Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:12]([O:14]CC)=[O:13])[S:11][CH2:10][CH2:9][CH2:8][S:7]1.[Li+].[OH-].CO>C1COCC1.O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:12]([OH:14])=[O:13])[S:7][CH2:8][CH2:9][CH2:10][S:11]1
Reactant: CCOC(=O)C1(CCCCCl)SCCCS1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(CCCCCl)SCCCS1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.9 %

Procedure:
Step AS (2): To a solution of ethyl 2-(4-chlorobutyl)-1,3-dithiane-2-carboxylate (550 mg, 1.94 mmol) in THF (5 mL) was added a solution of LiOH (233 mg, 9.72 mmol) in water (2 mL). Methanol (2 mL) was added and the resulting mixture was stirred at rt for 2 d. The solvents were removed in vacuo. Aqueous 1 N HCl (50 mL) was added. The mixture was extracted with EtOAc (80 mL). The organic layer was washed with water, dried over sodium sulfate, filter, and concentrated in vacuo to afford 2-(4-chlorobutyl)-1,3-dithiane-2-carboxylic acid (400 mg, 1.57 mmol, 81% yield). LC-MS (M+H)+ 253.0. The crude product was used for subsequent chemistry without purification.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][C@@H:9]2[CH2:14][O:13][C:12]3=[N:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][N:11]3[CH2:10]2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:23]=[C:24]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>CCO.C1(C)C=CC=CC=1.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:21][C:22]1[CH:23]=[C:24]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:25]=[CH:26][C:27]=1[C:2]1[S:6][C:5]([CH2:7][O:8][C@@H:9]2[CH2:14][O:13][C:12]3=[N:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][N:11]3[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Reactant: O=[N+]([O-])c1cn2c(n1)OC[C@@H](OCc1ccc(Br)s1)C2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(CO[C@@H]4COc5nc([N+](=O)[O-])cn5C4)s3)c(F)c2)C(=O)O1
Yield: 48.1 %

Procedure:
A mixture of (6S)-6-[(5-bromo-2-thienyl)methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (0.200 g, 0.555 mmol) and N-({(5S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (0.252 g, 0.666 mmol) in EtOH (3 mL), toluene (5 mL), DMF (8 mL) and K2CO3 (2 mL, 2 M, 4 mmol) was purged with nitrogen. PdCl2(dppf) (23 mg, 0.03 mmol) was added and the mixture was refluxed under nitrogen for 1 h then partitioned between EtOAc and water. Column chromatography (9:1 DCM/MeOH) gave a solid which was then reprecipitated from DCM/MeOH to give the titled compound (0.142 g, 48%) as a pale grey solid. APCI MS m/z 532 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.21 (t, J=5.7 Hz, 1H), 8.02 (s, 1H), 7.76 (t, J=8.9 Hz, 1H), 7.59 (dd, J=14.0, 2.1 Hz, 1H), 7.36-7.43 (m, 2H), 7.13 (d, J=3.3, 1H), 4.87 (d, J=13.6 Hz, 1H), 4.84 (d, J=13.6 Hz, 1H), 4.72-4.80 (m, 1H), 4.64 (bd, J=12.4 Hz, 1H), 4.47 (d, J=11.9 Hz, 1H), 4.21-4.30 (m, 3H), 4.15 (t, J=9.1 Hz, 1H), 3.74-3.81 (m, 1H), 3.43 (t, J=5.4 Hz, 2H), 1.84 (s, 3H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:14]N1C(=O)CCC1=O.C([O-])([O-])=O.[Na+].[Na+].S([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH:1]1([NH:6][C:7]2[C:12]([I:14])=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccc(NC2CCCC2)n1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(I)c(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a stirred solution of compound 315 (25.5 g, 143 mmol) in DMF (120 mL) was added N-iodosuccinimide (32 g, 143 mmol) in two portions at rt. The resulting mixture was stirred at rt for 2 h. Upon workup, the mixture was poured into ice and saturated Na2CO3 aqueous solution with some sodium sulfite and extracted with ethyl acetate (2×). The combined organics were washed with saturated Na2CO3 aqueous solution (3×), dried over Na2SO4, and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (methanol/DCM) to give compound 243 (39 g, 73% yield in 2 steps). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.89 (1 H, s), 6.18 (2 H, s), 5.63 (1 H, d, J=7.6 Hz), 4.30 (1 H, sxt, J=7.4 Hz), 1.84-1.96 (2 H, m), 1.61-1.74 (2 H, m), 1.42-1.58 (4 H, m). LCMS-ESI (POS), M/Z, M+1: Found 305.0.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)(=[O:4])=[O:3].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C@H:24]([O:27][C:28]2[CH:29]=[N:30][C:31](Cl)=[CH:32][CH:33]=2)[C@H:23]([F:35])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C@H:24]([O:27][C:28]2[CH:29]=[N:30][C:31]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)=[CH:32][CH:33]=2)[C@H:23]([F:35])[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(Cl)nc2)[C@H](F)C1
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(-n3ccc4cc(S(C)(=O)=O)ccc43)nc2)[C@H](F)C1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using 5-(methylsulfonyl)-1H-indole (intermediate 21) and cis(±)-tert-butyl-4-((6-chloropyridin-3-yl)oxy)-3-fluoropiperidine-1-carboxylate (intermediate 7).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[C:9]([C:22]([OH:24])=O)[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:14][C:15]=3[C:4]=2[N:3]=1.[NH:25]1[CH2:27][CH2:26]1.O>O1CCCC1>[N:25]1([C:22]([C:9]2[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:14][C:15]=3[C:4]3[N:3]=[C:2]([CH3:1])[N:6]([CH3:7])[C:5]=3[CH:8]=2)=[O:24])[CH2:27][CH2:26]1
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)O3
Reactant: C1CN1
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c3c(c(C(=O)N4CC4)cc2n1C)CCC(c1ccccc1)O3
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.9 %

Procedure:
To a suspension of 260 mg (0.81 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]-imidazole-5-carboxylic acid in tetrahydrofuran (10 ml) were added 157 mg (1.0 mmol) N,N′-carbonyl-diimidazole (CDI) and the reaction was stirred at room temperature overnight 105 mg (2.4 mmol) Aziridine were added and the mixture was stirred for 16 h at room temperature. The reaction was poured into water and extracted with dichloromethane. The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane/methanol=20:1) and crystallized from n-butanol to afford 56 mg (20%) of the title compound as a white solid. m.p. 201°-204° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].C(#N)C>CO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 83.4 %

Procedure:
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.) in methanol (5 ml). The mixture was heated to reflux and stirred for 2.25 h after which the starting material was not longer detected by HPLC. Then, acetonitrile (40 ml) was dripped into the solution in two portions over 1.5 h. The mixture was cooled slowly to room temperature and stirred for another 1.75 h. The product was isolated by filtration under nitrogen, washed with acetonitrile (20 ml) and dried at 50EC in a vacuum oven for 23 h to obtain 1.7 g (83.4%) of fluvastatin sodium Form VI.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:21][C:22]1[CH:26]=[C:25]([C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])[NH:24][C:23]=1[CH:36]=O>N1CCCCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:36][C:23]4[NH:24][C:25]([C:27]([N:29]5[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]5)=[O:28])=[CH:26][C:22]=4[CH3:21])[C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1C(=O)Cc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Reactant: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=O
Solvent: O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=C1C(=O)N(C)c2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 90 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-7-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (80 mg, 0.27 mmol), 3-methyl-5-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (1.2 equiv.) and piperidine (1 drop) in ethanol (2 mL) was stirred at 90° C. for 2 hours. The reaction was diluted with water and the precipitate was collected by vacuum filtration, washed with water, ethyl acetate and hexane and dried to give 120.5 mg (72%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 13.42 (br s, 1H, NH), 9.32 (brs, 1H), 8.40 (s, 1H), 7.71 (m, 1H), 7.35-7.41 (m, 3H), 6.60 (s, 1H), 3.69 (m, 14H, 2×CH2), 3.30 (s, 3H, CH3), 2.35 (m, 4H, 2×CH2), 2.21 (s, 3H, CH3), 2.20 (s, 3H, CH3). MS 510 [M++1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:16](=[O:17])[C:15]2[N:18]3[C:8](=[C:9]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#N)=[CH:21][CH:20]=4)[N:10]=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:7]1.C(O)=[O:34]>O=[Pt]=O.C1COCC1>[CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:16](=[O:17])[C:15]2[N:18]3[C:8](=[C:9]([C:19]4[CH:20]=[CH:21][C:22]([CH:23]=[O:34])=[CH:25][CH:26]=4)[N:10]=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:7]1
Reactant: COc1ccc(CN2Cc3c(-c4ccc(C#N)cc4)nc4cccc(n34)C2=O)c(OC)c1
Reactant: O=CO
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3c(-c4ccc(C=O)cc4)nc4cccc(n34)C2=O)c(OC)c1
Temperature: 60 °C

Procedure:
A suspension of (B2) and PtO2 (0.1 eq.) in a solvent mixture of HCO2H (80% sol. in water)/THF=2.5:1 (0.2 M) was heated to 60° C. for 4 h. After cooling, the catalyst was filtered through a pad of celite and the solvent was reduced in vacuo and the residue pardoned between sat. aq. NaHCO3 and DCM. The aqueous phase was separated and extracted several times with DCM. The combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent gave the title compound which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6, 300K) δ 10.0 (1H, s), 8.00 (4H, m), 7.75 (1H, d, J=9.0 Hz), 7.49 (1H, d, J=7.0 Hz), 7.38 (1H, dd, J=8.4, 7.0 Hz), 7.23 (1H, d, J=8.3 Hz), 6.61 (1H, d, J=2.0 Hz), 6.48 (1H, dd, J=8.3, 2.0 Hz), 5.40 (2H, s), 4.71 (2H, s), 3.86 (3H, s), 3.73 (3H, s). MS (ES+) C25H21N3O4 requires: 427, found: 428 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[O:14]=[C:4]1[CH:3]([CH2:2][O:1][C:29](=[O:30])[NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]1=2
Reactant: O=C=Nc1ccccc1
Reactant: O=C1c2ccccc2SCCC1CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)OCC1CCSc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxymethyl-3,4-dihydro-2H-benzo[b]thiepin-5-one (359 mg, 1.726 mmol) in 22 ml of tetrahydrofuran were added, at 0° C., triethylamine (0.26 ml, 1.9 mmol) and phenyl isocyanate (410 μl, 3.8 mmol). The mixture was stirred at room temperature for 2 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 tert-butyl methyl ether/cyclohexane). The product was obtained in a yield of 350 mg (62%).
Reaction SMILES: [I-:1].[Na+].[OH-].[Na+].[CH:5]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([F:18])=[CH:15][C:16]=2[F:17])=[CH:9][C:8]([C:19]([OH:21])=[O:20])=[C:7]([OH:22])[CH:6]=1.Cl[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>CO>[F:17][C:16]1[CH:15]=[C:14]([F:18])[CH:13]=[CH:12][C:11]=1[C:10]1[CH:9]=[C:8]([C:19]([OH:21])=[O:20])[C:7]([OH:22])=[C:6]([I:1])[CH:5]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: [I-]
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1cc(-c2ccc(F)cc2F)cc(I)c1O

Procedure:
An equivalent of sodium iodide (165 mg, 1.1 mmol) and an equivalent of sodium hydroxide (32 mg) were added to a solution of 200 mg (0.80 mmol) of diflunisal in 5 ml of methanol. A 4% solution of sodium hypochlorite was dropwise added to the previous solution over a period of 75 min, keeping the temperature at 0-3° C. After every addition, a reddish colour was observed which quickly disappeared. It was stirred at this temperature for another hour and treated with a 20% aqueous solution of sodium thiosulphate. A 5% solution of HCl was added and it was extracted with dichloromethane. After the work-up, the product was recrystalized.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]([C:17]2[C:18]([O:23][C:24]3[CH:32]=[CH:31][C:27]4=[N:28][O:29][N:30]=[C:26]4[CH:25]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])=[C:9]([F:33])[CH:8]=1)[CH3:5].COC(=O)COC1C=CC(CNC(C2C(OC3C=CC4OCOC=4C=3)=NC=CC=2)=O)=C(F)C=1>>[N:28]1[O:29][N:30]=[C:26]2[CH:25]=[C:24]([O:23][C:18]3[C:17]([C:15]([NH:14][CH2:13][C:10]4[CH:11]=[CH:12][C:7]([O:6][C@H:4]([CH3:5])[C:3]([OH:34])=[O:2])=[CH:8][C:9]=4[F:33])=[O:16])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:32]=[CH:31][C:27]=12
Reactant: COC(=O)[C@@H](C)Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nonc3c2)c(F)c1
Agent: COC(=O)COc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1
Product: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nonc3c2)c(F)c1)C(=O)O

Procedure:
The compound of Formula (5.5.10) was prepared in a manner analogous to that described in Example 1, substituting (R)-2-[4-({[2-(benzo[2,1,3]oxadiazol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid methyl ester for the corresponding [4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-acetic acid methyl ester material.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13](Br)=[CH:12][N:11]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH:28]1([Zn+])[CH2:30][CH2:29]1>C1COCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:28]2[CH2:30][CH2:29]2)=[CH:12][N:11]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1ccc(-n2cc(Br)c(=O)c(OCc3ccccc3)c2)cc1
Reactant: [Zn+]C1CC1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCc1ccc(-n2cc(OCc3ccccc3)c(=O)c(C3CC3)c2)cc1
Temperature: 60 °C

Procedure:
3-(Benzyloxy)-5-bromo-1-(4-butylphenyl)pyridin-4(1H)-one (37 mg, 0.09 mmol) was treated with 1,1′-bis(diphenylphosphino)ferrocene dichloro palladium(II) dichloromethane complex (6.6 mg, 0.009 mmol) and cyclopropylzinc bromide (0.54 mL of a 0.5 M solution in THF, 0.27 mmol). The reaction vessel was purged with N2, sealed, and heated at 60° C. for 1 h, after which it was concentrated under a stream of N2 and purified by flash chromatography (4 g SiO2, 0-55% ethyl acetate/hexanes) to provide 3-(benzyloxy)-1-(4-butylphenyl)-5-cyclopropylpyridin-4(1H)-one. LC/MS (M+H)+ 374.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([C@H:18]1[C:25]2[CH:24]=[N:23][N:22]([CH3:26])[C:21]=2[CH2:20][NH:19]1)=[O:17].[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=2)[CH:29]=[CH:28]1.CCN(C(C)C)C(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([C@H:18]1[C:25]2[CH:24]=[N:23][N:22]([CH3:26])[C:21]=2[CH2:20][N:19]1[C:36]([C:33]1[CH:34]=[C:35]2[C:30]([CH:29]=[CH:28][NH:27]2)=[CH:31][CH:32]=1)=[O:37])=[O:17]
Reactant: Cn1ncc2c1CN[C@H]2C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1ncc2c1CN(C(=O)c1ccc3cc[nH]c3c1)[C@H]2C(=O)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
A solution of (R)-1-methyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole-4-carboxylic acid [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide (example 1B), 38 mg), 6-indolecarboxylic acid (22 mg), 0.03 ml (DIPEA) and BOPCl (51 mg) in 2 ml acetonitrile was stirred for 2 hrs at 0° C. A consecutive basic and acidic work up delivered a yellow oil which was purified by chromatography (silica gel, AcOEt). (R)-5-(1H-Indole-6-carbonyl)-1-methyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole-4-carboxylic acid [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide was obtained as a white solid (13 mg). MS: 497.0 (M+H)+
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[C:9]([Br:15])[CH:10]=[C:11]([Br:14])[CH:12]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:3])C.[NH:16]1C2C3C(=CC=CC=3C1=O)C=CC=2.BrBr>C(O)(=O)C>[Br:15][C:9]1[C:8]2[C:13]3[C:12](=[C:11]([Br:14])[CH:10]=1)[NH:16][C:1](=[O:3])[C:4]=3[CH:5]=[CH:6][CH:7]=2
Reactant: CC(=O)c1cccc2c(Br)cc(Br)cc12
Reactant: O=C1Nc2cccc3cccc1c23
Agent: BrBr
Solvent: CC(=O)O
Product: O=C1Nc2c(Br)cc(Br)c3cccc1c23

Procedure:
The 1-acetyl-5,7-dibromonaphthalene used in the foregoing procedure was prepared by dibromination of benz[cd]indol-2-(1H)-one with bromine in glacial acetic acid to give 41 g of 6,8-dibromobenz[cd]indol-2(1H)-one, m.p. 259°-260° C. The latter (12.8 g) was heated under reflux for one hour in two liters of 5% potassium hydroxide, the reaction mixture was cooled, filtered and then treated with 28 g of a solution of sodium nitrite in 50 ml of water. The resulting solution, cooled to 0° C., was added dropwise to 800 ml of a 40% solution of sulfuric acid while maintaining the temperature at -5° C. The reaction mixture was stirred for one hour, then poured slowly into a solution of 140 g of sodium hypophosphite in 800 ml of water at 0° C. with stirring. The solid which separated was collected by filtration and dissolved in 3 liters of 2% sodium carbonate solution, and the resulting solution was filtered, acidified with concentrated hydrochloric acid and the mixture extracted with ethyl acetate. The combined organic extracts were dried and taken to dryness to give 8 g of 5,7-dibromo-1-naphthalenecarboxylic acid which was heated with thionyl chloride in the presence of a small amount of DMF. The resulting crude 5,7-dibromo-1-naphthalenecarboxylic acid chloride, together with 6.0 g of methoxymethylamine hydrochloride in 750 ml of MDC, was treated dropwise at 0° C. with 60 ml of tirethylamine in 250 ml of MDC. The reaction mixture was filtered, the filtrate was taken to dryness, and the resulting residue (12.0 g) was dissolved in THF and treated at 0° C. with stirring with a solution of 29.5 ml of 3M methyl magnesium bromide. The reaction mixture was stirred for ten minutes, quenched with water, taken to dryness and the residue partitioned between ethyl acetate and water. The mixture was filtered, the organic extracts were separated, dried and taken to dryness to give 9.9 g of 1-acetyl-5,7-dibromonaphthalene.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1N.Cl.N([O-])=O.[Na+].[BrH:17]>O>[Br:17][C:3]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1cccc([N+](=O)[O-])c1N
Reactant: Br
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 2-methyl-6-nitroaniline (75.0 g, 0.493 mole) and 40 ml of hydrochloric acid (48% solution) in 135 ml of water was cooled to 0°. During a one hour period a solution of sodium nitrite (36.2 g, 0.51 mole) in 60 ml of water was added to the reaction mixture. The mixture was suction filtered through a sintered glass funnel, collecting the filtrate in a flask cooled by a dry ice-acetone bath. The filtrate was placed in a jacketed addition funnel cooled by a dry ice-acetone bath. During a five minute period this solution was added to a stirred mixture of cuprous bromide (77.8 g, 0.51 mole) in 165 ml of hydrobromic acid (48% solution). After complete addition, the mixture was stirred at room temperature for approximately 18 hours, heated at reflux for two hours, then steam distilled. The distillate was extracted with methylene chloride and the extract washed with 2 N aqueous sodium hydroxide, followed by several portions of saturated aqueous sodium chloride solution. The organic phase was passed through phase separation filter paper and evaporated under reduced pressure to give 1-bromo-2-methyl-6-nitrobenzene (17 g) as a solid.
Reaction SMILES: N1C=CC=[CH:3][C:2]=1[CH:7]=O.C([Mg]Cl)(C)C.[F:14][CH:15]([F:36])[C:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:19]([CH:30]=[O:31])=[C:18]([C:32]([F:35])([F:34])[F:33])[N:17]=1.Cl>CCOCC.O>[F:36][CH:15]([F:14])[C:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:19]([CH:30]([OH:31])[CH:2]([CH3:7])[CH3:3])=[C:18]([C:32]([F:35])([F:33])[F:34])[N:17]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C=O)c1CC(C)C
Reactant: O=Cc1ccccn1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(O)C(C)C)c1CC(C)C
Reaction time: 3 h

Procedure:
This example illustrates the preparation of Compound 14, an example of the condensation of a pyridine aldehyde and an organometallic reagent, followed by oxidation of the secondary alcohol. A solution of 2M isopropylmagnesium chloride in ether (40 mL) (Aldrich) was added in a slow stream to a solution of methyl 2-(difluoromethyl)-5-formyl-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (7 g, 20 mmol) in anhydrous ether (30 mL) at -30° to -20° C. After the mixture was stirred for 3 h at <10° C., it was poured into iced water, acidified with conc. HCl, and extracted with methylene chloride. The organic extract was washed with brine, dried (MgSO4), and conc. to give 3 g of methyl 2-(difluoromethyl)-5-(1-hydroxy-2-methylpropyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate. A solution of this alcohol (3 g) in 20 mL of acetone was cooled to <10° C., and 8N Jones' reagent (4 mL) was added dropwise. The mixture was stirred at RT for 24 h. Ether and water were added and the aqueous layer separated and extracted with ether. The combined ether layers were washed with water and brine, dried (MgSO4), and conc. in vacuo. The residue was purified by flash chromatography on silica gel with 8% ethyl acetate/cyclohexane to give 1.6 g of the desired compound as a light yellow solid, a yield of 21.1%. m.p. 45°-47° C.