Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[CH:14][N:13](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:12]=3)[CH:9]=2)[N:4](C2CCCCO2)[N:3]=1.[CH3:41][C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:41][C:42]1[CH:47]=[CH:46][C:45]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[N:15]=[CH:14][NH:13][N:12]=4)[CH:9]=3)[NH:4][N:3]=2)=[CH:44][CH:43]=1
Reactant: Brc1nn(C2CCCCO2)c2ccc(-c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc12
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1ccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Yield: 185.9 %

Procedure:
To a solution of 2-{3-bromo-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazolyl}perhydro-2H-pyran (0.150 g, 0.254 mmol), in ethylene glycol dimethyl ether (3 mL) was added 4-methylphenyl boronic acid (0.052 g, 0.381 mmol), [1,1′-bis(diphenylphosphino)-ferrocene] complex with dichloromethane (1:1) (0.030 g, 0.0254 mmol) and potassium phosphate (0.269 g, 1.27 mmol). The reaction mixture was heated to reflux temperature for 5 hours. The solvent was then evaporated to dryness and the residue was dissolved in 20 mL of ethyl acetate. The heterogeneous solution was washed 3 times with 10 mL of water and once with 10 mL of brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The resulting brown solid was adsorbed on silica gel and purified by column chromatography (85:15 hexanes/ethyl acetate) to provide the title compound (0.130 g, 85% yield): ES-MS (m/z) 602 [M+1]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=1.[OH:10][C:11]([CH3:42])([CH3:41])[CH2:12][CH2:13][C:14]1([CH:38]([CH3:40])[CH3:39])[O:19][C:18](=[O:20])[N:17]([C@H:21]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[CH3:22])[CH2:16][CH2:15]1.[CH:43]1([C:46]2([CH2:69][C:70]([OH:73])([CH3:72])[CH3:71])[O:51][C:50](=[O:52])[N:49]([C@H:53]([C:55]3[CH:60]=[CH:59][C:58]([C:61]4[CH:66]=[CH:65][N:64]([CH3:67])[C:63](=[O:68])[CH:62]=4)=[CH:57][CH:56]=3)[CH3:54])[CH2:48][CH2:47]2)[CH2:45][CH2:44]1.C([O-])(O)=O.[Na+]>COCCOC.CCO.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>[OH:10][C:11]([CH3:41])([CH3:42])[CH2:12][CH2:13][C:14]1([CH:38]([CH3:39])[CH3:40])[O:19][C:18](=[O:20])[N:17]([C@H:21]([C:23]2[CH:24]=[CH:25][C:26]([C:2]3[CH:7]=[CH:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=3)=[CH:27][CH:28]=2)[CH3:22])[CH2:16][CH2:15]1.[CH:43]1([C:46]2([CH2:69][C:70]([OH:73])([CH3:72])[CH3:71])[O:51][C:50](=[O:52])[N:49]([C@H:53]([C:55]3[CH:60]=[CH:59][C:58]([C:61]4[CH:66]=[CH:65][N:64]([CH3:67])[C:63](=[O:68])[CH:62]=4)=[CH:57][CH:56]=3)[CH3:54])[CH2:48][CH2:47]2)[CH2:44][CH2:45]1
Reactant: Cn1ccc(I)cc1=O
Reactant: CC(C)C1(CCC(C)(C)O)CCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC(CC(C)(C)O)(C2CC2)OC1=O
Agent: O=C([O-])O
Solvent: CCO
Solvent: COCCOC
Product: CC(C)C1(CCC(C)(C)O)CCN([C@@H](C)c2ccc(-c3ccn(C)c(=O)c3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 4-iodo-1-methylpyridin-2(1H)-one (17 mg, 0.074 mmol) in DME (4.6 mL) was added Pd(PPh3)4 (6.7 mg, 0.007 mmol) under nitrogen. The mixture was stirred at room temperature for 1 h, and a solution of compound 6-(3-hydroxy-3-methylbutyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one isomer 1 (17 mg, 0.037 mmol) in EtOH (2 mL) and satd aq NaHCO3 (1.5 mL) were added. The mixture was stirred at 100° C. for 2 h, quenched with water, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give the compound 6-(3-hydroxy-3-methylbutyl)-6-isopropyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one isomer 1 (10.73 mg, 65.8%). LC-MS Method 2 Method 2 tR=1.03 min, m/z=463, 441; 1H NMR (CD3OD): δ 0.89 (m, 6H), 1.11 (s, 6H), 1.42 (m, 2H), 1.51 (m, 3H), 1.60 (m, 2H), 1.82-2.02 (m, 2H), 2.69 (m, 1H), 3.03 (m, 1H), 3.51 (s, 3H), 5.79 (m, 3H), 6.35 (d, 1H), 6.72 (s, 1H), 7.28 (d, 1H), 7.39 (d, 2H), 7.49 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[CH:8]([N:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]([CH2:22][C:23]([O:25]CC)=[O:24])[C:12](=[O:28])[CH:11]1[CH:29]([CH3:31])[CH3:30])=[O:9].C(OCC)(=O)C>C(O)C>[CH:8]([N:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]([CH2:22][C:23]([OH:25])=[O:24])[C:12](=[O:28])[CH:11]1[CH:29]([CH3:31])[CH3:30])=[O:9]
Reactant: CCOC(=O)CN1C(=O)C(C(C)C)N(C=O)C=C1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)C1C(=O)N(CC(=O)O)C(c2ccccc2)=CN1C=O

Procedure:
Potassium carbonate (983 mg) and water (6 ml) are added to a solution of ethyl {(3RS)-4-formyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate (1.96 g, Reference compound No. 50-1) in ethanol (14 ml), and the mixture is stirred overnight. Ethyl acetate is added to reaction mixture, and the whole is extracted with water. A 10% aqueous citric acid solution is added to the extract to acidify the system, and the whole is extracted with ethyl acetate again. The extract is washed with water and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure to give the titled reference compound (0.90 g).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[CH:27]([C:29]1[N:30]2[CH:36]=[N:35][CH:34]=[C:31]2[S:32][CH:33]=1)=[O:28]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:35]3[CH:34]=[C:31]4[S:32][CH:33]=[C:29]([CH:27]=[O:28])[N+:30]4=[CH:36]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: O=Cc1csc2cncn12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(C=O)[n+]4c3)[C@H](C)[C@H]12
Yield: 3.3 %

Procedure:
The same procedure as in Example 1 was repeated except that 93 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 58 mg of 3-formylimidazo[5,1-b]thiazole were used, thereby obtaining 3.2 mg of the title compound.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([C:7](=[O:19])[CH2:8][N+:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.C(=O)(O)[O-].[Na+].[C:36](#[N:39])[CH:37]=[CH2:38]>CN(C)C=O>[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:8]2[N:9]3[C:18]4[C:13]([CH:12]=[CH:11][C:10]3=[C:37]([C:36]#[N:39])[CH:38]=2)=[CH:14][CH:15]=[CH:16][CH:17]=4)=[O:19])=[CH:5][CH:4]=1
Reactant: C=CC#N
Reactant: O=C(C[n+]1cccc2ccccc21)c1ccc(Cl)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)c2ccc(Cl)cc2)n2c1ccc1ccccc12

Procedure:
The title compound was prepared from 1-(4-chloro-phenacyl)-quinolinium bromide (82.3 mg, 0.227 mmol), tetrapyridinecobalt(II) dichromate (151 mg, 0.248 mmol), sodium bicarbonate (49.5 mg, 0.589 mmol), acrylonitrile (100 μL, 1.52 mmol), and N,N-dimethylformamide (2.0 mL), similar to Example 1b, and yielded 15.6 mg (20%) as a yellow solid. 1H NMR (CDCl3): 8.03 (m, 3H), 7.86 (dd, J=7.97, 1.64 Hz, 1H), 7.75 (d, J=9.34 Hz, 1H), 7.68 (d, J=9.34 Hz, 1H), 7.62 (ddd, J=8.31, 7.07, 1.72 Hz, 1H), 7.55 (m, 3H), 7.41 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][CH:13]1[CH2:18][CH2:17][N:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([N:16]1[CH2:15][CH2:14][CH:13]([Cl:12])[CH2:18][CH2:17]1)[C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)=[O:6]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: Cc1ncc(C(CN)N2CCC(Cl)CC2)cn1
Product: Cc1ncc(C(CNC(=O)c2ccc(Cl)cc2Cl)N2CCC(Cl)CC2)cn1

Procedure:
From 2,4-dichlorobenzoic acid and 2-(4-chloropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.
Reaction SMILES: [C:1]([CH2:4][C:5]([O:7][C@H:8]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH:20]=1)[CH2:9][C:10]1[C:15]([Cl:16])=[CH:14][N+:13]([O-:17])=[CH:12][C:11]=1[Cl:18])=[O:6])([OH:3])=[O:2].[CH:34]1([CH2:37][O:38][C:39]2[CH:44]=[C:43]([CH2:45]O)[CH:42]=[CH:41][C:40]=2[N:47]([S:55]([CH3:58])(=[O:57])=[O:56])[C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:36][CH2:35]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:50]([O:49][C:48]([N:47]([C:40]1[CH:41]=[CH:42][C:43]([CH2:45][O:2][C:1](=[O:3])[CH2:4][C:5]([O:7][C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]3[CH2:32][CH2:33]3)[CH:20]=2)[CH2:9][C:10]2[C:15]([Cl:16])=[CH:14][N+:13]([O-:17])=[CH:12][C:11]=2[Cl:18])=[O:6])=[CH:44][C:39]=1[O:38][CH2:37][CH:34]1[CH2:35][CH2:36]1)[S:55]([CH3:58])(=[O:56])=[O:57])=[O:54])([CH3:53])([CH3:51])[CH3:52]
Reactant: O=C(O)CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CC(C)(C)OC(=O)N(c1ccc(CO)cc1OCC1CC1)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1ccc(COC(=O)CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-4-(2-(2-carboxyacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (50 mg, 0.099 mmol), tert-butyl 2-(cyclopropylmethoxy)-4-(hydroxymethyl)phenyl-(methylsulfonyl)-carbamate (73 mg, 0.2 mmol), DMAP (14.5 mg, 0.12 mmol), and ECD (57 mg, 0.3 mmol) in DMF (1.5 ml) was stirred at RT overnight. The reaction mixture was quenched with water, and the product was extracted with EtOAc. The organic phase was washed with HCl 1M, NaHCO3 sat. sol. and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude (70 mg) was used for the next step without any further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=1)[CH2:5]2.[CH3:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32](B(O)O)[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:11][C:9]1[CH:10]=[C:2]([C:32]2[CH:31]=[N:30][CH:29]=[C:28]([CH3:27])[CH:33]=2)[CH:3]=[C:4]2[C:8]=1[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:18][CH:19]=1)[CH2:5]2
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(Oc3ccccc3)cc1)C2
Reactant: Cc1cncc(B(O)O)c1
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
Product: Cc1cncc(-c2cc(C)c3c(c2)CN(Cc2ccc(Oc4ccccc4)cc2)C3=O)c1
Temperature: 110 °C
Reaction time: 15 h
Yield: 63.4 %

Procedure:
5-Bromo-7-methyl-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (100.0 mg, 0.24 mmol), 3-methylpyridine-5-boronic acid (67.1 mg, 0.49 mmol), 2M sodium carbonate (1 mL) and Pd(PPh3)4 (37.0 mg, 0.045 mmol) were suspended in DME (1 mL), and the mixture was heated to 110° C. After 15 hours, the reaction mixture was cooled to room temperature. The cooled reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by column chromatography (30-35% EtOAc in hexanes) to provide the title compound as an off-white gum (64 mg, 62%.) 1H NMR (300 MHz, CDCl3): δ 8.66 (d, 1H), 8.47 (d, 1H), 7.70 (s, 1H), 7.28-7.41 (m, 6H), 7.12 (t, 1H), 6.98-7.03 (m, 4H), 4.79 (s, 2H), 4.33 (s, 2H), 2.85 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][N:10]1[C:18]2[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=[CH:11]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)[NH2:25].C(O)(C)C>C(OCC)(=O)C>[CH3:21][C:22]1[CH:23]=[C:24]([NH:25][C:17]2[C:18]3[N:10]([CH2:9][CH2:8][NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=[CH:12][C:13]=3[N:14]=[CH:15][N:16]=2)[CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Cl)c21
Reactant: Cc1cc(N)ccc1Oc1cccc(C(F)(F)F)c1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2ncnc3ccn(CCNC(=O)OC(C)(C)C)c23)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (297 mg), 3-methyl-4-[3-(trifluoromethyl)phenoxy]aniline (401 mg) and isopropyl alcohol (2.97 mL) was stirred at 80° C. for 16 hrs. The reaction mixture was diluted with ethyl acetate (80 mL), and washed with aqueous sodium hydrogen carbonate (30 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→0/100) to give the title compound (528 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].[CH:15]([N-]C(C)C)(C)C.[Li+].CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.CI>O.C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:7]=1[CH2:8][CH3:15]
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1cc(-c2ccccc2)nnc1Cl
Agent: [Li+]
Solvent: O
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: CCc1cc(-c2ccccc2)nnc1Cl
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A RBF was charged with 3-chloro-4-methyl-6-phenylpyridazine (5.0 g, 24 mmol) and 120 mL of THF under nitrogen, and the solution was cooled to −78° C. Lithium diisopropylamide, 2.0M in heptane/THF/ethylbenzene (15 ml, 29 mmol) was added and the mixture was stirred at −78° C. for 5 min, followed by RT for 1 h. The mixture was cooled to −78° C. and methyl iodide (1.8 ml, 29 mmol), which had been passed through a plug of basic alumina prior to use, was added dropwise. After stirring at −78° C. for 5 min, the reaction was stirred at RT for 0.5 h. Water was added to quench the reaction, and the mixture was concentrated and partitioned between dichloromethane and water. The layers were separated and the aqueous portion was extracted with additional DCM. The combined organics were dried with MgSO4, filtered and concentrated. The crude material was purified by silica gel chromatography (100% DCM to 95/5 DCM/MeOH) to provide 3-chloro-4-ethyl-6-phenylpyridazine as a tan solid. MS m/z=219 [M+H]+. Calc'd for C12H11ClN2: 218.68.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[C:11](Cl)=[O:12].Cl.[CH2:23]([NH:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH3:25]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[C:11]([N:26]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:24][CH3:25])=[O:12]
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)Cl
Reactant: CCCNC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCN(C(=O)c1c(Cl)cccc1[Si](C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
Triethylamine (27.89 mL, 200 mmol) was added to a mixture of the compound of Example b (2.47 g, 10 mmol) and N-propyl-N-iso-propylamine hydrochloride (~ 92 mmol) in toluene (100 mL). The reaction was stirred overnight at ambient temperature, then was partitioned between ethyl acetate and dilute citric acid. The organic phase was washed with brine, dried (MgSO4), and concentrated to afford 2.50 g of the title compound as a waxy amber solid, an 80% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][C:15](=[O:17])[N:14]([C:18]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[S:20][C:19]=3[C:29]([OH:31])=[O:30])[C@H:13]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[N:46]1[CH:51]=[C:50](B(O)O)[CH:49]=[N:48][CH:47]=1>C(#N)C>[CH:32]1([C@@H:13]2[CH2:12][N:11]([S:8]([C:5]3[CH:6]=[N:7][C:2]([C:50]4[CH:51]=[N:46][CH:47]=[N:48][CH:49]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:16][C:15](=[O:17])[N:14]2[C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:20][C:19]=2[C:29]([OH:31])=[O:30])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CN(S(=O)(=O)c2ccc(Cl)nc2)C[C@H]1C1CCCCC1
Reactant: OB(O)c1cncnc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CN(S(=O)(=O)c2ccc(-c3cncnc3)nc2)C[C@H]1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18.4 %

Procedure:
To a solution of 3-[(R)-4-(6-chloro-pyridine-3-sulfonyl)-2-cyclohexyl-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylic acid (1.20 g, 2.14 mmol, 1.0 equiv) in acetonitrile (15.0 mL) was added potassium phosphate (8.58 ml, 1.0 M aqueous solution, 4.0 equiv) and chloro(2-dicyclohexyl phosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)[2-(2-amino ethyl)phenyl] Pd(II) Me-t-butyl ether adduct (0.32 g, 0.43 mmol, 0.2 equiv) at room temperature. The mixture was stirred at room temperature for 10 minutes to form a stock solution. To 0.8 mL of above solution was added 5-pyrimidinyl boronic acid (17.7 mg, 0.143 mmol, 2.0 equiv) and acetonitrile (0.5 mL) at room temperature. The mixture was stirred at 80° C. for 4 hours. The mixture was purified by HPLC (0.1% NH4OH) to afford the product (15.9 mg, 36.9%). MS: 603.2 [M−H+].
Reaction SMILES: C([O:8][C:9]1([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:25])[CH:22]=3)[CH:17]2[OH:26])[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:25])[CH:22]=3)[CH:17]2[OH:26])[CH2:11][CH2:10]1
Reactant: Cc1ccc(CC2(OCc3ccccc3)CCN(CC3Cc4cc(O)ccc4C3O)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(CC2(O)CCN(CC3Cc4cc(O)ccc4C3O)CC2)cc1
Yield: 99.5 %

Procedure:
A solution of (1RS,2RS)and (1RS,2SR)-2-[4-benzyloxy-4-(4-methyl-benzyl)-piperidine-1-ylmethyl]-indan-1,5-diol (0.83 g, 1.82 mmol) in MeOH (100 ml) and Pd/C 10% (100 mg) was stirred vigorously under a hydrogen atmosphere for 1 hr at ambient temperature. After removal of the catalyst and evaporation of the solvent the title compound (1RS,2RS) and (1RS, 2SR)-2-[4-hydroxy-4-(4-methyl-benzyl)-piperidine-1-ylmethyl]-indan-1,5-diol (664 mg, 1.81 mmol, 99%) was afforded as a white amorphous foam, (1:1) mixture of diastereoisomers, MS m/e=368.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][C:20]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:20]=3[CH3:19])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: Cc1ccc(C(=O)O)c(C)c1
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(C)cc3C)CC2)ccc1Cl
Yield: 8 %

Procedure:
The title compound (3 mg, 8%) was prepared analogously to example 8 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 2,4-dimethylbenzoic acid. MS: 401.4 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:21])[CH2:9][NH:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.OS([O-])(=O)=O.[K+]>C(Cl)Cl>[C:31]1([S:37]([N:10]([CH2:9][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[OH:21])[CH2:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:13])(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(CNCC(O)c1cccc(Br)c1)Nc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN(CC(O)c1cccc(Br)c1)S(=O)(=O)c1ccccc1)Nc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a cooled suspension of 2-[2-(3-bromo-phenyl)-2-hydroxy-ethylamino]-N-phenyl-acetamide (840 mg) and N,N-diisopropylethylamine (760 mL) in methylene chloride (20 mL) was added benzenesulfonyl chloride (0.31 mL). The mixture was stirred at 0° C. for 1 hour and at room temperature overnight. A 1M aqueous solution of KHSO4 was added, the phases were separated, and the inorganic one was extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, n-heptanelethyl acetate 1:1) to yield 2-{benzenesulfonyl-[2-(3-bromo-phenyl)-2-hydroxy-ethyl]-amino}-N-phenyl-acetamide (1.17 g, 99%) as a white foam, MS: 489.0 (M+H, 1Br)+.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[CH:6][C:7]([N+:29]([O-:31])=[O:30])=[C:8]([NH:10][C:11]2[S:12][C:13]([C:26]([NH2:28])=[O:27])=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[N:15]=2)[CH:9]=1.Cl>C(#N)C>[CH:3]([C:4]1[CH:5]=[CH:6][C:7]([N+:29]([O-:31])=[O:30])=[C:8]([NH:10][C:11]2[S:12][C:13]([C:26]([NH2:28])=[O:27])=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:23])([F:24])[F:25])[N:15]=2)[CH:9]=1)=[O:2]
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(Nc2nc(-c3ccccc3C(F)(F)F)c(C(N)=O)s2)c1
Agent: Cl
Solvent: CC#N
Product: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1ccccc1C(F)(F)F
Yield: 66.8 %

Procedure:
A solution of 0.23 g (0.48 mmole) of 2-(5-dimethoxymethyl-2-nitro-phenylamino)-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (VI.17a) in 9 mL mixture of acetonitrile and 2M hydrochloric acid (2:1) was heated at 60 degrees for 3 hours, cooled and concentrated under reduced pressure. The residue was diluted with dichloromethane and saturated sodium bicarbonate. The solid was collected by filtration, washed with water and dried to give 0.14 g of 2-(5-formyl-2-nitro-phenylamino)-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (VI.17b) as an orange solid. The filtrate was extracted twice with dichloromethane. The combined dichloromethane layers were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give additional product of 0.046 g as an orange solid. The combined material was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH:19]1([C:22]2[O:23][C:24]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:25]([C:27](O)=[O:28])[N:26]=2)[CH2:21][CH2:20]1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:27]([C:25]3[N:26]=[C:22]([CH:19]4[CH2:20][CH2:21]4)[O:23][C:24]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:28])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1nc(C2CC2)oc1-c1ccccc1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C4CC4)oc3-c3ccccc3)n2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-cyclopropyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.80 min; [M+H]+=433.17.