Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.C(O)(C)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH2:14])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1
Agent: [Pd]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(CN)cc1
Yield: 35.8 %

Procedure:
Add a solution of 4-(tert-butoxycarbonylamino)-benzonitrile (1 g, 4.58 mmol) in THF/iso-propanol (1:1, 142 mL) to 10% Pd/C (Degussa type E101, 0.56 g, 0.26 mmol) via syringe under N2. Purge the reaction mixture with nitrogen and submit the mixture to hydrogenation at 50 psi overnight. Filter the catalyst through Celite® and wash thoroughly with iso-propanol (100 mL) and THF (100 mL). Concentrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with DCM/2M ammonia in methanol (1:0 to 95:5 gradient over 30 min; 95:5 over 3 min; 95:5 to 9:1 gradient over 30 min and 9:1 over 30 min) to obtain the desired intermediate (0.364 g, 36%). MS (ES−) m/z: 220.1 (M−2H)−.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.Cl.[O:9]1[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[N:10]1.C(N(C(C)C)C(C)C)C>C(O)C>[O:9]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:2]2[CH2:6][S:5][C:4](=[O:7])[N:3]=2)=[N:10]1
Reactant: NCc1ccon1
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C1N=C(NCc2ccon2)CS1
Yield: 49.5 %

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (700 mg) in ethanol (20 mL) were added (isoxazol-3-ylmethyl)amine hydrochloride (707 mg) and N-ethyl-N-(1-methylethyl)propan-2-amine (1.42 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated, the residue was purified by silica gel column chromatography (methanol/ethyl acetate), and the obtained powder was washed with ethyl acetate to give the title compound (513 mg).
Reaction SMILES: [CH:1]([C:4]1[N:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[CH:1]([C:4]1[N:9]=[CH:8][C:7]([CH:10]=[CH:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(C=O)cn1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CC(C)c1ccc(C=CC(=O)O)cn1
Temperature: 110 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A mixture of 3.7 g of the crude 6-isopropyl-3-pyridinecarbaldehyde, 3.9 g of malonic acid, 0.5 ml of piperidine, and 18 ml of pyridine is stirred at 110° C. for 2 hours. The reaction mixture is concentrated, and 5 ml of water is added. The resulting precipitate is collected to give 4.0 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: OC[C@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 9.2 using 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 9.3) and (S)-1-pyrrolidin-3-yl-methanol to afford an off-white crystalline solid. HPLC (Condition 4) tR5.82 min, UPLC-MS (Condition 3) tR=1.14 min, m/z=476.2/478.3 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19]>C([O-])(O)=O.[Na+]>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:2](=[O:3])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(Nc1ccccc1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Benzyl chloroformate (11 mmol, 58% in toluene) was added drop wise to a stirred solution of 2-aminophenol in NaHCO3 (3M, 3.6 mL). The reaction mixture was further stirred for 15 hours at RT. Then the reaction mixture was washed with NaOH (3M, 20 mL) followed by water (20 mL) and diethyl ether (20 ml×3). Concentrated HCl was added to the aqueous part until precipitation of the targeted product as a light yellow solid (70%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[NH:4][CH2:5][C:6]#[CH:7].N1C=CC=CC=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>O1CCCC1>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[N:4]([C:24]([C:20]1[O:19][CH:23]=[CH:22][CH:21]=1)=[O:25])[CH2:5][C:6]#[CH:7]
Reactant: O=C(Cl)c1ccco1
Reactant: C#CCNc1c(C)cccc1C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C#CCN(C(=O)c1ccco1)c1c(C)cccc1C
Yield: 88.8 %

Procedure:
15.9 g (0.1 mol) of 2,6-dimethyl-N-propargylaniline and 8 g (0.1 mol) of pyridine were heated to the boil in 100 ml of tetrahydrofuran, and 13 g (0.1 mol) of furan-2-carboxylic acid chloride were added carefully. The reaction mixture was stirred under reflux for 15 minutes and then concentrated by distilling off the solvent in vacuo. The residue was taken up in methylene chloride and the methylene chloride mixture was washed with water. The organic phase was separated off, dried over sodium sulphate and concentrated. After triturating with petroleum ether, the residue crystallized. 22.5 g (89% of theory) of 2,6-dimethyl-N-(2-furoyl)-N-propargyl-aniline of melting point 109°-112° C. were obtained.
Reaction SMILES: [CH3:1][N:2]([CH:17]([CH3:19])[CH3:18])[C:3]1[C:4](=[O:16])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=O)=[CH:8][CH:7]=2.[CH3:20][C:21]([NH2:24])([CH3:23])[CH3:22].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl>[C:21]([NH:24][C:13]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:16])[C:3]([N:2]([CH3:1])[CH:17]([CH3:19])[CH3:18])=[N:12]2)=[O:15])([CH3:23])([CH3:22])[CH3:20]
Reactant: CC(C)(C)N
Reactant: CC(C)N(C)c1nc2cc(C(=O)O)ccc2[nH]c1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Product: CC(C)N(C)c1nc2cc(C(=O)NC(C)(C)C)ccc2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[methyl(propan-2-yl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxylic acid (1 g, 3.83 mmol) in dichloromethane (50 ml) was added 2-methylpropan-2-amine (560 mg, 7.66 mmol), TEA (967 mg, 9.56 mmol), and T3P (1.83 g, 7.66 mmol). The resulting solution was stirred overnight at room temperature and then concentrated in vacuo to afford N-tert-butyl-3-[methyl(propan-2-yl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxamide as yellow oil (1.5 g, crude).
Reaction SMILES: C(O[C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=O)C.[CH3:20][O:21][CH:22]=[CH:23][C:24]([O:26][Si](C)(C)C)=[CH2:25]>ClCCl.[I-].[Zn+2].[I-]>[Si:13]([O:12][C@@H:10]([C@@H:6]1[C@@H:5]([CH2:25][C:24](=[O:26])[CH:23]=[CH:22][O:21][CH3:20])[NH:8][C:7]1=[O:9])[CH3:11])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: C=C(C=COC)O[Si](C)(C)C
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: COC=CC(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 15 h
Yield: 43 %

Procedure:
(3R,4R) 4-acetoxy-3-[(1R)-(1-(tert-butyldimethylsilyloxy)ethyl)]azetidin-2-one (2 g, 56.96 mM) was dissolved in dichloromethane (150 ml) at ambient temperature and 4-methoxy-2-trimethylsilyloxybut-1,3-diene (1.5 ml, 7.65 mM) added followed by zinc iodide (2.2 g, 17 mM). The reaction mixture was shielded from light and stirred for 15 hours. The mixture was then washed with a 5% aqueous solution of sodium bicarbonate (30 ml) and then water (30 ml). The organic phase was dried with magnesium sulphate and the solvent evaporated. The residue was purified by chromatography on silica, eluting with ethyl acetate/dichloromethane (1:1) to give (3S,4R) 3-((1R)-1-(tert-butyldimethylsilyloxy)ethyl)-4-(4-methoxy-2-oxobut-3-en-1-yl)azetidin-2-one (0.96 g, 43%).
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][CH:9]=1)[CH3:6].[CH2:16]([O:18][C:19]([C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[NH2:26])=[O:20])[CH3:17].[BH3-]C#N.[Na+]>C(O)C>[CH2:16]([O:18][C:19]([C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[NH:26][CH2:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH2:5][CH3:6])[N:13]=1)=[O:20])[CH3:17]
Reactant: CCOc1cccc(C=O)n1
Reactant: CCOC(=O)c1[nH]ccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]ccc1NCc1cccc(OCC)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.5 %

Procedure:
Acetic acid (0.3 mL) was added to 6-ethoxy-pyridine-2-carbaldehyde (0.59 g, 3.9 mmol) and 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.30 g, 1.9 mmol) in ethanol (10 mL). After 1.5 h, NaCNBH3 (0.24 g, 3.9 mmol) was added, and the resulting mixture was stirred at ambient temperature for 19 h. The solvent was removed in vacuo, ethyl acetate was added to the residue, and insoluble material was removed by filtration. The filtrate was concentrated and the crude product was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 35% ethyl acetate), obtaining 0.25 g (45%) of the title product as a solid.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@H:20]([CH3:21])[O:19][CH:6](OC(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:5][C@H:4]1[NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25].[ClH:29]>C(Cl)Cl>[CH3:1][O:2][C@@H:3]1[C@@H:20]([CH3:21])[O:19][CH:6]([Cl:29])[CH2:5][C@@H:4]1[NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25]
Reactant: CO[C@H]1[C@H](C)OC(OC(=O)c2ccc([N+](=O)[O-])cc2)C[C@H]1NC(=O)C(F)(F)F
Reactant: Cl
Solvent: ClCCl
Product: CO[C@H]1[C@@H](NC(=O)C(F)(F)F)CC(Cl)O[C@@H]1C
Yield: 100 %

Procedure:
A solution of 1.76 g; 4.34 mmol of compound VIII in 48 ml of anhydrous methylene dichloride was saturated at 0° C. with anhydrous hydrogen chloride. The resulting precipitate of p-nitrobenzoic acid was filtered off under anhydrous conditions and the filtrate was evaporated to give a residue of 1.2 g (yield 100%) of 4-O-methyl-2,3,6-trideoxy-3-trifluoroacetamido-L-ribohexopyranosyl chloride (III).
Reaction SMILES: [CH3:1][C:2]1[C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:19].[CH:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH2:21].CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH2:23]([O:22][C:20]([C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:19])[O:5][CH2:4]2)=[CH2:21])[CH2:24][CH2:25][CH3:26]
Reactant: C=COCCCC
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)ccc2c1COC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(OCCCC)c1ccc2c(c1C)COC2=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a 1 L 3-neck was charged trifluoromethanesulfonic acid 4-methyl-1-oxo-1,3-dihydro-isobenzofuran-5-yl ester (63.0 g, 213 mmol), DMF (315 mL), butyl vinyl ether (138 mL, 1063 mmol) then Et3N (35.6 mL, 255 mmol). The solution was sparged with N2 for 20 min. To the solution was added Pd(OAc)2 (1.19 g., 5.32 mmol) and DPPP (2.41 g., 5.85 mmol) and sparged for an additional 10 min then heated to 80° C. After a 1 hr age, the solution was cooled to <10° C. then quenched with 630 mL EtOAc and washed with 5% NH4Cl (2×315 mL), 10% brine (2×315 mL), dried over MgSO4, filtered, concentrated by rotary evaporation and flushed with EtOAc (3×100 mL) to remove excess butyl vinyl ether, providing crude 5-(1-butoxy-vinyl)-4-methyl-3H-isobenzofuran-1-one.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)([O-:3])=[O:2].I[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].OO>CS(C)=O.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([O-:3])=[O:2]
Reactant: CCOC(=O)CI
Reactant: O=[N+]([O-])c1ccccc1-n1cccc1
Agent: OO
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1cccn1-c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 10.9 %

Procedure:
To a stirred mixture of 1.88 g of 1-(2-nitrophenyl)pyrrole, 4.80 g of ethyl iodoacetate and 2.22 g of FeSO4.7H2O in 40 ml of dimethyl sulfoxide is added dropwise 10 ml of 301 hydrogen peroxide while keeping the reaction mixture at room temperature with a cold water bath. The mixture is stirred at room temperature for one day. An additional 2.4 g of ethyl iodoacetate, 1.1 g of FeSO4.7H2O and 5 ml of 30% hydrogen peroxide is added and the mixture stirred at room temperature for 1 day. The mixture is diluted with water and extracted with diethyl ether. The organic extract is washed with water, brine and dried (Na2SO4). The solvent is removed and the residue (2.12 g) chromatographed on silica gel with ethyl acetate-hexane (1:4) as solvent to give 0.30 g of product as a brown gum.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][CH:29]([CH2:39]O)[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].N1C=CC=CC=1>ClCCl>[Br:8][CH2:39][CH:29]([F:28])[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCC(F)CO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(F)CBr
Reaction time: 0.17 h

Procedure:
To a suspension of NBS (20 g, 110 mmol, 3.0 equiv) in dichloromethane (250 mL) was added dropwise triphenylphosphine (28 g, 110 nmol, 3.0 equiv) in dichloromethane (100 mL). After addition was complete, the reaction mixture was stirred for 10 min and a solution of tert-butyl 2-fluoro-3-hydroxypropylcarbamate (1-8) (7.0 g, 36 mmol, 1 equiv) in dichloromethane (100 mL) followed by pyridine (3.5 g, 44 mmol, 1.2 equiv) were added. The resulting mixture was stirred at 23° C. under nitrogen for 16 h. The reaction solution was concentrated and purified by silica gel chromatography (100% hexanes to 100% ethyl acetate over 1 h, analysis by Ninhydrin stain) to yield tert-butyl 3-bromo-2-fluoropropylcarbamate (1-9) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 4.89-4.68 (m, 2H), 3.55-3.40 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][N:3]=1.[CH2:10]([NH2:12])[CH3:11]>C1COCC1>[CH2:10]([NH:12][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[N:7]=1)[CH3:11]
Reactant: CCN
Reactant: Cc1nccc(C=O)n1
Solvent: C1CCOC1
Product: CCNCc1ccnc(C)n1

Procedure:
prepared by reaction of 2-methyl-pyrimidin-4-carbaldehyde with 2M ethylamine in THF.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH2:13].C(O)(=O)C.[Cl:18][CH2:19][C:20](Cl)=[O:21].C([O-])(=O)C.[Na+]>O>[Cl:18][CH2:19][C:20]([NH:13][C:4]1[CH:5]=[C:6]([C:9]([F:11])([F:10])[F:12])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:21]
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(F)(F)F)cc1NC(=O)CCl
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
To a stirred and cooled (about 10° C.) solution of 11.7 parts of 2-methoxy-5-(trifluoromethyl)benzenamine in 50 parts of acetic acid were added dropwise 7.7 parts of chloroacetyl chloride at a temperature below 20° C. After stirring for 30 minutes, there was added dropwise a solution of 24.8 parts of sodium acetate in 62 parts of water (exothermic reaction). Upon completion, stirring was continued for 30 minutes at room temperature. The precipitated product was filtered off, washed with a lot of water and dried, yielding 15.5 parts (93.3%) of 2-chloro-N-[2-methoxy-5-(trifluoromethyl)phenyl]-acetamide; mp. 94.7° C. (intermediate 62).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:23])=[O:5])[CH3:2].[CH3:24][Sn](C)(C)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH3:24])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:23])=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccc(F)cc3)sc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C)c2nc(-c3ccc(F)cc3)sc2c1O
Temperature: 130 °C
Reaction time: 0.75 h
Yield: 56.7 %

Procedure:
A mixture of 4-bromo-2-(4-fluoro-phenyl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (140 mg, 0.35 mmol), tetramethyltin (98 μL, 0.70 mmol) and bis(triphenylphosphine)palladium(II) dichloride (25 mg, 0.03 mmol) in dimethylformamide (2.5 mL) was stirred at 130° C. for 45 min before it was cooled to room temperature, quenched with water, filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (66 mg): MS: (+) m/z 333.0 (M+1).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]([NH:19][C@H:20]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH3:33])[CH:27]=1)[C:21](OC)=[O:22])=[O:18].Cl>CN(C)C=O.ClCCl>[CH2:1]([N:8]1[CH2:16][C:17](=[O:18])[NH:19][C@H:20]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH3:33])[CH:27]=2)[C:21]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](Cc1ccc(C)c(C)c1)NC(=O)CCl
Reactant: NCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C[C@H]2NC(=O)CN(Cc3ccccc3)C2=O)cc1C
Temperature: 35 °C
Reaction time: 3 h

Procedure:
Benzylamine (5.4 ml) and potassium carbonate (4.08 g) were added successively to a solution of methyl (2R)-2-(2-chloroacetylamino)-3-(3,4-dimethylphenyl)propionate (5.33 g) in N,N-dimethylformamide (25 ml) at 20° C. After 3 hours of stirring at 35° C., the mixture was poured into a mixture of ice-water (40 ml) and dichloromethane (40 ml). After the mixture was adjusted to pH 6 with concentrated hydrochloric acid (ca. 1.4 ml), the organic layer was separated, washed with brine (20 ml), dried over magnesium sulfate, and evaporated under reduced pressure. The residue was triturated with n-hexane and filtered to give colorless powders of (3R)-1-benzyl-3-(3,4-dimethylbenzyl)-2,5-piperazinedione (1.51 g). The filtrate was evaporated under reduced pressure to give an oil of methyl (2R)-2-[(2-benzylaminoacetyl)amino]-3-(3,4-dimethylphenyl)propionate (5.67 g).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].C(=O)([O-])[O-].[K+].[K+].[NH2:11][C:12]1[C:16]([C:17]#[N:18])=[C:15]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20]2)[N:14]([CH2:33][C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[Cl:41])[C:13]=1[C:42]([O:44]CC)=O.C1(C)C=CC=CC=1>N1C=CC=CC=1>[Cl:41][C:35]1[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:34]=1[CH2:33][N:14]1[C:13]2[C:42](=[O:44])[N:2]([CH3:1])[C:3](=[S:4])[NH:11][C:12]=2[C:16]([C:17]#[N:18])=[C:15]1[N:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:27])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:20]1
Reactant: CCOC(=O)c1c(N)c(C#N)c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n1Cc1cc(F)ccc1Cl
Reactant: CN=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cn1c(=S)[nH]c2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c1=O
Temperature: 130 °C

Procedure:
Methyl isothiocyanate (7.36 ml) and potassium carbonate (14.86 g) were added to a solution (200 ml) of ethyl 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1-(2-chloro-5-fluorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate (27.96 g) in pyridine, and the resulting mixture was stirred with heating at 130° C. for 13 hours. After the reaction solution was cooled to 25° C., toluene (50 ml) was added thereto and the resulting mixture was concentrated under reduced pressure. This procedure was repeated three times. The resulting residue was adjusted to pH 2 with an aqueous potassium hydrogensulfate solution and the solid precipitated was collected by filtration and washed with water and then hexane. The solid thus obtained was dried at 45° C. under reduced pressure to obtain the title compound (28.56 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].O=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[B-]C#N.[Na+]>CO>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=2[C:4]([OH:6])=[O:5])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cccc(F)c1C(=O)O
Agent: [B-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(F)c2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
2-Amino-6-fluorobenzoic acid (2.01 g, 12.93 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (5.15 g, 25.9 mmol) were combined and dissolved in methanol (50 mL). Sodium cyanotrihydroborate (1.625 g, 25.9 mmol) was added in one portion at room temperature. Reaction stirred at room temperature for 1 hour. The solvent was removed in vacuo. The resulting foam was partitioned between dichloromethane (170 mL) and 1N sodium hydroxide (65 mL). Layers were separated. The dichloromethane layer was extracted with water (2×65 mL). The aqueous layers were combined and acidified with citric acid to pH around 3. The aqueous layer was extracted with ethyl acetate (3×100 mL). The ethyl acetate layers were combined, dried (Na2SO4), filtered and concentrated to dryness. Title compound was obtained as off-white solid in 92% yield. 1H NMR (400 MHz, MeOD) δ ppm 7.18-7.28 (m, 1 H) 6.57 (d, J=8.56 Hz, 1 H) 6.27 (dd, J=11.58, 8.06 Hz, 1 H) 3.83-3.95 (m, 2 H) 3.56-3.67 (m, 1 H) 3.00-3.15 (m, 2 H) 1.93-2.04 (m, 2 H) 1.44 (s, 9 H) 1.31-1.43 (m, 2 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@H:18]([OH:21])[CH2:19][Br:20])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-])=O.C1COCC1>C1(C)C=CC=CC=1>[NH2:1][C:4]1[CH:5]=[C:6]([C@H:18]([OH:21])[CH2:19][Br:20])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cc([C@H](O)CBr)ccc1OCc1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1cc([C@H](O)CBr)ccc1OCc1ccccc1
Yield: 69.6 %

Procedure:
A solution of the product of Step A) (18.7 g, 53.1 mmol) in toluene (40 mL) and THF (40 mL) was added to a Parr shaker bottle containing Pt2O (370 mg). This mixture was shaken under H2 (50 psi, 344.74 kpa) until the reaction was complete (18 h). The catalyst was removed by filtration, and the filtrate was concentrated to an oil. Column chromatography (1 kg silica gel packed in and eluted with CH2Cl2/MeOH, 19:1) gave 11.9 g (69.6%) of the title compound.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[N:10]=[C:9]([S:11][CH3:12])[NH:8][N:7]=1.[C:13]([CH2:21][C:22](=O)[CH3:23])(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)CCC>[CH3:23][C:22]1[CH:21]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]2[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:6]2[N:5]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: CSc1nc(N)n[nH]1
Solvent: CCCCCl
Solvent: CC(=O)O
Product: CSc1nc2nc(C)cc(-c3ccccc3)n2n1
Yield: 27.2 %

Procedure:
To 50 ml of stirring glacial acetic acid, 2.5 g (19.2 mmol) of 3-amino-5-methylthio-1,2,4-triazole and 3.1 g (19.1 mmol) of benzoylacetone was added followed by heating at reflux for 2 h. The solvent was evaporated in vacuo and excess water added to the residue followed by extraction with 200 ml of ethyl acetate. The extract was washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate and evaporated in vacuo to give an oil. Addition of n-butyl chloride resulted in crystallization of a solid which was filtered and washed with n-butyl chloride to give 1.33 g of the pure title compound, m.p. 121°-123° C.