Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([CH:13]3[NH:12][C:7]4[C:6]5[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=5[CH:10]=[CH:9][CH:8]=4)[CH:14]3[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:22][CH:23]=2)[CH2:32][CH2:31]1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
A mixture of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (150 mg, 0.4 mmol), N-methyl-piperazine (123 mg, 1.2 mmol) and acetic acid (120 mg, 1.2 mmol) in methanol (50 mL) was stirred at room temperature for 60 min. Then the mixture was cooled to 0° C. Sodium triacetoxyborohydride (130 mg, 0.6 mmol) was added. After the addition, the mixture was stirred at room temperature for overnight. Methanol was removed under reduced pressure. The crude product was purified by pre-HPLC to give 8-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (36 mg, yield 19%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.29 (s, 3H), 2.12-2.73 (br s, 8H), 3.47 (s, 2H), 4.30 (d, J=8.0 Hz, 1H), 4.74 (d, J=8.0 Hz, 1H), 7.08-7.10 (m, 2H), 7.18-7.21 (m, 6H), 7.23-7.25 (m, 2H), 7.55-7.57 (d, J=8.0 Hz, 1H), 7.62-7.64 (m, 1H). LC-MS (ESI) m/z: 452 (M+1)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH2:18][CH2:19]C(NC1SC=CN=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:28]([CH2:19][CH2:18][CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[N+:29]=[N-:30]
Reactant: O=C(CCC1c2ccccc2C(=O)N1Cc1ccccc1)Nc1nccs1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCC1c2ccccc2C(=O)N1Cc1ccccc1

Procedure:
The product from Example 1, Part B (2.0 g, 7.5 mmol), sodium azide (731 mg, 11.25 mmol), and K2CO3 (3.1 g, 225 mmol) were stirred in 20 mL DMF at 50° C. for 16 h. The mixture was poured into water and washed with EtOAc. The organic phase was washed with water and brine, then dried (Na2SO4), filtered and evaporated. The title compound was purified by silica gel chromatography (2.04 g, 93%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[C:20]([CH:24]([NH:26]C(=O)OC(C)(C)C)[CH3:25])[CH:21]=[CH:22][CH:23]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[NH2:26][CH:24]([C:20]1[CH:19]=[C:18]([NH:17][C:14]2[N:15]=[C:16]3[C:8]([C:6]([NH:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[CH:9][NH:10][C:11]3=[N:12][CH:13]=2)[CH:23]=[CH:22][CH:21]=1)[CH3:25]
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)c1cccc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
To a solution of tert-butyl 1-(3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)ethylcarbamate (150 mg, 257 mol) in dichloromethane (4 mL) was added trifluoroacetic acid (587 mg, 397 μL, 5.15 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated then re-dissolved in dichloromethane (4 mL), methanol (2 mL) and ammonium hydroxide (0.7 mL) and the mixture stirred at room temperature for 1 h. The reaction mixture was concentrated then purified by chromatography (silica, 6-10% methanol/dichloromethane) to give 2-(3-(1-aminoethyl)phenylamino)-N-tert-butyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (64 mg, 182 mol, 71%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 9.44 (s, 1H), 8.01 (s, 1H), 7.99 (d, J=7.9, 1 H), 7.98 (s, 1H), 7.77 (s, 1H), 7.22 (t, J=7.8, 1 H), 7.20 (s, 1H), 6.98 (d, J=7.8, 1 H), 4.05 (q, J=6.1, 1 H), 1.43 (s, 9H), 1.32 (d, J=6.5, 3 H); MS (EI/CI) m/z: 353.2 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][S:15]([C:18]3[CH:26]=[CH:25][C:21]([CH2:22][CH2:23][NH2:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[N:10]=2)=[CH:5][CH:4]=1.[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]([O:44][Si:45]([CH2:50][CH3:51])([CH2:48][CH3:49])[CH2:46][CH3:47])[CH2:42]I)=[CH:37][C:36]=1[NH:52][S:53]([CH3:56])(=[O:55])=[O:54])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C1COCC1>[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([C@@H:41]([O:44][Si:45]([CH2:46][CH3:47])([CH2:48][CH3:49])[CH2:50][CH3:51])[CH2:42][NH:24][CH2:23][CH2:22][C:21]2[CH:20]=[CH:19][C:18]([S:15]([CH2:14][C:11]3[N:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[O:13][N:12]=3)(=[O:16])=[O:17])=[CH:26][CH:25]=2)=[CH:37][C:36]=1[NH:52][S:53]([CH3:56])(=[O:54])=[O:55])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(-c2nc(CS(=O)(=O)c3ccc(CCN)cc3)no2)cc1
Reactant: CC[Si](CC)(CC)OC(CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[Si](CC)(CC)O[C@@H](CNCCc1ccc(S(=O)(=O)Cc2noc(-c3ccc(OC)cc3)n2)cc1)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Yield: 57.3 %

Procedure:
A solution of the amine of Example 17 (0.90 g, 1.78 mmol), 1(S)-(4-benzyloxy-3-(methylsulfonamido)phenyl-1-triethylsiloxy-2-iodoethane (0.665 g, 1.60 mmol) and triethylamine (0.50 mL, 3.56 mmol) in THF (4 mL) was heated at 100° C. in a sealed tube for 60 h. The reaction mixture was cooled and evaporated in vacuo. The residue was flash chromatographed (silica gel; dichloromethane/ethyl ether/methanol: 25/25/0.75) to yield 0.740 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([S:16][CH3:17])[CH:14]=3)[NH:9][C:8]=2[CH3:18])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([S:16][CH3:17])[CH:14]=3)[N:9]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:8]=2[CH3:18])=[CH:4][CH:3]=1
Reactant: CSc1ccc2[nH]c(C)c(Oc3ccc(Cl)cc3)c2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2cc(SC)ccc21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of the product from step (i) (0.45 g), potassium carbonate (0.415 g) and methyl bromoacetate (0.21 ml) in DMF (3 ml) was stirred at 50° C. for 3 h. The reaction was partitioned between ethylacetate/water. The organics were washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5-15% ethylacetate/iso-hexane. Yield 0.33 g
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH2:15]([S:17][S:18][CH2:19][C@H:20]1[C:24](=[O:25])[O:23][CH2:22][N:21]1C(OC(C)(C)C)=O)[CH3:16]>ClCCl>[CH2:15]([S:17][S:18][CH2:19][C@H:20]([NH:21][CH3:22])[C:24]([OH:25])=[O:23])[CH3:16]
Reactant: CCSSC[C@H]1C(=O)OCN1C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCSSC[C@H](NC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
Triethylsilane (4.46 ml, 27.9 mmol) and trifluoroacetic acid (6.88 ml, 89.0 mmol) were added to a solution of (R)-tert-butyl 4-((ethyldisulfanyl)methyl)-5-oxooxazolidine-3-carboxylate (Compound 2e-F) (819 mg, 2.79 mmol) in dichloromethane (14 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=100/0→60/40) to afford (R)-3-(ethyldisulfanyl)-2-(methylamino)propanoic acid (Compound 2f-F) (232 mg, 43%).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[C:6]([Cl:14])[C:7]([Cl:13])=[C:8]([OH:12])[CH:9]=2)[C:4]1=[O:15])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][C:24]#[N:25].[I-].[K+]>CC(C)=O>[O:15]=[C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:12][CH2:23][C:24]#[N:25])=[C:7]([Cl:13])[C:6]=2[Cl:14])[CH2:11][CH:3]1[CH2:1][CH3:2]
Reactant: CCC1Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC1Cc2cc(OCC#N)c(Cl)c(Cl)c2C1=O

Procedure:
A mixture of 2-ethyl-5-hydroxy-6,7-dichloroindanone (24.5 g., 0.1 mole), anhydrous potassium carbonate (13.8 g., 0.10 mole), chloroacetonitrile (7.55 g., 0.10 mole) and potassium iodide (1.66 g.) in acetone (0.5 l.) is refluxed for 18 hours. The product which precipitates upon addition of water to the reaction mixture (20 g., 71%) melts at 139°-141° C. after recrystallization from butyl chloride.
Reaction SMILES: [C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH:4]=[C:5]=[CH:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[OH-].[CH3:24][N+](C)(C)C>CO>[C:1]([O:22][CH3:24])(=[O:21])[CH2:2][CH2:3][CH:4]=[C:5]=[CH:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCC/C=C\CC=C=CCCC(=O)O
Reactant: C[N+](C)(C)C
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCC/C=C\CC=C=CCCC(=O)OC

Procedure:
A solution of 300 mg of 4,5,8Z-eicosatrienoic acid was treated with 0.52 ml of a 20% solution of tetramethylammonium hydroxide in methanol. After stirring for 5 minutes at room temperature the methanol was evaporated under reduced pressure at 30 C. and 5 ml of dimethyl formamide was then added. The resulting suspension was stirred and treated with 0.25 g of methyl iodide. After 30 minutes at room temperature the reaction mixture was diluted with 30 ml of water and extracted with 100 ml of ether. The ethereal solution was washed with water and brine and then dried over sodium sulfate. Evaporation of the ether gave methyl 4,5,8Z-eicosatrienoate.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:13]=[C:14]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)[CH:15]=1.CN([CH:35]=[O:36])C>C1COCC1.C(OCC)(=O)C>[CH3:9][C:10]1[CH:15]=[C:14]([C:16]2[S:20][C:19]([CH:35]=[O:36])=[N:18][CH:17]=2)[CH:13]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=2)[CH:11]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C=O)s2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a flask was added tetrahydrofuran (60 mL) and the solution was cooled to −78° C. Lithium diisopropylamide (19.8 mL, 35.7 mmol) was added and the mixture was allowed to cool to −78° C. INTERMEDIATE 4 (4.0 g, 11.90 mmol) was dissolved in THF (60 mL) and added in portion. The solution was stirred for 30 minutes. DMF (1.30 g, 17.84 mmol) was dissolved in THF (60 mL) and added over a period of five minutes. The solution was then allowed to warm to room temperature. The reaction mixture was then diluted with ethyl acetate, washed with saturated ammonium chloride, dried over magnesium sulfate, filtered and concentrated. The solid was purified by silica gel column chromatography to yield 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carbaldehyde (3.5 g, 81%). MS ESI: [M+H]+ m/z 364.8. 1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.91 (s, 1H), 8.86 (d, J=5.3, 1H), 8.57 (s, 1H), 8.19 (s, 1H), 7.54 (s, 1H), 7.38 (s, 1H), 731 (d, J=5.2, 1H), 2.35 (s, 3H).
Reaction SMILES: [C:1]([Mg]Br)#[C:2][CH3:3].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](S(C2C=CC=CC=2)(=O)=O)[N:8]=1>C1COCC1>[C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[N:8]=1)#[C:2][CH3:3]
Reactant: O=S(=O)(c1ccccc1)c1cccc(F)n1
Reactant: CC#C[Mg]Br
Solvent: C1CCOC1
Product: CC#Cc1cccc(F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.06 mol of propynylmagnesiumbromide and 25 ml of THF is added at 40°-40° C. [sic] to a mixture of 0.05 mol of 2A and 15 ml of THF. The mixture is stirred at room temperature for 2 hours and subjected to customary work-up. The unpurified product is processed further as in 10B.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1.[NH2:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([C:31]3[C:32]([CH3:45])=[CH:33][C:34]([F:44])=[C:35]([NH:37][C:38](=O)[O:39]C(C)=C)[CH:36]=3)[C:24](=[O:30])[N:25]2[CH2:28][CH3:29])=[CH:20][N:19]=1>O1CCOCC1.CN1CCCC1.CS(C)=O>[NH2:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([C:31]3[C:32]([CH3:45])=[CH:33][C:34]([F:44])=[C:35]([NH:37][C:38]([NH:6][C:5]4[CH:7]=[CH:8][C:2]([F:1])=[C:3]([CH2:9][N:10]5[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]5)[CH:4]=4)=[O:39])[CH:36]=3)[C:24](=[O:30])[N:25]2[CH2:28][CH3:29])=[CH:20][N:19]=1
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(N)cc3n(CC)c2=O)c(C)cc1F
Reactant: CN1CCN(Cc2cc(N)ccc2F)CC1
Agent: CN1CCCC1
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccc(F)c(CN4CCN(C)CC4)c3)c(F)cc2C)cc2cnc(N)cc21
Temperature: 80 °C
Yield: 21.9 %

Procedure:
A mixture of Example D2 (0.100 g, 0.448 mmol) and prop-1-en-2-yl (5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)carbamate (0.142 g, 0.358 mmol) in dioxane (3 mL) was treated with 1-methylpyrrolidine (3 drops) and heated at 80° C. overnight. The mixture was treated with DMSO (2 drops) and heated at 80° C. for an additional 24 h. The mixture was cooled to RT, concentrated to dryness and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over MgSO4 and concentrated to dryness to afford 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (44 mg, 22% yield). 1H NMR (400 MHz, pyridine-d5): δ 9.87 (s, 1H), 8.89 (s, 1H), 8.71 (m, 1H), 8.60 (s, 1H), 7.97 (dd, J=6.5, 2.8 Hz, 1H), 7.79 (dt, J=8.7, 3.6 Hz, 1H), 7.64 (s, 1H), 7.26 (s, 2H), 7.15 (t, J=9.2 Hz, 1H), 7.07 (d, J=12.0 Hz, 1H), 6.56 (s, 1H), 4.17 (q, J 7.1 Hz, 2H), 3.58 (s, 2H), 2.53 (s, 4H), 2.30 (m, 7H), 2.13 (s, 3H), 1.16 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 562.2 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][CH:5]([F:35])[C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27]OS(C)(=O)=O)=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:34])[CH3:33])=[O:7]>O1CCCC1>[CH3:1][N:2]([CH2:27][C:24]1[N:25]=[CH:26][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C@H:11]3[O:10][C:9]([CH3:34])([CH3:33])[N:8]([C:6](=[O:7])[CH:5]([F:35])[F:4])[C@@H:12]3[CH2:13][F:14])=[CH:16][CH:17]=2)=[CH:22][CH:23]=1)[CH3:3]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(COS(C)(=O)=O)nc3)cc2)[C@H](CF)N1C(=O)C(F)F
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 610.1 %

Procedure:
To a stirred solution of dimethyl amine (2.0M solution in tetrahydrofuran) (0.31 mL, 0.028 mmol) in tetrahydrofuran (5 mL) is added methanesulfonic acid 5-{4-[(4R,5R)-3-(2,2-difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyridin-2-ylmethyl ester (0.1 g, 0.212 mmol) and stirred at room temperature overnight. The solvent is evaporated in vacuo and the crude material is purified by combi-flash chromatography using 10% methanol in CH2Cl2 as an eluent to afford the title compound (0.072 g). 1H-NMR (400 MHz, DMSO-d6) δ: 1.53 (s, 3H), 1.60 (S, 3H), 2.21 (s, 6H), 3.56 (s, 2H), 4.56-4.58 (m, 0.5H), 4.66-4.72 (m, 1H), 4.80-4.84 (m, 0.5H), 4.90-4.94 (m, 1H), 5.26 (d, J=3.76 Hz, 1H), 6.64 (t, J=52.36 Hz, 1H), 7.50 (d, J=8.08 Hz, 1H), 7.59 (d, J=8.08 Hz, 2H), 7.78 (d, J=8.12 Hz, 2H), 8.07-8.09 (m, 1H), 8.81 (s, 1H). LC-MS (m/z): [M+H]=422.
Reaction SMILES: [I:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:13]O.S(=O)(=O)(O)O>O>[I:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: CO
Reactant: COc1cccc(C(=O)O)c1I
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cccc(OC)c1I
Temperature: 25 °C
Yield: 90 %

Procedure:
A stirred mixture of 2-iodo-3-methoxybenzoic acid (20 g, 0.07 mol; prepared in a manner similar to that described above), methanol (300 ml) and concentrated sulphuric acid (3.5 ml) was heated under reflux for 8 hours, cooled to ambient temperature and added to water (1500 ml). The product was extracted into dichloromethane (3×500 ml), the combined extracts were washed with 5% aqueous sodium hydroxide solution (3×500 ml), then they were dried (MgSO4) and the solvent was removed in vacuo to give methyl 2-iodo-3-methoxybenzoate (18.5 g, 90%) as a solid, m.pt. 58-61° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]([CH2:15][CH:16]1[O:21][CH2:20][CH2:19][NH:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].O=[CH:25][CH2:26][CH2:27][C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:23][C:2]([F:22])([F:1])[C:3]([N:5]([CH2:15][CH:16]1[CH2:17][N:18]([CH2:25][CH2:26][CH2:27][C:28]2[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=2)[CH2:19][CH2:20][O:21]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:4]
Reactant: CCOC(=O)c1ccc(CCC=O)cc1
Reactant: O=C(N(CC1CNCCO1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)c1ccc(CCCN2CCOC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(morpholin-2-ylmethyl)-N-((1R,2S)-2-phenylcyclopropyl)acetamide (150 mg, 0.457 mmol) in 1,2-dichloroethane (DCE) (3 mL) were added ethyl 4-(3-oxopropyl)benzoate (113 mg, 0.548 mmol) and sodium triacetoxyborohydride (145 mg, 0.685 mmol), and the mixture was stirred at room temperature for 18 h. The reaction was quenched with water (5 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 20 to 100% EtOAc/hexanes) to give 200 mg or product as colorless oil. MS: (M+H)+=395.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.34-1.46 (m, 4H), 1.56 (br. s., 1H), 1.71-1.94 (m, 3H), 2.07-2.22 (m, 1H), 2.29-2.46 (m, 2H), 2.57 (br. s., 1H), 2.67-2.78 (m, 3H), 3.12-3.22 (m, 1H), 3.53-3.69 (m, 3H), 3.75-3.94 (m, 2H), 4.29-4.43 (m, 2H), 7.07-7.46 (m, 7H), 7.89-8.04 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][N:7]=1)(=[O:4])=[O:3].[Cl:15][C:16]1[CH:17]=[N+:18]([O-:45])[CH:19]=[C:20]([Cl:44])[C:21]=1[CH2:22][C@@H:23]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[C:31]([O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[CH:30]=1)[O:24][C:25](=[O:28])[CH2:26]O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:44][C:20]1[CH:19]=[N+:18]([O-:45])[CH:17]=[C:16]([Cl:15])[C:21]=1[CH2:22][C@@H:23]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[C:31]([O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[CH:30]=1)[O:24][C:25](=[O:28])[CH2:26][O:13][C:12]([C:9]1[CH:8]=[N:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[N:11][CH:10]=1)=[O:14]
Reactant: CS(=O)(=O)Nc1ncc(C(=O)O)cn1
Reactant: O=C(CO)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CS(=O)(=O)Nc1ncc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cn1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
To a suspension of 2-(methylsulfonamido)pyrimidine-5-carboxylic acid (0.130 g, 0.599 mmol) in dry DCM (5.44 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-hydroxyacetoxy)ethyl)pyridine 1-oxide (See Scheme 21, step 6-9) (0.260 g, 0.544 mmol), EDC (0.313 g, 1.632 mmol), and DMAP (0.665 g, 0.544 mmol) were sequentially added with stirring at room temperature under nitrogen, and the mixture was stirred for 20 hours. The solvent was removed, and the crude was purified by flash chromatography on silica gel column (DCM:MeOH=97:3 to 95:5) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(2-(methylsulfonamido)pyrimidine-5-carbonyloxy)acetoxy)ethyl)pyridine 1-oxide as a pale yellow spongy solid (0.168 g, 0.248 mmol, 45.6% yield, MS/ESI+ 677.1 [MH]+, [αD]=−47.48, c=0.5, MeOH).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[H-].[Na+].Cl[C:10]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=1[CH:12]=O.Cl>CN(C)C=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:10]2[S:3][C:2]([C:1]([O:5][CH3:6])=[O:4])=[CH:12][C:11]=2[CH:14]=1)([O-:20])=[O:19]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: COC(=O)CS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
Methyl thioglycolate (19.62 mL, 0.216 mol) was added dropwise, via syringe pump, to a stirred suspension of 95% sodium hydride (5.99 g, 0.237 mol) in dry N,N-dimethyl-formamide (400 mL) at r.t. under nitrogen (CAUTION: hydrogen evolution). Upon complete addition, the reaction was stirred for 10 min and then a solution of 2-chloro-5-nitrobenzaldehyde (40.0 g, 0.216 mol) in DMF (120 mL) was added. The solution turned orange and a gentle exotherm was observed. After 1 h, the now yellow mixture was heated to 100° C. for 5 h. The mixture turned amber in appearance. After cooling to r.t. the mixture was poured into 1 N aqueous hydrochloric acid (500 mL). The resulting yellow precipitate was filtered off and washed with water (250 mL). The solid was suspended in hot methanol/ethyl acetate (1:1) (1000 mL) and allowed to cool to r.t. The resulting solid was filtered off and air dried to yield methyl 5-nitrobenzo[b]thiophene-2-carboxylate (33.77 g, 66%) as a tan amorphous solid. 1H NMR δ (d6-DMSO, 400 MHz) 3.92 (s, 3 H), 8.32 (dd, J=9, 2 Hz, 1 H), 8.37 (d, J=9 Hz, 1 H), 8.45 (s, 1 H), 9.00 (d, J=2 Hz, 1 H).
Reaction SMILES: [OH-].[K+].O.[CH3:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:13]=2[C:14]([O:16]C)=[O:15])[CH:8]=[CH:9][C:10]=1[F:11].[CH3:23]O>>[CH3:23][C:21]1[C:12]([C:7]2[CH:8]=[CH:9][C:10]([F:11])=[C:5]([CH3:4])[CH:6]=2)=[C:13]([CH:18]=[C:19]([F:22])[CH:20]=1)[C:14]([OH:16])=[O:15]
Reactant: CO
Reactant: COC(=O)c1cc(F)ccc1-c1ccc(F)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(-c2c(C)cc(F)cc2C(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium hydroxide (6 g) and water (50 mL) were added to a solution of methyl 2-(3-methyl-4-fluorophenyl)-5-fluorobenzoate (10.2 g, 40.0 mmol) in methanol (150 mL) and the mixture was stirred at room temperature for 18 h. The reaction mixture was then evaporated to near dryness, acidified with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, and concentrated to leave a residue which was chromatographed on silica gel using 30% ethyl acetate in hexane to provide 9.7 g of the acid.