Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:17]=2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].[Br:28]Br>C(Cl)(Cl)Cl>[Br:28][C:11]1[N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:17]=2)[C:13]2[C:9]([N:10]=1)=[C:8]([NH2:27])[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=2
Reactant: BrBr
Reactant: CCCCNc1nc(N)c2ncn(Cc3cccc(CC(=O)OC)c3)c2n1
Solvent: ClC(Cl)Cl
Product: CCCCNc1nc(N)c2nc(Br)n(Cc3cccc(CC(=O)OC)c3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
After 2-butylamino-9-(3-methoxycarbonylmethylbenzyl)adenine obtained by Reference example 36 (0.23 g, 0.61 mmol) was dissolved in chloroform (10 ml), bromine (0.15 g, 0.92 mmol) was added thereto and the mixture was stirred at room temperature for 1 hour. After removing the solvent, the residue was poured into water and extracted with chloroform. The organic layer was washed with saturated sodium hydrogencarbonate, saturated sodium hydrogensulfite and saturated brine in that order, dried over anhydrous magnesium sulfate and concentrated to give the captioned compound (0.23 g, 0.51 mmol, yield: 83%) as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[CH:10][C:11]([C:20]3[C:21]4[CH:30]=[CH:29][N:28]([S:31]([C:34]5[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=5)(=[O:33])=[O:32])[C:22]=4[C:23](=[O:27])[N:24]([CH3:26])[CH:25]=3)=[C:12]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]=2[N:4]=1.[CH:41]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][CH2:42]1>>[CH3:8][N:7]1[C:6]2[CH:9]=[CH:10][C:11]([C:20]3[C:21]4[CH:30]=[CH:29][N:28]([S:31]([C:34]5[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=5)(=[O:32])=[O:33])[C:22]=4[C:23](=[O:27])[N:24]([CH3:26])[CH:25]=3)=[C:12]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:5]=2[N:4]=[C:3]1[CH2:2][NH:1][C:45]([CH:41]1[CH2:44][CH2:43][CH2:42]1)=[O:46]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5c(nc(CN)n5C)c4Oc4ccccc4)cn(C)c(=O)c32)cc1
Reactant: O=C(Cl)C1CCC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5c(nc(CNC(=O)C6CCC6)n5C)c4Oc4ccccc4)cn(C)c(=O)c32)cc1

Procedure:
This compound was synthesized according to the procedure of Example 66, Step 2, using 4-[2-(aminomethyl)-1-methyl-4-phenoxy-1H-benzimidazol-5-yl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one and cyclobutanecarboxylic acid chloride as the starting materials. LCMS calculated for C35H34N5O5S (M+H)+: m/z=636.2. found: 636.2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:27]([NH:29][C:30]([N:32]([CH3:34])[NH2:33])=[O:31])[CH3:28].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:14]([F:17])([F:15])[F:16])[CH:8]=[CH:7][C:3]=1[C:4]([NH:33][N:32]([CH3:34])[C:30]([NH:29][CH2:27][CH3:28])=[O:31])=[O:5]
Reactant: CCNC(=O)N(C)N
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCNC(=O)N(C)NC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br

Procedure:
Prophetically, (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid can be reacted with N-ethyl-1-methylhydrazinecarboxamide in the presence of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC.HCl) and DMAP to furnish the title molecule (Org. Lett. 2004, 6, 929-931).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]([N:17]=[C:18]=S)([CH2:15][CH3:16])[CH3:14]>C(OCC)(=O)C>[CH:13]([NH:17][C:18]1[NH:1][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[S:9](=[O:11])(=[O:10])[N:12]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Reactant: CCC(C)N=C=S
Solvent: CCOC(C)=O
Product: CCC(C)NC1=NS(=O)(=O)c2ccc(Cl)cc2N1
Temperature: 150 °C
Yield: 6.9 %

Procedure:
A mixture of 2-amino-4-chlorobenzenesulfonamide (2.1 g, 10.16 mmol) and sec-butyl isothiocyanate (5.0 ml, 40.9 mmol) was heated at 150° C. for 4 h. The mixture was allowed to cool and then stirred with 25 ml of ethyl acetate for 1 h. The precipitate was isolated by filtration and recrystallised from ethanol to give 201 mg (7%) of the title compound as white crystals; m.p. 242-245° C.; 1H-NMR (DMSO-d6): δ 0.89 (t, 3H, CH2CH3), 1.15 (d, 3H, CHCH3), 1.50 (m, 2H, CH2), 3.76 (m, 1H, CH), 7.19 (br.s, 1H, NH), 7.29 (m, 2H, ArH), 7.68 (d, 1H,ArH), 10.35 (br.s, 1H, NH); MS: m/e 287/289 (M+); (C11H14Cl1O3S1) calc. C45.91 H, 4.90; N, 14.60; found C, 46.42; H, 5.08; N, 14.65.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11]C(=O)C(C)(C)C)[C:5]2=[N:4][C:3]=1C.S(=O)(=O)(O)O.[OH-].[Na+]>O>[NH2:11][C:10]1[C:5]2[N:6]([C:2]([Cl:1])=[CH:3][N:4]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1nc2c(NC(=O)C(C)(C)C)cccn2c1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cccn2c(Cl)cnc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A suspension of 3-chloro-2-methyl-8-pivaloylaminoimidazo[1,2-a]pyridine (4.0 g, 15 mmol) in 60% strength sulfuric acid (25 ml) is stirred at 100° C. for 1 h. After cooling to RT, water (100 ml) is added and the mixture is adjusted to pH 10 using 10 N sodium hydroxide solution. It is then extracted with ethyl acetate (3×50 ml). The combined organic extracts are washed with water (50 ml), dried over magnesium sulfate and concentrated. The residue is taken up in boiling toluene, clarified with silica gel and crystallized. The title compound is isolated as a beige solid. Yield 1.9 g (70%), m.p. 126-127° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[O:25]=[S:22]1[CH2:23][CH2:24][N:19]([C:4]2[C:5]3[N:11]=[CH:10][N:9]=[C:8]([S:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:6]=3[N:7]=[C:2]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:3]=2)[CH2:20][CH2:21]1
Reactant: O=S1CCN(c2nc(Cl)nc3c(Sc4ccccc4)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(Sc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-4-(1-oxido-thiomorpholino)-8-phenylthio-pyrimido-[5,4-d]-pyrimidine (m.p.: 253°-255° C.) and piperazine.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:12]([NH:14]C(C)(C2C=CC=CC=2)C)=[O:13])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1>C(O)(C(F)(F)F)=O>[NH2:14][C:12]([C:4]1[S:3][C:2]([Cl:1])=[N:6][C:5]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:13]
Reactant: CCOC(=O)c1nc(Cl)sc1C(=O)NC(C)(C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc(Cl)sc1C(N)=O
Yield: 40.8 %

Procedure:
A solution of 210 mg of ethyl 2-chloro-5-{[(1-methyl-1-phenylethyl)amino]carbonyl}-1,3-thiazole-4-carboxylate (Intermediate 233) in 5 ml TFA was stirred at room temperature overnight. Solvent was removed and the residue was dissolved in 5 ml MeOH. Solvent was again removed and the residue was triturated with ether to give 57 mg of a white solid. NMR (d6-DMSO): 1.3 (t, 3H), 4.3 (q, 2H), 8.2 (s, 1H), 8.8 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7]([CH:12]2[CH2:14][CH2:13]2)[N:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([C:5]1[N:10]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:21][CH:22]=2)[C:9](=[O:11])[CH:8]=[C:7]([CH:12]2[CH2:14][CH2:13]2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C2CC2)cc(=O)[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCc1nc(C2CC2)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 43.7 %

Procedure:
To a solution of 2-butyl-6-cyclopropylpyrimidin-4(3H)-one (6 g) and 4′-(bromomethyl)biphenyl-2-carbonitrile (9.34 g) in acetonitrile (180 mL) was added potassium carbonate (8.63 g), and the mixture was stirred at 50° C. for 12 hr. The insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (5.23 g, 44%) as a colorless viscous substance.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C([O-])([O-])=O.[Na+].[Na+].[I:16]I.Cl>O.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([I:16])[C:5]([OH:8])=[CH:4][C:3]=1[F:9]
Reactant: Oc1cnc(Cl)c(F)c1
Reactant: II
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1cc(F)c(Cl)nc1I
Reaction time: 2 h

Procedure:
To a solution of 6-chloro-5-fluoropyridin-3-ol (307.8 mg, 2.08 mmol) in water (11 mL) was added Na2CO3 (441 mg, 4.16 mmol) and I2 (549 mg, 2.08 mmol). After 2 hours, the reaction mixture was acidified with 1 N HCl to pH 3, diluted with EtOAc (100 mL), and washed with aq. NaHSO3 and brine (50 mL each). The organic layer was dried over Na2SO4, filtered and concentrated to afford 6-chloro-5-fluoro-2-iodopyridin-3-ol. LCMS=273.9 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.11 (d, J=8.5 Hz, 1H), 5.47 (d, J=1.4 Hz, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([O:28][CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[C:25]([NH2:27])[CH:26]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([O:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[C:25]([NH:27][S:2]([CH3:1])(=[O:4])=[O:3])[CH:26]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: Nc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an N2 atmosphere 39 μL (0.5 mmol) methanesulphonic acid chloride are added to a solution of 100 mg (0.24 mmol) 5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-phenylamine and 161 μL (2 mmol) pyridine in 10 mL DCM and the reaction mixture is stirred for 2 h at RT. To complete the reaction a further 160 μL pyridine and 39 μL methanesulphonic acid chloride are added and the mixture is stirred overnight. It is combined with 10% Na2CO3 solution, the organic phase is separated off and the solvent is eliminated i.vac. The residue is purified by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([C@H:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[OH:25])[CH2:9][C@:10]([CH3:23])([CH2:20][CH:21]=[CH2:22])[C:11]([NH:13][C@@H:14]([CH2:18][CH3:19])[C@@H:15]([OH:17])[CH3:16])=O)[CH:5]=[CH:6][CH:7]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.[NH4+].[NH4+].[O-][Mo]([O-])(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:9][C@:10]([C:11]2[O:17][C@@H:15]([CH3:16])[C@H:14]([CH2:18][CH3:19])[N:13]=2)([CH3:23])[CH2:20][CH:21]=[CH2:22])[C@H:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[OH:25])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@@](C)(C[C@H](c1cccc(Cl)c1)[C@@H](O)c1ccc(Cl)cc1)C(=O)N[C@@H](CC)[C@H](C)O
Agent: O=[Mo](=O)([O-])[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CC[C@@](C)(C[C@H](c1cccc(Cl)c1)[C@@H](O)c1ccc(Cl)cc1)C1=N[C@@H](CC)[C@H](C)O1
Temperature: 25 °C

Procedure:
To a solution of (S)-2-((2R,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N-((2S,3S)-2-hydroxypentan-3-yl)-2-methylpent-4-enamide (127 mg, 0.265 mmol) in toluene (5309 μl) was added ammonium molybdate ((NH4)2MoO4) (5.20 mg, 0.027 mmol) and heated to reflux under Dean-Stark conditions overnight. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with sat. NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated. Purification by column chromatography using 20 to 40% ethyl acetate in hexanes afforded (1R,2R,4S)-2-(3-chlorophenyl)-1-(4-chlorophenyl)-4-((4S,5S)-4-ethyl-5-methyl-4,5-dihydrooxazol-2-yl)-4-methylhept-6-en-1-ol
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[SH:10].[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Cl.Cl.CCCCCC>N1C=CC=CC=1.C1C=CC=CC=1>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][S:10][C:3]1[C:4](=[O:9])[O:5][C:6]([CH3:8])=[CH:7][C:2]=1[OH:1]
Reactant: Cc1cc(O)c(S)c(=O)o1
Reactant: Fc1ccccc1CCl
Agent: Cl
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: c1ccncc1
Product: Cc1cc(O)c(SCc2ccccc2F)c(=O)o1
Temperature: 90 °C
Yield: 46 %

Procedure:
4-Hydroxy-3-mercapto-6-methyl-2-pyrone (49.5 g., 0.313 mole) and o-fluorobenzyl chloride (45.3 g., 0.313 mole) were dissolved in pyridine (250 ml.). The temperature rose from 20° to 43°C. The solution was heated at 90°C. for two hours, cooled and poured over ice and concd. hydrochloric acid (500 ml.). This mixture was extracted with methylene chloride. The extract was dried (MgSO4) and evaporated to dryness, leaving an oily residue (80 g.) which is dissolved in hot benzene. Hexane was added to this hot benzene solution and an oil separated. The solution was decanted off. This was repeated until a solid separated. The mixture was cooled and filtered, giving 38.0 g. (46 percent) of the desired product. Recrystallization from benzene gave the pure product as a pale yellow solid, m.p. 123°-125°C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([C@@H:7]([CH3:18])[C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH2:4][O:3]1>C1COCC1.[Pd]>[O:1]=[C:2]1[NH:6][C@@H:5]([C@@H:7]([CH3:18])[C:8]([OH:10])=[O:9])[CH2:4][O:3]1
Reactant: C[C@@H](C(=O)OCc1ccccc1)[C@H]1COC(=O)N1
Agent: [Pd]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)O)[C@H]1COC(=O)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.1 %

Procedure:
To a solution of (R)-benzyl 2-((S)-2-oxooxazolidin-4-yl)propanoate (1.99 g, 7.98 mmol) in THF (18.7 mL) was added Pd/C (10% wt., Degussa; 0.425 g). The mixture was stirred under hydrogen atmosphere (balloon) at room temperature for 4 hr. The mixture was filtered through a plug of celite and rinsed several times with THF. The filtrate was concentrated under reduced pressure providing (R)-2-((S)-2-oxooxazolidin-4-yl)propanoic acid (1.17 g) as a white solid, which was directly used without further purification. MS m/z 160.0 (M+H)+; Rt-0.26 min. 1H NMR (400 Mhz, CD3OD) δ ppm 4.53-4.47 (m, 1H), 4.26 (dd, J=5.7, 9.1 Hz, 1H), 4.13 (td, J=6.0, 8.8 Hz, 1H), 2.69-2.61 (m, 1H), 1.18 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.B(F)(F)F.CCOCC.[Br:20][C:21]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]2[C:22]=1[CH2:23][CH2:24][C:25]2=[O:32].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[CH:24]1[CH2:23][C:22]2[C:26](=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:21]=2[Br:20])[C:25]1=[O:32])[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc(Br)c2c1C(=O)CC2
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(OCC)C1Cc2c(Br)ccc(OC)c2C1=O
Temperature: 0 °C

Procedure:
Triethyl orthoformate (16.5 ml) was cooled to -30° C. and 15.0 ml BF3.Et2O in 50 ml methylene chloride was added. The reaction was warmed to 0° C. for 15 min, and then cooled to -78° C. To the reaction was added 12.05 g of the product from Example 34 in 50 ml methylene chloride, followed by dropwise addition of 19.4 ml diisopropyl ethyl amine. The reaction was then warmed to -15° C. for 2 h, then quenched in 5% NaHCO3 solution and extracted with methylene chloride. The organic extracts were washed with brine, dried (MgSO4), and the solvent removed. The crude product was triturated with cold hexane, and the crystalline product collected to yield 14.60 g of a white solid, mp: 76-8° C. NMR (CDCl3) δ 1.05 (t, 3H), 1.27 (t, 3H), 3.03 (m, 2H), 3.30 (m, 1H), 3.43-3.80 (m, 4H), 3.95 (s, 3H), 5.00 (d, 1H), 6.71 (d, 1H), 7.63 (d, 1H).
Reaction SMILES: CO[C:3](=[O:20])[C:4]([C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][N:8]([CH3:10])C.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1CN>CCO>[CH3:19][O:18][C:16]([C:4]1[C:3](=[O:20])[N:8]([CH2:10][C:28]2[CH:27]=[CH:24][C:23]([O:22][CH3:21])=[CH:30][C:29]=2[O:31][CH3:32])[CH:7]=[CH:6][C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:17]
Reactant: CCOC(=O)C(C=CN(C)C)=C(C(=O)OC)C(=O)OC
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCO
Product: CCOC(=O)c1ccn(Cc2ccc(OC)cc2OC)c(=O)c1C(=O)OC
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A mixture of 5-dimethylamino-3-ethoxycarbonyl-2-methoxycarbonyl-penta-2,4-dienoic acid methyl ester (14.7 g, 51.7 mmol) and 2,4-dimethoxybenzylamine (8.2 mL, 54.3 mmol) in EtOH (90 mL) was refluxed for 5 h. The mixture was cooled to r.t., concentrated in vacuo, and the residual oil was partitioned between ether and 1 M HCl. The aqueous layer was extracted with additional ether, and the organic layers were combined, washed with water, and dried over MgSO4. Evaporation of the solvent in vacuo afforded 18.4 g of the title compound as a viscous orange oil. MS: (+) m/z 398.23 (M+Na).
Reaction SMILES: C(O)(=O)C.[CH:5]([OH:7])=O.C(OC(=O)C)(=O)C.[Cl:15][C:16]1[CH:38]=[CH:37][C:19]([C:20]([C:22]2[N:26]([CH3:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][N:30]=3)=[CH:24][C:23]=2[CH3:36])=[O:21])=[CH:18][CH:17]=1>C1COCC1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:22]2[N:26]([CH3:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][CH:5]=[O:7])=[CH:31][N:30]=3)=[CH:24][C:23]=2[CH3:36])=[O:21])=[CH:37][CH:38]=1
Reactant: O=CO
Reactant: Cc1cc(Cc2ccc(N)cn2)n(C)c1C(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(Cc2ccc(NC=O)cn2)n(C)c1C(=O)c1ccc(Cl)cc1
Temperature: 55 °C
Yield: 54 %

Procedure:
The mixed anhydride of formic and acetic acid was prepared by adding formic acid (1 ml, 98%) dropwise to acetic anhydride (2 ml) and heating the mixture at 55° C. for 2.5 h. This reagent (2.2 ml) was then added to a solution of N-{2-[5-(4-chlorobenzoyl)-1,4-di-methyl-1H-pyrrol-2-ylmethyl]-pyridin-5-yl}amine (0.3 g, 0.88 mmol) in THF (7 ml), and the reaction mixture was heated overnight at 60° C. The solvents were removed in vacuo and the residue was crystallized from chloroform-hexane to give N-{2-[5-(4-chloro-benzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}formamide (175 mg, 54%) as a solid, mp 166.6-167.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[C:10]([C:20]1[O:24][CH:23]=[N:22][CH:21]=1)=[CH:9]2.[N:30]([Si](C)(C)C)=[N+:31]=[N-:32].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:2]([Cl:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]1[NH:32][N:31]=[N:30][N:19]=1)[C:10]([C:20]1[O:24][CH:23]=[N:22][CH:21]=1)=[CH:9]2
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCCCn1c(-c2cnco2)cc2cc(OCc3c(Cl)cccc3Cl)ccc21
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Clc1cccc(Cl)c1COc1ccc2c(c1)cc(-c1cnco1)n2CCCc1nnn[nH]1
Yield: 78.3 %

Procedure:
To a solution of 4-[5-(2,6-dichlorobenzyloxy)-2-(oxazol-5-yl)indol-1-yl]butyronitrile (0.21 g, 0.49 mmol) in toluene (10 mL) was added azidotrimethylsilane (0.20 mL, 1.48 mmol) and dibutyltin oxide (0.037 g, 0.148 mmol). The reaction was refluxed for 16 h. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (silica gel, MeOH/CH2Cl2) to yield a yellow solid (0.18 g, 78%). MS(ES) m/e 469.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(C)=O)cc1
Temperature: 25 °C

Procedure:
p-Aminoacetophenone (87.6 g.) is heated with hexadecylbromide (198 g.) in dry hexamethylphosphoramide (300 ml.) containing anhydrous potassium carbonate (90 g.) for 16 hours at 100° C. The solution is cooled to room temperature, filtered to remove solids, and the filtrate is diluted with cold water (20 ml.). The amber solid so obtained is collected and washed with water. Recrystallization from ethanol followed by dichloromethane provides p-hexadecylaminoacetophenone.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.[NH2:11][C:12](N)=[O:13]>>[NH:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:9])[NH:11][C:12]1=[O:13]
Reactant: NC(N)=O
Reactant: COC(=O)c1sccc1N
Product: O=c1[nH]c(=O)c2sccc2[nH]1
Temperature: 190 °C

Procedure:
A mixture of methyl 3-amino-2-thiophenecarboxylate (13.48 g, 85.85 mmol) and urea (29.75 g, 5 eq.) was heated at 190° C. for 2 hours. The hot reaction mixture was then poured onto sodium hydroxide solution and any insoluble material removed by filtration. The mixture was then acidified (HCl, 2N) to yield 1H-thieno[3,2-d]pyrimidine-2,4-dione (63) as a white precipitate, which was collected by filtration and air dried (9.49 g, 66%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29](Br)[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:40])[CH3:39])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:46]([O:48][CH2:49][CH3:50])=[CH2:47])CCC>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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([C:46]([O:48][CH2:49][CH3:50])=[CH2:47])[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:40])[CH3:39])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)C(C)(C)C4)cn3)ncc12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)C(C)(C)C4)cn3)nc2n(C2CCCC2)c1=O
Yield: 99.7 %

Procedure:
4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.412 g, 0.673 mmol), tetrakis(triphenylphosphine)palladium (0.093 g, 0.081 mmol) and tributyl-(1-ethoxy-vinyl)-stannane (0.379 g, 1.05 mmol) were dissolved in toluene (3 mL) and slowly brought to reflux for 1 hour. The solvent was evaporated and the solid was redissolved in dichloromethane (8 mL) and purified by silica gel chromatography to give 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (0.405 g, 99.0%). 1H NMR δ (400 MHz, CDCl3) 8.73 (s, 1H), 8.15 (d, J=9.0 Hz, 1H), 8.00 (s, 1H), 7.85 (d, J=2.9 Hz, 1H), 7.18 (m, 1H), 5.90 (m, 1H), 4.52 (d, J=2.4 Hz, 1H), 4.18 (d, J=2.4 Hz, 1H), 3.93 (q, J=7.1 Hz, 2H), 3.80 (m, 2H), 3.38 (m, 2H), 3.26 (s, 2H), 2.41 (s, 3H), 2.35 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.64 (m, 2H), 1.49 (s, 9H), 1.45 (s, 6H), 1.36 (t, J=7.1 Hz, 3H).