Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[C:6]=1[F:17].Br[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[C:6]=1[F:17]
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(Oc2ccc(S(C)(=O)=O)cn2)c2cc(F)ccc2c1F
Temperature: 70 °C
Yield: 86.8 %

Procedure:
A mixture of (1,6-difluoro-4-hydroxy-naphthalen-2-yl)acetic acid methyl ester (50 mg, 0.198 mmol), 2-bromo-5-methanesulfonyl-pyridin (52 mg, 0.22 mmol), potassium carbonate (60 mg, 0.434 mmol) and N,N-dimethylformamide (2.0 mL) was heated at 70° C. for 3 hours. The resulting mixture was cooled to room temperature, acidified with 1 N hydrochloric acid to pH 3, and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over sodium sulfate, and concentrated in vacuo to afford [1,6-difluoro-4-(5-methanesulfonyl-pyridin-2-yloxy)-naphthalen-2-yl]-acetic acid methyl ester (70 mg, 87%) as a white solid which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:47][CH2:48][C:49]1[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][C:41]([NH:47][CH2:48][C:49]4[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=4)=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: NCc1ccncc1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NCc2ccncc2)CC1

Procedure:
In a manner analogous to the method described in example 99, {4-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid was coupled with 4-(Aminomethyl)pyridine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C41H48Cl2N7O3 [(M+H)+] 756.319, observed 756.3194.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[C:25]([C:28]1[CH:29]=[CH:30][C:31]([Cl:37])=[C:32](B(O)O)[CH:33]=1)(=[O:27])[CH3:26]>>[C:25]([C:28]1[CH:29]=[CH:30][C:31]([Cl:37])=[C:32]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)[CH:33]=1)(=[O:27])[CH3:26]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: CC(=O)c1ccc(Cl)c(B(O)O)c1
Product: CC(=O)c1ccc(Cl)c(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c1
Yield: 7 %

Procedure:
5′-Acetyl-2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid was prepared in 7% yield (for two steps) from 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6) and 5-acetyl-2-chlorophenylboronic acid (available from Combi-Blocks Inc.) using General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode. 1H NMR (300 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.58 (d, J=1.9 Hz, 1H), 8.50 (s, 1H), 8.30-8.38 (m, 2H), 8.10 (dd, J=8.4, 2.0 Hz, 1H), 7.98 (dd, J=8.3, 2.1 Hz, 1H), 7.90 (d, J=2.1 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 2.62 (s, 3H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]1([CH2:34][CH2:35][O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[S:12][C:11]2[CH:13]=[C:14]3[S:18][C:17]([CH2:26][CH2:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH2:19][CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:16][C:15]3=[CH:33][C:10]=2[S:9]1)([CH3:4])([CH3:3])[CH3:2].[I:41]I.S(=O)(O)[O-].[Na+]>>[C:29]([O:28][CH2:27][CH2:26][C:17]1([CH2:19][CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:18][C:14]2[C:13]([I:41])=[C:11]3[S:12][C:8]([CH2:34][CH2:35][O:36][C:37]([CH3:40])([CH3:39])[CH3:38])([CH2:7][CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[S:9][C:10]3=[CH:33][C:15]=2[S:16]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: II
Reactant: CC(C)(C)OCCC1(CCOC(C)(C)C)Sc2cc3c(cc2S1)SC(CCOC(C)(C)C)(CCOC(C)(C)C)S3
Agent: O=S([O-])O
Agent: [Na+]
Product: CC(C)(C)OCCC1(CCOC(C)(C)C)Sc2cc3c(c(I)c2S1)SC(CCOC(C)(C)C)(CCOC(C)(C)C)S3
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
A dry flask under argon was charged with 2,2,6,6-tetra(t-butoxyethyl)benzo[1,2-d:4,5-d']bis(1,3)dithiole (60.0 g, 95.08 mmol) and dry tetrahydroturan (2000 ml). The mixture was cooled to -20° C. and n-Butyl lithium (76 ml of a 2.5 M solution in hexane, 0.19 mol) was added over 3 minutes. The mixture was stirred for 20 minutes at -20° C. and then a solution of iodine (120 g, 0.475 mol) in tetrahydroturan (500 ml) was added. The reaction mixture was poured into an aqueous sodium bisulphite solution and extracted with diethyl ether. The organic phase was washed once with an aqueous solution of sodium bisulphite and once with brine, dried (MgSO4) and evaporated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:7]=1.[C:19](OC(=O)CC)(=O)[CH2:20][CH3:21].Cl>C(N(CC)CC)C>[CH2:20]([C:21]1[O:18][C:5]2[C:6]([C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:19]
Reactant: CCC(=O)OC(=O)CC
Reactant: O=C(Cc1cccc(F)c1)c1cc(F)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
Intermediate 73 (3.00 g, 12.08 mmoles) was taken in a RB flask and to this triethylamine (25 ml) and propionic anhydride (4.92 g, 37.82 mmoles) were added and the mixture was refluxed for 24 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-yellow solid (1.80 g, 52% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 7.80 (m, 1H), 7.76 (m, 2H), 7.51 (dd, J=8.0, 6.4 Hz), 7.22 (m, 1H), 7.18 (m, 2H), 2.56 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:4][C:5]2[CH2:6][CH2:7][C:8]3([CH2:18][CH2:19][CH3:20])[C:13]([C:14]=2[C:15]=1[Cl:16])=[CH:12][C:11](=[O:17])[CH2:10][CH2:9]3.C(N1C=CN=C1)(N1C=CN=C1)=O.O[C:39]([CH3:44])([CH3:43])[C:40]([OH:42])=[O:41]>O1CCCC1>[Cl:1][C:2]1[C:3]([O:21][CH2:22][C:23]([O:25][C:39]([C:40]([OH:42])=[O:41])([CH3:44])[CH3:43])=[O:24])=[CH:4][C:5]2[CH2:6][CH2:7][C:8]3([CH2:18][CH2:19][CH3:20])[C:13]([C:14]=2[C:15]=1[Cl:16])=[CH:12][C:11](=[O:17])[CH2:10][CH2:9]3
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)CC2
Reactant: CC(C)(O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCC12CCC(=O)C=C1c1c(cc(OCC(=O)OC(C)(C)C(=O)O)c(Cl)c1Cl)CC2
Temperature: 25 °C

Procedure:
[(3,4-Dichloro-6,7,8,8a,9,10-hexahydro-6-oxo-8a-propyl-2-phenanthrenyl)oxy]acetic acid (351 mg, 1 mmole) is dissolved in tetrahydrofuran (10 ml) and treated with 1,1'-carbonyldiimidazole (160 mg, 1 mmole) and the mixture stirred at room temperature for an hour. 2-Hydroxy-2-methylpropionic acid (105 mg, 1 mmole) is added and the mixture stirred for 18 hours at room temperature. The solvent is removed by evaporation in vacuo and the residue purified by column chromatography on silica gel using dichloromethane/tetrahydrofuran/acetic acid 100/2/1, v.v.v. to give 1-carboxy-1-methylethyl [(3,4-dichloro-6,7,8,8a,9,10-hexahydro-6-oxo-8a-propyl-2-phenanthrenyl)oxy]acetate.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[H-].[Na+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([O:2][CH2:1][CH2:3][NH2:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: NCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NCCOCc1ccccc1
Yield: 90.8 %

Procedure:
To a solution of ethanolamine (5 g, 81.8 mmol) in 100 mL of dried THF was added 60% NaH (3.27 g, 81.8mmol) at room temperature. The mixture was heated to reflux for 30min, then benzyl chloride (9.32 g, 73.6 mmol) was added. The resulting mixture was refluxed for 3 hours. The mixture was concentrated, the residue was diluted with 1 N aq. HCl, extracted with dichloromethane. The aqueous layer was adjusted to pH>14 with 10% aq. NaOH, extracted with dichloromethane. The organic was dried over MgSO4, concentrated to give desired product (10.11 g, 82%). 1H NMR (CDCl3): δ 7.34 (m, 5H), 4.54 (s, 2H), 3.54 (t, 2H), 2.93 (t, 2H).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([N:6]2[CH:10]=[C:9]([Br:11])[CH:8]=[N:7]2)[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1>CC#N>[Br:11][C:9]1[CH:8]=[N:7][N:6]([CH:4]2[CH2:5][N:2]([CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH2:3]2)[CH:10]=1
Reactant: BrCCOC1CCCCO1
Reactant: Brc1cnn(C2CNC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1cnn(C2CN(CCOC3CCCCO3)C2)c1
Yield: 91.3 %

Procedure:
To 1-Azetidin-3-yl-4-bromo-1H-pyrazole hydrochloride (0.3 g, 1.26 mmol) in CH3CN (15 ml) added K2CO3(0.78 g, 5.6 mmol) followed by 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.205 ml, 1.5 mmol) reaction heated at reflux 0/N. Reaction mixture filtered, solid washed with EtOAc, filtrate concentrated under reduced pressure, residue partitioned between CH2Cl2 and H2O. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the product (380 mg).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[CH3:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=[O:36])[CH:30]=[CH:31][C:32]=1[CH3:33].C(N(CC)CC)C.Cl>C(#N)C>[CH3:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:36])[CH:30]=[CH:31][C:32]=1[CH3:33]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(N=C=O)cc1C
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.00 mmol) and 3,4-dimethylphenylisocyanate (0.15 g, 1.00 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.00 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (20 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) and dried overnight in vacuo to give 1-(3,4-dimethyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.30 g, 71% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.02 min (97.86%); mp: 254-256° C.; 1H NMR (DMSO-d6) δ 1.93-2.06 (m, 1H), 2.12 (s, 3H), 2.15 (s, 3H), 2.30-2.47 (m, 1H), 2.60 (d, J=17.2 Hz, 1H), 2.82-3.00 (m, 1H), 4.31 (d, J=17.4 Hz, 1H), 4.36-4.50 (m, 3H), 5.11 (dd, J=5.0, 13.3 Hz, 1H), 6.66 (t, J=5.9 Hz, 1H), 6.96 (d, J=8.3 Hz, 1H), 7.11 (dd, J=1.7, 8.1 Hz, 1H), 7.18 (s, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.51 (s, 1H), 7.69 (d, J=7.7 Hz, 1H), 8.41 (s, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 18.60, 19.62, 22.49, 31.20, 42.77, 47.10, 51.56, 115.35, 119.15, 121.86, 122.91, 126.89, 128.67, 129.49, 130.26, 136.08, 138.03, 142.36, 144.96, 155.26, 167.95, 170.98, 172.85; Anal Calcd for C23H24N4O4: C, 65.70; H, 5.75; N, 13.33. Found: C, 65.48; H, 5.62; N, 13.20.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[SH:12].[C:13](#N)[CH2:14][C:15]#[N:16].Cl>C(O)C>[C:15]([CH2:14][C:13]1[S:12][C:3]2[CH:4]=[C:5]([S:8]([NH2:11])(=[O:9])=[O:10])[CH:6]=[CH:7][C:2]=2[N:1]=1)#[N:16]
Reactant: Nc1ccc(S(N)(=O)=O)cc1S
Reactant: N#CCC#N
Agent: Cl
Solvent: CCO
Product: N#CCc1nc2ccc(S(N)(=O)=O)cc2s1
Yield: 22.8 %

Procedure:
A suspension of 4-amino-3-mercaptobenzenesulfonamide (74 g, 208 mmol) and malononitrile (25 g, 375 mmol) in 650 mL of ethanol with 1.3 mL of conc. HCl was refluxed under argon overnight. The dark brown solids were isolated by filtration and were washed with ethanol and ether to yield approximately 30 g of the crude product. The volume of the filtrate was reduced by evaporation and the solids that precipitated were isolated by filtration to yield an additional 12 g of product. The crude material was purified by flash column chromatography eluting with CH2Cl2:MeOH:ammonia (60:20:1 mL) to yield a total of 22.2 g (35% for three steps) of the title compound as an orange powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:22][C:23]1[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([CH3:33])[C:23]=4[OH:22])[CH2:28]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(c1O)CCNC2
Reactant: Cc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: Cl
Product: Cc1ccc(-c2nc(C(=O)N3CCc4c(ccc(C)c4O)C3)c3ccccc3n2)cc1
Yield: 30 %

Procedure:
Reaction of 2-(4-methylphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 16 (30% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.25 and 2.28 (2s, 3H), 2.48 (s, 3H), 2.81 and 3.05 (2t, 2H), 3.60 and 4.23 (2t, 2H), 4.50 and 5.09 (2s, 2H), 6.36-6.92 (m, 2H), 7.08 (2d, 1H), 7.37-7.64 (m, 3H), 7.97-8.06 (m, 2H), 8.37 (m, 1H), 8.60 (m, 2H); MS (ESI) m/z 410 ([M+H]+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[NH:7][C:6]2=[O:14].[CH2:15]([NH2:17])[CH3:16]>C(#N)C>[CH3:13][C:8]1[NH:7][C:6](=[O:14])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][NH:17][CH2:15][CH3:16])[CH:4]=2)[N:9]=1
Reactant: Cc1nc2ccc(CBr)cc2c(=O)[nH]1
Reactant: CCN
Solvent: CC#N
Product: CCNCc1ccc2nc(C)[nH]c(=O)c2c1
Reaction time: 4 h

Procedure:
A mixture of 6-bromomethyl-3,4-dihydro-2-methylquinazolin-4-one (prepared as described in Example 3; 10 g), anhydrous ethylamine (7.9 ml) and acetonitrile (250 ml) was stirred rapidly at laboratory temperature for 4 hours. The mixture was evaporated to dryness, the residue was dissolved in water, filtered and the filtrate was evaporated. The residue was triturated in acetone to give N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-ethylamine, as its hydrobromide salt (8.5 g), m.p. >260° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 2-methoxyphenol (50 g, 402.8 mmol) and triethylamine (84.2 mL, 604.2 mmol) in anhydrous dichloromethane (300 mL), was added methanesulfonyl chloride (37.6 mL, 483.3 mmol) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 2 hours, quenched with ice water (250 mL) and transferred to a separatory funnel. The organic phase was washed with a solution of NaOH (8 g) in ice water (200 mL), brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a colorless liquid (81.44 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 3.32 (s, 3H), 3.83 (s, 3H), 6.96-7.0 (m, 1H), 7.18-7.2 (m, 1H), 7.27-7.33 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2C)=[O:9])[CH:3]=1.C(N(C(C)C)C(C)C)C.[NH2:28][C:29]1[C:30]([CH3:35])=[CH:31][CH:32]=[CH:33][CH:34]=1>C(O)C>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:4]2[CH:3]=[C:2]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[N:7]=[CH:6][N:5]=2)=[O:9])=[CH:16][CH:15]=1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: Cc1ccccc1N
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1Nc1cc(C(=O)Nc2ccc(O)cc2)ncn1
Temperature: 160 °C

Procedure:
A solution of 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide, Intermediate 7 (50.0 mg; 0.20 mmol) in ethanol (3 mL) was treated with N-ethyldiisopropylamine (69 μl; 0.4 mmol) and o-toluidine (Fluka, 21.5 μl; 0.20 mmol). The reaction mixture was heated at 160° C. for 3 hours under microwave irradiation. The solvents were removed in vacuo, EtOAc was added and the organic phase was washed with a citric acid solution, dried over magnesium sulfate then evaporated in vacuo. The crude product was purified by column chromatography (silica), eluting with cyclohexane containing an increasing amount of EtOAc. The title compound was obtained as a yellow solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)[N:19]2[CH2:23]CC[CH2:20]2)C2C=CC=CC=2N=N1.[C:34]([C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41](=[O:46])[CH2:40]2)(O)=[O:35].CNC.C(N(CC)CC)C>ClCCl>[CH3:20][N:19]([CH3:23])[C:34]([C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41](=[O:46])[CH2:40]2)=[O:35]
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 3.5 g, 6.72 mmol) was added to a mixture of 5-carboxy-2-oxindole (1 g, 5.6 mmol), dimethylamine (5.6 mL of 2.0 M in THF, 11.2 mmol) and triethylamine (2.0 mL, 14 mmol) in dichloromethane. After stirring at room temperature for 3 hours, the reaction was diluted with more dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried and concentrated. The residue was purified by column chromatography to give 480 mg (42%) of 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid dimethylamide.
Reaction SMILES: C[O:2][C:3](=O)[C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:14][NH:15][NH2:16]>CO.O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]2[N:15]([CH3:14])[NH:16][C:3](=[O:2])[CH:4]=2)=[CH:7][CH:8]=1
Reactant: CNN
Reactant: COC(=O)C#Cc1ccc(F)cc1
Solvent: O
Solvent: CO
Product: Cn1[nH]c(=O)cc1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 36.4 %

Procedure:
A suspension of (4-fluorophenyl)propynoic acid methyl ester (1.6 g, 9.0 mmol) in MeOH (10 mL) and H2O (10 mL) was heated at 60° C. and MeNHNH2 (0.5 mL, 9.4 mmol) was added. The reaction mixture was stirred at 60° C. for 20 min. then filtered. The residue was washed with H2O (10 mL) and MeOH (5 mL) and dried to give 5-(4-fluorophenyl)-1-methyl-1,2-dihydro-pyrazol-3-one (0.63 g, 36%). The filtrate was then concentrated under reduced pressure and the residue dissolved in EtOAc (20 ml) and washed with H2O (3×15 mL). The aqueous layer was acidified to pH 5.5 with 2 M citric acid solution (3×15 mL) and extracted with EtOAc (3×20 mL). The extracts were dried (MgSO4) and concentrated under reduced pressure to give 5-(4-fluoro-phenyl)-2-methyl-1,2-dihydro-pyrazol-3-one (0.2 g, 12%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH2:20][CH3:21])=[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Br:27]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH2:20][CH3:21])=[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:9]=2)[C:5]([Br:27])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(-c2ccnc(N)n2)[nH]c1-c1cc(Cl)ccc1CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2nc(N)ncc2Br)[nH]c1-c1cc(Cl)ccc1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
Ethyl 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-1H-pyrrole-3-carboxylate (450 mg, 1.21 mmol) in DMF (7.5 mL) was treated with N-bromosuccinimide (216 mg, 1.21 mmol). The mixture was stirred overnight at room temperature, then poured into water, extracted with EtOAc (2×30 mL). The separated organic phase was dried over sodium sulfate and the solvent evaporated. Crystallization from diethyl ether afforded the title compound (420 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:13][CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([Cl:12])[CH:8]=[CH:7][CH:6]=2.[Br:15]N1C(C)(C)C(=O)N(Br)C1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:15][CH:13]([C:3]1[C:2]([Cl:1])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:12])[N:4]=1)[CH3:14]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCc1nc2cccc(Cl)c2nc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1nc2cccc(Cl)c2nc1Cl
Temperature: 25 °C
Yield: 129 %

Procedure:
3,5-Dichloro-2-ethylquinoxaline (1.10 Kg, 4.84 mol) was dissolved in CCl4 (4.4 L) at rt. 1,3-dibromo-5,5-dimethylhydantoin (762 g, 2.66 mol) and benzoyl peroxide (116 g, 0.48 mol) were then added. The resulting suspension was heated at reflux for 2 h. At this time LC-MS analysis showed that the reaction was complete. After cooling to rt white crystals formed in the reaction vessel. The white crystals were collected by filtration, washed with saturated aqueous NaHCO3 (3×5 L), and dried under high vacuum to give 2-(1-bromoethyl)-3,5-dichloroquinoxaline as a white solid (1.05 Kg). 1H NMR (DMSO-d6) δ ppm 8.04-8.12 (m, 2H), 7.78-7.90 (m, 1H), 5.76-5.84 (m, 1H), 2.09 (d, J=6.7 Hz, 3H). Mass Spectrum (ESI) m/z=304.8 [(M+1) (79Br)], 306.9 [(M+1) (81Br)].