1([C:19]2[S:20][C:16]([C:11]3[CH:10]=[C:9]([NH:8][C:34]4[N:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][N:35]=4)[CH:14]=[C:13]([CH3:15])[CH:12]=3)=[CH:17][N:18]=2)[CH2:22][CH2:23][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: CCOC(=O)C1CCC(OC)(c2ncc(-c3cc(C)cc(N(C(=O)OC(C)(C)C)c4nccc(C(F)(F)F)n4)c3)s2)CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CCC(OC)(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1

Procedure:
To the product of Step 1 (0.15 g, 0.243 mmol) in dichlormethane (2 mL) was added trifluoroacetic acid (1.48 g, 12.98 mmol) and the reaction was stirred until complete. The reaction was diluted with water and the mixture extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate; filtered and concentrated to give ethyl 4-methoxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate. MS ESI: [M+H]+ m/z 521.2.
Reaction SMILES: C([CH:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)C1C=CC=CC=1.[N+:14]([O-:17])([O-])=[O:15].[K+].I[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1>FC(F)(F)C(O)=O>[N+:14]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:12]2[O:11][C:10](=[O:13])[NH:9][CH2:8]2)=[CH:22][CH:21]=1)([O-:17])=[O:15]
Reactant: O=C1NC(Cc2ccccc2)CO1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc(I)cc1
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCC(Cc2ccc([N+](=O)[O-])cc2)O1
Yield: 495.1 %

Procedure:
4-benzyl-2-oxazolidinone (5 g, 28 mmol), potassium nitrate (2.9 g, 29 mmol)and p-iodotoluene (0.5 g, 2 mmol) were stirred in trifluoracetic acid (50 ml) overnight. The mixture was then poured onto ice and extracted with ethyl acetate. This was washed with sodium bicarbonate solution, dried (MgSO4) and evaporated. Flash chromatography (70:30 ethyl acetate/hexane)gave the product (2.2 g, 35%) Mpt 150°-151° C., MS(ES)223 (M+1)+
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:15])=[CH:6][CH:7]=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].[Br:16]Br>C(O)(=O)C.O>[Br:16][C:7]1[CH:6]=[C:5]([CH3:15])[C:4]([O:3][CH2:1][CH3:2])=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1ccc(C)c(OCC)c1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(OCC)c(C)cc1Br
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of ethyl 5-ethoxy-4-methylbenzoate (500 mg, 2.40 mmol) in acetic acid (10 mL) and water (10 mL) at room temperature was added bromine (385 mg, 2.40 mmol). The resulting reaction mixture was stirred at 60° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with hexanes/ether (80/20). Layers were separated and the organic layer was washed with saturated Na2CO3, brine, dried over Na2SO4, filtered and concentrated. The residue was purified on a silica gel column eluting with 5 to 10% EtOAc in hexanes to yield the title intermediate (660 mg, 2.23 mmol) as light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([NH:14][CH3:15])[CH3:13]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:14]([CH2:12][CH3:13])[CH3:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCNC
Solvent: ClCCl
Product: CCN(C)S(=O)(=O)c1ccc(Br)cc1
Yield: 27.7 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and N-Ethyl-N-methylamine (0.33 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-ethyl-N-methylbenzenesulfonamide (0.12 g, 28%) was provided after purification. MS (ESI) m/z 278. HPLC purity 99.2% at 210-370 nm, 8.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 mm.
Reaction SMILES: [ClH:1].C1(C2C=CC([C:14]3[S:15][C:16](N)=[C:17]([C:19]4[CH:20]=[C:21]([C:26]([NH2:28])=[NH:27])[S:22][C:23]=4[S:24][CH3:25])[N:18]=3)=CC=2)CCCCC1.Br.[CH:31]1([C:37]2[CH:42]=[CH:41][C:40]([NH:43]C3SC=C(C4C=C(C(OC)=S)SC=4C)N=3)=[CH:39][CH:38]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[ClH:1].[CH:31]1([C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:14]3[S:15][CH:16]=[C:17]([C:19]4[CH:20]=[C:21]([C:26]([NH2:28])=[NH:27])[S:22][C:23]=4[S:24][CH3:25])[N:18]=3)=[CH:41][CH:42]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CSc1sc(C(=N)N)cc1-c1nc(-c2ccc(C3CCCCC3)cc2)sc1N
Reactant: COC(=S)c1cc(-c2csc(Nc3ccc(C4CCCCC4)cc3)n2)c(C)s1
Agent: Br
Agent: Cl
Product: CSc1sc(C(=N)N)cc1-c1csc(Nc2ccc(C3CCCCC3)cc2)n1
Yield: 47 %

Procedure:
4-{2-(4-Cyclohexylphenyl)amino(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine hydrochloride: Methyl 4-{2-[(4-cyclohexylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide (31.1 mg, 0.059 mmol) was treated as described in Example 154, step (b) to give 12.8 mg (47% yield) of 4-{2-[(4-cyclohexylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine hydrochloride. 1H NMR (DMSO-d6, 300 MHz) δ 1.33-1.40 (m, 5H), 1.68-1.79 (m, 5H), 2.44 (m, 1H), 2.73 (s, 3H), 7.12 (s, 1H), 7.18 (d, 2H, J=8.7 Hz), 7.68 (d, 2H, J=8.7 Hz), 8.47 (s, 1H), 8.85 (bs, 2H), 9.32 (bs, 2H), 10.28 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C21H24N4S3, 428.64 (M+H), found 429.2.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[I:11].[OH-].[K+].[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17].Cl>CS(C)=O.O>[I:11][C:3]1[C:2]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])=[N:7][CH:6]=[C:5]([CH:4]=1)[C:8]([OH:10])=[O:9]
Reactant: OCC(F)(F)F
Reactant: O=C(O)c1cnc(Cl)c(I)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cnc(OCC(F)(F)F)c(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
6-Chloro-5-iodo-3-pyridinecarboxylic acid (CAN 59782-87-5, 4.7 g, 16.6 mmol) was dissolved in DMSO (49.5 ml). Potassium hydroxide pellets (2.79 g, 49.7 mmol) and 2,2,2-trifluoroethanol (2.16 g, 1.55 ml, 21.6 mmol) were added slowly at room temperature under argon. The reaction mixture was stirred for 2 h at rt; water (35 mL) was added and the mixture was cooled to 0-5° C. Concentrated HCl solution (8 mL) was added drop by drop and the precipitated solid was collected, washed with cold water and dried. The crude material was purified by flash chromatography (silica gel, 150 g, 0% to 20% i-propyl acetate in n-heptane +10% of acetic acid) to give the title compound (1.6 g, 28%) as colorless solid; MS (ESI) 345.7 (M−H)−.
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:34]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35]3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)[C:13]=12>ClCCl>[O:27]([C:24]1[CH:23]=[CH:22][C:21]([C:20]2[C:13]3[C:14](=[N:15][CH:16]=[N:17][C:12]=3[NH2:11])[N:18]([CH:34]3[CH2:38][CH2:37][NH:36][CH2:35]3)[N:19]=2)=[CH:26][CH:25]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
A mixture of trifluoroacetic acid/dichloromethane (20:80, 8 mL) was added to a solution of tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyrrolidinecarboxylate (240 mg, 0.508 mmol) in dichloromethane (1 mL) at 0° C. After 15 minutes, the ice-bath was removed and the reaction mixture was stirred at room temperature for 5 hours. Solvents were then evaporated and the residue was dissolved in ethyl acetate. Saturated sodium bicarbonate was added to adjust the pH to about 8. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated give 3-(4-phenoxyphenyl)-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.157 mg, 91%). 1H NMR (DMSO-d6) δ 1.99-2.21 (m, 2H), 2.94 (m, 1H), 3.04-3.23 (m, 3H), 5.31 (m, 1H), 7.14 (m, 5H), 7.44 (m, 2H), 7.67 (m, 2H), 8.24 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][N:11]3[CH:18]=2)=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C(N(CC)CC)C>C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([NH:20][OH:21])=[NH:17])=[CH:12][N:11]3[CH:18]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc2nc(-c3ccc(F)cc3)cn2c1
Reactant: NO
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: N=C(NO)c1ccc2nc(-c3ccc(F)cc3)cn2c1

Procedure:
2-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridine-6-carbonitrile (example 52, 537 mg, 2.26 mmol), hydroxylamine hydrochloride (943.8 mg, 13.58 mmol) and triethylamine (2.19 ml, 15.84 mmol) were stirred in 40 ml of isopropanol at 90° C. for 5 hours. The solvent was removed in vacuo and water was added. The solid was filtered, washed with diluted hydrochloric acid, water and was dried. Yield: 610 mg, 99%. MS: M+H+=271.03.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Br:10])=[CH:8][C:7]([CH3:11])=[CH:6][N:5]=1.Cl[C:13]1[C:14](=[O:29])[N:15]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH:16]=[C:17]([Cl:19])[N:18]=1>O1CCCC1>[Br:10][C:9]1[C:4]([NH:3][C:13]2[C:14](=[O:29])[N:15]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH:16]=[C:17]([Cl:19])[N:18]=2)=[N:5][CH:6]=[C:7]([CH3:11])[CH:8]=1
Reactant: COc1ccc(Cn2cc(Cl)nc(Cl)c2=O)cc1
Reactant: Cc1cnc(N)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(Cl)nc(Nc3ncc(C)cc3Br)c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
An oven dried, 2 L, three necked round bottom flask was charged with NaH (60% dispersion in oil, 11.9 g, 298.11 mmol), suspended in anhydrous tetrahydrofuran (500 mL) and cooled in an ice bath. To the cooled mixture, was added the solution of 2-amino-3-bromo-5-methylpyridine (39.4 g, 210.433 mmol, 150 mL of anhydrous THF). The ice bath was removed and the reaction was allowed to warm to room temperature over a 1 h period. Via addition funnel, the solution of 3,5-dichloro-1-(4-methoxybenzyl)pyrazin-2(1H)-one (50.0 g, 175.36 mmol, 150 mL anhydrous tetrahydrofuran) was added in a rapid, drop-wise fashion, attached a reflux condenser and stirred in an oil bath heated at 72° C. (exothermic reaction occurred upon heating). After 3 h, the flask was removed from the oil bath, cooled to room temperature, quenched with isopropanol (15 mL) and BHT (0.075 g), and concentrated in vacuo to a dark crude. Chromatography on silica gel plug with ethyl acetate/DCM (3/97) afforded the desired product as a light tan solid. The mix fractions were combined, concentrated and the desired product was purified by recrystallization in ethyl acetate/diethyl ether and isolated by vacuum filtration. The two solid pools were combined (43 g, 56% yield) and verified by 1H-NMR and analytical LCMS. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.30 (s, 3H) 3.74 (s, 3H) 5.00 (s, 2H) 6.93 (d, J=8.84 Hz, 2H) 7.39 (s, 2H) 7.42 (s, 1H) 8.01 (s, 1H) 8.28 (s, 1H) 9.50 (s, 1H). ESI-MS: m/z 437.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:46][CH2:47][CH2:48][OH:49]>CN(C=O)C.CC(OC)(C)C>[CH2:35]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:11]([CH2:46][CH2:47][CH2:48][OH:49])[CH:12]=1)=[O:7])[CH2:36][CH2:37][CH3:38]
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CCCCN(CCCC)C(=O)c1cn(CCCO)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Temperature: 40 °C
Yield: 30.7 %

Procedure:
To a stirred solution of methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (200 mg, 0.38 mmol) in DMF (8 mL) was added K2CO3 (107 mg, 0.77 mmol) and 3-bromopropanol (54 mg, 0.38 mmol). The reaction mixture was heated at 40° C. for 4 h, cooled to room temperature, diluted with MTBE, and quenched with water. The organic layer was separated and the aqueous layer was extracted with MTBE (3×). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to provide crude product. The crude material was purified by flash chromatography (gradient from 10 to 50% EtOAc/hexanes) to provide the title compound (67 mg, 32%). 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.19-8.15 (m, 1H), 8.04 (dd, J=11.2, 1.6 Hz, 1H), 7.62 (s, 0.5H), 7.55 (s, 0.5H), 7.50-7.46 (m, 1H), 7.25-7.14 (m, 3.5H), 6.94 (d, J=7.2 Hz, 0.5H), 4.84-4.59 (m, 2H), 4.29-4.13 (m, 2H), 3.96 (s, 3H), 3.82-3.70 (m, 2H), 3.50-3.35 (m, 4H), 3.31-2.88 (m, 4H), 1.89-1.87 (m, 2H), 1.55-1.49 (m, 2H), 1.40-1.05 (m, 6H), 0.93-0.88 (m, 3H), 0.74 (t, J=7.2 Hz, 1.5H), 0.65 (t, J=7.2 Hz, 1.5H); MS(ESI+) m/z 575.6 (M+H)+.
Reaction SMILES: CC(C)(O[C:5]([NH:7][C@H:8]([C:28]([O:30][CH3:31])=[O:29])[CH2:9][NH:10][C:11]([O:13][CH2:14][CH:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])=[O:6])C.C1C2C(COC(NC[C@@H](C(OC)=O)N)=O)C3C(=CC=CC=3)C=2C=CC=1.F[C:59](F)(F)[C:60]([OH:62])=O.ClCCl.[Cl:68][C:69]1[CH:77]=[C:76]([C:78]([NH:80][CH2:81][C:82]2[CH:87]=CC=[C:84](O)[CH:83]=2)=[O:79])[CH:75]=[CH:74][C:70]=1C(O)=O.C1C=NC2N(O)N=NC=2C=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.O>[Cl:68][C:69]1[CH:77]=[C:76]([C:78]([NH:80][CH2:81][C:82]2[CH:83]=[CH:84][CH:59]=[C:60]([OH:62])[CH:87]=2)=[O:79])[CH:75]=[CH:74][C:70]=1[C:5]([NH:7][C@H:8]([C:28]([O:30][CH3:31])=[O:29])[CH2:9][NH:10][C:11]([O:13][CH2:14][CH:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])=[O:6]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Reactant: COC(=O)[C@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: COC(=O)[C@@H](N)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of N-[(1,1-dimethylethoxy)carbonyl]-3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine, methyl ester (Example 62; 1.50 g, 3.4 mmol) was converted to crude 3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine, methyl ester (1.30 g, 112% of the theoretical amount) by treatment with trifluoroacetic acid/dichloromethane (1:1). A portion of this material (0.50 g) was combined with 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid (449 mg, 1.5 mmol), HOAT (219 mg, 1.6 mmol) and dicyclohexylcarbodiimide (363 mg, 1.8 mmol) in N,N-dimethylformamide (5 mL) and the reaction mixture was stirred at room temperature over the weekend. Water was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried, filtered, evaporated, and chromatographed (2–10% methanol/dichloromethane) to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine, methyl ester (0.57 g, 62%) as a white solid.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=[O:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:14][C:15]([CH3:20])([CH3:19])[C:16]([N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:1]1)=[O:17]
Reactant: CC(C)(C)C(=O)Cl
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1CCc2c([nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To a solution of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2 g, 11.6 mmol) dissolved in methylene chloride (20 mL) is added 2,2-dimethyl-propionyl chloride (1.42 mL, 11.6 mmol) followed by the addition of triethylamine (1.61 mL, 11.6 mmol). The reaction mixture is stirred at room temperature for 30 minutes. The reaction is quenched with water and extracted with methylene chloride three times. The combined organic extracts are washed with saturated sodium bicarbonate, a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo to give 2.8 g (94%) of the title compound as a grey solid.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10][CH3:11])=[O:9])[N:6]2[C:12](=[O:25])[CH:13]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[C@H:5]2[S:4][CH2:3]1.[N+](=[CH2:28])=[N-]>O1CCOCC1.CCOCC>[CH3:28][O:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:13]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[C:12](=[O:25])[N:6]2[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: C=[N+]=[N-]
Reactant: COC(=O)C1C(=O)CS[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N12
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)C1=C(OC)CS[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 3-oxo-7-phthalimidocepham-4-carboxylate (b) thus prepared by above methods is dissolved in dioxane, mixed with a solution of diazomethane in ether, and stirred for 1 hour at room temperature. The reaction mixture is evaporated under reduced pressure to give methyl 3-methoxy-7-phthalimido-3-cephem-4-carboxylate in nearly quantitative yield. Recrystallization from a mixture of acetone and ether gives pure crystals, m.p. 225°-227° C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:37])([F:36])[C:10]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][C@@H:23]2[CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]2[CH3:35])=[CH:18][CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].C(N(CC)CC)C.[Cl:45][C:46]1[N:51]=[CH:50][C:49]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:47]=1>C(Cl)Cl>[Cl:45][C:46]1[N:51]=[CH:50][C:49]([S:52]([N:25]2[CH2:26][CH2:27][N:22]([C:19]3[CH:20]=[CH:21][C:16]([C:10]([OH:15])([C:9]([F:8])([F:36])[F:37])[C:11]([F:14])([F:13])[F:12])=[CH:17][CH:18]=3)[C@@H:23]([CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@H:30]3[CH3:35])[CH2:24]2)(=[O:54])=[O:53])=[CH:48][CH:47]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: C[C@H]1COCCN1C[C@H]1CNCCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The 1,1,1,3,3,3-hexafluoro-2-(4-((2R)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate (115 mg, 0.172 mmol) was dissolved in CH2Cl2 (30 mL) and was chilled to 0° C. To this solution was triethylamine (96 μl, 0.687 mmol) followed by 6-chloropyridine-3-sulfonyl chloride (40.1 mg, 0.189 mmol, Organic Process Research & Development 2009, 13, 875). The mixture was warmed slowly to room temp and stirred for 2 h. Afterwards, the mixture was concentrated to give 2-(4-((S)-4-((6-chloropyridin-3-yl)sulfonyl)-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:6][C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][S:10][N:11]=1)[C:4]#[CH:5]>CC(C)=O>[I-:2].[CH2:3]([O:6][C:7]1[C:8]([C:12]2[CH:13]=[N+:14]([CH3:1])[CH:15]=[CH:16][CH:17]=2)=[N:9][S:10][N:11]=1)[C:4]#[CH:5]
Reactant: CI
Reactant: C#CCOc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: C#CCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.45 ml, 7.2 mmol) and 3-(4-propargyloxy-1,2,5-thiadiazol-3-yl)pyridine (430 mg, 2.4 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.58 g (67%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:22][CH:23]([CH2:26][C:27](OCC)=[O:28])[CH2:24][N:25]=1)[NH:6]2.[BH4-].[Li+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[OH:28][CH2:27][CH2:26][CH:23]1[S:22][C:21]([C:5]2[NH:6][C:7]3[C:3]([CH:4]=2)=[C:2]([CH3:1])[CH:10]=[CH:9][C:8]=3[N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[N:25][CH2:24]1
Reactant: CCOC(=O)CC1CN=C(c2cc3c(C)ccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(CCO)S3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a mixture of ethyl (2-{4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (0.12 g), lithium borohydride (20 mg) and tetrahydrofuran (10 mL) was added methanol (2 mL), and the mixture was stirred at room temperature for 3 hr. Aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (103 mg, yield: 94%) as pale-yellow crystals. MS: 436 (MH+). melting point 168-169° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]=O)[O:10][N:9]=1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)[Cl:44]>>[Cl:44][C:6]1[CH:5]=[CH:4][C:3]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][N:26]3[CH2:27][CH2:28][N:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:24][CH2:25]3)[O:10][N:9]=2)=[CH:2][CH:7]=1
Reactant: ClCCl
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2ccccc2Cl)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Clc1ccc(-c2cc(CCCN3CCN(c4ccccc4)CC3)on2)cc1
Yield: 70 %

Procedure:
About 2 min after dissolving 3-[3-(2-chlorophenyl)isoxazol-5-yl]propanal (15.8 mg, 0.09 mmol) and 1-phenylpiperazine (13.4, 0.07 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (42.6 mg, 0.2 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 36 hr and followed the same processes as in Example 1 to obtain 17.9 mg (70.0%) of the target compound.