Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:5]=[CH:4][N:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][N:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[S:25]([CH3:24])(=[O:27])=[O:26])[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1nccc(-c2cccc(CNCCc3ccccn3)c2)n1
Product: CS(=O)(=O)N(CCc1ccccn1)Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 16 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 403.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:24])=O.[NH2:25][C:26]([NH2:28])=[S:27]>CCO>[CH3:23][O:22][CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:25]=[C:26]([NH2:28])[S:27][CH:2]=3)=[C:6]([CH3:24])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: COCCOc1ccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: COCCOc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 41.4 %

Procedure:
A mixture of 2-bromo-1-{4-(4-(2-methoxyethoxy)phenoxy)-2,6-dimethylphenyl}ethanone (12-5, 835.6 mg, 2.1 mmol) and thiourea (161.7 mg, 2.1 mmol) in 95% EtOH (5.0 mL) was heated at reflux for 2.0 h. The solution was concentrated and added with water (10 mL) and saturated aqueous Na2CO3 (10.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were collected and dried under vacuum to give 4-{4-(4-(2-methoxyethoxy)phenoxy)-2,6-dimethylphenyl}thiazol-2-amine (12-6, 322.2 mg), which was used directly for the next step without further purification.
Reaction SMILES: [C:1]([N:4]([C:6]1[C:11]([Cl:12])=[CH:10][C:9]([C:13]2[NH:14][C:15]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[C:16]([CH3:18])[N:17]=2)=[C:8]([O:25][CH3:26])[CH:7]=1)C)(=O)C.Cl>O.C(O)C>[Cl:12][C:11]1[C:6]([NH:4][CH3:1])=[CH:7][C:8]([O:25][CH3:26])=[C:9]([C:13]2[NH:14][C:15]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[C:16]([CH3:18])[N:17]=2)[CH:10]=1
Reactant: COc1cc(N(C)C(C)=O)c(Cl)cc1-c1nc(C)c(-c2cccnc2)[nH]1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNc1cc(OC)c(-c2nc(C)c(-c3cccnc3)[nH]2)cc1Cl
Temperature: 25 °C
Yield: 93.5 %

Procedure:
A solution of 2-[4-(N-acetyl-N-methylamino)-5-chloro-2-methoxyphenyl]-4-methyl-5-(3-pyridyl)imidazole (0.70 g) and conc. hydrochloric acid (7 ml) in a mixture of water (7 ml) and ethanol (7 ml) was refluxed for 7 hours with stirring. After allowed to cool to ambient temperature, the mixture was evaporated under reduced pressure. The resulting oil was poured into water (20 ml). After neutrallized with aqueous potassium bicarbonate the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off to give 2-(5-chloro-4-methylamino-2-methoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (0.58 g).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[OH:28])=[CH:11][CH:10]=1.[CH2:33](Br)[CH:34]=[CH2:35]>>[CH2:35]([O:28][CH:16]1[CH:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]3[CH:29]=[CH:30][CH:31]=[CH:32][C:2]=3[Cl:1])=[CH:14][CH:13]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1)[CH:34]=[CH2:33]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccccc3Cl)cc2)C(O)C1
Product: C=CCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOc2ccccc2Cl)cc1

Procedure:
Analogously to Method D, 2.01 g of tert-butyl 4-{4-[3-(2-chlorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.74 ml of allylbromide are reacted. The title compound is obtained as a colourless oil. Rf=0.80 (1:1 EtOAc-heptane); Rt=6.13.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11].Cl.Cl[CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].N1CCCCC1>CC(C)=O.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:6][C:5]=1[OH:11]
Reactant: ClCc1cccnc1
Reactant: COC(=O)c1ccc(O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCNCC1
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2cccnc2)cc1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.1 %

Procedure:
A mixture in acetone (40 mL) and water (10 mL) of 2,4-dihydroxybenzoic acid methyl ester (1.19 g, 7.08 mmol), prepared as in Example 240A, 3-chloromethylpyridine hydrochloride (2.32 g, 14.2 mmol) and potassium carbonate (2.44 g, 21.2 mmol) was stirred at reflux for 24 hours, then acetone (10 mL) and piperidine (1 g) were added and reflux was continued for 12 hours. The reaction mixture was cooled to ambient temperature, poured into water, and extracted with ethyl acetate (3×). The combined organic extracts were washed with aqueous sodium hydroxide and water, dried, filtered and concentrated in vacuo. The residue was recrystallized from aqueous ethanol to give 4-(3-pyridylmethyloxy)-2-hydroxybenzoic acid methyl ester (0.57 g, 31%).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[C:24]([C:32]1[CH:58]=[CH:57][C:35]2[N:36]=[C:37]([C:39]3[C:40]([CH3:56])=[C:41]([C:45]([N:47]4[CH2:52][CH2:51][CH:50]([C:53]([OH:55])=O)[CH2:49][CH2:48]4)=[O:46])[NH:42][C:43]=3[CH3:44])[NH:38][C:34]=2[CH:33]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH3:59][N:60]([CH3:64])[CH2:61][CH2:62][NH2:63]>N1C=CC=CC=1>[CH3:59][N:60]([CH2:61][CH2:62][NH:63][C:53]([CH:50]1[CH2:51][CH2:52][N:47]([C:45]([C:41]2[NH:42][C:43]([CH3:44])=[C:39]([C:37]3[NH:38][C:34]4[CH:33]=[C:32]([C:24](=[O:31])[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:58]=[CH:57][C:35]=4[N:36]=3)[C:40]=2[CH3:56])=[O:46])[CH2:48][CH2:49]1)=[O:55])[CH3:64]
Reactant: CN(C)CCN
Reactant: Cc1[nH]c(C(=O)N2CCC(C(=O)O)CC2)c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: Cc1[nH]c(C(=O)N2CCC(C(=O)NCCN(C)C)CC2)c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 60 °C
Reaction time: 10 h
Yield: 54.3 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31 mg, 0.16 mmol) and 1-hydroxybenzotriazole monohydrate (25 mg, 0.16 mmol) were added to a pyridine (4 ml) solution of the ((4-(5-benzoylbenzimidazol-2-yl)-3,5-dimethylpyrrol-2-yl)-carbonyl)piperidine-4-carboxylic acid (70 mg, 0.15 mmol) obtained in Example 45. N,N-Dimethylethylenediamine (13 mg, 0.15 mmol) was added to the reaction mixture and heated. The reaction mixture was stirred at 60° C. (internal temperature) for 10 hours, and then allowed to cool to room temperature with stirring. The solvent was evaporated, and the residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2) to afford N-dimethylaminoethyl-1-((4-(5-benzoylbenzimidazol-2-yl)-3,5-dimethylpyrrol-2-yl)-carbonyl)piperidine-4-carboxamide (44 mg, 55%) as white crystals.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:17][CH2:16][C:15]([CH3:20])([CH3:19])[CH3:14])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of 1-boc-piperazine (8.19 g, 43.9 mmol) in methanol/acetic acid (99:1, v/v, 100 ml) was added 3,3-dimethylbutyraldehyde (4.0 g, 40.0 mmol) and the resulting mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (3.27 g, 51.9 mmol) was added, and the resulting mixture was stirred at room temperature for 18 h then concentrated in vacuo. The residue was dissolved in EtOAc and the resulting solution was washed with saturated NaHCO3, water and brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% EtOAc) to yield the title compound (9.1 g, 84%).
Reaction SMILES: [O:1]=[C:2]1[CH:11]([CH2:12][C:13]([OH:15])=O)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C[CH2:17][N:18]=[C:19]=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.CNC>C1COCC1.C(#N)C.O.C(N(CC)CC)C>[CH3:17][N:18]([CH3:19])[C:13](=[O:15])[CH2:12][CH:11]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CC1Cc2ccccc2NC1=O
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C)C(=O)CC1Cc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
To the mixed solution of 2-oxo-1,2,3,4-tetrahydro-3-quinolineacetic acid (810 mg) in THF (10 ml) and acetonitrile (10 ml), WSC (1.15 g), HOBt (610 mg), dimethylamine hydrochloride (650 mg) and triethylamine (1.67 ml) were added subsequently, which was stirred at room temperature overnight. Water was added to the reaction mixture, which was extracted with a mixed solvent of ethyl acetate-THF (1:1). The organic layer was washed subsequently with 0.1N aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution, then dried and concentrated to obtain the entitled compound (620 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[NH2:2].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][C:19]([C:20](=O)[CH2:21]Br)=[CH:18][CH:17]=1>>[F:14][C:15]([F:26])([F:27])[C:16]1[CH:17]=[CH:18][C:19]([C:20]2[N:2]=[C:1]([C:4]3[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=3)[C:7]([O:9][CH3:10])=[O:8])[O:3][CH:21]=2)=[CH:24][CH:25]=1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cccc(C(N)=O)c1
Product: COC(=O)c1cccc(-c2nc(-c3ccc(C(F)(F)F)cc3)co2)c1
Yield: 30 %

Procedure:
In the same manner as in Example 1, methyl 3-carbamoylbenzoate was reacted with 4-trifluoromethylphenacyl bromide to obtain methyl 3-[4-(4-trifluoromethylphenyl)-2-oxazolyl]benzoate. The product was recrystallized from ethanol. Yield: 30%. Pale yellow prisms. Melting Point: 151 to 152° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC.Br[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH:47]([CH3:49])[CH3:48])=[CH:42][CH:41]=1>C1(C)C=CC=CC=1.CCOC(C)=O.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH:47]([CH3:49])[CH3:48])=[CH:42][CH:41]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:16]=[CH:17][C:18]([C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:19][CH:20]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Reactant: CC(C)Oc1ccc(Br)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2n1-c1ccc(OC(C)C)cc1
Yield: 95.1 %

Procedure:
5-(4-tert-Butylphenyl)indole-2-carboxylic acid ethyl ester (198 mg, 0.60 mmol; see step (a) above), CuI (12 mg, 0.06 mmol), K3PO4 (254 mg, 1.2 mmol), N,N′-dimethyl-1,2-diaminoethane (20 μL, 0.18 mmol) and 1-bromo-4-isopropoxybenzene (258 mg, 1.2 mmol) in toluene (2 mL) was heated at 110° C. for 17 h. The mixture was diluted with EtOAc and washed with NaHCO3 (aq. sat.), HCl (aq. 0.1 M), brine and then dried over Na2SO4. Concentration and purification by chromatography gave the sub-title compound (260 mg, 94%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:9]=2)[CH2:4]1.[C:20](O)(=[O:29])[C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22].C(N(CC)CC)C.[Cl-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:15]([CH2:14][O:13][C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][CH2:12][C@H:3]([NH:2][C:20](=[O:29])[C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[OH:22])[CH2:4]2)=[CH:9][CH:8]=1)([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@@H](N)CC2
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc2c(c1)C[C@@H](NC(=O)[C@H](O)c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 55 %

Procedure:
To a suspension of 5.7 g of (S)-2-amino-7-carbethoxymethoxytetraline hydrochloride, 3 g of (R)-mandelic acid and 8 g of benzotriazolyl-N-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) in 100 ml of anhydrous methylene chloride, there is slowly added 5.6 ml of triethylamine, then the solution thus obtained is left under stirring at room temperature for 5 hours. After addition of 150 ml of a saturated solution of sodium chloride, the mixture is left under stirring for 30 minutes at room temperature, added with 500 ml of ethyl acetate. The organic phase is washed at first with a 1N solution of hydrochloric acid, then with a saturated solution of sodium bicarbonate and sodium chloride. The organic solution is dried on sodium sulfate, filtered and evaporated to dryness. The oil thus obtained is purified by flash chromatography by using a mixture of ethyl acetate/cyclohexane 55/45 as a solvent. The resulting solid is triturated in 20 ml of ethyl ether and the product thus obtained is crystallized from ethyl acetate to give N-[(2S)-7-carbethoxymethoxy-1,2,3,4 -tetrahydronaphth-2-yl]-(R)-mandelamide; m.p. 115°-117° C.; /alpha/=-98.3° (methanol, c=1%). Yield: 55%.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][CH2:10][C:11]([O:13]C)=[O:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>>[C:1]1([C@H:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CN[C@H](C)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: C[C@@H](NCC(=O)O)c1ccccc1
Yield: 91.1 %

Procedure:
Methyl 2-{[(1R)-1-phenylethyl]amino}acetate (Intermediate 44, 587.0 g, 3.0 mol) was refluxed in aqueous KOH (3.36 g, 0.06 mol dissolved in 2.5 L water) overnight. The phases were then separated and the aqueous solution was washed with EtOAc (3×1 L). The combined organic solutions were concentrated in vacuo to give the title compound (490 g, 90%) as white solid; 1H NMR: 1.48 (3H, d), 2.89 (1H, d), 3.00 (1H, d), 4.20 (1H, m), 7.37-7.43 (5H, m).
Reaction SMILES: [Na].Cl.[CH:3]([NH2:5])=[NH:4].[CH2:6]([N:13]1[CH2:19][CH2:18][C:17](Cl)=[C:16]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=O)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[CH2:6]([N:13]1[CH2:14][CH2:15][C:16]2[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:4][CH:3]=[N:5][C:17]=2[CH2:18][CH2:19]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N=CN
Reactant: O=C(C1=C(Cl)CCN(Cc2ccccc2)CC1)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: c1ccc(CN2CCc3ncnc(-c4ccccc4)c3CC2)cc1
Temperature: 6 °C
Reaction time: 0.25 h
Yield: 39.5 %

Procedure:
16.8 g sodium was added to 500 mL ethanol at 10° C. Then, 48.5 g formamidine hydrochloride was added and the reaction was stirred 15 min at 6° C. 28 g (1-benzyl-5-chloro-2,3,6,7-tetrahydro-1H-azepin-4-yl)-phenyl-methanone was added and the reaction was stirred 17 h at RT and 1 h at 40° C. The mixture was filtered and the solvent was removed. The residue was dissolved in ethyl acetate. The layers were separated and the organic layer was washed with water and evaporated. The residue was crystallized with diethylether to yield 10.7 g of the desired product. Fp: 81-82° C.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C[O-].[Na+].CO.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[CH2:24][CH2:25][C:26](Cl)=[N:27]O>O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[CH2:24][CH2:25][C:26]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:1]([CH:2]([CH3:4])[CH3:3])[O:5][N:27]=1
Reactant: ON=C(Cl)CCc1c(Cl)cccc1Cl
Reactant: COC(=O)CC(=O)C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(CCc2c(Cl)cccc2Cl)noc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
A solution of methyl isobutyrylacetate (0.662 g, 5.8 mmol) in tetrahydrofuran (1.16 mL) was stirred at 0° C. as 0.5 N sodium methoxide in methanol solution (11.6 mL, 5.8 mmol) was added. A solution of 3-(2,6-dichlorophenyl)-N-hydroxypropanimidoyl chloride (1.04 g, 4.82 mmol) in tetrahydrofuran (3.8 mL) was added and the solution was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated and the residue triturated with water and filtered to yield a white solid which was dried in a 45° C. oven with P2O5 under reduced pressure to yield the title compound (0.926 g, 56%).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([N:15]=[CH:16][C:17](=O)[NH:18]2)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([N:15]=[CH:16][C:17]([Cl:3])=[N:18]2)=[CH:13][CH:12]=1
Reactant: O=c1cnc2ccc(Br)cc2[nH]1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Clc1cnc2ccc(Br)cc2n1
Temperature: 80 °C
Reaction time: 17 h
Yield: 74.6 %

Procedure:
Thionyl chloride (407.5 mL; 5.59 mol), then N,N-dimethylformamide (34.6 mL; 0.45 mol) were added dropwise to a mixture of 7-bromo-2(1H)-quinoxalinone (500 g; 2.24 mol) in toluene (7.61 L). The reaction mixture was stirred at 80° C. for 17 hours then cooled to 35° C. and poured cautiously onto water. The bi-phasic mixture was stirred for 30 minutes and then decanted. The organic layer was evaporated to dryness and the residue crystallized in methyl-tert-butyl ether, filtered and the precipitate washed with methyl-tert-butyl ether and dried to give 407 g (74.7%) of 7-bromo-2-chloro-quinoxaline. Filtrate was evaporated and re-crystallized in methyl-tert-butyl ether to provide a second fraction of 72 g (13.2%) of 7-bromo-2-chloro-quinoxaline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.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>[CH3:10][S:9][C:4]1[N:3]=[C:2]([NH2:1])[CH:7]=[C:6]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([C:12]([F:23])([F:22])[F:11])[CH:18]=2)[N:5]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CSc1nc(N)cc(Cl)n1
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: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CSc1nc(N)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a stirred solution of 4-amino-6-chloro-2-methylthiopyrimidine (3.5 g) in toluene (45 mL) under a nitrogen atmosphere was added, sequentially, (3-trifluoromethylphenyl)boronic acid (4.15 g), potassium carbonate (25 mL, 2M) and tetrakis(triphenylphosphine)palladium(0) (1.16 g). The mixture was heated to reflux for ten hours and stirred at room temperature over the weekend. Ethyl acetate (150 mL) was added and the mixture washed with water (2×100 mL). Organics were separated, washed with saturated sodium chloride (100 mL), dried over sodium sulphate and solvent was evaporated under reduced pressure to yield crude product. Purification by flash chromatography yielded product 2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-ylamine (3.45 g)
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[CH3:27]COCC>>[C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([O:10][CH3:27])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C(=C(\C(=O)O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Reactant: CCOCC
Product: COC(=O)/C(=C(\COC(C)=O)c1ccc(S(C)(=O)=O)cc1)c1ccccc1

Procedure:
To a suspension of the acid from Example 4 (100 mg) in Et2O (20 mL) was added dropwise excess CH2N2 solution in Et2O. The solution was concentrated and the solid was swished with 2:1 hexane/EtOAc to give 90 mg of the title compound as a white solid.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:15]([OH:17])=O)[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:18][NH:19][CH3:20]>C(O)C>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@@H:12]([CH2:13][OH:14])[C:15]([N:19]([CH3:20])[CH3:18])=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Reactant: CNC
Solvent: CCO
Product: CN(C)C(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-carbobenzoxy-L-serine (5.00 g) in ethanol (70 mL) were added dimethylamine (2.51 mL) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (6.23 g), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate/tetrahydrofuran and water. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.23 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:13]=[C:12]([CH3:14])[N:11]([CH3:15])[C:10]=1[C:16]([O:18]CC)=O.[Na].C(O)(=O)C>C(O)C>[CH3:15][N:11]1[C:10]2[C:16](=[O:18])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][C:9]=2[CH:13]=[C:12]1[CH3:14]
Reactant: CCOC(=O)c1c(Nc2ccccc2N)cc(C)n1C
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc2c(n1C)C(=O)Nc1ccccc1N2

Procedure:
2.73 g (0.01 mole) of ethyl 3-(2-aminophenyl)amino-1,5-dimethyl-1H-pyrrole-2-carboxylate in a solution of 0.25 g (0.011 mole) of sodium in 40 ml of dry ethanol are boiled under reflux for 2 hours. After the mixture has cooled, it is neutralized carefully with acetic acid; the solvent is stripped off in vacuo, and the yellowish residue is recrystallized from dioxane. Yield: 1.9 g.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]1=2.[CH3:20][S:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:23])=[O:22]>>[CH3:15][O:14][C:12]1[CH:11]=[CH:10][C:9]2[C:3](=[CH:2][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][S:21]([CH3:20])(=[O:23])=[O:22])[C:4]3[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=3[CH2:6][CH2:7][C:8]=2[CH:13]=1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Reactant: COc1ccc2c(c1)CCc1ccccc1C2=CBr
Product: COc1ccc2c(c1)CCc1ccccc1C2=Cc1ccccc1NS(C)(=O)=O

Procedure:
Following the procedures essentially as described in Example 219, below, and using 5-bromomethylene-2-methoxy-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (E/Z mixture, 100 mg, 0.32 mmol) with 4-methanesulfonylaminophenylboronic acid (75 mg, 0.35 mmol) to give 35 mg (27%) of an E/Z mixture of the title compound. MS (ES) 406 (M+1), 404 (M−1). HPLC shows 53% of the E isomer and 44% of the Z isomer.