Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[C:30]1([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][N:37]1[C:46]2[C:41](=[N:42][CH:43]=[C:44](Br)[CH:45]=2)[C:40](=[O:48])[C:39]([C:49]([O:51][CH2:52][CH3:53])=[O:50])=[CH:38]1.[Mg+2].[Cl-].C[Zn+].[Cl-].[Cl-]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:30]1([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][N:37]1[C:46]2[C:41](=[N:42][CH:43]=[C:44]([CH3:1])[CH:45]=2)[C:40](=[O:48])[C:39]([C:49]([O:51][CH2:52][CH3:53])=[O:50])=[CH:38]1
Reactant: CCOC(=O)c1cn(Cc2ccccc2-c2ccccc2)c2cc(Br)cnc2c1=O
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Zn+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(Cc2ccccc2-c2ccccc2)c2cc(C)cnc2c1=O
Temperature: 55 °C
Reaction time: 0.08 h
Yield: 33.5 %

Procedure:
Another 2-neck 50 mL round bottom flask was charged with palladium(II) acetate (67.4 mg, 0.3 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (246 mg, 0.6 mmol) at room temperature under a nitrogen atmosphere. Then, it was dissolved in tetrahydrofuran (2 mL). After 5 minutes, a solution of ethyl 1-(biphenyl-2-ylmethyl)-7-bromo-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (695 mg, 1.5 mmol) in tetrahydrofuran (5 mL) was added, followed by the above prepared white suspension of methylzincchloride magnesium in tetrahydrofuran. The resulting brown suspension was heated to 55° C. and stirred for 15 h at which time it turned to a black solution and LCMS analysis indicated the absence of starting material. Then, the reaction mixture was quenched with saturated ammonium chloride solution and the organic compound was extracted into ethylacetate (3×70 mL). The combined extracts were washed with water and brine solution, and dried over anhydrous MgSO4. Filtration and concentration gave the crude product (1.2 g) which was purified using an ISCO (80 g) column chromatography, eluting with ethyl acetate in hexanes (0 to 100%) and then 10% methanol and dichloromethane. The desired fractions were combined and the solvent was removed under vacuum to obtain ethyl 1-(biphenyl-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (20) (80 mg, 13.4% yield) as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][C@@H:6]([CH2:11][N+:12]([O-:14])=[O:13])[CH2:7][CH:8]([CH3:10])[CH3:9])C.[OH-].[K+:17].Cl.[Cl-].[K+]>O>[K+:17].[CH3:9][CH:8]([CH3:10])[CH2:7][C@H:6]([CH2:11][N+:12]([O-:14])=[O:13])[CH2:5][C:4]([O-:15])=[O:3]
Reactant: CCOC(=O)C[C@H](CC(C)C)C[N+](=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CC(C)C[C@@H](CC(=O)[O-])C[N+](=O)[O-]
Reaction time: 5 h

Procedure:
830 mg of (S)-5-methyl-3-nitromethyl-hexanoic acid ethyl ester (VIII, R1=ethyl) were suspended in 0.8 mL of H2O. 900 mg of 50% aqueous KOH were added. After 5 h at 25° C. conversion was complete (determination by HPLC). 4.2 mL of 1M aqueous HCl were added and the solvent was removed under reduced pressure to give a solid consisting of the title compound and KCl.
Reaction SMILES: Cl.Cl.C([O:6][C:7]([C:9]1[CH:24]=[CH:23][C:12]2[N:13]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:14]([CH3:16])=[N:15][C:11]=2[CH:10]=1)=[O:8])C=C.[OH-].[Na+].C(O)(=O)C.[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[F:42])[CH:37]=O)[CH3:32].C([BH3-])#N.[Na+]>CO.O.C(O)C>[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[F:42])[CH2:37][N:20]1[CH2:21][CH2:22][CH:17]([N:13]2[C:12]3[CH:23]=[CH:24][C:9]([C:7]([OH:8])=[O:6])=[CH:10][C:11]=3[N:15]=[C:14]2[CH3:16])[CH2:18][CH2:19]1)[CH3:32]
Reactant: CCOc1cc(C=O)ccc1F
Reactant: C=CCOC(=O)c1ccc2c(c1)nc(C)n2C1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CCOc1cc(CN2CCC(n3c(C)nc4cc(C(=O)O)ccc43)CC2)ccc1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
To a solution of 2-methyl-1-piperidin-4-yl-1H-benzoimidazole-5-carboxylic acid allyl ester dihydrochloride (55.8 mg, 0.15 mmol, 1.0 equiv; intermediate A1) in methanol (0.8 mL) and water (0.4 mL) was added a solution of 10 M NaOH (60 μL), acetic acid (86 μL, 90.3 mg, 1.50 mmol, 10 equiv), 3-ethoxy-4-fluoro-benzaldehyde (30.3 mg, 0.18 mmol, 1.2 equiv; intermediate B1, vide infra) and sodium cyanoborohydride (47.1 mg, 0.75 mmol, 5.0 equiv), dissolved in ethanol (0.5 mL). The reaction mixture was stirred at 70° C. overnight. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 13.4 mg (22%) of the title compound. MS (ISP): 412.3 [M+H]+.
Reaction SMILES: [CH:1]([Si:4]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[O:5][CH:6]([CH2:9][NH2:10])[CH2:7][NH2:8])([CH3:3])[CH3:2].[C:17](SC)(=[O:20])SC>CO>[CH:14]([Si:4]([CH:11]([CH3:13])[CH3:12])([CH:1]([CH3:3])[CH3:2])[O:5][CH:6]1[CH2:7][NH:8][C:17](=[O:20])[NH:10][CH2:9]1)([CH3:16])[CH3:15]
Reactant: CC(C)[Si](OC(CN)CN)(C(C)C)C(C)C
Reactant: CSC(=O)SC
Solvent: CO
Product: CC(C)[Si](OC1CNC(=O)NC1)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 20 h

Procedure:
To a solution of 2-triisopropylsilanyloxy-propane-1,3-diamine (Step P10) (27.8 g, 113 mmol) in MeOH (450 mL) was added S,S-dimethyl carbonodithioate (17.7 mL, 169 mmol) and the mixture was stirred at 60° C. for 20 h. The reaction mixture was concentrated. The residue was purified by flash chromatography(CH2Cl2/MeOH, 100:0→5:1) to afford the title compound. ESI-MS: [M+H]+273.3 (LC-MS 1-flow injection).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12]>C(N(CC)CC)C>[CH2:11]([N:13]([CH2:14][CH3:15])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)[CH3:12]
Reactant: CCNCC
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
4-Iodobenzoyl chloride (10.0 g) was added portionwise to diethylamine (2.92 g) in triethylamine (40 ml) at 20°. The resulting slurry was stirred at room temperature for 1 h, diluted with ER (150 ml), filtered and evaporated to give the title compound as an orange solid (10.2 g) m.p. 68°-70°.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:20][C:19]2[C@H:14]([CH2:15][CH2:16][C:17](=[O:21])[CH:18]=2)[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([OH:22])[CH2:7][CH2:6]1)[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].O>N1C=CC=CC=1>[C:23]([O:22][C@H:8]1[CH2:7][CH2:6][C@H:5]2[C@H:4]3[C@H:13]([CH2:12][CH2:11][C@:9]12[CH3:10])[C@@H:14]1[C:19](=[CH:18][C:17](=[O:21])[CH2:16][CH2:15]1)[CH2:20][C@H:3]3[CH2:1][CH3:2])(=[O:25])[CH3:24]
Reactant: CC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
i)—A solution of (7α,17β)-7-ethyl-17-hydroxyestr-4-en-3-one (Example 1, 2.0 g) in dry pyridine (15 ml) was treated with acetic anhydride (1.86 ml) and the reaction mixture was stirred at room temperature for 6.5 h; additional acetic anhydride (1.86 ml) was added after 3 h. The mixture was cooled to 0° C.; water was added and stirring was continued for 30 min. The product was extracted into ethyl acetate; the combined organic phases were washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure, to give (7α,17β)-17-(acetyloxy)-7-ethylestr-4-en-3-one (2.15 g). The product was used in the next step without further purification.
Reaction SMILES: [CH:1]1([N:7]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[C:8](=[O:31])[CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12](C(=O)C3C=CC(Cl)=CC=3)[C:11]=2[CH3:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>ClCCl.CO.[OH-].[Na+]>[CH:1]1([N:7]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[C:8](=[O:31])[CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[NH:12][C:11]=2[CH3:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2c(c1)c(CC(=O)N(c1nccs1)C1CCCCC1)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2[nH]c(C)c(CC(=O)N(c3nccs3)C3CCCCC3)c2c1

Procedure:
A solution of 2.42 g (0.0045 mol) of N-Cyclohexyl-N-thiazol-2-yl-1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetamide in 2.4 mL of dichloromethane, 48 mL of methanol and 24 mL of 1N aqueous NaOH solution was stirred at rt for 90 min. During this time, the title compound formed as a precipitate. It was filtered, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C@@H:22]([CH2:26][OH:27])[CH2:23][CH2:24][CH3:25]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C@H:22]([CH2:23][CH2:24][CH3:25])[CH2:26][OH:27])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CCC[C@@H](N)CO
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@H](CO)Nc1nc(Cl)nc2c1SCC2
Temperature: 120 °C

Procedure:
1.4 g 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (II) are placed in 9 ml dioxane, then 3.5 ml diisopropylethylamine are added followed by 0.9 g D-norvalinol. The reaction mixture is heated in the microwave at 120° C. until there is no further reaction then cooled and evaporated down. The residue is treated with petroleum ether/ethyl acetate 9:1 in the ultrasound bath, the solid is suction filtered and dried. 1.5 g (III-3) are obtained in the form of a solid. 1H NMR (400 MHz, DMSO): 4.67 (1H, t); 0.86 (3H, t).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([OH:9])[CH:3]=1.[C:10](O)(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.B(O)(O)O.O>C1(C)C(C)=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]2[N:6]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1ccc(Br)cc1O
Agent: OB(O)O
Solvent: Cc1ccccc1C
Solvent: ClCCl
Solvent: O
Product: Brc1ccc2nc(-c3ccccc3)oc2c1

Procedure:
38.65 g (205.56 mmol) 4-bromo-2-hydroxy-aniline are boiled together with 25.10 g (205.56 mmol) benzoic acid and 12.75 g (205.56 mmol) boric acid in 500 ml of xylene for 6 days using the water separator. The solv. is eliminated in vacuo and the residue is taken up in DCM. The mixture is extracted 1× each with 1N sodium hydroxide solution, water, 2N hydrochloric acid and again with water. The org. phase is concentrated i. V. by rotary evaporation and the residue is separated through silica gel (eluant cyclohexane/EA).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:34]4[CH2:39][CH2:38][N:37]([CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])[CH2:36][CH2:35]4)=[N:21][N:22]3[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[Cl:33][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[Cl:32])[CH2:25][N:22]1[C:23]2[C:19](=[CH:18][CH:17]=[C:16](/[CH:15]=[CH:14]/[CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:24]=2)[C:20]([CH:34]2[CH2:35][CH2:36][N:37]([CH2:40][C:41]([OH:43])=[O:42])[CH2:38][CH2:39]2)=[N:21]1
Reactant: CC(C)(C)OC(=O)CN1CCC(c2nn(Cc3ccc(Cl)c(Cl)c3)c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCC(c2nn(Cc3ccc(Cl)c(Cl)c3)c3cc(/C=C/C4CCNCC4)ccc23)CC1
Yield: 74 %

Procedure:
4-{2-[3-(1-Tert-butoxycarbonylmethyl-piperidin-4-yl)-1-(3,4-dichloro-benzyl)-1H-indazol-6-yl]-(E)-vinyl}-piperidine-1-carboxylic acid tert-butyl ester (110 mg; 0.161 mmol) was stirred at 23° in trifluoroacetic acid (4 ml) under nitrogen for 5 h. The solvent was evaporated in vacuo and the residue triturated with dry ether to give the title compound as a white solid (90 mg; 74%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([CH2:12][C:13]([NH:15][CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]1([CH2:7][C@@H:8]([C:9]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:11])[CH2:12][C:13]([NH:15][CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C1COCCN1
Reactant: O=C(C[C@@H](CC1CCCCC1)C(=O)O)NCCNc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C[C@@H](CC1CCCCC1)C(=O)N1CCOCC1)NCCNc1ccc(F)cc1
Yield: 48.1 %

Procedure:
(R)-2-cyclohexylmethyl-N-[2-(4-fluoro-phenylamino)-ethyl]-succinamic acid (220 mg, 0.52 mmol) was treated with morpholine (110 μL, 1.26 mmol, 2.4 eq.) and HATU (238 mg, 0.72 mmol, 1.4 eq.). The reagents were dissolved in dry dichloromethane (4 mL) and treated with diisopropylethylamine (315 μL, 1.81 mmol, 3.5 eq.). The reaction was judged to completion by LC/MS, volatiles were evaporated and the reaction was purified by prep-LC/MS and provided 131 mg (0.25 mmol, 40%) of a off-white solid: HPLC-MS calcd. for C23H34FN3O3 (M+H+) 420.3. found 420.5.
Reaction SMILES: [C:1]([CH:3]1[CH2:5][NH:4]1)#[N:2].[CH2:6]1[O:19][C:18]2[CH:17]=[CH:16][C:10]([C:11]([N:13]=[C:14]=[O:15])=[O:12])=[CH:9][C:8]=2[O:7]1.C1OC2C=CC(C(N)=O)=CC=2O1>C1(C)C=CC=CC=1>[CH2:6]1[O:19][C:18]2[CH:17]=[CH:16][C:10]([C:11]([NH:13][C:14]([N:4]3[CH2:5][CH:3]3[C:1]#[N:2])=[O:15])=[O:12])=[CH:9][C:8]=2[O:7]1
Reactant: O=C=NC(=O)c1ccc2c(c1)OCO2
Reactant: N#CC1CN1
Agent: NC(=O)c1ccc2c(c1)OCO2
Solvent: Cc1ccccc1
Product: N#CC1CN1C(=O)NC(=O)c1ccc2c(c1)OCO2
Temperature: 0 °C

Procedure:
0.26 g. 2-Cyanoaziridine are dissolved in 5 ml. toluene and introduced, while stirring at 0° C., into a solution of 0.73 g. 3,4-methylenedioxybenzoyl isocyanate in 25 ml. toluene. The reaction mixture is further stirred for 1 hour at 0° C. and the precipitated material (0.65 g.) is filtered off with suction at ambient temperature and briefly boiled with isopropanol, 0.2 g. of the desired 1-(N-3,4-methylenedioxybenzoyl-carbamoyl)-2-cyanoaziridine thereby remaining undissolved (m.p. 145°-153° C., at 172° C. a clear melt is obtained). It is contaminated with a little 3,4-methylenedioxybenzamide.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]=2[C:4](=[O:11])[NH:3][CH:2]=1.Cl[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=1.O1CCOCC1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.CC(O)C.CN(C)C(=O)C>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([N:9]2[CH2:8][CH2:7][C:6]3[N:1]=[CH:2][NH:3][C:4](=[O:11])[C:5]=3[CH2:10]2)=[N:14][CH:15]=1
Reactant: Cc1ccc(Cl)nc1
Reactant: O=c1[nH]cnc2c1CNCC2
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N2CCc3nc[nH]c(=O)c3C2)nc1
Temperature: 150 °C
Yield: 48.5 %

Procedure:
Into a 20 mL microwave tube was combined 5,6,7,8-tetrahydro-3H-pyrido[4,3-d]pyrimidin-4-one (0.280 g, 1.83 mmol), 2-chloro-5-methylpyridine (0.47 g, 3.7 mmol), 1,4-dioxane (2.5 mL), N,N-diisopropylethylamine (0.64 mL, 3.7 mmol) and N,N-dimethylacetamide (0.5 mL). The mixture was heated via microwave at 150° C. for 4 hours. The mixture was reduced in vacuo and taken up in chloroform:IPA (3:1) (50 mL). The organic phase was washed with sodium bicarbonate and brine (1×50 mL), dried over sodium sulfate, and reduced in vacuo. The residue was purified by flash chromatography on silica gel (0-10% methanol/methylene chloride) to give a bright yellow solid (0.215 g, 47.9%). MS: 243.3 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9](S(C(F)(F)F)(=O)=O)=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:7]=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([O:34][CH3:33])[CH:40]=2)=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:7]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1S(=O)(=O)C(F)(F)F
Product: COc1cccc(-c2c(OC)nc(Oc3ccc(F)c(F)c3)nc2-c2ccc(Cl)cc2Cl)c1

Procedure:
This derivative was prepared by the method described in Example 132 using 2-(3,4-difluorophenoxy)-4-methoxy-5-trifluoromethansulfonyl-6-[2,4-dichlorophenyl]pyrimidine (53 mg, 0.1 mmol) as described in Reference Example 17 and 3-methoxybenzeneboronic acid (Lancaster, 16 mg, 0.1 mmol). HPLC Rt=4.63 min. 1H-NMR 500 MHz (CDCl3): 3.77 (s, 3H), 4.12 (s, 3H), 6.51 (m, 1H), 6.72 (m, 2H), 6.75 (m, 1H), 6.90 (dd, J=8 Hz, J=2 Hz, 1H), 7.07 (q, J=9 Hz, 1H), 7.25 (t, J=4 Hz, 1H), 7.43 (d, J=2 Hz, 2H), 7.49 (d, J=2 Hz, 1H).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH:12](OCC)(OCC)[O:13][CH2:14][CH3:15].C(OC(=O)C)(=O)C>>[C:1]([C:6](=[CH:12][O:13][CH2:14][CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCCC(=O)C(=COCC)C(=O)OCC

Procedure:
A mixture of ethyl butyrylacetate (100 g, 0.63 mol), triethyl orthoformate (210 ml, 1.26 mol) and acetic anhydride (60 ml, 0.63 mol) was heated under reflux for 6 hours, then excess triethyl orthoformate evaporated in vacuo. The residue consisted mainly of ethyl 2-butyryl-3-ethoxyacrylate as a mixture of E and Z isomers, and was used without further purification.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:32])[CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:14][C:13]=1[C:33]([NH:35][CH2:36][C:37]12[CH2:46][CH:41]3[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]3)[CH2:38]1)[CH2:44]2)=[O:34].C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:21][CH2:20]2)=[O:32])=[CH:14][C:13]=1[C:33]([NH:35][CH2:36][C:37]12[CH2:38][CH:39]3[CH2:40][CH:41]([CH2:42][CH:43]([CH2:45]3)[CH2:44]1)[CH2:46]2)=[O:34]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 66.2 %

Procedure:
To dimethyl sulphoxide (0.155 ml) in anhydrous dichloromethane (11 ml) at −78° C. was added oxalyl chloride (0.086 ml) and the mixture was stirred for 5min. at −78° C. A solution of 4-[[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]hydroxymethyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (0.47 g, Example 64) in anhydrous dichloromethane (3 ml) was added dropwise and the mixture was stirred for 15 min. at −78° C. Triethylamine (0.633 ml) was then added and the solution was warmed to room temperature. After 45 min. at room temperature, the reaction mixture was poured onto water and the layers were separated. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC eluting a gradient of 0-5% ethanol in dichloromethane to give the subtitle compound as a white foam (0.31 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:13]([C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:16]=1[CH2:17]Cl)[CH3:14].[I-].[K+].C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC>[CH3:11][C:9]1[N:10]=[C:3]2[C:2]([NH:1][CH2:17][C:16]3[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:15]=3[CH2:13][CH3:14])=[CH:7][CH:6]=[CH:5][N:4]2[C:8]=1[CH3:12]
Reactant: CCc1cccc(C)c1CCl
Reactant: Cc1nc2c(N)cccn2c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: COCCOC
Product: CCc1cccc(C)c1CNc1cccn2c(C)c(C)nc12
Yield: 42.6 %

Procedure:
8-Amino-2,3-dimethylimidazo[1,2-a]pyridine (0.3 g, 1.86 mmol) and 2-ethyl-6-methylbenzylchloride (0.31 g, 1.84 mmol) were dissolved in 5 ml dimethoxyethane. Potassium iodide (0.2 g, 1.2 mmol) and Na2CO3 (0.3 g, 2.8 mmol) were added and the mixture was refluxed for 4 hours. The solvent was evaporated and the residue was purified by column chromatography on silica gel using a mixture of methylene chloride and ethyl acetate (60:40) as eluent. 230 mg (42%) of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=2)[C:10]1=[O:31].[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[NH:32]([C:14]1[N:13]=[C:12]2[N:11]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=3)[C:10](=[O:31])[N:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH2:18][C:17]2=[CH:16][N:15]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccc(CO)cc1)C(=O)N(c1ccc(Cl)cc1Cl)C2
Reactant: Nc1ccccc1
Product: O=C1N(c2ccc(Cl)cc2Cl)Cc2cnc(Nc3ccccc3)nc2N1c1ccc(CO)cc1
Temperature: 120 °C
Yield: 57 %

Procedure:
A mixture of 350 mg (0.7 mmol) of 3-(2,4-dichlorophenyl)-3,4-dihydro-1-[4-(hydroxymethyl)phenyl]-7-methanesulfonyl-pyrimido[4,5-d]pyrimidin-2(1H)-one and 2 ml of aniline was heated at 120° C. for 3 hours. The reaction was cooled to room temperature then partitioned between 2M hydrochloric acid (20 ml) and dichloromethane (20 ml). The organic layer was separated, washed with saturated aqueous sodium bicarbonate (20 ml), dried over magnesium sulfate, filtered and evaporated to give 200 mg (57%) of 7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydro-1-[4-(hydroxymethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a yellow solid of melting point 121-125° C. [Mass spectrum (ESI) MH+ =492].
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Al+3].[Cl-].[Cl-].[Cl-].[N+](C)([O-])=O.[CH3:20][O:21]C(Cl)Cl>ClCCCl>[CH:20]([C:5]1[CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:2]([CH3:1])[CH:6]=1)=[O:21]
Reactant: COC(Cl)Cl
Reactant: CCOC(=O)c1cccn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCCl
Product: CCOC(=O)c1cc(C=O)cn1C
Temperature: -30 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
Ethyl 1-methyl-1H-pyrrole-2-carboxylate (3.69 g, 28.24 mmol; see step (ii) above) and AlCl3 (8.02 g, 60.11 mmol) were added to a solution of nitromethane (40 mL), and 1,2-dichloroethane (40 mL) at −30° C. Dichloromethyl methyl ether (2.5 mL, 28 mmol) in 1,2-dichloroethane (10 mL) was added rapidly to the solution and the mixture was allowed to stir at −30° C. for 16 h. The solution was then poured onto ice (50 g) and the layers were separated. The aqueous layer was then extracted with ether (50 mL). The combined organic fractions were dried (MgSO4), filtered and the solvent removed under reduced pressure, to yield the title compound as a crystalline brown/black solid (4.77 g, 94%).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7].S(Cl)([Cl:14])=O>>[C:6]([O:8][Cl:14])(=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:10][CH3:11])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)CCCCC(=O)[O-]
Product: COC(=O)CCCCC(=O)OCl

Procedure:
Chloro methyl adipate was prepared from mono-methyl adipate (10 g, 62.4 mmol) by refluxing with thionyl chloride (20 mL) for 2 h. Distillation gave the acid chloride (bp 80° C., 0.35 mm Hg, 7.4 g).