Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[Cl:11][CH2:12][C:13](Cl)=[O:14]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:13](=[O:14])[CH2:12][Cl:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: COc1cc(N)cc(Br)c1
Product: COc1cc(Br)cc(NC(=O)CCl)c1

Procedure:
In a manner similar to Preparation 3, react 3-bromo-5-methoxybenzeneamine with chloroacetyl chloride to obtain the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.[Br:11][C:12]1[N:13]=[C:14](Br)[C:15]2[N:16]([CH:18]=[CH:19][N:20]=2)[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[O:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:14]3[C:15]4[N:16]([CH:18]=[CH:19][N:20]=4)[CH:17]=[C:12]([Br:11])[N:13]=3)[CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: Nc1ccc2cnoc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1cn2ccnc2c(Nc2ccc3cnoc3c2)n1

Procedure:
A quantity of 0.13 g (1 mmole) of Benzo[d]isoxazol-6-ylamine is treated with 0.27 g (1 mmole) of 6,8-Dibromo-imidazo[1,2-a]pyrazine in acetonitrile with 3 eq. of K2CO3 at reflux for 16 hrs. The reaction mixture is cooled partitioned between ethyl acetate and water, the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford Benzo[d]isoxazol-6-yl-(6-bromo-imidazo[1,2-a]pyrazin-8-yl)-amine.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH3:18][N:19]=[C:20]=[S:21].C(OCC)(=O)C>C(O)C>[C:1]([NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([NH:17][C:20]([NH:19][CH3:18])=[S:21])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CN=C=S
Reactant: CC(=O)NCc1cccc(-c2csc(N)n2)n1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNC(=S)Nc1nc(-c2cccc(CNC(C)=O)n2)cs1
Temperature: 25 °C
Yield: 20.7 %

Procedure:
A mixture of 4-(6-acetylaminomethylpyridin-2-yl)2-aminothiazole (7.0 g) and methyl isothiocyanate (6.2 g) in ethanol (140 ml) was heated under reflux for 40 minutes and then the mixture was cooling to ambient temperature. To the mixture was added ethyl acetate (140 ml) and isolated precipitate was collected by filtration to give 4-(6-acetylaminomethylpyridin-2-yl)-2-(3-methylthioureido)thiazole (1.88 g).
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C(N(CC)CC)C.[CH3:43][N:44]([CH3:50])[S:45]([CH:48]=[CH2:49])(=[O:47])=[O:46]>>[CH3:43][N:44]([CH3:50])[S:45]([CH2:48][CH2:49][N:33]1[CH2:34][CH2:35][CH:30]([C:28]2[CH:27]=[CH:26][C:23]3[C:24]4[N:25]=[C:16]([C:15]5[N:11]([CH:8]([CH3:10])[CH3:9])[N:12]=[CH:13][N:14]=5)[S:17][C:18]=4[CH2:19][CH2:20][O:21][C:22]=3[CH:29]=2)[CH2:31][CH2:32]1)(=[O:47])=[O:46]
Reactant: C=CS(=O)(=O)N(C)C
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(CCS(=O)(=O)N(C)C)CC3)ccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 375 (188 mg, 0.37 mmol) and triethylamine (0.18 mL, 1.3 mmol) in IMS (3 mL) was added ethenesulfonic acid dimethylamide and the reaction mixture stirred at RT for 18 h before being concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 5% MeOH in DCM) to give 499 as a beige solid (145 mg, 74%). LCMS: RT=3.47 min, [M+H]+=531. 1H NMR δ (ppm) (DMSO-d): 8.23 (1 H, d, J=8.19 Hz), 8.05 (1 H, s), 7.04 (1 H, dd, J=8.26, 1.80 Hz), 6.88 (1 H, d, J=1.76 Hz), 5.82-5.72 (1 H, m), 4.30 (2 H, t, J=5.02 Hz), 3.37 (2 H, t, J=5.04 Hz), 3.19 (2 H, t, J=7.23 Hz), 2.95 (2 H, d, J=10.97 Hz), 2.75 (6 H, s), 2.65 (2 H, t, J=7.25 Hz), 2.04 (2 H, t, J=11.43 Hz), 1.75 (2H, d, J=12.62 Hz), 1.67-1.53 (2 H, m), 1.50 (6 H, d, J=6.58 Hz). 1 H obscured by solvent
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][C:8]([C:10]3[O:11][C:12]4[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([O:20][CH2:21][C:22]5[N:23]=[C:24]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=6)[S:25][CH:26]=5)[C:13]=4[CH:14]=3)=[CH:9][N:4]2[N:3]=1.[CH3:33][OH:34].C[O-].[Na+]>ClCCl>[F:19][C:17]1[CH:16]=[C:15]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[S:25][CH:26]=2)[C:13]2[CH:14]=[C:10]([C:8]3[N:7]=[C:5]4[N:4]([CH:9]=3)[N:3]=[C:2]([O:34][CH3:33])[S:6]4)[O:11][C:12]=2[CH:18]=1
Reactant: Fc1cc(OCc2csc(-c3ccccc3)n2)c2cc(-c3cn4nc(Br)sc4n3)oc2c1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1nn2cc(-c3cc4c(OCc5csc(-c6ccccc6)n5)cc(F)cc4o3)nc2s1
Reaction time: 0.42 h
Yield: 64 %

Procedure:
2-Bromo-6-(6-fluoro-4-((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)imidazo[2,1-b][1,3,4]thiadiazole (17 mgs, 0.032 mmol) was dissolved in dichloromethane (1.3 mL) (some heat and sonication were required). Methanol was then added (0.3 mL) followed by sodium methoxide (14.74 μL, 0.064 mmol) in one shot. The reaction was stirred at r.t for 25 min., then quenched with HCl 1.0 N and stirred until the reaction color changes to yellow. Sat. NaHCO3 was then added and this was extracted with dichloromethane (4×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (BIOTAGE® 12 g column using 100% dichloromethane to 5% ethyl acetate in dichloromethane (increment of 1%) to give the title material (10 mgs, 64%) as a yellowish solid. LC (Method A): 2.488 min. HRMS (ESI) calcd for C23H15FN4O3S2 [M+H]+ m/z 479.0570, found 479.0661. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.94-8.03 (m, 2H), 7.89 (s, 1H), 7.43-7.53 (m, 3H), 7.39 (s, 1H), 7.19 (s, 1H), 6.85-6.94 (m, 1H), 6.59-6.68 (m, 1H), 5.40 (s, 2H), 4.23 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N+:3]=1[O-:11].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N+:3]([O-:11])=[CH:4][C:5]([C:6]([N:34]2[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)[n+]([O-])c1
Reactant: CN1CCNCC1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClC(Cl)Cl
Product: CN1CCN(C(=O)c2ccc(Cl)[n+]([O-])c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
6-Chloronicotinic acid 1-oxide (0.347 g, 2.0 mmol) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (0.544 g, 2.2 mmol) were mixed in chloroform (8 mL) at 0° C. 1-Methylpiperazine (0.30 g, 3.0 mmol) was added after 5 min and the reaction mixture was stirred for 16 h at room temperature. The solvent was removed in vacuo and the residual oil was purified on a silica gel column using chloroform/methanol/triethylamine, (100:20:1), as the eluent to give 0.18 g, (35% yield) of the title compound as a brownish solid: 1H NMR (DMSO-d6, 400 MHz) δ 8.56 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 3.63 (br s, 2H), 3.39 (br s, 2H), 2.43 (br s, 2H), 2.34 (br s, 2H), 2.25 (s, 3H); MS (EI) m/z 256 and 258 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[O:30][CH2:29][C:25]1([CH2:28][O:27][CH2:26]1)[C:5]12[CH2:9][O:8][C:7]([N:10](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:6]1.O1CCOCC1.[NH:40]1[C:48]2[C:43](=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=2)[CH:42]=[N:41]1.C([O-])([O-])=O.[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH:40]1[C:48]2[C:43](=[C:44]([C:2]3[CH:3]=[C:4]4[C:31](=[CH:32][CH:33]=3)[O:30][CH2:29][C:25]3([CH2:28][O:27][CH2:26]3)[C:5]34[CH2:9][O:8][C:7]([NH2:10])=[N:6]3)[CH:45]=[CH:46][CH:47]=2)[CH:42]=[N:41]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OCC21COC1
Reactant: OB(O)c1cccc2[nH]ncc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=NC2(CO1)c1cc(-c3cccc4[nH]ncc34)ccc1OCC21COC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
Under argon atmosphere, to a mixture of di-tert-butyl (6′-bromodispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)imidodicarbonate (300 mg, 0.571 mmol), dioxane (3.0 mL) and water (1.5 mL) were added 1H-indazol-4-ylboronic acid (185 mg, 1.14 mmol), K2CO3 (237 mg, 1.71 mmol) and bis(triphenylphosphine)palladium(II) dichloride (40 mg, 0.057 mmol), and the mixture was stirred for 3 hours at 100° C. The reaction mixture was cooled down to ambient temperature, partitioned between H2O and 10% MeOH in CHCl3. The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated at reduced pressure. The residue was dissolved with dioxane (3.0 mL), and silica gel (neutral; 900 mg) was added to the mixture. After stirring for 2.5 hours at 110° C., the reaction mixture was cooled down to ambient temperature, and concentrated at reduced pressure. Purification of the residue with column chromatography on silica gel (CHCl3-EtOH, a linear gradient of EtOH from 0 to 20%) afforded 6′-(1H-indazol-4-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-amine (142 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[CH:23]1([NH:26][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])[CH2:25][CH2:24]1
Reactant: NC1CC1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NC4CC4)cc3)c2)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 39 %

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (59 mg, 0.2 mmol), cyclopropylamine (11 mg, 0.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.2 mmol) were suspended in dry DCM (7 ml) and stirred at room temperature under nitrogen for 20 h. Cyclopropylamine (33 mg, 0.6 mmol) was added and the reaction stirred at room temperature for 21 h. 1-Hydroxybenzotriazole (27 mg, 0.2 mmol) was added and the reaction heated at 35° C. for 70 h. Water (10 ml) was added to the cooled reaction, and the organic fraction separated. The organic phase was absorbed onto a silica flash column and eluted with DCI/ethanol/ammonia (300:8:1). Solvent was evaporated from the product fractions under vacuum to give N-(cyclopropyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide (26 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:25]2[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])=[CH:17][CH:16]=1)=[O:22]
Reactant: Cc1cccc(C)c1B(O)O
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cccc(C)c1-c1ccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 47.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 2,6-dimethyl phenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.034 g (47%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([N:29]2[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]2)[N:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:27]2[CH:28]=[CH:23][N:24]=[C:25]([N:29]3[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]3)[N:26]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: OC1CCN(c2nccc(Cl)n2)C1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccnc(N4CCC(O)C4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide and 1-(4-chloropyrimidin-2-yl)pyrrolidin-3-ol as the starting materials.
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:15]>>[CH2:1]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][NH2:15])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: ClCc1csc(Cc2ccccc2)n1
Product: NCc1csc(Cc2ccccc2)n1
Yield: 50 %

Procedure:
2-Benzyl-4-chloromethylthiazole [Pharmazie 1972, 27, 146] (223.7 g, 1 mol) was stirred with liquid ammonia (600 ml) in an autoclave for 24 hours. The ammonia was removed and the product was distilled in vacuo [bp (0.02 mmHg) 141-144° C.] to give the title compound (102 g, 50%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([CH3:17])[CH:9]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)Cl.O>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)=[O:14])=[C:10]([CH3:17])[CH:9]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Br)ccc1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.850 ml (10 mmol) oxalyl chloride in 20 ml CH2Cl2 is added dropwise to a iced-cooled solution of 1.10 g (5 mmol) 4-bromo-2-methylbenzoic acid in 30 ml CH2Cl2. After complete addition, the cooling bath is removed and stirring maintained for 1 h at RT. The solvent is evaporated to dryness, the resultant colorless residue is dried under vacuum and then diluted with 25 ml CH2Cl2. This solution is then added dropwise to a mixture of 1.01 g (10 mmol) of N-methylpiperazine in 25 ml CH2Cl2. After 1 h 30, the reaction mixture is diluted with water and the two phases are separated. The aqueous phase is re-extracted with CH2Cl2 and the combined organic extracts are successively washed with a sat.solution of NaHCO3, water, sat. brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo to afford, after drying in HV, the title compound which is used in the next step without further purification.
Reaction SMILES: [CH3:1][Mg+].[Br-].[CH3:4][O:5][C:6]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH:11]([C:15](N(OC)C)=[O:16])[CH2:10]1>C1COCC1.O>[C:15]([CH:11]1[CH2:10][N:9]([CH2:8][C:7]2[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:6]=2[O:5][CH3:4])[C:13](=[O:14])[CH2:12]1)(=[O:16])[CH3:1]
Reactant: COc1ccc(CN2CC(C(=O)N(C)OC)CC2=O)c(OC)c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2CC(C(C)=O)CC2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
MeMgBr (2.3 mL, 6.8 mmol) was added to a mixture of 1-(2,4-dimethoxybenzyl)-N-methoxy-N-methyl-5-oxopyrrolidine-3-carboxamide (2.0 g, 6.2 mmol) in THF (40 mL) at −10° C. The mixture was stirred at 0° C. for 1 hour then diluted with water and the mixture was extracted with EtOAc. The EtOAc layer was dried over sodium sulfate and concentrated under reduced pressure to afford 4-acetyl-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one. 1H NMR (400 MHz, CDCl3) δ 7.10-7.13 (m, 1H), 6.43-6.45 (m, 2H), 4.41-4.42 (m, 2H), 3.79-3.82 (m, 6H), 3.46-3.20 (m, 3H), 2.61-2.64 (m, 2H), 2.04-2.15 (d, J=7.2 Hz, 3H). MS ESI calc'd. for C15H20NO4 [M+H]+ 278. found 278.
Reaction SMILES: [OH-].[Na+].CN(C=O)C.[CH2:8]([SH:10])[CH3:9].Br[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([Br:18])[CH:17]=1>O>[Br:18][C:16]1[CH:15]=[N:14][CH:13]=[C:12]([S:10][CH2:8][CH3:9])[CH:17]=1
Reactant: Brc1cncc(Br)c1
Reactant: CCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80.5 %

Procedure:
Under a nitrogen atmosphere, NaOH (1.25 g, 31.3 mmol) was added to anhydrous DMF (40 mL). Ethanethiol (2.60 mL, 2.20 g, 35.5 mmol) was then added by syringe and the mixture was stirred for 6 h at 25° C. while the NaOH dissolved. The solution was cooled to 0° C., and 3,5-dibromopyridine (5.92 g, 25.0 mmol) was added. After stirring for 15 min at 0° C. and 45 min at 25° C., the mixture was poured into water (250 mL) and extracted with ether (2×100 mL). Drying (Na2SO4) and evaporation of the ether, followed by vacuum distillation of the crude product gave 4.39 g (80.6% yield) of colorless oil, bp 91-95° C. at 0.30 mm Hg.
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]1([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO.C(Cl)Cl>[C:11]1([NH:17][S:18]([C:21]2[CH:22]=[CH:23][C:24]([N:27]([CH3:28])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCCCCCCCl
Reactant: CNc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCN(C)c1ccc(S(=O)(=O)Nc2ccccc2)cc1

Procedure:
The procedure of Example 17 was carried out using nonyl chloride and the product from Step 2 above. mp: 113-116° C.; TLC Rf =0.38 in MeOH/CH2Cl2 ; 1H NMR (CDC13, ppm) δ 7.9 (d, 2H), 7.6 (d, 5H), 7.3 (d, 2H), 7.0 (bs, 1H), 3.0 (s, 3H), 2.0 (t, 2H), 1.4 (m, 12H), 0.9 (t, 3 H)
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.CO.[CH3:34][N:35]([CH3:61])[CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([NH:47][S:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=2)(=[O:50])=[O:49])=[CH:43][CH:42]=1>C1COCC1>[CH3:61][N:35]([CH3:34])[CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:42]=[CH:43][C:44]([N:47]([CH3:1])[S:48]([C:51]2[CH:52]=[CH:53][C:54]([C:57]([F:59])([F:60])[F:58])=[CH:55][CH:56]=2)(=[O:50])=[O:49])=[CH:45][CH:46]=1
Reactant: CN(C)CCCCOc1ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CCCCOc1ccc(N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A solution of 98 mg (0.375 mmol) triphenylphosphine in 0.5 ml THF was treated at 0° C. with 0.06 ml (0.375 mmol) DEAD, then with 0.012 ml (0.3 mmol) methanol in 0.33 ml THF and finally with 104 mg (0.25 mmol) of N-[4-(4-Dimethylamino-butoxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide in 0.3 ml THF. The reaction mixture was stirred over night at RT, evaporated and extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phases were dried over Na2SO4 evaporated and purified by flash column chromatography on silica gel with CH2Cl2/MeOH (99:1 to 95:5) to yield 80 mg (74%) of N-[4-(4-Dimethylamino-butoxy)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide, mp: 151-153° C.; MS: 431 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.O.[CH:26]([NH2:28])=[O:27]>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[NH:28][CH:26]=[O:27]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Reactant: NC=O
Solvent: O
Solvent: O=CO
Product: O=CNC(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 160 °C
Reaction time: 16 h
Yield: 22.5 %

Procedure:
A mixture of 2-[3-chloro-4-(4-chlorobenzoyl)phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (0.081 mol) in formic acid (120 ml) and formamide (300 ml) was stirred for 16 hours at 160° C. The reaction mixture was cooled, poured out into water (600 ml) and the resulting precipitate was filtered off and dried. This fraction was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was stirred in DIPE, filtered off, and dried, yielding 8.78 g (22.5%) of (±)-N-[[2-chloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenyl](4-chlorophenyl)methyl]formamide (interm. 64).
Reaction SMILES: [NH2:1][C:2]1[C:25]([Cl:26])=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:11]2)=[O:7])=[C:4]([O:27][CH2:28][CH3:29])[CH:3]=1.[OH:30]O>CO>[NH2:1][C:2]1[C:25]([Cl:26])=[CH:24][C:5]([C:6]([NH+:8]([O-:30])[CH2:9][CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:11]2)=[O:7])=[C:4]([O:27][CH2:28][CH3:29])[CH:3]=1
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(Cc2ccccc2Cl)CCO1
Reactant: OO
Solvent: CO
Product: CCOc1cc(N)c(Cl)cc1C(=O)[NH+]([O-])CC1CN(Cc2ccccc2Cl)CCO1
Reaction time: 24 h
Yield: 14.5 %

Procedure:
To a stirred solution of 4-amino-5-chloro-N-[[4-(2-chlorobenzyl)-2-morpholinyl]methyl]-2-ethoxybenzamide (4.0 g) in methanol (150 ml) is added 30% aqueous hydrogen peroxide (1.2 g). After the mixture is heated under reflux for 8 hours, an additional 30% aqueous hydrogen peroxide (1.2 g) is added, and the reaction mixture is refluxed with stirring for an additional 24 hours. The solvent is distilled off under reduced pressure, and chloroform and water are added to the residue. The mixture is stirred for about 30 minutes. The precipitate is collected and recrystallized from isopropyl alcohol-diisopropyl ether to give the title compound (0.6 g), mp 154°-157° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[O:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:3]=1.[CH3:15][NH2:16].CCO>CO>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[O:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:3]=[C:2]([NH:16][CH3:15])[N:7]=1
Reactant: Cc1ccc(-c2cc(Cl)nc(Cl)n2)o1
Reactant: CN
Solvent: CCO
Solvent: CO
Product: CNc1nc(Cl)cc(-c2ccc(C)o2)n1
Temperature: 80 °C
Yield: 22 %

Procedure:
A solution of 2,4-dichloro-6-(5-methylfuran-2-yl)pyrimidine (0.70 g, 3.07 mmol) in MeOH (5 mL) was treated with 2-M methylamine in EtOH (2 mL, 4 mmol), heated at 80° C. for 30 min, cooled, concentrated in vacuo and purified by chromatography [SiO2; hexane:EtOAc (100:0-90:10)] to give the title compound (0.17 g, 22%) as a white solid; NMR δH (400 MHz, CD3OD) 2.38 (3H, s), 2.93 (3H, s), 6.22-6.23 (1H, m), 6.83 (1H, s) and 7.12-7.13 (1H, m); M/Z 224, 226 (M+H)+
Reaction SMILES: [Pb](SC#N)[S:2][C:3]#[N:4].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]>C(Cl)Cl>[Br:8][C:9]1[CH:14]=[C:13]([S:2][C:3]#[N:4])[CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: N#CS[Pb]SC#N
Reactant: Oc1ccccc1Br
Solvent: ClCCl
Product: N#CSc1ccc(O)c(Br)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a suspension of lead thiocyanate (6.49 g, 20.05 mmol) in CH2Cl2 (125 mL) under nitrogen at 0° C. PhICl2 (4.41 g, 16.05 mmol) was added in one portion. After 20 min at 0° C. a solution of 2-bromophenol (2.31 g, 1.55 mL, 13.37 mmol) in CH2Cl2 (10 mL) was added. After stirring the mixture for 45 min at 0° C. the salts were filtered and the solvent evaporated. The crude mixture was purified by silica gel flash chromatography (hexane-EtOAc 5:1→2:1) to yield 1 (2-bromo4-thiocyanatophenol) (1031 mg, 33%) as a pale yellow oil.