Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[N:16]2[CH:17]=[CH:18][CH:19]=[C:15]2[C:14](=[O:20])[N:13]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:12]1=[O:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].O>CN(C)C=O>[C:38]([O:37][C:35](=[O:36])[CH2:34][C:11]1([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[N:16]2[CH:17]=[CH:18][CH:19]=[C:15]2[C:14](=[O:20])[N:13]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:12]1=[O:30])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(OCc1ccccc1)C1C(=O)N(Cc2ccc(Cl)c(Cl)c2)C(=O)c2cccn21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC1(C(=O)OCc2ccccc2)C(=O)N(Cc2ccc(Cl)c(Cl)c2)C(=O)c2cccn21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a stirred solution of 2-(3,4-dichlorobenzyl)-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid benzyl ester (9.4 g) in anhydrous dimethylformamide (40 ml) was added portionwise sodium hydride (63% dispersion in mineral oil, 0.7 g) under ice cooling, while a stream of nitrogen was passed over the mixture. The resulting mixture was stirred at 25° C. for 1 hour and thereto was added tert-butyl bromoacetate (4.3 g). The mixture was stirred at 25° C. for 15 hours, poured into water, and extracted with ethyl acetate. The extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel using n-hexane/ethyl acetate (20:1) as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (9.2 g, 78.0%) as colorless crystals, mp 86°-88° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:45])[O:11][C:12]1[CH:16]=[C:15]([N:17]2[C:25]3[CH:24]=[C:23]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[N:22]=[CH:21][C:20]=3[N:19]=[CH:18]2)[S:14][C:13]=1[C:35]([O:37]C)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:46]>CO>[Si:1]([O:8][CH2:9][C@@H:10]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:45])[O:11][C:12]1[CH:16]=[C:15]([N:17]2[C:25]3[CH:24]=[C:23]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[N:22]=[CH:21][C:20]=3[N:19]=[CH:18]2)[S:14][C:13]=1[C:35]([NH2:46])=[O:37])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@@H](CO[Si](C)(C)C(C)(C)C)c1ccccc1Cl
Reactant: N
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCc1cc2c(cn1)ncn2-c1cc(O[C@@H](CO[Si](C)(C)C(C)(C)C)c2ccccc2Cl)c(C(N)=O)s1

Procedure:
In a similar manner as described for example A5, 500 mg of methyl 3-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(2-chlorophenyl)ethoxy]-5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxylate and 40 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [OH:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:7]([CH3:14])[C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1.[H-].[Na+].[CH3:22]I.[Cl-].[Na+]>O1CCCC1>[CH3:22][O:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:7]([CH3:14])[C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1
Reactant: CI
Reactant: CCOC(=O)c1c2c3c(cccc3n1C)C(O)CC2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c2c3c(cccc3n1C)C(OC)CC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61 %

Procedure:
Ethyl 1,3,4,5-tetrahydro-5-hydroxy-1-methyl-benz[cd]indole-2-carboxylate (0.25 g, 0.96 mmol) was added to a suspension of 60% sodium hydride (0.039 g, 0.96 mmol) in tetrahydrofuran (10 ml), followed by stirring at room temperature for 20 minutes. After the reaction mixture was cooled to 0°-5° C., methyl iodide (0.27 g, 1.93 mmol) was added thereto and the resulting mixture was stirred at 0°-5° C. for 1 hour and then at room temperature for 2.5 hours. The reaction mixture was poured into a 5% aqueous sodium chloride solution, followed by extraction with ethyl acetate (twice). The extract solution was washed twice with a 5% aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/98) to obtain ethyl 1,3,4,5-tetrahydro-5-methoxy-1-methyl-benz[cd]indole-2-carboxylate (0.16 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+]([O-])=O.CC(C)([O-])C.[K+].C(Cl)(Cl)Cl.[F:23][C:24]([F:31])([C:27]([F:30])([F:29])[F:28])[CH2:25][OH:26]>>[CH3:1][C:2]1[CH:3]=[N+:4]([O-:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[O:26][CH2:25][C:24]([F:31])([F:23])[C:27]([F:30])([F:29])[F:28]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: Cc1c[n+]([O-])cc(C)c1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1c[n+]([O-])cc(C)c1OCC(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 18 h
Yield: 80.6 %

Procedure:
To a solution of 3,5-dimethyl-4-nitropyridine-1-oxide (2.0 g) in 2,2,3,3,3-pentafluoropropanol (10 g) was added at 0° C. little by little potassium t-butoxide (2 g) over 15 minutes. The mixture was stirred at 60° C. for 18 hours. To the reaction mixture was added chloroform, which was subjected to filtration with celite. The filtrate was chromatographed on a column of silica gel (80 g), eluted with ethyl acetate-hexane (1:1), then with 20% methanol-ethyl acetate, and recrystallized from ether-hexane to yield 2.6 g of 3,5-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine-1-oxide as crystals, m.p. 89°-91° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]=[C:4]([C:11]([OH:13])=[O:12])[CH:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([C:2]2[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]=[C:4]([C:11]([OH:13])=[O:12])[CH:3]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1cc(Cl)cc(C(=O)O)n1
Reactant: C1CCNC1
Product: O=C(O)c1cc(N2CCCC2)cc(C(=O)O)n1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
4-chloropyridine-2,6-dicarboxylic acid (0.238 mol, 48.0 g) is slowly added under stirring to a solution of pyrrolidine (0.952 mol, 67.8 g) at room temperature. Take care to avoid a too-fast addition leading to local temperature increase. Observe precipitation of a solid. The reaction mixture is heated at 120° C. for 2 hr. By gradually heating, the reaction mixture becomes solid. After cooling at 60° C., H20 (80 ml) is added and the mixture is stirred for 30 min until the solid is completely dissolved. The solution is then acidified with HCl (2M) until pH=1. The formed precipitate is filtered, washed twice H2O and dried overnight at 70° C. (93%).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Br:7][C:8]1[CH:20]=[CH:19][C:11](/[CH:12]=C/N2CCCC2)=[C:10]([N+:21]([O-:23])=[O:22])[CH:9]=1>C1COCC1.O>[Br:7][C:8]1[CH:20]=[CH:19][C:11]([CH:12]=[O:2])=[C:10]([N+:21]([O-:23])=[O:22])[CH:9]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=[N+]([O-])c1cc(Br)ccc1/C=C/N1CCCC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 15 h
Yield: 85.3 %

Procedure:
To a solution of sodium periodate (298 g, 1.40 mol) in THF—H2O (4 L, 1:1) at 0° C. was added (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine (138 g, 464 mmol). The mixture was stirred for 15 h and then filtered to remove solid precipitates. The aqueous layer from the filtrate was separated and extracted with EtOAc (4×200 mL). The combined organic layers were washed with H2O (2×200 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product that was purified by silica gel flash column chromatography (5% EtOAc in hexanes) to afford 91 g (86%) of 4-bromo-2-nitrobenzaldehyde.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][S:13][C:12]3=[N:15][CH:16]=[C:17]([C:18]([OH:20])=O)[N:11]23)=[CH:6][CH:5]=1)#[N:3].Cl.[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]2=[O:35])[CH:26]=[CH:27][CH:28]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>>[ClH:22].[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][N:32]([C:18]([C:17]3[N:11]4[C:12]([S:13][CH2:14][CH:10]4[C:7]4[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][CH:8]=4)=[N:15][CH:16]=3)=[O:20])[CH2:31][C:30]2=[O:35])[CH:26]=[CH:27][CH:28]=1
Reactant: N#Cc1ccc(C2CSc3ncc(C(=O)O)n32)cc1
Reactant: O=C1CNCCN1c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C2CSc3ncc(C(=O)N4CCN(c5cccc(Cl)c5)C(=O)C4)n32)cc1

Procedure:
The carboxylic acid from Step D (5.14 g, 16.1 mmol), 1-(3-chlorophenyl)piperazin-2-one hydrochloride (3.97 g, 16.1 mmol) (prepared as described in U.S. Pat. No. 5,856,326), EDC hydrochloride (3.70 g, 19.3 mmol), HOBT (2.61 g, 19.3 mmol), and N,N-diisopropylethylamine (14.0 mL, 80.4 mmol) were stirred in dry, degassed DMF (50 mL) at 25° C. for 16 hours. The reaction was poured onto saturated aqueous sodium bicarbonate solution and extracted with methylene chloride (3×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide a yellow oil. The crude product was purified by column chromatography (3→5% methanol/methylene chloride) and converted to the HCl salt to provide the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9](OCC)(=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].O.Cl>CCO>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1ccccc1S
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1nc2ccccc2s1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
A solution of 2-aminothiophenol (10.7 mL, 0.1 mol) in diethyl oxalate (27.3 mL, 0.2 mol) is heated at reflux for 4 hr. The solution is cooled to rt and poured into a solution consisting of water (150 mL), conc. HCl (50 mL) and 95% EtOH (70 mL). With stirring, the oil dissolved and a solid formed. The solution is cooled in an ice bath, the solid is collected by vacuum filtration and the solids are washed with a solution consisting of EtOH/water (25/75) to afford a dark solid. This material is purified by crystallization from hot (68° C.) ligroin to yield ethyl 2-benzothiazolecarboxylate (7.5 g, 36%). Elemental analysis for C10H9NO2S: Calc: C, 57.95; H, 4.38; N, 6.76. Found: C, 57.99; H, 4.28; N, 6.78.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19](=[O:31])[CH2:20][C:21]1([NH2:30])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:16]([O:18][C:19](=[O:31])[CH2:20][C:21]1([NH:30][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)[CH3:17]
Reactant: CCOC(=O)CC1(N)Cc2ccccc2C1
Reactant: Cc1cccc(C(=O)O)c1OC1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 2-cyclobutyloxy-3-methylbenzoic acid (210 mg-1.02 mmol), 2-aminoindan-2-acetic acid ethyl ester (A6) (260 mg-1.02 mmol) and HATU (470 mg-1.224 mmol-1.2 eq) in dry DMF (10 mL) is added diisopropylethylamine (0.36 mL-2.24 mmol-2.2 eq) and the resulting solution is stirred at RT overnight. After the removal of the DMF in vacuo, the residue is dissolved in EtOAc (60 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organic layer is dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography (120 g silica gel, 15% EtOAc in heptane) to give the pure product as colorless oil (400 mg, 96%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[BH4-].[Na+].[CH2:16]1[CH2:20]OC[CH2:17]1.CO>>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:16]([CH3:20])[CH3:17])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of 3 (3.0 g, 10.8 mmol) in THF/MeOH (10 mL/10 mL) was slowly added NaBH4 (407 mg, 10.8 mmol). The mixture was stirred for 10 min, quenched by saturated NH4Cl and partitioned between EtOAc and H2O. The organic layer was washed with sat NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to give 4 (3.0 g, 99%), which was used without further purification. LRMS (M+H+) m/z 281.0.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:4][C:3]=1[C:25]#[C:26][C:27]1[N:31]2[N:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][CH:28]=1.[Cl:36]C1C=CC(C2NC3C=C(CN4CCN(C)CC4)C=CC=3N=2)=CC=1I>>[Cl:36][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([CH2:17][N:18]4[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]4)[CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:4][C:3]=1[C:25]#[C:26][C:27]1[N:31]2[N:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][CH:28]=1
Reactant: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1C#Cc1cnc2cccnn12
Reactant: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(I)c4)[nH]c3c2)CC1
Product: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(C#Cc5cnc6cccnn56)c4)[nH]c3c2)CC1

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine (as prepared in Example 3) and 2-(4-chloro-3-iodophenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzoimidazole in a manner similar to that described for in Example 1. The intermediate compound 2-(4-chloro-3-iodophenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole was made as for Example 1 (Step 4 to 7) with the spectra below: 1H NMR (300 MHz, CDCl3) δ: 8.52 (1 H, s), 7.95-7.98 (1 H, d, J=9.0 Hz), 7.45-7.48 (1 H, d, J=9.0 Hz), 7.43-7.46 (1 H, d, J=9.0 Hz), 7.23 (1 H, s), 7.21-7.24 (1 H, d, J=9.0 Hz), 3.59 (2 H, s), 2.51 (8H, brs), 2.29 (3 H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17](=[O:18])[C:16]3[C@@H:15]4[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]4)[C:11]=3[NH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.I[CH2:24][CH3:25].CCOCC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17](=[O:18])[C:16]3[C@@H:15]4[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]4)[C:11]=3[N:10]2[CH2:24][CH3:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCI
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3cc(Cl)cc(Cl)c3)c(=O)c12
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCn1c2c(c(=O)n1-c1cc(Cl)cc(Cl)c1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 95 °C
Yield: 6.8 %

Procedure:
A mixture of (4S,7R)-2-(3,5-dichloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 45; 400 mg, 1.2 mmol) and iodoethane (480 μL, 5.95 mmol) in dimethylformamide (5 mL) was heated at 95° C. for 7 h and then a further portion of iodoethane (480 μL, 5.95 mmol) was added. The solution was heated at 95° C. overnight. The solvent was evaporated, dichloromethane (100 mL) was added and the solution was washed with water (3×50 mL), saturated aqueous sodium thiosulfate (50 mL), and brine (50 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 20% ethyl acetate/petroleum ether, and dried under high vacuum over the weekend to give a pale orange solid. The solid was stirred in a small amount of ether, and the insoluble material was filtered off and dried under high vacuum overnight to give (4S,7R)-2-(3,5-dichloro-phenyl)-1-ethyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (30 mg, 7%). ES(+)-MS (M+H) 351.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:34])[C@@H:10]([CH2:31][O:32][CH3:33])[NH:11]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>C(O)C>[CH2:1]([NH:8][C:9](=[O:34])[C@@H:10]([CH2:31][O:32][CH3:33])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCc1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: COC[C@@H](N)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 3 product (i.e., N-benzyl-O-methyl-N2-trityl-D-serinamide, 50 g) in absolute ethanol (100 ml), acetic acid (1.25 mole eq.) was added at room temperature. This solution was stirred for 30 minutes at room temperature and then the solvent was completely recovered under vacuum at 40° C. Water (250 ml) was added to it at room temperature and the aqueous layer was neutralized with aqueous ammonia (20 ml). The aqueous layer was extracted with toluene (2×200 ml). The toluene was then completely recovered under vacuum at 50° C. to 55° C. to get an oil. Yield=18 gm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][C:38](Cl)=[O:39]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:38](=[O:39])[CH2:37][C:33]4[S:32][CH:36]=[CH:35][CH:34]=4)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)Cc1cccs1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCNC2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1cccs1)N1CCC[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of N-(3,4-dichlorophenyl)-4-[(3R)-piperidin-3-ylmethyl]piperazine-1-carboxamide (150 mg) and triethylamine (0.11 mL) in tetrahydrofuran (5 mL) at room temperature was added 2-thiopheneacetyl chloride under argon at room temperature. The solution was stirred for 30 minutes and then quenched with methanol. The mixture was loaded onto a SCX-2 column and eluted with methanol then 7M NH3 in methanol. The basic fraction was concentrated and the residue purified by silica column chromatography, eluting with a gradient of 0 to 10% methanol in dichloromethane to give the title compound as a yellow oil (150 mg, 75%).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[N:8][N:9]([C:11]([CH3:18])([CH3:17])[C:12](=[NH:16])OCC)[CH:10]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([C:33]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:34])[CH2:28]2)=[N:24][C:25]=1N>C(O)C>[Cl:5][C:6]1[CH:7]=[N:8][N:9]([C:11]([C:12]2[NH:16][C:25]3=[N:24][C:23]([N:27]4[CH2:32][CH2:31][CH2:30][C@@H:29]([C:33]([N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)=[O:34])[CH2:28]4)=[CH:22][CH:21]=[C:20]3[N:19]=2)([CH3:17])[CH3:18])[CH:10]=1
Reactant: CCOC(=N)C(C)(C)n1cc(Cl)cn1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(c1nc2ccc(N3CCC[C@@H](C(=O)N4CCCC4)C3)nc2[nH]1)n1cc(Cl)cn1
Yield: 25 %

Procedure:
Acetic acid (2.9 mL, 48.58 mmol) and ethyl 2-(4-chloro-1H-pyrazol-1-yl)-2-methylpropanimidate (Intermediate 54) were added to a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone in ethanol, prepared in the previous step. The reaction mixture was heated at reflux for 18 h. The mixture was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was purified via column chromatography (100-200 mesh silica gel, 5% methanol in ethyl acetate) to afford the title compound (530 mg, 25% yield over 2 steps). 1H NMR (500 MHz, CDCl3) δ 1.53-1.65 (m, 1H) 1.74-2.00 (m, 7H) 2.10 (s, 6H) 2.58-2.70 (m, 1H) 2.88-2.93 (m, 1H) 3.01-3.09 (m, 1H) 3.40-3.50 (m, 3H) 3.55-3.63 (m, 1H) 4.22 (d, 1H) 4.43 (d, 1H) 6.63 (d, 1H) 7.57 (d, 2H) 7.79 (d, 1H) 10.08 (br s, 1H). MS (ES+APCI) (M+H) 442.2; LCMS retention time 2.216 min (Method N1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])/[CH:5]=[CH:6]/[C:7]1[N:8]=[CH:9][NH:10][CH:11]=1.C(N(CC)CC)C.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:12])/[CH:5]=[CH:6]/[C:7]1[N:8]=[CH:9][N:10]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:11]=1
Reactant: COC(=O)/C=C/c1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of trans-4-imidazoleacrylic acid methyl ester hydrochloride (20.0 g, 106 mmol) and triethylamine (44 ml, 318 mmol) in chloroform (500 ml) was added a solution of trityl chloride (29.5 g, 318 mmol) in chloroform (100 ml). The resulting suspension was stirred at room temperature for 24 h. The reaction mixture was then washed with water and dried over MgSO4. Filtration and removal of the solvent in vacuo to gave the title compound as a tan solid: 1H NMR (CDCl3) d 3.75 (s, 3 H), 6.54 (d, J=16 Hz, 1 H) 7.03 (s, 1 H), 7.13-7.34 (m, 15 H) 7.46 (s, 1 H), 7.51 (d, J=16 Hz 1 H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28](=[O:41])[NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[CH:21]=1)[C:4](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:5])[CH3:2].[OH:42]O.O.[OH-].[Li+].Cl>O.O1CCCC1>[CH2:1]([CH:3]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28](=[O:41])[NH:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=2)[CH:21]=1)[C:4]([OH:5])=[O:42])[CH3:2]
Reactant: OO
Reactant: CCC(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)C(=O)O
Reaction time: 0.03 h
Yield: 20 %

Procedure:
(4S)-3-[2-ethyl-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propionyl]-4-benzyl-2-oxazolidinone (860 mg, 1.51 mmol) was mixed with 8 ml of mixed solution of tetrahydrofuran with water (4:1 v/v), which was cooled with ice under an atmosphere of argon. Under stirring, 611 ml of 30% aqueous hydrogen peroxide was added over 2 minutes, further 101 mg of lithium hydroxide monohydrate dissolved in 2.7 ml of water was added thereto over 2 minutes. After the mixture was stirred for 1 hour under cooling with ice, sodium sulfite 7-hydrate dissolved in 4 ml of water was added, and the mixture was stirred for 5 minutes at 0° C. The reaction mixture was poured into 5% aqueous solution of hydrochloric acid, which was extracted with ethyl acetate. The extract was washed with brine, then dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized by adding ethyl acetate and n-hexane to obtain 125 mg (20%) of the title compound as colorless prisms.