Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])(OCC)=O.CCOCC>C(#N)C.O>[C:31]1(=[O:40])[N:2]([CH:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]12
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: COC(=O)CC(c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A mixture of methyl 3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride (1.38 g, 5.00 mmol), sodium carbonate (0.53 g, 5.00 mmol), and N-carbethoxyphthalimide (1.10 g, 5.0 mmol) in 40 mL of acetonitrile/water (1/1) was stirred for 1 hour at room temperature. The reaction solution was then partially concentrated under reduced pressure to remove the acetonitrile. This afforded a white gum in water. To the mixture was then added 5 mL of ether and the mixture was stirred for 2 hours. The resulting slurry was filtered, the solid was washed with a copious amount of water and air-dried overnight to afford 1.69 g (92%) of methyl 3-phthalimido-3-(3,4-dimethoxyphenyl)propionate as a white solid: mp 114.1-115.6° C.; 1H NMR (DMSO-d6, 250 MHz)δ 7.80-7.95 (m, 4H, Ar), 6.80-7.10 (m, 3H, Ar), 5.65 (dd, 1H, J1 =7 Hz, J2 =9 Hz), 3.74 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.55 (s, 3H, OCH3), 3.30-3.67 (m, 2H); 13C NMR (DMSO-d6)d 170.8, 167.6, 148.6, 148.4, 134.7, 131.1, 131.0, 123.2, 119.3, 111.7, 111 0, 55.5, 51.6, 49.9, 35.6. Anal. Calcd for C20H19NO6. Theoretical C, 65.03; H, 5.18; N, 3.79. Found C, 65.17; H, 5.14; N, 3.75. HPLC 99%.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:12](=O)[C:13]([Cl:19])=[C:14]([Cl:18])[C:15]([OH:17])=[O:16])=[CH:9][C:8]([CH3:21])=[CH:7][CH:6]=2)[CH3:2].[CH2:22]([N:29]1[C:37]2[C:32](=[CH:33][C:34]([F:38])=[CH:35][CH:36]=2)[CH:31]=[CH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN1C2C(=CC=CC=2)C=C1C>>[CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:12]1([C:31]3[C:32]4[C:37](=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=4)[N:29]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:30]=3)[O:16][C:15](=[O:17])[C:14]([Cl:18])=[C:13]1[Cl:19])=[CH:9][C:8]([CH3:21])=[CH:7][CH:6]=2)[CH3:2]
Reactant: Fc1ccc2c(ccn2Cc2ccccc2)c1
Reactant: CCc1[nH]c2ccc(C)cc2c1C(=O)C(Cl)=C(Cl)C(=O)O
Agent: Cc1cc2ccccc2n1C
Product: CCc1[nH]c2ccc(C)cc2c1C1(c2cn(Cc3ccccc3)c3ccc(F)cc23)OC(=O)C(Cl)=C1Cl

Procedure:
Following a procedure similar to that described above in part B of this example except that 4-(2-ethyl-5-methyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid is used in place of 4-(1,2-dimethyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid and 1-benzyl-5-fluoroindole is substituted for 1,2-dimethylindole, there is obtained 5-(2-ethyl-5-methyl-3-indolyl)-5-(1-benzyl-5-fluoro-3-indolyl)-3,4-dichloro-2(5H)-furanone (Formula V: R=R3 =H; R1 =CH3CH2 ; R2 =C6H5CH2 ; Y=5-CH3 ; Y1 =5-F).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][N:3]=1.ClCCl.ClC1C=CC=CN=1.[NH2:30][NH2:31]>>[CH3:13][C:11]1[O:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:30][NH2:31])=[N:3][CH:4]=2)=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1
Reactant: NN
Reactant: Cc1nc(-c2ccccc2)c(-c2ccc(Cl)nc2)o1
Agent: Clc1ccccn1
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)c(-c2ccc(NN)nc2)o1
Temperature: 70 °C

Procedure:
A mixture of 120 mg of 2-chloro-5-(2-methyl-4-phenyl-oxazol-5-yl)-pyridine in 1 mL of hydrazine (98%) was heated at 70° C. for 45 min before adding 0.5 mL of dichloromethane to get better mixing of the hydrazine and the chloro-pyridine. When the dichloromethane had evaporated 0.5 mL of ethanol was added and the mixture was heated for 11 hours. The layers were separated. The ethanol layer was diluted with ethyl acetate and washed with aqueous sodium carbonate (2×), dried (magnesium sulfate), filtered, and the filtrate was evaporated to give 110 mg of crude 5-(2-Methyl-4-phenyl-oxazol-5-yl)-pyridin-2-yl-hydrazine as an orange solid. This material was used with out purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:5]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:4]([NH:22][NH2:23])[N:3]=1.Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Cl:1][C:2]1[N:3]2[C:25](=[O:27])[NH:23][N:22]=[C:4]2[C:5]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:7]=1
Reactant: NNc1nc(Cl)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of a mixture of 2-chloro-4,5-bis(4-chlorophenyl)-6-hydrazinylpyrimidine and its regioisomer prepared above (900 mg, 2.46 mmol) in THF (10 mL) at room temperature under argon was added triphosgene (1.46 g, 4.91 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled in an ice bath and carefully quenched with water (10 mL) and then extracted with EtOAc (15 mL×2). The combined organic extracts were washed with water and then saturated aqueous NaCl. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluted with 20% ethyl acetate-hexanes to obtain 400 mg of the title compound as a yellow solid. HPLC/MS: retention time=3.923 min, [M+H]+=391; 1H NMR (DMSO-d6, 500 MHz): δ 12.68 (s, 1H), 7.39 (d, J=8.25 Hz, 2H), 7.31 (d, J=8.25 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.8 Hz, 2H). Regioisomeric product derived from starting material regioisomeric impurity: HPLC/MS: retention time=3.545 min.
Reaction SMILES: Br[CH:2]([CH2:15][CH2:16][CH2:17][CH2:18]Br)[C:3]([O:5][CH:6]([CH3:14])[C:7](=[O:13])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4].[Na+].[I-].C(N(CC)CC)C.Cl.[CH2:30]([NH2:33])[CH:31]=[CH2:32]>O1CCCC1>[CH2:30]([N:33]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:2]1[C:3]([O:5][C@@H:6]([CH3:14])[C:7](=[O:13])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4])[CH:31]=[CH2:32]
Reactant: C=CCN
Reactant: CC(OC(=O)C(Br)CCCCBr)C(=O)N1CCCC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN1CCCCC1C(=O)O[C@@H](C)C(=O)N1CCCC1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
TO 1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2,6-dibromohexanoate (295 mg, 0.75 mmol), NaI (225 mg, 1.5 mmol), triethylamine (303 mg, 3.0 mmol) and tetrahydrofuran (4 mL) were added. Subsequently, allylamine hydrochloride (84.2 mg, 0.9 mmol) and tetrahydrofuran (4 mL) were added thereto. The mixture was stirred at 20° C. for 4 hours and then at 40° C. for 15 hours. It was confirmed with NMR analysis of the reaction solution that the conversion ratio was 100% and the diastereo ratio was 75:25.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH:6]([C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH3:20])[N:14]=1)C.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH3:20][NH:19][C:15]1[N:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[CH2:5][C:4]([OH:27])=[O:3])[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(CCCCCCc1cccc(NC)n1)c1cncnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CNc1cccc(CCCCCCC(CC(=O)O)c2cncnc2)n1
Reaction time: 0.5 h

Procedure:
To a solution of 6-13a (0.215 g, 0.580 mmol) in THF/MeOH/H2O 3:1:1(10 mL)) was added NaOH (1.16 mL of 1N solution in water, 1.16 mmol). After 30 minutes, the mixture was neutralized with HCl (1.16 mL of 1N solution in water, 1.16 mmol) and the solvents were evaporated. The residue chromatographed on silica gel (15% MeOH/CHCl3) to give 6-14a as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].[CH3:18][C:19]1[O:23][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:21][C:20]=1[CH2:30][CH2:31]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:31][CH2:30][C:20]2[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:23][C:19]=2[CH3:18])=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1C
Yield: 72.6 %

Procedure:
A mixture of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (4.50 g, 18.9 mmol), toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester (Japan Tobacco Inc WO 9518125) (8.43 g, 23.6 mmol), and Cs2CO3 (7.68 g, 23.6 mmol) was heated at 55° C. in DMF (45 mL) for 20 h. Additional toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester (2.81 g, 7.86 mmol) and Cs2CO3 (2.56 g, 7.86 mmol) were added, and the mixture was heated at 55° C. in DMF (45 mL) for 6 h. The reaction mixture cooled and partitioned between EtOAc (200 mL) and H2O (100 mL). The organic layer was washed with brine (50 mL). The aqueous layers were extracted further with EtOAc (200 mL). The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography using hexanes:ethyl acetate (6:1 to 4:1) to give an oil (5.81 g, 73%): 1H NMR (400 MHz, CDCl3) δ 1.27 (t, 3H, J=7.1 Hz), 1.51 (s, 6H), 2.18 (s, 3H), 2.36 (s, 3H), 2.95 (t, 2H, J=6.6 Hz), 4.17 (t, 2H, J=6.6 Hz), 4.24 (q, 2H, J=7.1 Hz), 6.57 (dd, 1H, J=2.9, 8.8 Hz), 6.65 (d, 1H, J=9.3 Hz), 6.69 (d, 1H, J=2.9 Hz), 7.38-7.45 (m, 3H), 7.98-8.00 (m, 2H); MS (ES) m/e 424.2 [M+1].
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[OH:16][C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([CH2:25][C:26](O)=[O:27])=[CH:19][C:18]=1[O:29][CH3:30].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.Cl>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:26](=[O:27])[CH2:25][C:20]3[CH:21]=[C:22]([O:23][CH3:24])[C:17]([OH:16])=[C:18]([O:29][CH3:30])[CH:19]=3)[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: COc1cc(CC(=O)O)cc(OC)c1O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)Nc2cnn(Cc3c(C)noc3C)c2)cc(OC)c1O
Yield: 28.8 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a) (376 mg, 1.7 mmol), 2-(4-hydroxy-3,5-dimethoxyphenyl)acetic acid (350 mg, 1.7 mmol), PyBop (1 g, 2 mmol) and triethylamine (605 mg, 6 mmol) were stirred together in DMF (10 mL) at room temperature for 2 hours. The reaction mixture was diluted with aqueous 1N HCl (100 mL) and extracted with DCM (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated on the rotovap. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to afford N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3,5-dimethoxyphenyl)acetamide (189 mg, 29%) as a white solid. 1H NMR (CDCl3, 400 MHz) 2.10 (s, 3H), 2.36 (s, 3H), 3.40 (s, 2H), 3.70 (s, 6H), 5.07 (s, 2H), 6.53 (s, 2H), 7.39 (s, 1H), 7.92 (s, 1H), 8.18 (s, 1H), 10.03 (s, 1H). LC/MS; [M+H] calculated for C, 19; H, 22; N, 4; O, 5; expected 387.16; found 387.6. Melting point: 187-188° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[C:18]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19].O>ClCCl>[CH2:11]([O:10][C:8]([CH:5]1[CH2:4][CH2:3][CH:2]([O:1][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:7][CH2:6]1)=[O:9])[CH3:12]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a solution of ethyl 4-hydroxycyclohexane carboxylate (5 g, 29.03 mmol) in dichloromethane (200 mL) was added imidazole (4.97 g, 73 mmol) and tert-butylchlorodiphenylsilane (15.96 g, 15.2 mL, 58 mmol). The reaction mixture was allowed to stir at room temperature over night. The reaction mixture was poured into water (125 mL) in a separatory funnel and the phases were separated. The aqueous phase was extracted with dichloromethane (2×200 mL). The combined organic solutions were washed with brine, dried over Na2SO4, and concentrated under vacuum. Purification by column chromatography on silica gel eluting with ethyl acetate in heptanes (0-10%) afforded 10.55 g (89%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[C:13]([C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:34])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:18]=[CH:19][CH:20]=1)#[N:14].C(N(CC)CC)C>C(#N)C>[C:13]([C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:34])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=3)(=[O:31])=[O:32])=[CH:26][CH:25]=2)[CH:18]=[CH:19][CH:20]=1)#[N:14]
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)Cl)cc2)c1
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3cccc(C(F)(F)F)c3)cc2)c1
Reaction time: 72 h
Yield: 97.3 %

Procedure:
3-Trifluoromethylbenzylamine (0.52 g, 1 eq.) was added to a solution of 4-[3-(3-cyanophenyl)-ureido]-benzenesulfonyl chloride (1 g, 1 eq.) and triethylamine (1.05 ml, 1.6 eq.) in acetonitrile (10 ml) under inert atmosphere. The mixture was stirred for 3 d, concentrated in vacuo and water was added. The resulting precipitate was filtered off and dried in vacuo to yield 1.37 g (97%) of 4-[3-(3-cyanophenyl)-ureido]-N-(3-trifluoromethylbenzyl)-benzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:4][C:5]2[S:10](=[O:12])(=[O:11])[NH:9][CH2:8][NH:7][C:6]=2[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:24][CH2:25][CH2:26]Br.C(C(Br)C([O-])=O)C1C=CC=CC=1>>[Br:24][CH2:25][CH2:26][N:9]1[CH2:8][NH:7][C:6]2[CH:13]=[C:2]([Cl:1])[C:3]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:4][C:5]=2[S:10]1(=[O:12])=[O:11]
Reactant: BrCCBr
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)NCNS2(=O)=O
Agent: O=C([O-])C(Br)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: NS(=O)(=O)c1cc2c(cc1Cl)NCN(CCBr)S2(=O)=O

Procedure:
Treat 6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine with Cs2CO3 and substitute 1,2-dibromoethane for benzylbromoacetate in the procedure of Example 7, step A to obtain 2-(2-bromoethyl)-6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH:17]1([NH:23][C:24]([N:26]2[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>C(O)CC(C)C>[CH:17]1([NH:23][C:24]([N:26]2[CH2:32][CH2:31][CH2:30][N:29]([C:2]3[N:11]=[C:10]([NH2:12])[C:9]4[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=4)[N:3]=3)[CH2:28][CH2:27]2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(NC1CCCCC1)N1CCCNCC1
Agent: Cl
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCCN(C(=O)NC4CCCCC4)CC3)nc(N)c2cc1OC
Reaction time: 8 h

Procedure:
A solution prepared by dissolving 479 mg. (2 mmole) of 2-chloro-4-amino-6,7-dimethoxyquinazoline and 451 mg. (2 mmole) of N-cyclohexylcarbamoyl-homopiperazine (oily substance, showing IR absorption spectrum at 3340, 2920, 1630 cm-1) in 10 ml of isoamyl alcohol was refluxed for 4 hours, followed by standing overnight. The precipitates were collected by filtration to obtain 310 mg. of the desired hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[O:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@H:18]([CH2:19][N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]2=[O:29])[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=2)=[O:15])[O:10][C:11]=1[CH3:12]
Reactant: Cc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Reactant: N[C@@H](Cc1ccc(F)c(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1oc(C(=O)N[C@@H](Cc2ccc(F)c(F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.5 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (150 mg, 0.62 mmol), 2-[(2S)-2-amino-3-(3,4-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (207 mg, 0.65 mmol)[prepared according to the procedure of Preparation 6] and N,N-diisopropylethyl amine (0.33 ml, 1.87 mmol) in DCM (10 ml) was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (436 mg, 0.94 mmol). After stirring at ambient temperature for 20 h, the mixture was concentrated and purified using silica gel and eluting with a gradient of 0-50% ethyl acetate/hexane to afford the title compound as an off-white foam (200 mg, 0.35 mmol, 57% yield): LC-MS (ES) m/z 539 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[C:9](Cl)(Cl)=S.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[C:21]1[NH:22][C:23]2[CH:29]=[C:28]([C:30]([NH:32][NH2:33])=[O:31])[CH:27]=[CH:26][C:24]=2[N:25]=1.CCN=C=NCCCN(C)C>C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].CCOC(C)=O.CN(C=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[C:21]1[NH:22][C:23]2[CH:29]=[C:28]([C:30]3[O:31][C:9]([NH:1][C:2]4[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=4)=[N:33][N:32]=3)[CH:27]=[CH:26][C:24]=2[N:25]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(F)cn1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1ccc(Nc2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 2-amino-5-fluoro-pyridine (68 mg, 0.606 mmol) in a biphasic solution of CHCl3 (15 mL) and saturated NaHCO3 (15 mL). Add thiophosgene (46 uL, 0.606 mmol) to the organic phase and stir the reaction vigorously for 1 hr. Add 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (146 mg, 0.455 mmol) and stir for 7 hr. Add additional 2-amino-5-fluoro-pyridine (68 mg, 0.606 mmol) and stir overnight. Filter the reaction and wash the collected solid with DCM. Concentrate the organic phase of the filtrate and combine with the solid. Add DMF (3 mL) and EDCI (174 mg, 0.910 mmol) and heat the reaction to 80° C. for 1 hr. Allow the reaction to cool to room temp. Dilute with EtOAc (75 mL) and extract with water (15 mL). Dry the organic phase over Na2SO4 and concentrate. Purify the concentrate by silica gel chromatography (3-6% MeOH/DCM) followed by reversed phase HPLC (20-60% ACN/H2O+5 mM NH4OH) to afford the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) ppm 7.62-7.68 (m, 1 H) 7.70 (s, 1 H) 7.72 (d, J=1.77 Hz, 1 H) 7.74-7.94 (m, 3 H) 8.01 (dd, J=9.22, 3.66 Hz, 1 H) 8.05 (tautomer, s, 1 H) 8.19 (tautomer, s, 1 H) 8.35 (d, J=3.03 Hz, 1 H) 11.37 (br. s., 1 H) 13.29 (s, 1 H); MS m/z=441.7 (M+1).
Reaction SMILES: [F:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].[F:7][C:8]([F:16])([F:15])[CH:9]([OH:14])[C:10]([F:13])([F:12])[F:11].C(N(CC)CC)C>O>[F:1][C:2](=[CH2:6])[C:3]([O:14][CH:9]([C:10]([F:13])([F:12])[F:11])[C:8]([F:16])([F:15])[F:7])=[O:4]
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: C=C(F)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(F)C(=O)OC(C(F)(F)F)C(F)(F)F
Reaction time: 3 h

Procedure:
12 g of 2-fluoroacryloyl chloride and 27 g of 1,1,1,3,3,3-hexafluoro-2-propanol were introduced into a round-bottomed flask placed in an ice bath. 16 g of triethylamine were added portionwise to the reaction mixture. After reacting for an additional 3 h, approximately 70 ml of water were added. The aqueous and organic phases were subsequently separated and the organic phase was analysed by GC. The conversion of the 1,1,1,3,3,3-hexafluoroisopropanol was 68%. The yield of ester, based on the amount of 2-fluoroacrylic acid employed in the first stage, was 66%.
Reaction SMILES: [CH2:1]([N:3]=C=O)[CH3:2].[CH3:6][O:7][C:8](=[O:34])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[C:13]2[C:30](=[CH:31][CH:32]=1)[O:29][C:16]1([CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=[O:23])[CH2:18][CH2:17]1)[CH2:15][C:14]2=[O:33]>C(Cl)Cl>[CH3:6][O:7][C:8](=[O:34])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[C:13]2[C:30](=[CH:31][CH:32]=1)[O:29][C:16]1([CH2:17][CH2:18][N:19]([C:22](=[O:23])[NH:3][CH2:1][CH3:2])[CH2:20][CH2:21]1)[CH2:15][C:14]2=[O:33]
Reactant: CCN=C=O
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Solvent: ClCCl
Product: CCNC(=O)N1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)OC)ccc1O2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.5 %

Procedure:
TEA (0.185 ml, 1.33 mmol) and ethylisocyanate (38 mg, 0.53 mmol) were added to a suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester hydrochloride (150 mg, 0.44 mmol, Intermediate 1) in DCM (4 ml), and the mixture was stirred at RT for 1.5 h. The mixture was partitioned between aqueous NaHCO3 (saturated solution) and DCM and the organic phase was dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (eluent:DCM/MeOH/NH4OH 97:3:0.3) to give (E)-3-{1′-ethylcarbamoyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (150 mg).
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]([O:9][C:10](=[O:21])[CH:11]([NH:17][C:18](=[O:20])[CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:8].[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>C1COCC1>[CH2:15]([O:14][C:12](=[O:13])[C:11]([NH:17][C:18](=[O:20])[CH3:19])([C:25]([CH:22]1[CH2:24][CH2:23]1)=[O:26])[C:10]([O:9][CH2:7][CH3:8])=[O:21])[CH3:16]
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(NC(C)=O)(C(=O)OCC)C(=O)C1CC1
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To a solution of 6 eq KOt-Bu in THF at room temperature was added 6 eq 2-acetylamino-malonic acid diethyl ester and after 5 min 1 eq cyclopropane-carbonylchloride. After 15 min, the mixture was concentrated and partitioned between EtOAc and H2O. The organic layer was concentrated to give the desired product in 60% yield.