Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O>C(OC(=O)C)(=O)C>[C:6]1(=[O:8])[O:10][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CCCCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCCC(=O)O1
Yield: 84.9 %

Procedure:
A solution of adipic acid (10.0 g, 68 mmol) in acetic anhydride (50 ml) was heated to reflux for 3 hours. An excess of acetic anhydride was then distilled off in vacuo leaving adipic anhydride (7.4 g). 2-Amino-3,4,6-trifluorothiophenol (200 mg, 1.1 mmol) was dissolved in NMP (1 ml) under a nitrogen stream. To the resultant solution was gradually added adipic anhydride (143 mg, 1.1 mmol) and the mixture was stirred at 100° C. for 6 hours. After naturally cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted with aqueous sodium bicarbonate. The alkaline phase was acidified with 10% hydrochloric acid and re-extracted with ethyl acetate. The combined organic phases were dried and then evaporated to yield a residue, which was recrystallized from acetonitrile to give 5-(4,5,7-trifluorobenzothiazol-2-yl)pentanoic acid (81 mg, 26%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:10]O)[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>COCCOC.[Fe](Cl)Cl>[Cl:1][C:2]1[N:7]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:8]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: ON=C(Cc1cccc(Cl)n1)c1ccc(F)cc1
Agent: Cl[Fe]Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Fc1ccc(-c2cc3cccc(Cl)n3n2)cc1
Temperature: 15 °C
Reaction time: 1.5 h
Yield: 68.3 %

Procedure:
To a solution of 2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (109.2 g, 414 mmol) in 1,2-dimethoxyethane (500 mL) at 0° C. was added trifluoroacetic anhydride (59 mL, 414 mmol), keeping the temperature below 10° C. After the addition was complete, the reaction was warmed to 15° C. The solution was then cooled to 4° C. and a solution of triethylamine (116 mL, 828 mmol) in 1,2-dimethoxyethane (60 mL) was added over 0.5 hours. After warming to room temperature, the mixture was stirred for 1.5 hours. To this was added iron(II) chloride (0.52 g, 4.1 mmol) and the reaction was heated to reflux for 3 hours. The reaction was concentrated and the resulting solid was recrystallized from ethyl acetate-hexanes to give 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine (69.7 g. 68%) as off-white needles. 1H NMR (CDCl3): δ 8.03 (m, 2 H), 7.54 (d, 1 H), 7.16 (m, 3 H), 6.93 (d, 1 H), 6.91 (s, 1 H); MS m/z 247 (M+1); mp 156–157° C.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11].[C:13](O)(=O)[CH:14]([CH3:16])[CH3:15].[OH-].[Na+]>Cl>[CH:14]([C:16]1[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([OH:2])=[O:12])[C:5]=2[N:11]=1)([CH3:15])[CH3:13]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: CC(C)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1nc2c(C(=O)O)cccc2[nH]1
Temperature: 10 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
A slurry of 2,3-diaminobenzoic acid methyl ester (21.5 g, 0.13 mol) and isobutyric acid (36.2 mL, 0.39 mol) in aqueous hydrochloric acid (4M, 210 mL) was stirred under reflux for 24 h to afford a homogenous solution. The solution was cooled to 10° C. and the pH raised to 3.5 using aqueous sodium hydroxide solution (4M, approx. 210 mL), while maintaining the temperature below 30° C. The reaction mixture was stirred at room temperature for 2 h, cooled to 10° C., and the resultant precipitate filtered off. The solid cake was transferred to a beaker and acetonitrile (300 mL) was added. The slurry was stirred at room temperature for 1 h then and filtered to afford a grey solid. The solid was dried under vacuum to afford the title intermediate (23 g, 0.11 mol, 87%). (m/z): [M+H]+ calcd for C11H12N2O2 calcd. 205.09; found 205.3. 1H NMR (300 MHz, DMSO-d6): δ (ppm) 1.27 (d, 6H), 3.39 (m, 1H), 7.29 (t, 1H), 7.78 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][CH:11]([C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])[CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:30]1([C:36]2[O:37][C:38]([C:43]([F:46])([F:45])[F:44])=[C:39]([CH2:41]O)[N:40]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:30]1([C:36]2[O:37][C:38]([C:43]([F:46])([F:45])[F:44])=[C:39]([CH2:41][O:18][C:17](=[O:19])[C:16]3[CH:20]=[CH:21][C:13]([CH2:12][CH:11]([S:10][CH2:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:27])[Cl:28])=[O:23])=[CH:14][CH:15]=3)[N:40]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: OCc1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(OCc1nc(-c2ccccc2)oc1C(F)(F)F)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
To a solution of 4-[2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-2-(2,2,2-trichloro-ethoxy-carbonyl)-ethyl]-benzoic acid (278 mg, 0.58 mmol) and (2-phenyl-5-trifluoromethyl-oxazol-4-yl)-methanol (155 mg, 0.64 mmol) in anhydrous DCM (20 mL) was first added EDC×HCl (144 mg, 0.75 mmol) then DMAP (1.0 mg, 0.006 mol) under nitrogen atmosphere at 0° C. After complete addition the cooling bath was removed and the reaction mixture was stirred at ambient temperature until no starting material was left. The mixture was diluted with water and aq. HCl (2N) and extracted with DCM. The combined organic layers were dried (MgSO4) and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography using n-heptane/EtOAc 4:1 as the eluent to afford the final product as an oil (289 mg, 56.6%). 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 2H), 7.93 (d, 1H), 7.40-7.47 (m, 2H), 7.19-7.29 (m, 4H), 7.02 (dt, 2H), 6.89 (dt, 2H), 5.34 (d, 2H), 4.64 (q, 2H), 3.50 (dd, 1H), 3.18-3.24 (dd, 1H), 2.73-2.98 (m, 5H), 1.1 (s, 2H). Mass Spectrum: M−H+ 703.91.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([F:27])[CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH3:28])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([F:27])[CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH3:28])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccc(Br)cc3-c3ccccc3C2C)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC1c2ccccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(O)c(F)c1
Yield: 31.5 %

Procedure:
The title compound was prepared from 2-bromo-5-[(3-fluoro-4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.5 g, 1.08 mmol), cyclohexene, (0.27 mL, 3.58 mmol), and 1.0 M boron tribromide in dichloromethane (6.49 mL, 6.49 mmol) according to the procedure and in the same manner as described in Example 4, step b. The crude product was purified by re-crystallization from dichloromethane to yield 4-[(2-bromo-6-methylphenanthridin-5(6H)-yl)sulfonyl]-2-fluorophenol (0.15 g, 0.34 mmol, 31%) as an off-white solid, m.p. 203-206° C.;
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][O:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].COC(C1CC2C(=CC=C(S(Cl)(=O)=O)C=2)OC1)=O>>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1=Cc2ccccc2OC1
Agent: COC(=O)C1COc2ccc(S(=O)(=O)Cl)cc2C1
Product: COC(=O)C1COc2ccccc2C1

Procedure:
Compound 17A was prepared according to the method of example 3A utilizing compound 16C. Compound 17A was prepared in 95% yield. MS: 193 (M−1)+. Preparation of 6-Chlorosulfonyl-chroman-3-carboxylic acid methyl ester (Compound 17B)
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(=O)(O)[O-].[Na+].O>CC(C)=O>[CH2:1]([O:8][C:9]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CCCNC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of benzylchloroformate (9.4 g, 5.5 mmol) in acetone (15 ml) was added dropwise to a mixture of 4-aminobutanoic acid (5.2 g, 5 mmol), sodium bicarbonate (8.6 g, 10 mmol), water (25 ml) and acetone (25 ml) causing vigorous effervescence. The solution was allowed to stir overnight. The acetone was removed using a rotary evaporator to leave an aqueous phase which was washed with ether (2×25 ml). The resulting aqueous layer was acidified to pH2 with dilute hydrochloric acid and then extracted with dichloromethane (3×50 ml). The dichloromethane extracts were combined, dried over magnesium sulphate and volatile components removed under reduced pressure to leave 4-[(benzyloxycarbonyl)amino]butanoic acid as a white solid in a good state of purity. This material was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[P:7](Cl)([O:11][CH3:12])([O:9][CH3:10])=[O:8].[C:14]([C:16]1[S:17][C:18]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][C:20]=1[OH:21])#[N:15]>C(#N)C>[C:14]([C:16]1[S:17][C:18]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][C:20]=1[O:21][P:7]([O:11][CH3:12])([O:9][CH3:10])=[O:8])#[N:15]
Reactant: COP(=O)(Cl)OC
Reactant: CCCCOc1cc(O)c(C#N)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOc1cc(OP(=O)(OC)OC)c(C#N)s1
Temperature: 20 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
7.7 g of potassium carbonate and 7.7 g of O,O-dimethyl chlorophosphate were added to a solution of 11 g of 2-cyano-3-hydroxy-5-n-butoxy-thiophene in 150 ml of acetonitrile and the mixture was stirred for 16 hours at 20° C. and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in ether. The ether solution was washed with water containing 100 g/l of sodium chloride and then with 0.1 N sodium hydroxide solution containing 100 g/l of sodium chloride. The ether phase was dried and treated with activated carbon, filtered and concentrated to dryness to obtain 12.5 g of 2-cyano-3-(dimethoxyphosphoryloxy)-5-n-butoxy-thiophene with a refractive index of nD20 =1.511.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C(#N)C.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(N(CC)CC)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)Cl
Reactant: Cn1ccnc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1nccn1C
Temperature: -20 °C
Yield: 59.9 %

Procedure:
N-methylimidazole (320 g, 3.9 mol) was combined with 2 L acetonitrile and 1 L triethylamine in a 12 L flask equipped with a mechanical stirrer and the solution cooled to −20° C. Ethyl chloroformate (1000 g, 9.2 mol) was added with stirring, keeping the temperature between −20° C. and 25° C. The reaction was allowed to slowly warm to room temperature and stir for 36 h. Precipitated triethylamine hydrochloride was removed by filtration and the solution concentrated in vacuo at 65° C. The resulting oil was purified by distillation under reduced pressure (2 torr, 102° C.) to provide Ethyl 1-methylimidazole-2-carboxylate as a white solid (360 g, 82% yield). TLC (7:2 benzene/ethyl acetate v/v) Rf 0.2; 1H NMR (DMSO-d6) δ7.44 (d, 1H, J=2.8 Hz), 7.04 (d, 1H, J=2.8 Hz), 4.26 (q, 2H, J=3.5 Hz), 3.91 (s, 3H), 1.26 (t, 3H, J=3.5 Hz); 13C NMR (DMSO-d6) δ159.3, 129.1, 127.7, 61.0, 36.0, 14.5; IR(KBr) 3403, 3111, 2983, 1713, 1480, 1422, 1262, 1134, 1052, 922, 782, 666; FABMS m/e 155.083 (M+H 155.083 calc. for C7H11N2O2).
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[C:37]([C:41]1[CH:74]=[CH:73][C:44]([C:45]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:62]=[C:61]4[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:71])[CH3:70])[C:65]([O:67]C)=[O:66])[C:60]4=[O:63])=[CH:56][CH:55]=3)=[C:50]([Cl:72])[CH:49]=2)=[O:46])=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38]>>[C:37]([C:41]1[CH:74]=[CH:73][C:44]([C:45]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:62]=[C:61]4[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:70])[CH3:71])[C:65]([OH:67])=[O:66])[C:60]4=[O:63])=[CH:56][CH:55]=3)=[C:50]([Cl:72])[CH:49]=2)=[O:46])=[CH:43][CH:42]=1)([CH3:38])([CH3:40])[CH3:39]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cc3Cl)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cc3Cl)cc2C1=O
Yield: 77 %

Procedure:
The compound of example 480 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 479.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:13]3=[N:14][C:15]([NH:18][C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[N:16][CH:17]=[C:12]3[CH:11]=[N:10]2)[CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)Cl>[CH3:24][N:22]1[CH:23]=[C:19]([NH:18][C:15]2[N:14]=[C:13]3[N:9]([CH2:8][C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[N:7]=4)[N:10]=[CH:11][C:12]3=[CH:17][N:16]=2)[CH:20]=[N:21]1
Reactant: C1COCCN1
Reactant: Cn1cc(Nc2ncc3cnn(Cc4cccc(F)n4)c3n2)cn1
Solvent: ClCCl
Product: Cn1cc(Nc2ncc3cnn(Cc4cccc(N5CCOCC5)n4)c3n2)cn1
Temperature: 180 °C
Yield: 64 %

Procedure:
1-((6-fluoropyridin-2-yl)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (27 mg, 0.08 mmol) was dissolved in morpholine (0.6 ml) in a microwave tube under Nitrogen which was sealed and heated at 180° C. for 1 h. The mixture was diluted with DCM, washed with water and the water re-extracted with DCM. The combined organics were dried over Na2SO4, filtered and the solvent evaporated to give the title compound as a yellowish solid (20 mg, 64% yield). 1H NMR (d6-DMSO) δ 9.78 (br s, 1H), 8.91 (s, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 7.52 (s, 1H), 7.46 (t, 1H), 6.68 (d, 1H), 6.28 (br s, 1H), 5.46 (s, 2H), 3.78 (s, 3H), 3.62 (t, 4H), 3.35 (t, 4H); LC-MS method B, (ES+) 392.0, RT=6.84 min.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:13][N:14](C=O)C>C(=O)(O)[O-].[Na+].ClCCl.[C-]#N.[Zn+2].[C-]#N.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>[CH3:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:13]#[N:14])[CH:10]=2)[CH2:6][C:7]1=[O:12]
Reactant: CN1C(=O)Cc2ccc(Br)cc21
Reactant: CN(C)C=O
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: [C-]#N
Solvent: ClCCl
Product: CN1C(=O)Cc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 1.67 h

Procedure:
To a solution of 6-bromo-1-methyl-1,3-dihydro-indol-2-one (226 mg, 1.0 mmol) in DMF (6.0 mL) was added zinc cyanide (117 mg, 1.0 mmol). Then the reaction mixture was degassed and placed under an argon atmosphere and tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.1 mmol) was added. The reaction was then placed at 95° C. for 100 minutes, at which time it was cooled to room temperature, and diluted with saturated aqueous sodium bicarbonate and dichloromethane. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane 0 to 4%) to furnish 1-methyl-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile; MS: (ES+) m/z 173.0 (M+H)+.
Reaction SMILES: [N:1]1C=CC=CC=1.[C:7](Cl)(=[O:11])[C:8](Cl)=[O:9].[CH2:13]([O:17][C:18](=[O:20])[OH:19])[CH:14]([CH3:16])[CH3:15].N1CCC1=O>C(#N)C>[CH2:13]([O:17][C:18](=[O:19])[OH:20])[CH:14]([CH3:16])[CH3:15].[C:7]1(=[O:11])[NH:1][C:8]1=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccncc1
Agent: CC(C)COC(=O)O
Agent: O=C1CCN1
Solvent: CC#N
Product: O=c1[nH]c1=O

Procedure:
Pyridine was added to a solution of pNB oxalylchloride in acetonitrile. After 20 minutes the TES azetidinone isobutyl carbonate was added. The reaction was given an aqueous work up, the organics were concentrated in vacuo to afford TES oxalimide isobutyl carbonate (15.2 g) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH2:9].[N:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=[C:11]=[O:12]>>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:10][C:11]([NH:9][CH2:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:12])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)c1ccc(N=C=O)cc1
Reactant: NCCc1ccccn1
Product: CC(C)c1ccc(NC(=O)NCCc2ccccn2)cc1
Yield: 50 %

Procedure:
Prepared in a similar manner to example 158 using 2-(pyridine-2-yl)ethanamine and 1-isocyanato-4-isopropylbenzene. Purified via column chromatography (1% MeOH in CH2Cl2 to 3% MeOH in CH2Cl2) to afford 1-(4-isopropylphenyl)-3-(2-(pyridine-2-yl)ethyl)urea (130 mg, 50%) as a white solid. mp: 72-73° C. 1H NMR (500 MHz, CDCl3): δ 1.25 (d, 6H), 2.89 (m, 1H), 3.06 (t, 2H), 3.70 (t, 2H), 5.80 (br s, 1H), 6.55 (br s, 1H), 7.19 (m, 5H), 7.24 (d, 1H), 7.68 (dt, 1H), 8.46 (d, 1H). MS (M+H, 284).
Reaction SMILES: [O:1]([C@@H:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[CH:27][C:28]3[N:33]4[C:34](=[O:47])[O:35][C@@H:36]([CH2:37][NH:38][C:39]([C:41]5[S:42][C:43]([Cl:46])=[CH:44][CH:45]=5)=[O:40])[C@@H:32]4[CH2:31][O:30][C:29]=3[CH:48]=2)[C:21](=[O:49])[CH2:20]1)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:46][C:43]1[S:42][C:41]([C:39]([NH:38][CH2:37][C@H:36]2[C@H:32]3[N:33]([C:28]4[CH:27]=[CH:26][C:25]([N:22]5[CH2:23][CH2:24][C@@H:19]([OH:1])[CH2:20][C:21]5=[O:49])=[CH:48][C:29]=4[O:30][CH2:31]3)[C:34](=[O:47])[O:35]2)=[O:40])=[CH:45][CH:44]=1
Reactant: CC(C)(C)[Si](O[C@@H]1CCN(c2ccc3c(c2)OC[C@H]2[C@H](CNC(=O)c4ccc(Cl)s4)OC(=O)N32)C(=O)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NC[C@@H]1OC(=O)N2c3ccc(N4CC[C@@H](O)CC4=O)cc3OC[C@@H]12)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
Compound N-(((3S,3aS)-7-((R)-4-(t-butyldiphenylsiloxy)-2-oxopiperidin-1-yl)-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-yl)methyl)-5-chlorothiophene-2-carboxamide (0.36 g, 0.502 mmol) was dissolved in THF. TBAF (1M/L, 0.50 ml) was added and stirred at room temperature for 2 h. After the reaction completed, the resulting mixture was washed with water, extracted with EA (20 ml×4), dried over anhydrous sodium sulfate, and dried by spinning. Column chromatography afforded white solid 0.13 g, yield 56.2%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[H-].[Na+].[CH2:21]([OH:23])[CH3:22]>O>[Cl:8][C:6]1[CH:7]=[C:2]([O:23][CH2:21][CH3:22])[N:3]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:5]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (0.50 g) in ethanol (5 mL) was added 60% sodium hydride (72 mg) and the reaction mixture was stirred at ambient temperature for 6 h. The mixture was diluted with H2O and extracted with EtOAc (×2). The combined organic layers were dried (MgSO4), filtered and evaporated to give the subtitle compound as a clear, colourless oil. Yield: 0.53 g
Reaction SMILES: [C:1]1([C:14]([O:16]C)=[O:15])[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([O:12]C)=[O:11])[C:5]=12.CO.[OH-].[K+]>O>[C:1]1([C:14]([OH:16])=[O:15])[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([OH:12])=[O:11])[C:5]=12
Reactant: COC(=O)c1ccn2c1C(C(=O)OC)CCC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccn2c1C(C(=O)O)CCC2

Procedure:
A solution of 8.6 g. of dimethyl 5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-1,8-dicarboxylate in 100 ml. of methanol is treated with a solution of 9.0 g. of potassium hydroxide in 100 ml. of water, and the reaction mixture is refluxed for 24 hours. The cooled solution is evaporated to dryness at a temperature of 30° C. and the residue is dissolved in the minimum amount of saturated sodium chloride solution. The resultant solution is acidified with concentrated hydrochloric acid and the precipitated solid is collected by filtration, washed with water and dried in vacuo. The mother liquor is extracted with ethyl acetate 3 times and the combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure and recrystallization of the combined residues from methanol yields 5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-1,8-dicarboxylic acid (VIII, R=H, n=1), m.p. 236°-237° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:35])[CH2:33]Br)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:35])[CH2:33][N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[N:13]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)c1ccc(-c2nccc(NS(=O)(=O)c3ccc(Cl)cc3)n2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)c1ccc(-c2nccc(N(CC(=O)OC(C)(C)C)S(=O)(=O)c3ccc(Cl)cc3)n2)cc1

Procedure:
{(4-Chloro-benzenesulfonyl)-[2-(4-isopropyl-phenyl)-pyrimidin-4-yl]-amino}-acetic acid tert-butyl ester was prepared (97 mg) from 4-chloro-N-[2-(4-isopropyl-phenyl)-pyrimidin-4-yl]-benzenesulfonamide (100 mg, 0.26 mmol) (Prepared in Example 158) and bromoacetic acid tert-butyl ester by following the general procedure S (method 1). LCMS m/z: 503 (M+1)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[S-:13][C:14]#[N:15].[K+].O>C(O)C>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:13][C:14]#[N:15]
Reactant: N#C[S-]
Reactant: O=C(CBr)c1ccc(F)cc1F
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 74.6 %

Procedure:
A solution of 2-bromo-1-(2,4-difluorophenyl)ethanone (5.0 g, 21.3 mmol) and potassium thiocyanate (2.07 g, 21.3 mmol) in ethanol (50 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was poured to the reaction mixture. A crystal was collected by filtration and washed with 50% aqueous ethanol to give 3.39 g (74.7%) of the desired product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[N:48]=[CH:47][C:46]([CH3:49])=[CH:45][N:44]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:50])=[CH:38][C:39]([C:43]6[N:44]=[CH:45][C:46]([CH3:49])=[CH:47][N:48]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cnc(-c2cc(C)c(Br)c(C)c2)nc1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ncc(C)cn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-bromo-3,5-dimethyl-phenyl)-5-methyl-pyrimidine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 9): tR=1.27 min; Mass spectrum (ESI+): m/z=539 [M+H]+.