Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2]O.[Br:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH:16]=O)=[CH:10]2>CS(C)=O.C(OCC)(=O)C>[Br:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([C:16]#[N:2])=[CH:10]2
Reactant: O=Cc1ccc2c(Br)cc(F)cc2c1
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc2c(Br)cc(F)cc2c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
Hydroxylamine hydrochloride (0.5 g, 7.9 mmol) was added to a solution of 32 (1.0 g, 4.0 mmol) in DMSO (5.0 mL), and the mixture was stirred for 16 h at 100° C. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL), and washed with saturated NaHCO3 aqueous solution (2×50 mL). The organic was dried over anhydrous Na2SO4, filtered, concentrated by rotary evaporation, and purified by column chromatography to give 5-bromo-7-fluoro-2-naphthonitrile (33) (28%). 1H NMR (400 MHz, CDCl3) δ 10.20 (s, 1H), 8.34 (d, J=8.8 Hz, 1H), 8.29 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.77 (dd, J=8.0, 2.3 Hz, 1H), 7.64 (d, J=8.6 Hz, 1H). GC-MS (ES) for C11H5BrFN [M+1]+ 250.
Reaction SMILES: [C:1]([N:5]([CH2:11][CH2:12][C:13]#[N:14])[C:6](=[O:10])[C:7](=O)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl.[H][H]>C(O)C.[Pt]=O>[C:1]([N:5]1[CH2:11][CH2:12][CH2:13][NH:14][CH:7]([CH3:8])[C:6]1=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)C(=O)N(CCC#N)C(C)(C)C
Agent: O=[Pt]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC1NCCCN(C(C)(C)C)C1=O

Procedure:
N-(tert-butyl)-N-(2-cyanoethyl)-2-oxopropanamide obtained in Step A (440 mg) and platinum oxide (60 mg) were suspended in ethyl alcohol (40 mL) containing chloroform (0.3 mL) and mixed on a Parr shaker over an atmosphere of hydrogen at 40 psi for 16 h. The mixture was filtered, the catalyst was washed with methanol/dichloromethane (10:90) and the combined filtrate was evaporated and purified by Biotage® flash chromatography (silica gel, 5–10% methanol/dichloromethane) to yield the desired product.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C1C(=O)N([Cl:18])C(=O)C1>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([Cl:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Brc1cnc2[nH]ccc2n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1c[nH]c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 141 %

Procedure:
To a solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (1.8 g, 9.09 mmol) in 18 mL of DCM and 18 mL of DMF was added NCS (1.46 g, 10.9 mmol) at RT. The reaction mixture was stirred at RT overnight, then partitioned between EtOAc and brine. The organic layer was dried (MgSO4) concentrated to give 2.98 g of impure 2-bromo-7-chloro-5H-pyrrolo[2,3-b]pyrazine as a yellow oil which was used for the next step without any purification.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[CH3:31][C:32]1[C:36](B(O)O)=[C:35]([CH3:40])[O:34][N:33]=1>>[CH3:31][C:32]1[C:36]([C:7]2[NH:6][C:5]([CH:9]=[O:10])=[C:4]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C:3]=2[CH2:1][CH3:2])=[C:35]([CH3:40])[O:34][N:33]=1
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Reactant: Cc1noc(C)c1B(O)O
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2c(C)noc2C)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 3,5-dimethylisoxazol-4-ylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C20H21N2O4 (M+H): 353.1502. Found 353.1496
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([S:30][CH3:31])[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:41])C=1>ClCCl.CO>[C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([S:30]([CH3:31])=[O:41])[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of {4-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 8 supra) (800 mg, 1.8 mmol) in a mixture of dichloromethane and methanol (200 mL, 1:1) was added m-CPBA (710 mg, 1.8 mmol) slowly. The reaction mixture was stirred at room temperature for 25 minutes. The solvent was then removed under reduced pressure and the residue was purified by column chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1) to afford {4-[3-(2-Methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 440 mg, 53.1%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25](O)=O)=[CH:18][CH:17]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:25]([CH2:24][CH2:23][CH2:22][C:19]4[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=4)=[N:13][N:12]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COc1ccc(CCCC(=O)O)cc1
Reactant: NNC(=O)c1ccc2occc2c1
Product: COc1ccc(CCCc2nnc(-c3ccc4occc4c3)o2)cc1
Yield: 15 %

Procedure:
In the same manner as in Example 14 and using 1-benzofuran-5-carbohydrazide instead of 1H-benzotriazole-5-carbohydrazide and 4-(4-methoxyphenyl)butyric acid instead of 3-(3-cyanophenyl)propionic acid, the title compound (yield 15%) was obtained as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[NH2:16]>C1(C)C=CC=CC=1.C1COCC1>[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[N:16]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[N:5]=1)[CH3:11]
Reactant: Nc1c(F)cccc1F
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1cccc(C(C)=Nc2c(F)cccc2F)n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 19.9 %

Procedure:
2,6-Diacetylpyridine (4.04 g, 24.7 mmol) and 2,6-difluoroaniline (3.2 g, 24.7 mmol) were dissolved in 50 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 5 days at room temperature, the mixture was filtered. The solvent was removed in vacuo. From the resulting mixture of 2,6-diacetylpyridine, monoimine, and diimine. Most of the 2,6-diacetylpyridine was removed by sublimation in vacuo at 80-90° C. The residue contained based on 1H-NMR data 0.35 mmol 2,6-diacetylpyridine , 1.28 mmol diimine and 5.46 mmol monoimine. This mixture was reacted with 162 mg (1.28 mmol) FeCl2 in 10 ml THF to remove the diimine. After stirring for 16 h at room temperature, the solvent was removed in vacuo. Toluene (50 ml) was added to the resulting mixture. The precipitated complex was filtered off over a small layer of silica, yielding a yellow solution. The solvent was removed in vacuo. Crystallisation from ethanol yielded 1.35 g of 2-[1-(2,6-difluorophenylimino)ethyl]-6-acetylpyridine (18) (19.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([C:20]3[C:21]([O:26][CH3:27])=[N:22][CH:23]=[CH:24][CH:25]=3)[C:11]=2[OH:28])=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1.CCOC(C)=O>[C:16]([C:14]1[CH:13]=[C:12]([C:20]2[C:21]([O:26][CH3:27])=[N:22][CH:23]=[CH:24][CH:25]=2)[C:11]([OH:28])=[C:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:3][CH:4]=2)[CH:15]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncccc1-c1cc(C(C)(C)C)cc(CCc2ccc(N)cc2)c1O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ncccc1-c1cc(C(C)(C)C)cc(CCc2ccc(NS(C)(=O)=O)cc2)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
step 5—To a solution of 54 (156 mg, 0.415 mmol) in pyridine (5 mL) at 0° C. was added methanesulfonyl chloride (0.050 mL, 0.643 mmol). The reaction was gradually warmed to RT and stirred for 1.5 h then diluted with EtOAc. The organic layer was washed sequentially with saturated aqueous CuSO4, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 50% EtOAc) to afford 115 mg (61%) of N-(4-{2-[5-tert-butyl-2-hydroxy-3-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-phenyl)-methanesulfonamide (56) as a colorless oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]1[CH2:62][CH2:61][CH:60]([NH2:63])[CH2:59][CH2:58]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:63][CH:60]5[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]5)=[O:28])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methylbenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42-2.04 (m, 16 H) 2.10-2.22 (m, 3 H) 2.29 (s, 3 H) 2.77 (d, J=11.1 Hz, 2 H) 3.72 (dd, J=7.3, 4.0 Hz, 1 H) 3.98 (t, J=14.0 Hz, 2 H) 4.60 (t, J=8.2 Hz, 1 H) 7.64 (d, J=8.3 Hz, 1 H) 7.68-7.80 (m, 2 H) 8.08 (d, J=7.8 Hz, 1 H) 8.19 (s, 1 H) 8.60 (s, 1 H). [M+H] calc'd for C27H35F2N7O2, 528; found 528.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C1(C)C=CC=CC=1>O1CCCC1>[N:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCCC1
Temperature: 0 °C

Procedure:
To an ice bath-cooled solution of 213.4 g (3 mol) of pyrrolidine in 450 mL of tetrahydrofuran was added dropwise over about 2 hours 250.5 g (1.5 mol) of ethyl bromoacetate, maintaining the temperature below 30° C. To this solution was added 150 mL of toluene to precipitate pyrrolidinium bromide, which was separated by filtration. The filtrate was evaporated under vacuum to provide a residue of about 241 g of ethyl 1-pyrrolinidineacetate.
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:10]=[CH:9][N:8](COC(=O)C(C)(C)C)[C:7]2=[O:31]>CO.C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:10]=[CH:9][NH:8][C:7]2=[O:31]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCN(C)CC1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(=O)[nH]cnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.9 %

Procedure:
A saturated solution of ammonia in methanol (14 ml) was added to a solution of 6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.38 g, 3.3 mmol) in methanol (5 ml). After stirring for 20 hours at ambient temperature, the suspension was diluted with methylene chloride (10 ml). The solution was filtered. The filtrate was evaporated under vacuum and the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-3,4-dihydroquinazolin-4-one (910 mg, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH3:11][C:12]1([CH3:33])[CH:20]2[CH:16]([CH2:17][N:18]([C:21](=[O:31])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:19]2)[C:15](=[O:32])[CH:14]=[CH:13]1.[Cl-].[Ce+3].[Cl-].[Cl-].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:11][C:12]1([CH3:33])[CH:20]2[CH:16]([CH2:17][N:18]([C:21](=[O:31])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:19]2)[C:15]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])([OH:32])[CH:14]=[CH:13]1
Reactant: COc1ccccc1CC(=O)N1CC2C(=O)C=CC(C)(C)C2C1
Reactant: COc1ccccc1[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1CC(=O)N1CC2C(C1)C(O)(c1ccccc1OC)C=CC2(C)C
Temperature: 15 °C
Yield: 54.7 %

Procedure:
To a suspension of 22.73 g of 2-methoxyphenylmagnesium bromide in 70 cm3 of tetrahydrofuran, cooled to 15° C., are added, dropwise and with stirring, a solution of 6.77 g of (3aRS,7aRS)7, 7-dimethyl-2-[(2-methoxyphenyl)acetyl]-2,3,3a,4,7,7a -hexahydro-1H-4-isoindolone in 10 cm3 of tetrahydrofuran, followed by 5.3 g of anhydrous cerium chloride. The reaction mixture is stirred at room temperature for 18 hours, treated with 80 cm3 of saturated aqueous ammonium chloride solution, taken up in 100 cm3 of ethyl acetate and washed with 100 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 5.5 cm, height 30 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting 75 cm3 fractions. Fractions 17 to 40 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). 4.98 g of (3aRS,4RS,7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]2,3,3a,4,7,7a-hexahydro-1H-4-isoindolol are obtained in the form of a colourless oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1.[C-:10]#[N:11].[K+].C1OCCOCCOCCOCCOCCOC1.C(P(CCCC)CCCC)CCC>C(#N)C.O>[C:10]([CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1)#[N:11]
Reactant: [C-]#N
Reactant: Cc1cc(CO)ccn1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCCCP(CCCC)CCCC
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(CC#N)ccn1
Temperature: 25 °C
Reaction time: 25 h
Yield: 62 %

Procedure:
To a stirred mixture of 4-hydroxymethyl-2-methyl-pyridine [CAS No. 105250-16-6] (3.37 g, 27.4 mmol), potassium cyanide (3.56 g, 54.7 mmol) and 18-crown-6 (0.72 g, 2.74 mmol) in acetonitrile (75 ml) was added dropwise at 15-20° C. a solution of tributylphosphine (7.16 g, 30.1 mmol) in acetonitrile (25 ml). The reaction mixture was stirred at room temperature for 25 h, poured into water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water (3×100 ml), brine (100 ml) dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate) to yield 4-cyanomethyl-2-methyl-pyridine (2.26 g, 62%) as a brown oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[CH:12]3[CH2:13][CH2:14][CH:8]2[CH2:9][O:10][CH2:11]3)[S:5][CH:6]=1.C(O)C.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:3]=[C:4]([N:7]3[CH:12]4[CH2:13][CH2:14][CH:8]3[CH2:9][O:10][CH2:11]4)[S:5][CH:6]=2)=[CH:21][CH:20]=1
Reactant: Brc1csc(N2C3CCC2COC3)n1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Clc1ccc(-c2csc(N3C4CCC3COC4)n2)cc1
Temperature: 92.5 °C
Yield: 86.9 %

Procedure:
To a solution of 8-(4-bromothiazol-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (Step-1 of o compound 56, 0.29 g, 1.05 mmol) in a mixture of toluene:ethanol (1.5 ml:4.5 ml) were added (4-chlorophenyl) boronic acid (0.18 g, 1.16 mmol) and potassium carbonate (0.29 g, 2.11 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.06 g, 0.05 mmol) under nitrogen and the tube was sealed. The reaction mixture was heated at 90-95° C. for 18 hr with stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite. The residue was washed with mixture of 10% methanol in dichloromethane (2×10 ml). The filtrate was concentrated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 10% ethyl acetate in hexanes as an eluent to obtain the title compound (0.28 g, 88.0%). MS: m/z 307 (M+1).
Reaction SMILES: [C:1](=[O:23])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[NH2:24][C@@H:25]([CH2:29][S:30]([O-:33])(=[O:32])=[O:31])[C:26]([O-:28])=[O:27].[Na+].[Na+].OC1C=CC(NC(=O)C)=CC=1.C(Cl)(=O)OC1C=CC([N+]([O-])=O)=CC=1>C(#N)C.O>[C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][C:1]([NH:24][C@@H:25]([CH2:29][S:30]([OH:33])(=[O:32])=[O:31])[C:26]([OH:28])=[O:27])=[O:23])=[CH:8][CH:7]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: N[C@@H](CS(=O)(=O)[O-])C(=O)[O-]
Agent: CC(=O)Nc1ccc(O)cc1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1ccc(OC(=O)N[C@@H](CS(=O)(=O)O)C(=O)O)cc1
Yield: 43 %

Procedure:
(2R)-2-[(4-Acetamidophenoxy)carbonylamino]-3-sulfo-propanoic acid (13a) was prepared according to the General Method for the Reaction of Alkali Metal Salts of Amino Acid Derivatives with 4-Acetamidophenyl 4-Nitrophenyl Carbonate (3). A solution of 500 mg (2.35 mmol) of disodium (2R)-2-amino-3-sulfonato-propanoate (9) in approximately one (1) mL of water was reacted with a solution of 4-acetamidophenyl 4-nitrophenyl carbonate (3) (844 mg, 2.67 mmol) dissolved in 5 mL of acetonitrile (MeCN). The mixture was heated to about 55° C. for two (2) hours. After work-up procedures, the aqueous layer was lyophilized off to afford 400 mg (43% yield) of the crude 2-[(4-acetamidophenoxy)carbonylamino]-3-sulfo-propanoic acid (13a). The material thus obtained was contaminated with some sodium chloride (NaCl) and other sodium salts. The crude product was further purified by preparative HPLC using a gradient consisting of acetonitrile and water containing 0.1 vol-% of formic acid. Samples eluting at 2% acetonitrile and 98% water were collected, frozen, and lyophilized off to afford 83 mg (9% yield) the target compound (13a) as a colorless solid. Rt=3.10 min. 1H NMR (300 MHz, D2O): δ=7.25 (d, J=9.0 Hz, 2H), 6.99 (d, J=9.0 Hz, 2H), 4.54-4.50 (m, 1H), 3.32-3.27 (m, 2H), 1.98 (s, 3H). LC/MS (ESI): m/z=347.0 [M+H]+, 714.8 [2M+Na]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1[S:8][CH2:9][CH2:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[Cl:20]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:20][C:5]1[S:6][C:7]([S:8][CH2:9][CH2:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:3]([CH2:2][Cl:1])[N:4]=1
Reactant: O=S(=O)(CCSc1scnc1CCl)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(CCSc1sc(Cl)nc1CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.8 %

Procedure:
To a solution of 4-chloromethyl-5-(2-phenylsulfonylethyl)thio-1,3-thiazole (400 mg, 1.2 mmol) in N,N-dimethylformamide (3 mL) was added N-chlorosuccinimide (160 mg, 1.2 mmol), and the mixture was stirred at room temperature for 16 h. The resulting mixture was poured into water and extracted with ethyl acetate. The organic solution was washed with water, dried over sodium sulfate, and concentrated; The residue was chromatographed (silica gel, 20% ethyl acetate-hexane), affording 260 mg of the title compound. 1H NMR (CDCl3) δ 3.09 (2H), 3.36 (2H), 4.60 (2H), 7.5-7.9 (5H).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.[NH2:14][C@@H:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C@H:16]1[OH:28]>O1CCCC1>[CH:8]1([C:11]([NH:14][C@@H:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17][C@H:16]2[OH:28])=[O:12])[CH2:10][CH2:9]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)C2CC2)[C@H](O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (4.85 mL, 34.8 mmol) and cyclopropanecarbonyl chloride (3.18 mL, 35.0 mmol) were added to a 0° C. solution of tert-butyl trans-4-amino-3-hydroxypiperidine-1-carboxylate (7.52 g, 34.8 mmol) in tetrahydrofuran (100 mL), and the reaction was allowed to warm to room temperature and stir for 18 hours. After concentration in vacuo, the crude product was diluted with ethyl acetate, insoluble material was removed by filtration, and the solids were washed with ethyl acetate (3×50 mL). The combined filtrates were concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Gradient: 0% to 5% methanol in ethyl acetate) to afford the product as a solid. Yield: 1.30 g, 4.57 mmol, 13%. LCMS m/z 285.6 [M+H]+. 1H NMR (400 MHz, CDCl3), observed peaks: δ 5.79 (br d, J=5 Hz, 1H), 4.21-4.34 (br m, 1H), 4.03-4.21 (br m, 1H), 3.70-3.79 (m, 1H), 3.34-3.42 (m, 1H), 2.66-2.79 (br m, 1H), 2.59 (br dd, J=12, 11 Hz, 1H), 1.88-1.96 (m, 1H), 1.46 (s, 9H), 1.37-1.44 (m, 1H), 1.01-1.05 (m, 2H), 0.77-0.87 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10](Cl)(Cl)=[O:11]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:7]=[C:10]=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: NCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=C=NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 119.3 %

Procedure:
To a solution of 4-chlorobenzylamine (0.50 g, 3.5 mmol) in toluene (15 mL) was added phosgene (7.3 mL, 14 mmol, 1.93 M solution in toluene). The resulting mixture was stirred at ambient temperature for 15 minutes, then heated to reflux. After 2 hours at reflux, the mixture was cooled to ambient temperature and concentrated in vacuo to afford 0.70 g (100% yield) of 4-chlorobenzylisocyanate, a compound of formula (Y), as a yellow liquid; NMR (CDCl3) 7.4-7.2 (m, 4), 4.4 (m, 2) ppm.