Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:16][F:17])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11](/[CH:13]=[N:14]/[OH:15])=[CH:12][C:4]1=2.C1C(=O)N(Cl)C(=O)C1.[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([C:35]([F:38])([F:37])[F:36])=[CH2:34])[CH:30]=[C:29]([Cl:39])[C:28]=1[Cl:40].Cl>CN(C=O)C.O>[F:17][CH2:16][C:3]1([CH2:2][F:1])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11]([C:13]3[CH2:34][C:33]([C:31]4[CH:30]=[C:29]([Cl:39])[C:28]([Cl:40])=[C:27]([Cl:26])[CH:32]=4)([C:35]([F:38])([F:37])[F:36])[O:15][N:14]=3)=[CH:12][C:4]1=2
Reactant: O/N=C/c1ccc2c(c1)C(CF)(CF)OB2O
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: OB1OC(CF)(CF)c2cc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)ccc21
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 15.9 %

Procedure:
To a solution of (E)-3,3-bis(fluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (440 mg, 1.83 mmol) in DMF (10 mL) at rt was added NCS (294 mg, 2.19 mmol). The reaction mixture was warmed to 45° C., stirred for 2.5 h and cooled to rt. To a solution of 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (577 mg, 2.10 mmol) and TEA (403 mg, 4.0 mmol) in DMF (10 mL) was added the above mixture dropwise at 0° C. The mixture was stirred at 0° C. for 1 h, then stirred at rt overnight. The mixture was acidified with HCl (3 N) to pH of 2, then poured into water and extracted with EA (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EA=2:1) to give the final title compound (150 mg, 16%) as white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.74 (s, 1H), 7.96-7.80 (m, 5H), 4.89-4.80 (m, 2 H), 4.73-4.64 (m, 2H), 4.46 (d, J=17.4 Hz, 1H), 4.35 (d, J=17.4 Hz, 1H) ppm; HPLC purity: 95.3% at 214 nm; MS: m/z=516 (M+1, ESI+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:16][CH2:17][CH3:18])[CH2:10][NH:11][NH:12][C:13](=[O:15])C.[CH:19](O)=[O:20]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:16][CH2:17][CH3:18])[CH2:10][N:11]([CH:19]=[O:20])[NH:12][CH:13]=[O:15]
Reactant: O=CO
Reactant: CCCC(CNNC(C)=O)c1ccc(Cl)cc1Cl
Product: CCCC(CN(C=O)NC=O)c1ccc(Cl)cc1Cl

Procedure:
5.0 g (0.017 mol) of 1-[2-(2,4-dichlorophenyl)-pentyl-2-acetylhydrazine in 20 ml of 85% aqueous formic acid are heated for 18 hours at 100° C. Column-chromatography of the residue obtained after concentration by evaporation yields pure 1-[2-(2,4-dichlorophenyl)-pentyl]-1,2-diformylhydrazine:
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=4)=[O:21])=[CH:15][CH:14]=3)[C:9]([CH2:11][OH:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH2:34](N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=4)=[O:21])=[CH:15][CH:14]=3)[C:9]([CH2:11][O:12][CH3:34])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccnc(NC(=O)Nc2ccc(-c3c(CO)cn4ncnc(N)c34)cc2)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COCc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C)ccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of DCM (5 mL) was added N-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(4-methylpyridin-2-yl)urea (Example 262) (40 mg, 0.10 mmol) followed by 2M thionyl chloride in DCM (0.51 mL, 1.03 mmol). The solution was stirred at rt for 1 h and was then evaporated in vacuo. THF (5 mL) and MeOH (5 mL) were added to the crude reaction followed by triethylamine (43 μL, 0.31 mmol). The solution was heated to 50° C. for 3 d and then evaporated in vacuo and purified by MPLC (Isco) 0-5% MeOH/DCM. The resulting purified fractions were combined and evaporated producing 25 mg of the title compound (0.061 mmol, yield 60%). 1H-NMR (DMSO-d6) δ 10.86 (s, 1H), 9.46 (s, 1H), 8.14 to 8.13 (d, J=6.3 Hz, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.65 to 7.63 (d, J=8.7 Hz, 2H), 7.36 to 7.34 (d, J=8.6 Hz, 2H), 7.27 (s, 1H), 6.87 to 6.86 (d, J=5.0 Hz, 1H), 4.27 (s, 2H), 3.20 (s, 3H), 2.30 (s, 3H); MS [M+H]+=404.0; LCMS RT=1.99 min.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:12])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([O:12][C:13](=[O:15])[CH3:14])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)CCCC(O)CCCCl
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC(CCCCl)CCCC(C)C

Procedure:
A mixture of 1-chloro-8-methyl-4-nonanol (22.73 g.; 0.118 mole) and acetic anhydride (24.07 g.; 0.236 mole) is heated on a steam bath for 11/2 hours.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.C([Li])CCC.Cl>O1CCCC1.CCCCCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([B:17]([OH:22])[OH:18])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(Br)ccc1OCc1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Under nitrogen stream, 1-(benzyloxy)-4-bromo-2-fluorobenzene (12.0 g, 43 mmol) was dissolved in tetrahydrofuran, followed by addition of triisopropyl borate (11.8 mL, 51 mmol), and then the mixture was cooled to −78° C. Butyl lithium (1.55M hexane solution) (30 mL, 47 mmol) was slowly added dropwise, and the mixture was stirred for 1 hour at −78° C. A 1N aqueous hydrochloric acid solution (100 mL) was added to the reaction mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was distilled off under reduced pressure. The aqueous phase was extracted with ethyl acetate, the extracted solution was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue obtained was suspended in hexane, and was then collected by filtration to give the title compound (9.27 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:11]=[C:10]([CH3:12])[NH:9][N:8]=2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>>[Br:13][C:11]1[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:8][NH:9][C:10]=1[CH3:12]
Reactant: Cc1cc(-c2ccc(Cl)s2)n[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: Cc1[nH]nc(-c2ccc(Cl)s2)c1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
3-(5-chloro-2-thienyl)-5-methyl-1H-pyrazole (111 mmol) was dissolved in 200 mL dry 1V, N-dim ethyl formamide and cooled to 0° C. under nitrogen atmosphere. N-Bromosuccinimide (118 mmol) was added in small portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The solution was poured into a mixture of saturated aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution (1:1) at room temperature. The precipitate was filtered, washed thoroughly with water, dissolved in ethyl acetate, dried over MgSO4, filtered and evaporated to afford 19.5 g of 4-bromo-3-(5-chloro-2-thienyl)-5-methyl-1H-pyrazole (64% yield) that was used without further purification.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([CH2:26][OH:27])[CH2:23]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]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[N:35]1>>[OH:27][CH2:26][CH:24]1[CH2:25][N:22]([C:3]2[C:2]([C:36]3[NH:35][N:34]=[CH:38][CH:37]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 37 using 5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 39.1) and 1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester. UPLC-MS (Condition 3) tR=0.87 min, m/z=434.2 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 2.59-2.68 (m, 1H) 3.47 (d, J=6.02 Hz, 2H) 3.53-3.61 (m, 2H) 3.77-3.87 (m, 2H) 6.45 (d, J=1.88 Hz, 1H) 7.35 (d, J=8.66 Hz, 2H) 7.79 (br. s, 1H) 7.86 (d, J=9.03 Hz, 2H) 8.10 (s, 1H) 8.69 (d, J=1.69 Hz, 1H) 10.28 (s, 1H).
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH2:16]([C:23]1[CH:24]=[C:25]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]#[N:39])=[CH:32][C:31]=2[CH2:40][CH:41]([CH3:43])[CH3:42])[CH:26]=[CH:27][C:28]=1O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>N1C=CC=CC=1>[CH2:16]([C:23]1[CH:24]=[C:25]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]#[N:39])=[CH:32][C:31]=2[CH2:40][CH:41]([CH3:43])[CH3:42])[CH:26]=[CH:27][C:28]=1[O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)Cc1cc(CCC#N)ccc1-c1ccc(O)c(Cc2ccccc2)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: CC(C)Cc1cc(CCC#N)ccc1-c1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
0.10 ml (0.59 mmol, 1.8 eqv) triflic anhydride was added to a solution of 116.8 mg (0.32 mmol) 3-(3′-Benzyl-4′-hydroxy-2-Isobutyl-1,1′-biphenyl-4-yl)propanenitrile (25) in 5 ml pyridine at 0° C. The resulting mixture was stirred at 0° C. for 30 min and then at rt for 18 h. After that, water was added and the mixture was extracted with Et2O. The comb. org. fractions were washed with brine, dried over MgSO4 and evaporated. Column chromatography (Hexanes/EtOAc (1+1)) yielded 136.9 mg (0.27 mmol, 85%) 26 as a pale violet solid: Rf (Hexanes/EtOAc (1+1)) 0.59, 1H NMR (500 MHz, CDCl3) δ 0.64 (d, 6H, J=6.62 Hz), 1.51 (m, 1H), 2.31 (d, 2H, J=7.25 Hz), 2.61 (t, 2H, J=7.41 Hz), 2.93 (t, 2H, J=7.41 Hz), 4.07 (s, 2H), 7.03-7.08 (m, 4H), 7.13-7.21 (m, 4H), 7.24-7.31 (m, 3H); LRMS (EI) m/z 503 (10), 502 (36), 501 (100), 369 (17), 368 (45), 326 (14), 91 (43); HRMS (EI) Calcd. for C27H26F3NO3S: 501.158551. Found: 501.158983.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][C@H:36]1[CH2:40][OH:41]>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH:36]2[CH2:40][OH:41])=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Reactant: NCCCCN1CCC[C@H]1CO
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCCC3CO)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and (S)-[1-(4-amino-butyl)-pyrrolidin-2-yl]-methanol by the procedure analogous to Example 6. HPLC ret. time: 3.2 minutes. 1H NMR (400 MHz, CD3OD) δ 7.18 (dd, 1H, J=6.0, 9.2 Hz), 7.04 (dd, 1H, J=6.4, 10 Hz), 5.45 (s, 2H), 3.62-3.56 (m, 2H), 3.29-3.23 (m, 2H), 3.02 (m, 1H), 2.78 (m, 1H), 2.83 (m, 1H), 2.51 (m, 2H), 2.24 (d, 3H, J=1.6 Hz), 2.02 (m, 1H), 1.88-1.56 (m, 7H) ppm; MS (APCl, m/z): 498 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:7][CH:8]=1.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[Cl:23][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(OCCc2ccc(CO)cn2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(OCCc2ccc(CCl)cn2)cc1
Yield: 96.7 %

Procedure:
To a solution of 5-hydroxymethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine (9.4 g) in chloroform (100 ml) was added thionyl chloride (7.0 g) and the mixture was stirred under reflux for 30 minutes. After cooling, the reaction mixture was washed with saturated aqueous solution of sodium bicarbonate and then water, dried over magnesium sulfate and concentrated under reduced pressure to obtain 5-chloromethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine (9.7 g, yield: 85%). The compound was recrystallized from ethyl acetate-hexane to obtain colorless needles, m.p. 77°-78° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].C(N(CC)CC)C.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH:18]([Cl:22])[C:19]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:1]#[CH:2])[CH:4]=1)=[O:20]
Reactant: C#Cc1cccc(N)c1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#Cc1cccc(NC(=O)C(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Ethynylaniline (2.61 g, 22.3 mmol) was dissolved in anhydrous dichloromethane (20 mL) with triethylamine (3.1 mL, 22.3 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (2.21 mL, 23 mmol) in anhydrous dichloromethane (20 mL) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature for 2 h. The reaction mixture was then washed successively with water, 10% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a beige solid (m.p. 99–100° C.). NMR (300 MHz, CDCl3): 8.05 (broad s, 1H, NH), 7.69 (s, 1H), 7.62 (m, 1H), 7.33 (m, 2H), 6.04 (s, 1H), 3.10 ppm (s, 1H, acetylenic).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20](S(C)(=O)=O)[C:15]=3[CH:14]=2)=[CH:4][CH:3]=1.CC1([N:34]2C(C3SC4N=CN=C(S(C)(=O)=O)C=4C=3)=CN=C2)C=CC=CC1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:34])[C:15]=3[CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC1(n2cncc2-c2cc3c(S(C)(=O)=O)ncnc3s2)C=CC=CC1
Reactant: Cn1cnc(-c2ccc(I)cc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Product: Cn1cnc(-c2ccc(I)cc2)c1-c1cc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 6-[4-(4-Iodophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (Intermediate 63) in place of 6-(1-Methylphenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 17). Solid (116 mg, 74%);
Reaction SMILES: O=C1COCC(=O)N1.CS([O-])(=O)=O.[C:14]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][O:16][CH2:15]1.[NH2:22][CH2:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][CH2:23][NH:22][C:18](=[O:19])[CH2:17][O:16][CH2:15][C:14]([OH:20])=[O:21]
Reactant: O=C1COCC(=O)O1
Reactant: NCCCO
Agent: CS(=O)(=O)[O-]
Agent: O=C1COCC(=O)N1
Product: O=C(O)COCC(=O)NCCCO

Procedure:
4-[2-(4-Bis(2-bromo-p-tolyl)methyl)piperidino)propyl]-3,5-dioxomorpholine.methanesulfonate by (a) reacting diglycolic anhydride and 3-aminopropanol to produce [2-(3-hydroxypropyl)amino-2-oxoethoxy]acetic acid, (b) heating to cyclize the latter to obtain 4-(3-hydroxypropyl)-3,5-dioxomorpholine, (c) esterifying the latter with methanesulfonyl chloride to produce 3-(3,5-dioxomorpholino)propyl methanesulfonate and (d) reacting the mesylate with 4-[bis(2-bromo-p-tolyl)methyl]piperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH3:15][O-:16].[Na+]>>[NH2:1][C:2]1[CH:7]=[C:6]([O:16][CH3:15])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: C[O-]
Reactant: Nc1cc(Cl)nc(-c2ccccc2)n1
Agent: [Na+]
Product: COc1cc(N)nc(-c2ccccc2)n1

Procedure:
Using the method of Example 33, 4-amino-6-chloro-2-phenylpyrimidine was reacted with sodium methoxide to provide solid 4-amino-6-methoxy-2-phenylpyrimidine. The structural assignment was supported by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:53]=[C:54]([NH2:67])[C:55]4[C:59]([CH:60]=3)=[N:58][N:57](C3CCCCO3)[CH:56]=4)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1>CN(C=O)C>[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:60]=[C:59]4[C:55]([CH:56]=[N:57][NH:58]4)=[C:54]([NH:67][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:53]=3)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ccccc1
Reaction time: 0.08 h

Procedure:
Benzoic acid (10 mg, 0.08 mmol) in DMF (0.2 mL) was treated with HATU (27 mg, 0.07 mmol) in DMF (0.2 mL) and DIPEA (30 μL, 0.24 mmol). The reaction mixture was shaken for five minutes prior to treatment with 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (20 mg, 0.06 mmol) in DMF (0.2 mL). Reaction mixture was shaken for five minutes and left to stand at 22° C. for 18 hrs. Solvent was removed in vacuo and the product re-dissolved in methanol (1 mL) prior to application on to an SCX cartridge (1 g). Product was eluted after 1 hr with 2M ammonia in methanol (2×3 mL), fractions were combined and concentrated under a stream of nitrogen using blow down apparatus. Purification by MDAP (Method D) afforded the title compound.
Reaction SMILES: [F:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C2[O:36]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.O1CN1>C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH2:7][CH2:6][C:5]([OH:36])([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: O=C(OCc1ccccc1)C1CC=C(F)CC1
Agent: C1NO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)C1(O)CC=C(F)CC1
Temperature: -78 °C

Procedure:
A mixture of benzyl 4-fluorocyclohex-3-ene-1-carboxylate (1.77 g, 7.56 mmol) and 38 mL of THF was stirred vigorously and cooled to −78° C. To the reaction mixture was added dropwise over 15 minutes a solution of 0.5 M potassium bis(trimethylsilyl)amide in toluene (2.56 g, 12.8 mmol. The reaction mixture was allowed to stir vigorously for 1 hour. In a separate flask, 3-phenyl-2-(phenyl-sulfonyl)oxaziridine (2.17 g, 8.31 mmol) was dissolved in 2 mL of THF. The oxaziridine solution was then added to the reaction mixture dropwise. The reaction mixture was allowed to stir for 2 hours more and quenched with a saturated aqueous ammonium chloride solution. The biphasic reaction was separated and the aqueous layer was extracted three times with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered, concentrated and purified by chromatography on silica gel, eluting with 0-15% EtOAc in hexanes, to give benzyl 4-fluoro-1-hydroxycyclohex-3-ene-1-carboxylate as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[S:5][C:6]=1[NH2:7].C(N(CC)CC)C.[F:21][C:22]([F:28])([F:27])[CH2:23][C:24](Cl)=[O:25]>C1COCC1>[F:21][C:22]([F:28])([F:27])[CH2:23][C:24]([NH:7][C:6]1[S:5][C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:3][C:2]=1[CH3:1])=[O:25]
Reactant: O=C(Cl)CC(F)(F)F
Reactant: Cc1nc(-c2cccnc2)sc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cccnc2)sc1NC(=O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
286 mg (1.49 mmol) of 4-methyl-2-(pyridin-3-yl)-1,3-thiazole-5-amine were dissolved in THF, 0.52 ml of triethylamine was added, and 263 mg of trifluoropropionyl chloride were added while cooling with an ice bath. The mixture was stirred at room temperature overnight and then concentrated. Ethyl acetate, saturated sodium chloride solution and aqueous phosphate buffer pH=7 were added to the residue, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by chromatography (silica gel, cyclohexane, acetone).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:10][C@H:11]([CH2:19][C:20]1[N:21]=[N:22][N:23]([CH2:25][CH2:26]O)[CH:24]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:42]C(F)(C(F)(F)F)C(F)(F)C(F)(F)S(F)(=O)=O.F.F.F.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:10][C@H:11]([CH2:19][C:20]1[N:21]=[N:22][N:23]([CH2:25][CH2:26][F:42])[CH:24]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1cn(CCO)nn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1cn(CCF)nn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 144 h

Procedure:
Di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-{[1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl]methyl}-L-glutamate (74 mg, 152.7 μmol) was dissolved in tetrahydrofuran (5 ml) and triethyl amine (319 μl, 2.3 mmol), Nonafluorobutanesulfonyl fluoride (185 mg, 611 μmol), and Triethylamine trihydrofluoride (98 mg, 611 mmol) were added subsequently. The mixture was stirred at room temperature for 6 days. The mixture was than concentrated in vacuo, and the residue was purified by silica gel chromatography to yield 30 mg (40%) of slightly impure product, which was used in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([N:11]2[C:19]3[C:14](=[C:15]([CH3:23])[CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[NH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:34]([O:33][C:31](=[O:32])[C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:24][CH3:25])(=[O:9])=[O:10])=[C:15]([CH3:23])[CH:16]=2)=[O:21])=[CH:37][CH:36]=1)[CH3:35]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2c(C)cc(C(=O)O)cc21
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)c2cc(C)c3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CC3)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
A solution of 1-(5-chloro-2-methoxy-benzenesulfonyl)-4-methyl-2,3-dihydro-1H-indole-6-carboxylic acid (150 mg, 0.393 mmol), ethyl 4-aminobenzoate (130 mg, 0.786 mmol), 4-methylmorpholine (199 mg, 1.96 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (224 mg, 0.589 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at room temperature for 15 min, then 4-(dimethylamino)pyridine (49 mg, 0.39 mmol) was added, and the solution was stirred at 60° C. for 18 h. After cooling, the reaction mixture was partitioned between water, heptane, and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-4-methyl-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester (190 mg, 91%). White solid, MS (ISP): m/e 529.2 (M+H).