Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:30]2[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH2:28][CH2:29]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccccn4)CC3)c(OC)nc2c1
Yield: 94 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(2-pyridyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 94%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=1.Cl.CN.[CH2:24]([N:26](CC)CC)C>C(O)C>[CH3:9][NH:8][C:6]1[N:5]=[C:4]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=[C:2]([NH:26][CH3:24])[N:7]=1
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(F)cc2)n1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2ccc(F)cc2)nc(NC)n1
Temperature: 140 °C
Reaction time: 17 h
Yield: 43.8 %

Procedure:
0.36 g (0.0011 mol) of N-(6-chloro-2-methylamino-pyrimidin-4-yl)-4-fluoro-benzenesulfonamide was dissolved in 10 ml of ethanol, treated with 1.2 g (0.018 mol) of methylamine hydrochloride and 4.0 ml (0.029 mol) of triethylamine and stirred in an autoclave at 140° C. for 17 hours. The mixture was freed completely from solvent, the residue was partitioned in ethyl acetate/water, the insoluble constituents were filtered off under suction and extracted. The extract and the solid were combined and recrystallized from methanol/diethyl ether. There was obtained 0.15 g (43%) of N-(2,6-bis-methylamino-pyrimidin-4-yl)-4-fluoro-benzenesulfonamide as white crystals; m.p. 261-263° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[OH-].[K+].ClC(Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>O.C1(C)C=CC=CC=1>[NH:10]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3](=[O:4])[O:2][C:1]1=[O:16]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1sccc1N
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1[nH]c2ccsc2c(=O)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
40 g (250 mmol) 3-Amino-thiophene-2-carboxylic acid methyl ester were suspended in 250 ml water with 21.0 g (374 mmol) potassium hydroxide. The mixture was boiled in a microwave oven (500 W) for 30 min and afterwards it was cooled to 0° C. A solution of 37.1 g (125 mmol) triphosgene in 200 ml toluene was added drop wise and the reaction mixture stirred for 2 h at room temperature. The residue was isolated by filtration. The product was washed with water and sodium bicarbonate solution. For further purification it can be washed with ethyl ether and methanol after drying.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:11][C@@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@:9]2([CH3:20])[C@@H:7]([O:8]2)[CH2:6]1)(=O)C.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>CO>[Si:13]([O:12][C@H:10]1[C@:9]2([CH3:20])[C@@H:7]([O:8]2)[CH2:6][C@H:5]([OH:4])[CH2:11]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(=O)O[C@H]1C[C@@H]2O[C@]2(C)[C@H](O[Si](C)(C)C(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)C[C@@H]2O[C@@]21C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
The compound of Example 16C (9.20 g, 30.6 mmol) was dissolved in 105 mL of methanol. K2CO3 (10.1 g, 72.1 mmol, 2.35 equivalents) was added and the reaction mixture was stirred at ambient temperature for 2 hours. 6.60 mL (115 mmol, 3.77 equivalents) of acetic acid were added to the reaction mixture; after mixing for 10 minutes, the solids were filtered off and rinsed with 40 mL of methanol. The combined filtrate and rinses were concentrated to a residue which was mixed with 106 mL of water. The layers were separated, and the aqueous layer was extracted three times with 50 mL of ethyl acetate. The combined organic layers were washed twice with 45 mL of brine, dried over MgSO4, filtered and concentrated to afford the titled compound (7.72 g, 98%).
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[CH2:25]([OH:27])[CH3:26]>>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:6]=[CH:5][N:4]=[C:3]2[CH:26]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:25]1=[O:27]
Reactant: CCO
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: Cl
Product: COc1cc2c(C3C(=O)Nc4ccccc43)ncnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
2M Hydrochloric acid (3 ml, 6 mmol) was added to a solution of 4-(1-diethoxymethyloxindol-3-yl)-6-methoxy-7-3-morpholinopropoxy)quinazoline (295 mg, 0.55 mmol), (prepared as described in Example 5), in ethanol (20 ml) at 80° C. The mixture was stirred for 45 minutes at 80° C. After cooling of the reaction mixture, partial evaporation of the solvents led to the crystallisation of the compound. The solid was collected by filtration, washed with ethanol and then ether and dried under vacuum at 50° C. to give 6-methoxy-7-(3-morpholinopropoxy)-4-(oxindol-3-yl)quinazoline as a hydrochloride salt (207 mg, 84%) as an orange solid.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.Cl.[NH2:21][C@H:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH2:25])=[O:24].CCN(C(C)C)C(C)C>>[O:8]=[C:6]1[N:7]=[C:3]([NH:21][C@H:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([NH2:25])=[O:24])[S:4]/[C:5]/1=[CH:9]\[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2
Reactant: NC(=O)[C@H](N)c1ccccc1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[C@H](NC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1)c1ccccc1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (R)-2-amino-2-phenyl-acetamide hydrochloride and DIEA to give (R)-2-{4-oxo-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-4,5-dihydro-thiazol-2-ylamino}-2-phenyl-acetamide. LC-MS m/e 389 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[OH:21][C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH:27]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][O:29]2)=[CH:24][CH:23]=1>O>[C:35]([O:34][C:32]([CH:27]1[CH2:26][C:25]2[C:30](=[CH:31][C:22]([O:21][CH2:2][C:3]3[N:4]=[C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[O:6][C:7]=3[CH3:8])=[CH:23][CH:24]=2)[O:29][CH2:28]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CC(C)(C)OC(=O)C1COc2cc(O)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2c(c1)OCC(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.2 %

Procedure:
To a stirred solution of 4-(chloromethyl)-5-methyl-2-phenyl-1,3-oxazole (103.5 mg, 0.5 mmol) and potassium carbonate (138.4 mg, 1 mmol), tert-butyl 7-hydroxychromane-3-carboxylate (125 mg, 0.5 mmol) was added and the reaction mixture was stirred at room temperature for 48 hrs. Water (50 ml) was added and the precipitated product was extracted with 25 ml of diethyl ether. Ether layer was washed with water (25 ml) twice and dried. On evaporation of solvent, the product was obtained as pale yellow gum (150 mg, 36%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:6][C:7]1[S:8][C:9](Cl)=[N:10][N:11]=1>C(O)C>[NH2:6][C:7]1[S:8][C:9]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)=[N:10][N:11]=1
Reactant: C1CCNC1
Reactant: Nc1nnc(Cl)s1
Solvent: CCO
Product: Nc1nnc(-n2cccc2)s1
Temperature: 40 °C

Procedure:
Pyrrolidine (200 μl) was added to a solution of 2-amino-5-chloro-1,3,4-thiadiazole (60 mg) in ethanol (2 ml) and the mixture heated in a sealed vial at 40° C. for 6 hours. The precipitate was filtered off and washed with a little methanol to give 2-amino-5-pyrrol-1-yl-1,3,4-thiadiazole.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[H][H]>C(O)(=O)C.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:12]([OH:14])(=[O:13])[CH3:11]
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1ccc2c(c1)CCO2
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ccc2c(c1)CCO2

Procedure:
Ethyl (E)-3-(2,3-dihydrobenzofuran-5-yl)propenoate (50.0 g, 227 mmol) was dissolved in acetic acid (312 g), and the reaction system was replaced with nitrogen. Then, 5% Pd/C (4.96 g, as dry weight) was added to the solution and pressurized with hydrogen to 196 to 294 kPa. The mixture was reacted at 50° C. for 1 hr under a pressure of 196 to 294 kPa. The catalyst was filtered, and washed with acetic acid (208 g) to give a solution of the title compound in acetic acid (amount 569 g, apparent yield 100%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][O:4][CH2:3]1.Cl[C:7]1[N:11]=[C:10]([CH:12]2[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH2:15][N:14]([C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])[CH2:13]2)[O:9][N:8]=1>O1CCOCC1>[N:30]1([C:28]([N:14]2[CH2:15][CH:16]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=3)[CH2:17][CH:12]([C:10]3[O:9][N:8]=[C:7]([O:1][CH:2]4[CH2:5][O:4][CH2:3]4)[N:11]=3)[CH2:13]2)=[O:29])[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Reactant: OC1COC1
Solvent: C1COCCO1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(OC3COC3)no2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 83.3 mg (1.12 mmol) of 3-hydroxyoxetane in 4.00 ml of 1,4-dioxane were added, at RT, 4 Å molecular sieve and 0.23 ml (0.45 mmol; 2 M solution in THF) of phosphazene P4 base. Subsequently, 100 mg (0.225 mmol) of the oxadiazole from Example 23A in 2.0 ml of 1,4-dioxane were added and the reaction mixture was stirred at RT for 2 h. The reaction mixture was filtered, diluted with dichloromethane and washed with 1 N aqueous hydrogen chloride solution. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by means of preparative HPLC. Yield: 18.6 mg (17% of theory)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:24])[C:5]2[O:9][C:8]([CH: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)=[N:7][C:6]=2[CH:23]=1.[F:25][C:26]1[CH:31]=[C:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:29]=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1>>[F:24][C:4]1[C:5]2[O:9][C:8]([CH: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)=[N:7][C:6]=2[CH:23]=[C:2]([C:27]2[CH:28]=[CH:29][C:30]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:31][C:26]=2[F:25])[CH:3]=1
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2F)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(Br)cc(F)c3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(S(C)(=O)=O)cc4F)cc(F)c3o2)CC1
Yield: 20.3 %

Procedure:
Following the General Procedure-1, the titled compound (50 mg) was prepared from Intermediate 12 (200 mg, 0.50 mmol) and Intermediate 3 (151 mg, 0.50 mmol) as an off-white solid. M.P.: 155.3-158.4° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.82 (dd, J 1.8, 8.1, 1H), 7.78 (dd, J 1.7, 9.4, 1H), 7.69-7.63 (m, 2H), 7.29 (td, 1.3, 10.6, 1H), 4.16 (d, J 11.2, 2 H), 3.22-3.16 (m, 1H), 3.11 (s, 3H), 3.00 (t, J 13.3, 2H), 2.21-2.14 (m, 2H), 2.00-1.88 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:11]=[CH:12][N:13]=2)[N:5]=[C:6]([Cl:10])[C:7]=1[CH2:8][CH3:9].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[Cl:10][C:6]1[C:7]([CH2:8][CH3:9])=[C:2]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]2[N:4]([CH:11]=[CH:12][N:13]=2)[N:5]=1
Reactant: CCc1c(Cl)nn2ccnc2c1Br
Reactant: Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1c(Cl)nn2ccnc2c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
A mixture of 8-bromo-6-chloro-7-ethylimidazo[1,2-b]pyridazine (60 mg, 0.2 mmol, 1 eq) from 1d, aniline (20.3 μL, 0.22 mmol, 1.1 eq) and potassium tert-butoxide (0.51 mL, 0.51 mmol, 2.5 eq) were suspended in DMF (3 mL) and stirred at RT for 1 h. The mixture was quenched with ethyl acetate and washed with lithium chloride saturated solution, dried with sodium sulfate and concentrated in vacuo. The residue was purified using an ISCO chromatography system (4 g silica cartridge, 5% ethyl acetate in heptane) to provide 6-chloro-N-phenyl-7-ethylimidazo[1,2-b]pyridazin-8-amine (22 mg). LC/MS, m/e 273.14 (M+1). HPLC Rt, 2.24 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:32]CS(C)(=O)=O)C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4]([O:38][CH3:39])[CH:3]=1.[CH3:40][O:41]C1C(OC)=CC=CC=1B(O)O>CCCCCCC.CCOC(C)=O>[CH3:39][O:38][C:4]1[C:3]([O:41][CH3:40])=[CH:2][CH:7]=[CH:6][C:5]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][CH3:32]
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COc1cccc(B(O)O)c1OC
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CNc1cnccc1-c1cccc(OC)c1OC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 98, intermediate b) and 2,3-dimethoxyphenylboronic acid (CAS RN 28611-39-4) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Light yellow solid (79%). MS (ESI): m/z=245.128 [M+H]+.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[C:6]([O:14][C@@H:15]1[C@@H:38]([O:39][C:40](=[O:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:48][C:49](=[O:56])[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@@H:36]([CH2:57][O:58][C:59](=[O:66])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[O:35][C@H:16]1[O:17][C:18]1[C:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][C:25]=2[CH3:31])=[C:21]([CH:32]([CH3:34])[CH3:33])[NH:20][N:19]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:6]([O:14][C@@H:15]1[C@@H:38]([O:39][C:40](=[O:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:48][C:49](=[O:56])[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@@H:36]([CH2:57][O:58][C:59](=[O:66])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[O:35][C@H:16]1[O:17][C:18]1[C:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27](/[CH:4]=[CH:3]/[CH2:2][CH2:1][OH:5])=[CH:26][C:25]=2[CH3:31])=[C:21]([CH:32]([CH3:34])[CH3:33])[NH:20][N:19]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=CCCO
Reactant: Cc1cc(Br)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n[nH]c1C(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(/C=C/CCO)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n[nH]c1C(C)C
Temperature: 90 °C
Yield: 70.6 %

Procedure:
Add 3-buten-1-ol (0.58 mL, 6.8 mmol) to a solution of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside (3 g, 3.4 mmol) in acetonitrile (30 mL) and triethylamine (20 mL). Degas the solution with nitrogen over 10 minutes. Add tri-o-tolylphosphine (205 mg, 0.67 mmol) and palladium acetate (76 mg, 0.34 mmol). Reflux at 90° C. for 2 hours. Cool to room temperature and concentrate to remove the solvent under the reduced pressure. Purify the residue by flash chromatography to yield the title compound (2.1 g, 2.4 mmol). MS (m/z): 878.4 (M+1).
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:9]=[C:8]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:30])[N:27]([CH3:29])[CH3:28])=[CH:21][CH:20]=2)[N:7]=1)(=N)N.BrC[C:33]#[N:34].[OH-].[Na+]>CN(C=O)C.O>[C:33]([CH2:1][S:4][CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:9]=[C:8]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:30])[N:27]([CH3:28])[CH3:29])=[CH:21][CH:20]=2)[N:7]=1)#[N:34]
Reactant: N#CCBr
Reactant: C[C@H]1COCCN1c1cc(CSC(=N)N)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1COCCN1c1cc(CSCC#N)nc(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
3-[4-[4-(Carbamimidoylsulfanylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-1,1-dimethyl-urea (0.38 mmol) was dissolved in DMF (2 mL). This was treated with bromoacetonitrile (0.030 mL) and then the sodium hydroxide (61 mg) in water (1 mL) and stirred at RT for 15 minutes. The reaction mixture was concentrated in vacuo and the residue loaded onto a SCX-2 column, washed with methanol and the desired material removed with 7N ammonia in methanol. The desired material was isolated and used without further chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH:10]([CH3:19])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH:10]([CH3:19])[C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C(=O)c1ccccc1)n1cc(Cl)cnc1=O

Procedure:
A solution of 5-chloropyrimidin-2-one (394 mg) and α-bromopropiophenone (0.5 ml) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 2.75 hours. The solution was evaporated and the residue was triturated with water (50 ml) giving an oily solid. This was extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine (50 ml), dried (MgSO4) and evaporated to a gum. This was crystallised from acetone-petrol (b.p. 40°-60°) to give the title pyrimidinone (306 mg,); m.p. 125°-127°; λmaxEtOH 232 nm (ε 15400), 245 nm (ε 15480), 335 nm (ε 3970).
Reaction SMILES: [CH3:1][C:2]([C:22]1[N:27]=[CH:26][C:25]([C:28]2[N:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([O:18][CH2:19]SC)[CH:17]=2)=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].[Xe](F)[F:39]>ClCCCl>[F:39][CH2:19][O:18][C:16]1[CH:17]=[C:12]([C:9]2[CH:8]=[CH:7][C:6]([C:2]([C:22]3[N:27]=[CH:26][C:25]([C:28]4[N:29]=[N:30][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)([CH3:1])[CH:3]([CH3:4])[CH3:5])=[CH:11][CH:10]=2)[CH:13]=[N:14][CH:15]=1
Reactant: F[Xe]F
Reactant: CSCOc1cncc(-c2ccc(C(C)(c3ccc(-c4ccc(C(F)(F)F)nn4)cn3)C(C)C)cc2)c1
Solvent: ClCCCl
Product: CC(C)C(C)(c1ccc(-c2cncc(OCF)c2)cc1)c1ccc(-c2ccc(C(F)(F)F)nn2)cn1
Reaction time: 2 h

Procedure:
A solution of 6b (18.0 mg, 0.0340 mmol) in 1,2-dichloroethane (2.00 mL) was added to a stirred solution of xenon difluoride (58.0 mg, 0.340 mmol) in 1,2-dichloroethane (1.00 mL) at 0° C. After approximately 2 h, the reaction mixture was quenched with triethylamine (0.250 mL) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 10%-30% EtOAc/hexanes as eluent) afforded the title compound 6c. m/z (ES) 497 (MH)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3([C:27](=[O:30])[NH:28][CH3:29])[CH2:26][CH2:25]3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:31][N:32](C)[C:33](=O)OC(C)(C)C)[CH:9]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3([C:27]([NH:28][CH3:29])=[O:30])[CH2:25][CH2:26]3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:31][NH:32][CH3:33])[CH:9]=1
Reactant: CNC(=O)C1(COc2ccc(S(=O)(=O)n3cc(CN(C)C(=O)OC(C)(C)C)cc3-c3ccccc3F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(OCC3(C(=O)NC)CC3)cc2)c1
Reaction time: 1 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((4-((1-(methylcarbamoyl)cyclopropyl)methoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 6a (100 mg, 0.18 mmol) was dissolved in 3 mL of dichloromethane, followed by addition of 1 mL of trifluoracetic acid and then the reaction solution was stirred for 1 h. 10 mL of saturated sodium bicarbonate solution were added, and the reaction solution was extracted with dichloromethane (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography with elution system A to obtain the title product 1-((4-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)methyl)-N-methylcyclopropylcarboxamide 6 (30 mg, a yellow oil) in 37% yield.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([NH2:22])=[O:21])[C:3]1=[O:23].[NH:24]1[C:28](=O)[CH2:27][CH2:26][C@H:25]1[C:30]([OH:32])=O>CN(C)C=O>[NH:24]1[C:28]2[C:27](=[CH:3][CH:2]=[CH:8][CH:7]=2)[CH:26]=[C:25]1[C:30]([NH:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([NH2:22])=[O:21])[C:3]1=[O:23])=[O:32]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: NC(=O)CN1C(=O)[C@@H](N)[C@H](c2ccccc2)Cc2ccccc21
Solvent: CN(C)C=O
Product: NC(=O)CN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)[C@H](c2ccccc2)Cc2ccccc21

Procedure:
In 20 ml of dimethylformamide are dissolved 1.00 g of trans-3-amino-2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetamide as obtained in (ii) of Example 30 and 0.42 g of L-pyroglutamic acid, and the same reaction and treatment as in Example 3 is carried out to give A isomer (0.41 g) and B isomer (0.42 g) of trans-2-oxo-3-[5-oxo-2(S)-pyrrolidinecarboxamido]-4-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetamide.