Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].Cl[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[CH:8][C:9]=1[NH:10][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[O:4]
Reactant: C=CCOC(=O)Cl
Reactant: COC(=O)c1sc(-c2cccc(Cl)c2)cc1N
Solvent: Cc1ccccc1
Product: C=CCOC(=O)Nc1cc(-c2cccc(Cl)c2)sc1C(=O)OC

Procedure:
To a solution of 3-Amino-5-(3-chloro-phenyl)-thiophene-2-carboxylic acid methyl ester (15 g, 56.0 mmol) in toluene (200 mL) was added a solution of allyl chloroformate (8.10 g, 67.2 mmol) in toluene (5.0 mL) and the resulting reaction solution was heated under reflux for 3 h. Toluene was stripped down and the crystals were collected and washed with ether/hexane to afford a yellow crystalline compound, mp 101-103° C. 1H NMR (DMSO-d6) δ3.85 (s, 3H), 4.68-4.71 (d, 2H, J=5.46 Hz), 5.26-5.30 (dd, 1H, J=1.35, 9.84 Hz), 5.36-5.42 (dd, 1H, J=1.57, 15.68 Hz), 5.96(m, 2H), 7.50-7.52 (m, 2H), 7.67-7.71 (m, 1H), 7.79 (s, 1H), 8.10 (s, 1H); MS(+APCI) m/z 352(M+H); Anal. Calc. For C16H14ClNO4S: C, 54.63; H, 4.01; N, 3.97. Found: C, 54.05; H, 4.17; N, 3.84.
Reaction SMILES: [CH3:1][C:2]([OH:8])([C:4]([CH3:7])([OH:6])[CH3:5])[CH3:3].CC(C(C)C)=C.OO.[CH:17](O)=[O:18]>>[CH:17]([O:6][C:4]([C:2]([OH:8])([CH3:3])[CH3:1])([CH3:7])[CH3:5])=[O:18]
Reactant: O=CO
Reactant: CC(C)(O)C(C)(C)O
Agent: C=C(C)C(C)C
Agent: OO
Product: CC(C)(O)C(C)(C)OC=O

Procedure:
A process for preparing 2,3-dimethyl-2,3-butandiol which comprises introducing into a reaction vessel containing formic acid at 50° to 70° C. while stirred, 2,3-dimethylbutene and hydrogen peroxide, said 2,3-dimethylbutene and hydrogen peroxide being introduced into said formic acid simultaneously but separately and thereafter hydrolyzing pinacol monoformate so formed.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[C:22](=[O:23])[C:21]3[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19]2=[O:24])=[N:2]1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: O=C1c2ccccc2C(=O)N1c1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 4.4 %

Procedure:
Compound 2 (0.06 g, 0.25 mmol) was dissolved in xylene (2.0 mL) and the solution was added with phthalic anhydride (83 mg, 0.56 mmol) and triethylamine (89 μL, 0.64 mmol), followed by stirring at 60° C. for 2 hours. Then, the reaction mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethanol to obtain Compound 159 (4.0 mg, 4%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13]>CS(C)=O.ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([CH3:13])[CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(Br)nc1
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C)C(=O)c1ccc(Br)nc1
Reaction time: 24 h
Yield: 46 %

Procedure:
N,N′-Carbonyldiimidazole (1 g, 6.17 mmol) was added to a solution of 6-bromonicotinic acid (1 g, 4.95 mmol) in dimethylsulfoxide (4.16 mL) and the mixture was stirred for 24 hours. Dimethylamine (40% in water, 8.3 mL, 37 mmol) was then added and the mixture was stirred for a further 18 hours. The reaction mixture was then diluted with dichloromethane (20 mL) and washed with water (10 mL). The organic layer was dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate to afford the title compound in 46% yield, 520 mg.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][C:6]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].C(N(C(C)C)C(C)C)C.[F:31][C:32]([F:50])([F:49])[C:33]1[CH:34]=[C:35]([C:43]([CH3:48])([CH3:47])[C:44](Cl)=[O:45])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:31][C:32]([F:50])([F:49])[C:33]1[CH:34]=[C:35]([C:43]([CH3:48])([CH3:47])[C:44]([N:2]([CH3:1])[C:3]2[CH:4]=[N:5][C:6]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:45])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(N2CCOCC2)cc1-c1ccccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 37.5 °C

Procedure:
A solution of 1.46 g (5.15 mmol) methyl-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-amine and 1.32 ml (7.73 mmol) N-ethyldiisopropylamine in 15 ml dichloromethane was cooled in an ice bath and 1.8 g (5.67 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride were added dropwise. The reaction mixture was warmed to 35-40° C. for 3 h, cooled to room temperature again and was stirred with 25 ml saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 2.9 g (quantitative) of the title compound as white crystals. M.p. 131-132° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([O:14][CH:15]([F:17])[F:16])=[C:9]([CH3:18])[CH:8]=1.[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=2[C:41]#[N:42])=[N:27]S(C(C)(C)C)=O)[CH:23]=[CH:22][N:21]=1.Cl.C(=O)(O)[O-].[Na+]>C1COCC1.CO.ClCCl>[Cl:19][C:20]1[CH:25]=[C:24]([C:26]2([C:7]3[CH:8]=[C:9]([CH3:18])[C:10]([O:14][CH:15]([F:17])[F:16])=[C:11]([CH3:13])[N:12]=3)[C:34]3[C:35](=[C:36]([F:40])[CH:37]=[CH:38][CH:39]=3)[C:41]([NH2:42])=[N:27]2)[CH:23]=[CH:22][N:21]=1
Reactant: CC(C)(C)S(=O)N=C(c1ccnc(Cl)c1)c1cccc(F)c1C#N
Reactant: Cc1cc(Br)nc(C)c1OC(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(C2(c3ccnc(Cl)c3)N=C(N)c3c(F)cccc32)nc(C)c1OC(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 36 %

Procedure:
n-Butyllithium (2.5 M in hexane, 0.144 mL, 0.36 mmol) was added dropwise to a solution of 6-bromo-3-difluoromethoxy-2,4-dimethyl-pyridine (0.29 g, 1.15 mmol) in dry THF (1 mL) at −78° C. The reaction mixture was stirred for 5 minutes and a solution of N-[(2-chloro-4-pyridyl)-(2-cyano-3-fluoro-phenyl)methylene]-2-methyl-propane-2-sulfinamide (0.28 g, 0.77 mmol) in dry THF (1 mL) was added dropwise at −78° C. The stirring was continued for 1 hour, a solution of HCl in CH3OH (1.25M, 1.1 mL) was added dropwise at −78° C. and the mixture was allowed to warm slowly to room temperature and stirred overnight. Dichloromethane (20 mL) and saturated sodium bicarbonate solution (50 mL) were added and the phases separated. The organic layer was washed with H2O, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 5% CH3OH in DCM to afford the title compound (120 mg, 36%).
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=1>>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([N:10]2[CH2:11][CH2:12][C:8]3([CH2:14][CH2:15][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[C:9]2=[O:13])=[CH:18][CH:19]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Reactant: CC(C)(C)c1ccc(Br)cc1
Product: CC(C)(C)c1ccc(N2CCC3(CCC4(CC3)OCCO4)C2=O)cc1

Procedure:
The title compound was prepared in analogy to example 336, step 1 from 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (described in example 133, step 3) and 1-bromo-4-tert-butyl-benzene. White solid (84%). MS (m/e): 344.2 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:10]([F:27])([F:26])[C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH2:19][O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:13][N:12]=1>CCO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:10]([F:27])([F:26])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:13][N:12]=1
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(/C=C/COCC(F)(F)F)cn1
Agent: [Pd]
Solvent: CCO
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(CCCOCC(F)(F)F)cn1
Reaction time: 2 h
Yield: 75 %

Procedure:
To a stirred solution of (E)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(3-(2,2,2-trifluoroethoxy)prop-1-enyl)pyridin-2-yl)propan-2-ol (6; 140 mg, 0.28 mmol) in EtOH (10 mL) was added 10% Pd/C (14 mg), and the mixture was stirred under hydrogen atmosphere for 2 h. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of Celite® and the Celite® cake was washed thoroughly with EtOAc (3×20 mL). The filtrate was concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 30% EtOAc/hexanes) afforded 45 (105 mg, 0.21 mmol, 75%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.74 (s, 1H), 8.34 (s, 1H), 7.84 (s, 1H), 7.64 (d, J=6.5 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.40-7.36 (m, 1H), 6.78-6.74 (m, 1H), 6.69-6.65 (m, 1H), 5.52 (d, J=14.0 Hz, 1H), 5.12 (d, J=14.0 Hz, 1H), 3.81 (q, J=8.0 Hz, 2H), 3.59 (t, J=6.0 Hz, 2H), 2.78 (t, J=8.0 Hz, 2H), 1.95-1.90 (m, 2H). MS (ESI): m/z 494 (M+H)+. HPLC: 96%
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[C-:11]#[N:12].[K+]>>[C:11]([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:1]([OH:3])=[O:2])#[N:12]
Reactant: O=C1OCc2ccccc21
Reactant: [C-]#N
Agent: [K+]
Product: N#CCc1ccccc1C(=O)O
Yield: 88.7 %

Procedure:
5.0 g (37.3 mmol) of phthalide and 5.0 g (76.8 mmol) of potassium cyanide, finely ground with a mortar and under vigorous stirring, were heated to 180° C. for 3.5 h in an open round-bottom flask. In the course of this, the melt darkened in color and had solidified after the reaction time. The solid was dissolved in 50 ml of dist. H2O and the solution was extracted twice with 100 ml each time of ethyl acetate. The combined organic phases contain unconverted phthalide and were discarded. The aqueous phase was admixed with 5.0 g of FeSO4.7H2O in order to bind excess cyanide and acidified with concentrated HCl down to a pH of 2. The precipitated solid was filtered off with suction through a frit filled with kieselguhr and washed with ethyl acetate, and the filtrate was transferred to a separating funnel. After phase separation, the aqueous phase was extracted twice more with 100 ml each time of ethyl acetate, the combined organic phases were dried over MgSO4 and the solvent was removed under reduced pressure. 5.34 g (33.1 mmol, 88.7%) of o-cyanomethylbenzoic acid were obtained and were used for the following reaction without further purification.
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:36][O:37][C:38](=[O:49])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47]Br)=[CH:41][CH:40]=1.CCOC(C)=O>C(Cl)Cl.CO>[CH3:36][O:37][C:38](=[O:49])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][N:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:25])[CH3:24])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[CH:41][CH:40]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(F)c1
Reactant: COC(=O)c1ccc(CCCBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(Cc2cccc(F)c2)O[Si](C)(C)C(C)(C)C)cc1
Yield: 72.9 %

Procedure:
Analogous to the procedure described in Example 1A, Step D, 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-fluoro-phenyl)-butyl]-pyrrolidin-2-one (254.7 mg, 0.697 mmol) was alkylated with NaHMDS (1M in THF, 0.84 mL, 0.84 mmol) and 4-(3-bromo-propyl)-benzoic acid methyl ester (200 mg, 0.778 mmol). Purificaton by medium pressure chromatography (5:1 hexanes:EtOAc to 1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) provided 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-fluoro-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (275.3 mg). 1H NMR (CDCl3) (selected peaks) δ7.94 (d, 2H), 7.23 (m, 3H), 6.87 (m, 3H), 3.88 (s, 3H), 3.86 (m, 1H), 3.63 (m, 1H), 3.50 (m, 1H), 2.94 (m, 1H), 0.84 (s, 9H).
Reaction SMILES: [Li].N.CCOC(CBr)=O.[C:10]([C:12]1([CH2:18][C:19]([OH:21])=[O:20])[CH:17]=[CH:16][CH2:15][CH:14]=[CH:13]1)#[N:11].[H][H]>[OH-].[NH4+].[Pd].C(#N)C1C=CC=CC=1>[CH2:15]1[CH2:14][CH2:13][C:12]([CH2:10][NH2:11])([CH2:18][C:19]([OH:21])=[O:20])[CH2:17][CH2:16]1
Reactant: N#CC1(CC(=O)O)C=CCC=C1
Reactant: [H][H]
Agent: [Pd]
Agent: CCOC(=O)CBr
Agent: N
Solvent: N#Cc1ccccc1
Product: NCC1(CC(=O)O)CCCCC1

Procedure:
In U.S. Pat. No. 6,294,690, benzo nitrile was subjected to a Birch reduction with lithium and liquid ammonia and the reduction intermediates trapped with ethyl bromo acetate. The resultant product was hydrolysed to (1-cyano cyclo hexa-2,5-dienyl) acetic acid which was hydrogenated in methanolic ammonium hydroxide for 3.5 hrs at 50 deg C. and 50 psi hydrogen pressure and on 5% palladium charcoal catalyst. The mixture was filtered and the filtrate concentrated to give crude gabapentin.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([I:12])[CH:7]=1)[OH:5].[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16].C(N(CC)CC)C>C(Cl)Cl>[F:13][C:14]([F:21])([F:20])[C:15]([NH:1][CH2:2][CH2:3][CH:4]([OH:5])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([I:12])[CH:7]=1)=[O:16]
Reactant: NCCC(O)c1cccc(I)c1
Reactant: CCOC(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCC(O)c1cccc(I)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-amino-1-(3-iodophenyl)propan-1-ol (105) (3.9 g, 14 mmol) in DCM (50 mL) were added ethyl trifluoroacetate (2 mL, 17 mmol) and triethylamine (2.95 mL, 21 mmol) and the mixture was stirred at RT for 4 h during which the reaction was found to be complete. Concentration under reduce pressure gave (2,2,2-trifluoro-N-(3-hydroxy-3-(3-iodophenyl)propyl)acetamide) as a yellow oil. The product was pure enough to be used as such for the next transformation. Yield (4.9 g, 93%): 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 4.79-4.82 (m, 1H), 3.67-3.72 (m, 1H), 3.37-3.42 (m, 1H), 2.96 (bs, 1H), 1.87-1.99 (m, 2H).
Reaction SMILES: Cl(O)(=O)(=O)=O.CC1(C)[O:11][C@@H:10]2[O:12][C@H:13]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[C@H:14]([CH2:15][CH2:16][N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[C@@H:9]2[O:8]1.O1CCCC1>C(#N)C.C(OCC)(=O)C.O>[OH:8][C@@H:9]1[C@H:10]([OH:11])[O:12][C@H:13]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:32][CH:31]=2)[C@@H:14]1[CH2:15][CH2:16][N:17]1[C:18](=[O:27])[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]1=[O:26]
Reactant: CC1(C)O[C@@H]2O[C@H](CCc3ccc(C(F)(F)F)cc3)[C@H](CCN3C(=O)c4ccccc4C3=O)[C@@H]2O1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC[C@@H]1[C@H](O)[C@H](O)O[C@@H]1CCc1ccc(C(F)(F)F)cc1
Temperature: 55 °C

Procedure:
Perchloric acid (0.2 mL) was added to a solution of the compound obtained from step e above (0.225 g) in acetonitrile (4 mL), water (1 mL), and tetrahydrofuran (0.5 mL) at room temperature. The reaction mixture was heated to 55° C. for 30 minutes. The reaction mixture was then quenched using a sodium bicarbonate solution. The solvents were evaporated at reduced pressure. The residue thus obtained was taken in ethyl acetate and water. The organic layer was separated, washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was concentrated under reduced pressure to yield the title compound (0.22 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](OC2C=CC([N+]([O-])=O)=CC=2)=[O:9])=[C:6]([NH:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:7]([C:8]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])=[O:9])=[C:6]([NH:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)nc(Nc2cccc(Cl)c2C(=O)Oc2ccc([N+](=O)[O-])cc2)n1
Reactant: CS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(Nc2cccc(Cl)c2C(=O)NS(C)(=O)=O)n1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, Step I, using equimolar amounts of 4-nitrophenyl 6-chloro-2-(4,6-dimethoxypyrimidin-2-ylamino)benzoate, methanesulfonamide, and potassium carbonate in acetonitrile, yielding 2-[3-chloro-2-(methylsulfonylaminocarbonyl)phenylamino]-4,6-dimethoxypyrimidine, Compound 39 of Table 1.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[CH:8][N:7]=[C:6]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[C:5]=12.CN(C=O)C.[Br:28]N1C(=O)CCC1=O>O>[Br:28][C:9]1[N:4]2[N:3]=[N:2][N:1]=[C:5]2[C:6]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)=[N:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccn3nnnc23)CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)n3nnnc23)CC1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
A 3 L round bottom flask was charged with tert-butyl 4-(tetrazolo[1,5-a]pyrazin-8-yl)piperazine-1-carboxylate (500 g, 1.6 mol) and DMF (2 L). To the above was added N-bromosuccinimide (320 g, 1.8 mol) in portions at 10° C. The resulting mixture was stirred at 10° C. for 0.5 h. Work-up: the reaction mixture was poured into water (3 L). The resulting crystalline solid was collected by filtration, washed with water (300 mL), and dried to afford 500 g (79%) of the product as a red solid. MS m/z: 384 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][CH:15]=[O:16])[CH2:12][N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:10](=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl([O-])=[O:26].[Na+].P([O-])(O)(O)=O.[Na+].CCOC(C)=O>CC(O)(C)C.CC(=CC)C.O>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][C:15]([OH:26])=[O:16])[CH2:12][N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:10](=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2cccc(Cl)c2)C[C@@H]1CC=O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)N(c2cccc(Cl)c2)C[C@@H]1CC(=O)O
Reaction time: 0.75 h

Procedure:
To a solution of the aldehyde from Step A (1.52 g, 4.31 mmol) in 2-methyl-2-propanol (50 mL) and 2-methyl-2-butene (10 mL) at room temperature was added a solution of sodium chlorite (585 mg, 5.17 mmol) and sodium dihydrogenphosphate (595 mg, 4.31 mmol) in 10 mL of water. The reaction turned yellow, then slowly faded to light pink over 45 minutes. The solution was poured into EtOAc, and washed with sat. sodium bisulfite soln. The aqueous layer was acidified to pH 3 with 2.75M KHSO4 soln., and extracted several times with EtOAc. The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30]C(=O)OC(C)(C)C)[C@@H:27]([S@@:38]([CH3:40])=[O:39])[C@@H:26]([CH3:41])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:42].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][C@H:28]1[C@@H:27]([S@@:38]([CH3:40])=[O:39])[C@@H:26]([CH3:41])[CH2:25][C@@H:24]([C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH:17][C:15](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([F:42])=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:14]=2)[CH2:29]1
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1[S@@](C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)[C@H]1[S@@](C)=O
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-((R)-methylsulfinyl)cyclohexylcarbamate in DCM (0.10 M) was added TFA (30.0 equiv.). The solution was capped and left standing at rt for 1 hr. The volatiles were removed in vacuo; the residue was dissolved in DMSO and purified by reverse phase HPLC. The product fractions were lyophilized directly to yield N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-((R)-methylsulfinyl)cyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 54% yield. LC/MS (m/z)=503.2 (MH+), Rt=0.57 min. 1H NMR (400 MHz, <dmso>) δ ppm 10.48 (s, 1H), 8.58 (d, J=4.0, 1H), 8.50 (d, J=4.0, 1H), 8.34 (dd, J=8.0, 4.0, 1H), 8.20 (dd, J=8.0, 8.0, 1H), 8.20 (dd, J=16.0, 4.0, 1H), 7.67-7.74 (m, 1H), 7.42 (d, J=4.0, 1H), 7.36 (dd, J=8.0, 8.0, 2H), 3.40-3.42 (m, 1H), 3.06-3.20 (m, 1H), 2.92 (s, 3H), 2.06-2.20 (m, 1H), 1.95-2.04 (m, 2H), 1.70-1.80 (m, 1H), 1.56-1.70 (m, 1H), 0.86 (d, J=8.0, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]=2[N:4]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:3]1=[O:30])=[CH:21][CH:20]=[CH:19][CH:18]=3.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>N1C=CC=CC=1>[CH2:35]([O:34][C:32]([O:1][C@@H:2]1[C@H:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]=2[N:4]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:3]1=[O:30])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:33])[CH3:36]
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)O[C@H]1C(=O)N(CCN(C)C)c2ccc3ccccc3c2S[C@H]1c1ccc(OC)cc1
Yield: 96.1 %

Procedure:
To a solution of 0.8 g of (±)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[1,2-b]-1,4-thiazepin-4(5H)-one in 10 mL of pyridine (dried over potassiuwm hydroxide) in an ice-bath, 0.4 g of ethyl chloroformate was added dropwise then stored in the freezer overnight. The mixture was concentrated under reduced pressure and the residue was partitioned between ether and dilute sodium hydroxide. The ether solution was washed with brine then dried (magnesium sulfate) and removal of the solvent gave 0.9 g (97%) of (±)-cis-3-[(ethoxycarbonyl)oxy]-2,3-dihydro-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[1,2-b]-1,4-thiazepin-4(5H)-one. A sample was crystallized from ether--pet. ether, mp 168°-169°.