Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>CC#N>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:6]1[CH2:7][CH2:8][C:9]2[NH:1][N:2]=[CH:3][C:4]=2[CH2:5]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1n[nH]c2c1CNCC2
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(CN1CCc2[nH]ncc2C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (300 mg) in MeCN (10 mL) was added Cs2CO3 (1.49 g) followed by benzyl bromoacetate (0.253 mL). The reaction mixture was stirred at RT overnight and evaporated to dryness. The residue was taken up in EA and washed with water and brine. The aq. layers were extracted with EA, the combined org. layers were dried (MgSO4), filtered off and evaporated in vacuo. The residue was purified by CC (Biotage, SNAP 10 g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8/2; gradient in % B: 15 for 7CV, 15 to 25 over 3CV, 25 for 5CV) to afford (1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)acetic acid benzyl ester (218 mg, pale yellow oil). LC-MS (B): tR=0.50 min; [M+H]+: 272.12. 1H-NMR (CDCl3): 7.40-7.33 (m, 5H); 7.30 (s, 1H); 5.21 (s, 2H); 3.73 (s, 2H); 3.52 (s, 2H); 3.50 (s, 1H); 2.98 (t, 2H, 6.0 Hz); 2.85 (t, 2H, 5.8 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C@H:9]2[C@:7]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)([CH2:8]2)[CH2:6]1.[OH:21][C:22]1[NH:27][C:26](=[O:28])[N:25]=[CH:24][C:23]=1[C:29]1[O:33][N:32]=[C:31]([CH3:34])[N:30]=1.[I-].[Na+].CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[CH3:34][C:31]1[N:30]=[C:29]([C:23]2[C:22](=[O:21])[NH:27][C:26](=[O:28])[N:25]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][C@H:9]4[C@:7]([C:11]5[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=5)([CH2:8]4)[CH2:6]3)[CH:24]=2)[O:33][N:32]=1
Reactant: Cc1noc(-c2cnc(=O)[nH]c2O)n1
Reactant: FC(F)(F)c1ccc([C@]23C[C@H]2CN(CCCCl)C3)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(-c2cn(CCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
In a 0.5/2 mL sealed MW vial (1S,5R)-3-(3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (Prep5, 62.6 mg, 0.206 mmol) was dissolved in Dimethyl Sulfoxide (DMSO) (0.8 ml), and, 6-hydroxy-5-(3-methyl-1,2,4-oxadiazol-5-yl)-2(1H)-pyrimidinone (Prep33, 40 mg, 0.206 mmol), Sodium iodide (46.3 mg, 0.309 mmol) and Dipea (0.126 mL, 0.721 mmol) were then added. The red mixture so obtained was heated at 120° C. for 4 h, then left at 80° C. overnight. The day after DIPEA (0.054 mL, 0.310 mmol) was added and the mixture and the heated at 120° C. for further 4 h. The mixture was treated with EtOAc and washed with NH4Cl sat. sol. The organic phase was dried over Na2SO4 anhydrous, filtered and evaporated under reduced pressure providing a brown residue. The crude was purified first by SCX cartridge and then by Biotage Si 12+M cartridge with a gradient of DCM/DCM/MeOH (9:1). 19 mg of the title compound were obtained as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([CH3:32])([CH3:31])[CH2:26][C:27]([O:29]C)=[O:28])=[CH:20][CH:19]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([CH3:32])([CH3:31])[CH2:26][C:27]([OH:29])=[O:28])=[CH:20][CH:19]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CC(C)(C)Cc1ccc(OCCc2cccc(NC(=O)OC(C)(C)C)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(CC(=O)O)Cc1ccc(OCCc2cccc(NC(=O)OC(C)(C)C)n2)cc1
Temperature: 0 °C

Procedure:
A mixture of the product of STEP 7 (0.5 g) in methanol (2 mL) and a solution of NaOH (1 g) in water (6 mL) was heated to reflux for 30 minutes. The mixture was cooled to 0° C., acidified to pH=4 and extracted with ethyl acetate. The extract was dried over MgSO4 and concentrated in vacuo to provide the above product as a white solid.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1.C[O:18][C:19]([NH:21][NH2:22])=[S:20]>C1(C)C=CC=CC=1>[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][CH:3]2[CH2:2][S:20][C:19](=[O:18])[NH:21][NH:22]2)=[CH:7][CH:8]=1)(=[O:15])[CH3:14]
Reactant: COC(=S)NN
Reactant: CC(=O)Nc1ccc(C=CC(=O)CCl)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(C=CC2CSC(=O)NN2)cc1

Procedure:
A mixture containing 4.0 g of 1-chloro-4-(4-acetamidophenyl)-2-oxo-3-butene (J. Org. Chem., 28, 2446, 1963) and 2.3 g of hydrazinecarbothioic acid O-methylester in 150 ml of toluene was refluxed for 3 h. The crystals were filtered and washed with toluene. Yield 3.0 g (65%), mp. 235°-240° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH3:13])[CH:12]=2)=[N:4]1)[CH3:2].[I:14]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:1]([N:3]1[CH:7]=[C:6]([I:14])[C:5]([C:8]2[S:9][CH:10]=[C:11]([CH3:13])[CH:12]=2)=[N:4]1)[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCn1ccc(-c2cc(C)cs2)n1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(I)c(-c2cc(C)cs2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of 1-ethyl-3-(4-methyl-2-thienyl)-1H-pyrazole (6.2 mmol) in 20 mL dry N,N-dimethylformamide under argon atmosphere was added N-iodosuccinimide (6.6 mmol) in small portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h, then extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane:dichloromethane 100:0 to 0:100) to afford 1.56 g 1-ethyl-4-iodo-3-(4-methyl-2-thienyl)-1H-pyrazole (76% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=1
Reactant: COC(=O)c1ccc(Cl)cc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(Cl)ccc1C(=O)OC
Yield: 84.7 %

Procedure:
To a solution of methyl 4-chloro-2-hydroxybenzoate (21 g, 112.55 mmol) in acetone (200 mL) was added ethyl 2-bromoacetate (28.3 g, 169.46 mmol) and potassium carbonate (23.4 g, 169.31 mmol). After refluxing for 3 h, the solids were collected by filtration. The resulting mixture was concentrated under vacuum, dissolved in petroleum ether (300 mL) and filtered to give methyl 4-chloro-2-(2-ethoxy-2-oxoethoxy)benzoate as a red solid (26 g, 85%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:20][N:21]=[N+]=[N-])([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.O>[C:1]([N:8]1[CH2:9][CH2:10][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)([CH2:20][NH2:21])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CN=[N+]=[N-])(C2CCCCC2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CN)(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 26.5 %

Procedure:
A 25-mL, round-bottomed flask was charged with Intermediate 1c (0.259 g, 0.803 mmol), 8 mL of THF, and triphenylphosphine (0.32 g, 0.884 mmol). The mixture was stirred at room temperature for 3.5 h and then 0.10 mL of water was added. The resulting reaction mixture was stirred at room temperature for 66 h, and then diluted with ethyl acetate and water. The layers were separated, and the organic phase was washed with water and saturated sodium chloride solution, dried over potassium carbonate, filtered and concentrated. The crude product was purified by column chromatography (gradient elution: 1:4 ethyl acetate-hexane, 9:1 ethyl acetate-methanol, and then 100% methanol) to give the free amine (0.063 g) as a clear oil.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[C:13]2[N:12]=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[CH2:7][CH2:6][CH2:5]1.[CH3:15][N:16]=[C:17]=[S:18]>C(#N)C>[CH3:15][NH:16][C:17]([NH:3][CH:4]1[C:13]2[N:12]=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)=[S:18]
Reactant: Cc1cnc2c(c1)CCCC2N
Reactant: CN=C=S
Agent: Cl
Solvent: CC#N
Product: CNC(=S)NC1CCCc2cc(C)cnc21
Yield: 99.9 %

Procedure:
The 8-amino product of Example 3 (free base) (3 g) was dissolved in acetonitrile (30 ml.) and the solution treated with methylisothiocyanate (1.35 g.) and heated at reflux for 2 hours. The solvent was removed in vacuo and the residual solid recrystallised from absolute ethanol to give the title compound as colourless needles (3 g.) m.p. 113° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH3:17])[CH:10]=1)[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>CO.O>[OH:1][CH2:2][CH:3]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH3:17])[CH:10]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(CO)c1cc(C)cc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C)cc(C(CO)C(=O)O)c1

Procedure:
A solution of ethyl 3-hydroxy-2-(3-methoxy-5-methylphenyl)-propionate (1.7 g; 7.1 mmol; from step (vi) above) and NaOH (7.0 g, 180 mmol) in 200 mL MeOH:H2O (1:1) was stirred at room temperature for 2 hours. The reaction mixture was then concentrated, washed with ether and acidified. The resulting mixture was extracted twice with ether, and the combined organic layers were washed with water, dried (Na2SO4), and evaporated to yield 1.47 g (98%).
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[CH:4]=[CH:3]1.[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].C(OCC)(=O)C>N1C=CC=CC=1>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH:9]=2)[CH:4]=[CH:3]1
Reactant: CC(C)C(=O)Cl
Reactant: Cn1ccc2ccc(N)cc21
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)C(=O)Nc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.8 %

Procedure:
To a solution of 1-methyl-1H-indol-6-amine (45 mg, 0.31 mmol) in pyridine (2 mL) at room temperature was added isobutyryl chloride (35 μL, 0.34 mmol). The resulting mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic layer was washed three times with brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 24.3 mg (36%) of the title compound (LCMS RT=5.73 min, MH+ 217.2)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:15][C:14]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:12])[CH2:5]2.Cl[CH2:39][CH2:40][O:41][CH2:42][CH2:43]Cl.CCN(C(C)C)C(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1C(=O)CCC1>[CH2:31]([O:30][C:14]1[CH:15]=[C:16]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:17]([CH:19]([CH3:21])[CH3:20])=[CH:18][C:13]=1[C:11]([N:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([N:1]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:3]=2)[CH2:7]1)=[O:12])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: ClCCOCCCl
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(N)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)c1cc(C(=O)N2Cc3ccc(N4CCOCC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 150 °C

Procedure:
A mixture of (5-amino-1,3-dihydro-isoindol-2-yl)-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-methanone (100 mg; 0.2 mmol), bis(2-chloroethyl)ether (30 μl; 1.1 equiv.), Hunigs base (125 μl; 3.5 equiv.) and tetrabutylammonium iodide (10 mg) in NMP (1 ml) was heated in a CEM microwave synthesiser at 150° C. for 30 minutes. A further 30 μl of Hunigs base and 125 μl of bis(2-chloroethyl)ether were added and heating repeated for the same time. The reaction mixture was partitioned between EtOAc and saturated NH4Cl solution, the EtOAc layer was separated, washed with more saturated NH4Cl solution, then brine, dried (MgSO4) and evaporated. Purification by flash column chromatography (1:2 then 1:1 then 2:1 EtOAc/P.E. as eluant) gave 60 mg of (2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-morpholin-4-yl-1,3-dihydro-isoindol-2-yl)-methanone. MS: [M+H]+ 328.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[Br:16]C1C=C(CC(OCC)=O)C=CC=1>>[Br:16][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:2]=1
Reactant: CCOC(=O)CCCc1ccc(Br)cc1
Reactant: CCOC(=O)Cc1cccc(Br)c1
Product: CCOC(=O)CCCc1cccc(Br)c1

Procedure:
Employing the same general multistep preparation as for ethyl 4-(4-bromophenyl)butanoate (Compound C), 60 g (246 mmol) of ethyl (3-bromophenyl)acetate (Compound B) was converted into the title compound (oil) using 255 ml (255 mmol) of diisobutylaluminum hydride (DIBAL-H, 1M in hexane), 85.8 g (250 mmol) of (carbethoxymethylene)triphenylphosphorane and 1.7 g of 10% Pd/C.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:19])=[CH:7][C:8]([C:12]3[C:13]([CH3:18])=[N:14][O:15][C:16]=3[CH3:17])=[CH:9][C:10]=2[I:11])[CH2:3][CH2:2]1.C1N=CN([C:25](N2C=NC=C2)=[O:26])C=1>C1COCC1>[CH:1]1([N:4]2[C:5]3[C:10]([I:11])=[CH:9][C:8]([C:12]4[C:13]([CH3:18])=[N:14][O:15][C:16]=4[CH3:17])=[CH:7][C:6]=3[NH:19][C:25]2=[O:26])[CH2:3][CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1noc(C)c1-c1cc(N)c(NC2CC2)c(I)c1
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(I)c2c(c1)[nH]c(=O)n2C1CC1
Temperature: 120 °C

Procedure:
To a mixture of N1-cyclopropyl-4-(3,5-dimethylisoxazol-4-yl)-6-iodobenzene-1,2-diamine (170 mg, 0.46 mmol, 1 equiv.) in a pressure tube was added THF (5 mL) and CDI (223 mg, 1.38 mmol, 3 equiv.). The mixture was heated to 120° C. for 30 minutes in a microwave reactor. The reaction was concentrated in vacuo and purified by HPLC to provide 1-cyclopropyl-5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1H-benzo[d]imidazol-2(3H)-one LCMS (m/z+1) 396.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13]CC(C)=C.C(OCC)(=O)C.N1[C:33]2[C:28](=[CH:29]C=CC=2)[CH:27]=CC=1>>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[C:4]([OH:13])[C:5]=1[CH2:29][C:28]([CH3:33])=[CH2:27]
Reactant: c1ccc2ncccc2c1
Reactant: C=C(C)COc1cc(C(=O)OC)ccc1OC
Solvent: CCOC(C)=O
Product: C=C(C)Cc1c(C(=O)OC)ccc(OC)c1O
Temperature: 185 °C

Procedure:
20 g of methyl 4-methoxy-3-(2-methyl-2-propenyloxy)benzoate are dissolved in 60 ml of quinoline and the mixture is heated at 180-190° C. for 2 h. After cooling, it is treated with ethyl acetate and the quinoline is extracted using 2N HCl. The organic phase is washed a further 2 times with water and concentrated. The oily residue is chromatographed on a silica gel column using ethyl acetate/petroleum ether (4:6). The chromatographically pure fractions are combined, concentrated and dried in a high vacuum. 15.6 g of the title compound are obtained as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:40]CC2C=CC=CC=2)[C@@H:15]([N:25](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:48][O:49]CC2C=CC=CC=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:40])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=2)[CH2:12][O:11][C@@H:10]([CH2:48][OH:49])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](COCc2ccccc2)OC[C@@H]1[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H](CO)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Yield: 88.3 %

Procedure:
Dissolve (1S,2S)-5-(R)-[1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-(R)-benzyloxymethylmorpholine-4-carboxylic acid tert-butyl ester (4.750 g, 6.226 mmol) in ethanol (63 mL) and add 20% palladium hydroxide on carbon (4.750 g). Stir under one atmosphere of hydrogen gas for 42 hours, flush with nitrogen, dilute slurry with ethanol (175 mL), filter through a filtering agent, wash with ethanol and concentrate to give the desired compound (2.213 g, 88.3%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>CN(C=O)C.ClCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1c(F)cccc1F
Yield: 76.9 %

Procedure:
A mixture of 2,6-difluorobenzoic acid (10 g, 63.3 mmol) and DMF (3 drops) in dichloromethane (150 ml) was treated with thionyl chloride (23 ml, 316.5 mmol). The mixture was heated at reflux overnight. The solvent was removed in vacuo and the residue azeotroped (toluene 3×50 ml) to give 2,6-difluorobenzoyl chloride as an oil (8.59 g, 77%). N Boc-L4-aminophenylalanine methyl ester (100.92 g, 40.6 mmol) and NMM (5.3 ml, 48.7 mmol) were added to a solution of the above acid chloride in DMF (50 nm). The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and aqueous. The aqueous layer was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried (MgSO4) and evaporated in vacuo to give a pale brown oily solid. Trituration with ether gave the title compound as a white solid (6.93 g). δH(d6 DMSO) 7.67-7.53 (3H, m), 7.27-7.20 (5H, m), 4.19-4.11 (1H, m), 3.62 (3H, s), 3.00-2.73 (2H, m), 1.33 (9H, s); m/z (ESI, 70V) 457 (M++Na).
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:8]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[N+:17]([O-])=O)[C:4]([O:6][CH3:7])=[O:5].O.O.Cl[Sn]Cl>CO>[OH:1][CH2:2][CH:3]([N:8]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)(=[O:22])=[O:21])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[NH2:17])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(CO)N(Cc1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COC(=O)C(CO)N(Cc1ccc(Cl)cc1N)S(=O)(=O)c1ccc(OC)cc1

Procedure:
A mixture of 0.454 g (1 mmol) of methyl 3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(4-chloro-2-nitrobenzyl)amino]propionate and 0.451 g (2 mmol) of SnCl2.2H2O in 12 ml of methanol was refluxed for 2 hours. An additional 0.451 g (2 mmol) of SnCl2.2H2O was added and the mixture refluxed for 2 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:19](Cl)[C:20]1[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[CH:22][CH:21]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6][CH2:7][C:8](=[O:12])[N:9]([CH2:19][C:20]3[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[CH:22][CH:21]=3)[C:10]=2[N:11]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CSc2ccc(Cl)nc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CSc3ccc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 6-chloro-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one (prepared as described in WO 2010/041194, 0.8 g, 3.99 mmol), Cs2CO3 (1.56 g, 4.78 mmol) and PMB-Cl (0.61 mL, 4.39 mmol) in DMF (8 mL) was stirred at rt for 4 h. The solvent was evaporated to dryness and the residue was partitioned between EA (20 mL) and water (25 mL). The aq. layer was extracted once with EA (15 mL) and the combined org. layers were washed with brine (20 mL), dried over Na2SO4 and concentrated to dryness. The residue (1.39 g) was crystallized in a mixture of ether/Hept (2:3). After filtration, the title compound was obtained as an orange solid (1.2 g, 93% yield).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[S:12][C:13]4[C:19]([C:20]5[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=5)=[C:18]([C@H:27]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]([CH3:38])=[CH:16][C:14]=4[N:15]=3)=[CH:8][CH:9]=2)[N:4]([CH3:39])[N:3]=1.[CH3:40][N:41]1[CH2:46][CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH2:43][CH2:42]1.C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1>[C:34]([O:33][C@@H:27]([C:18]1[C:17]([CH3:38])=[CH:16][C:14]2[N:15]=[C:11]([C:7]3[CH:6]=[C:5]4[C:10]([C:2]([C:44]5[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH:43]=5)=[N:3][N:4]4[CH3:39])=[CH:9][CH:8]=3)[S:12][C:13]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(Br)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)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: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(C5=CCN(C)CC5)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A vial was charged with (S)-ethyl 2-(2-(3-bromo-1-methyl-1H-indazol-6-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (36 mg, 57 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (13 mg, 57 mmol), KHCO3 (6.3 mg, 63 μmol), Pd(PPh3)4 (6.7 mg, 5.7 mmol), 2 M aq K2CO3 (250 mL), and dioxane (1 mL). The vessel was sealed and heated to 100° C. for 1 h. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C36H39ClN4O3S: 643.2, 645.2 (M+H+); Found: 643.0, 645.0 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.27 (s, 1H), 8.10 (d, J=8.7 Hz, 1H), 7.97-7.82 (m, 2H), 7.72-7.48 (m, 4H), 6.61 (s, 1H), 5.27 (s, 1H), 4.38-4.18 (m, 2H), 4.14 (s, 3H), 4.06-3.93 (m, 2H), 3.65-3.46 (m, 1H), 3.21-3.07 (m, 3H), 3.03 (s, 3H), 2.61 (s, 3H), 1.26 (t, J=7.1 Hz, 3H), 1.00 (s, 9H).
Reaction SMILES: [I:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH:26]([CH2:30][CH3:31])[CH2:27][O:28][CH3:29])(=O)=O)=CC=1>CN(C=O)C>[I:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:26]([CH2:30][CH3:31])[CH2:27][O:28][CH3:29])[CH:3]=1
Reactant: CCC(COC)OS(=O)(=O)c1ccc(C)cc1
Reactant: COc1nccc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(COC)n1cc(I)c2c(OC)nccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution of 3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (0.500 g) in DMF (15 mL) was added sodium hydride (60% dispersion in mineral oil, 18.3 mg), and the mixture was stirred at room temperature for 1 hr, 1-methoxybutan-2-yl 4-methylbenzenesulfonate (1.18 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (589 mg).